Research

JAMA | Original Investigation

Pharmacotherapy for Alcohol Use Disorder

A Systematic Review and Meta-Analysis
Melissa McPheeters, PhD, MPH; Elizabeth A. O’Connor, PhD; Sean Riley, MSc, MA; Sara M. Kennedy, MPH;
Christiane Voisin, MSLS; Kaitlin Kuznacic, PharmD; Cory P. Coffey, PharmD; Mark D. Edlund, MD, PhD;
Georgiy Bobashev, PhD; Daniel E. Jonas, MD, MPH

Supplemental content
IMPORTANCE Alcohol use disorder affects more than 28.3 million people in the United States CME Quiz at
and is associated with increased rates of morbidity and mortality. jamacmelookup.com

OBJECTIVE To compare efficacy and comparative efficacy of therapies for alcohol use disorder.

DATA SOURCES PubMed, the Cochrane Library, the Cochrane Central Trials Registry, PsycINFO,
CINAHL, and EMBASE were searched from November 2012 to September 9, 2022 Literature
was subsequently systematically monitored to identify relevant articles up to August 14,
2023, and the PubMed search was updated on August 14, 2023.

STUDY SELECTION For efficacy outcomes, randomized clinical trials of at least 12 weeks’
duration were included. For adverse effects, randomized clinical trials and prospective cohort
studies that compared drug therapies and reported health outcomes or harms were included.

DATA EXTRACTION AND SYNTHESIS Two reviewers evaluated each study, assessed risk of bias,
and graded strength of evidence. Meta-analyses used random-effects models. Numbers
needed to treat were calculated for medications with at least moderate strength of evidence
for benefit.

MAIN OUTCOMES AND MEASURES The primary outcome was alcohol consumption. Secondary
outcomes were motor vehicle crashes, injuries, quality of life, function, mortality, and harms.

RESULTS Data from 118 clinical trials and 20 976 participants were included. The numbers
needed to treat to prevent 1 person from returning to any drinking were 11 (95% CI, 1-32) for
acamprosate and 18 (95% CI, 4-32) for oral naltrexone at a dose of 50 mg/d. Compared with
placebo, oral naltrexone (50 mg/d) was associated with lower rates of return to heavy
drinking, with a number needed to treat of 11 (95% CI, 5-41). Injectable naltrexone was
associated with fewer drinking days over the 30-day treatment period (weighted mean
difference, −4.99 days; 95% CI, −9.49 to −0.49 days) Adverse effects included higher
gastrointestinal distress for acamprosate (diarrhea: risk ratio, 1.58; 95% CI, 1.27-1.97) and
naltrexone (nausea: risk ratio, 1.73; 95% CI, 1.51-1.98; vomiting: risk ratio, 1.53; 95% CI,
1.23-1.91) compared with placebo.

CONCLUSIONS AND RELEVANCE In conjunction with psychosocial interventions, these findings

support the use of oral naltrexone at 50 mg/d and acamprosate as first-line Author Affiliations: RTI
pharmacotherapies for alcohol use disorder. International–University of
North Carolina at Chapel Hill
Evidence-Based Practice Center,
Chapel Hill (McPheeters, Riley,
Kennedy, Voisin, Jonas); RTI
International, Research Triangle Park,
North Carolina (McPheeters,
Kennedy, Edlund, Bobashev); Center
for Health Research, Kaiser
Permanente, Portland, Oregon
(O’Connor); Department of Internal
Medicine, The Ohio State University,
Columbus (Riley, Voisin, Coffey,
Jonas); College of Pharmacy, The
Ohio State University, Columbus
(Kuznacic).
Corresponding Author: Melissa
McPheeters, PhD, MPH,
RTI International, 3040 E
Cornwallis Rd, Research Triangle Park,
JAMA. 2023;330(17):1653-1665. doi:10.1001/jama.2023.19761 NC 27709 (mmcpheeters@rti.org).

(Reprinted) 1653
© 2023 American Medical Association. All rights reserved.
 Research Original Investigation
U
nhealthy alcohol use is the third leading preventable
cause of death in the United States, accounting for
145 000 deaths annually.1 Data from the 2020 Na-
tional Survey on Drug Use and Health suggested that more than
28.3 million people aged 12 years or older in the United States
met Diagnostic and Statistical Manual of Mental Disorders
(Fifth Edition) (DSM-5) criteria for alcohol use disorder (eTable 1
in Supplement 1) in the past year.2,3 The COVID-19 pandemic
may have been associated with increased numbers of people
with alcohol use disorder.2,3 Among the 29.5 million people
reporting a past-year alcohol use disorder in 2021, an esti-
mated 0.9%, or 265 000 people, received pharmacotherapy for
alcohol use disorder.4
This systematic review and meta-analysis evaluated effi-
cacy and comparative efficacy of 9 therapies for alcohol use
disorder that are either approved by the US Food and Drug Ad-
ministration (FDA) (eTable 2 in Supplement 1) or more com-
monly used in the United States for alcohol use disorder.
Methods
The protocol was registered with PROSPERO (CRD42022324376).
A full technical report that addressed 5 questions (eTable 3 in
Supplement 1) details methods, search strategies, and addi-
tional information.
Data Sources and Searches
PubMed, the Cochrane Library, the Cochrane Central Trials
Registry, PsycINFO, CINAHL, and EMBASE were searched for
English-language studies of adults aged 18 years or older
from November 1, 2012, to September 9, 2022; eligible
articles published before these searches were obtained from
a previously published (2014) systematic review on this
topic.5,6 A librarian (C.V.) performed all searches. A second
librarian peer-reviewed the searches using the validated Peer
Review of Electronic Search Strategies (PRESS) checklist.7
Reference lists of pertinent reviews and trials were manually
searched for additional relevant citations. After September 9,
2022, an ongoing systematic monitoring of the literature was
conducted through article alerts. An updated search of
PubMed was conducted on August 14, 2023, to identify stud-
ies published since that may affect the conclusions or under-
standing of the evidence; those searches did not identify new
studies for inclusion.
Study Selection
Studies that enrolled adults with alcohol use disorder and
evaluated an FDA-approved medication (acamprosate, disul-
firam, or naltrexone) or any of 6 off-label medications (ba-
clofen, gabapentin, varenicline, topiramate, prazosin, and
ondansetron) for at least 12 weeks of treatment in an outpa-
tient setting were eligible for inclusion. Twelve weeks of
treatment were required because longitudinal studies
reported that shorter treatment may yield misleading conclu-
sions about efficacy due to fluctuations in drinking behavior.
Eligible studies were required to assess 1 of the following
outcomes: (1) alcohol consumption, consisting of return to
1654 JAMA November 7, 2023 Volume 330, Number 17 (Reprinted)
© 2023 American Medical Association. All rights reserved.
Pharmacotherapy for Alcohol Use Disorder
Key Points
Question Which pharmacotherapies are associated with
improved outcomes for people with alcohol use disorder?
Findings In this systematic review and meta-analysis that
included 118 clinical trials and 20 976 participants, 50 mg/d of oral
naltrexone and acamprosate were each associated with
significantly improved alcohol consumption-related outcomes
compared with placebo.
Meaning These findings support oral naltrexone at 50 mg/d and
acamprosate as first-line therapies for alcohol use disorder.
any drinking, return to heavy drinking, percentage of drink-
ing days, percentage of heavy drinking days (≥4 drinks per
day for women; ≥5 drinks per day for men), or number of
drinks per drinking day; (2) health outcomes—motor vehicle
crashes, injuries, quality of life, function, or mortality; or
(3) adverse events.
For efficacy outcomes, double-blind randomized clinical
trials (RCTs) that compared 1 of the FDA-approved or off-
label medications listed above with placebo or with another
medication were eligible for inclusion. For adverse effects, in
addition to the double-blind RCTs included for efficacy, stud-
ies with the following designs were eligible if they compared
2 drugs of interest: nonrandomized or open-label trials, sub-
group analyses from trials, prospective cohort studies, and
case-control studies. Nonrandomized and observational stud-
ies were included to address harms because RCTs had insuf-
ficient sample sizes and duration to identify rare harms.
Two investigators independently reviewed each title and
abstract. Studies marked for possible inclusion by either
reviewer underwent independent full-text review by 2 review-
ers. If the reviewers disagreed, they resolved conflicts by dis-
cussion and consensus or by consulting a third, senior mem-
ber of the team.
Data Extraction, Risk-of-Bias Assessment,
and Strength of Evidence
Structured data extraction forms were used to gather rel-
evant data from each article. At least 2 investigators reviewed
all data extractions for completeness and accuracy.
To assess the risk of bias of studies, the investigators
used predefined criteria based on established guidance.8-10 The
studies were rated as having low, medium, high, or unclear risk
of bias.8,9 Questions were included about adequacy of ran-
domization, allocation concealment, similarity of groups at
baseline, masking, attrition, validity and reliability of mea-
sures, approaches to analyses, and methods of handling miss-
ing data. Two independent reviewers assessed risk of bias
for each study. Disagreements were resolved by consensus.
The strength of evidence was graded as high, moderate,
low, or insufficient based on established guidance.11 The ap-
proach incorporated 4 key domains: risk of bias, consistency,
directness, and precision. Two reviewers assessed each
domain for each outcome and determined an overall grade.
Differences were resolved by consensus.
jama.com
Pharmacotherapy for Alcohol Use Disorder Original Investigation Research

Figure 1. Study Identification and Review for Medications Used in the Treatment of Alcohol Use Disorder

2860 Citations identified through database searches

from years 2013- 2022, hand searches

2543 Citations excluded at title

and abstract stage

317 Full-text articles reviewed

267 Full-text articles excluded

80 Ineligible evidence type or study design
58 Ineligible outcome
50 Ineligible intervention
33 Duplicate or superseded
20 Ineligible comparator
13 Ineligible population
6 Ineligible time period
4 Ineligible length of follow-up
2 Ineligible language
1 Ineligible setting

106 Articles (81 studies) included from 50 Articles (37 studies) from database
2014 systematic review searches met inclusion criteria

156 Articles (118 studies) met criteria

111 Studies included for alcohol 31 Studies included for health 99 Studies included for
consumption outcomes outcomes adverse events

In these analyses, results are presented for medications for

which there was at least low strength of evidence for benefit
for some outcomes.
Data Synthesis and Analysis
The primary outcome was alcohol consumption, defined as any
alcohol use, return to heavy drinking, and number of drinks
per week. Meta-analyses of RCTs were performed using ran-
dom-effects models.12 We used the DerSimonian and Laird es-
timator for our primary analyses, with sensitivity analyses
using a restricted maximum likelihood model when the pooled
effects were statistically significant. For continuous out-
comes, weighted mean differences (WMDs) and 95% CIs were
calculated. For binary outcomes, risk ratios (RRs) between
groups and 95% CIs were calculated. The I2 statistic was cal-
culated to assess statistical heterogeneity.13,14 Potential sources
of heterogeneity were examined by analyzing subgroups de-
fined by patient population (eg, US vs non-US studies). Analy-
ses were conducted using Stata version BE-17 (StataCorp).
Statistical significance was assumed when 95% CIs of pooled
results did not cross 0. All testing was 2-sided. Numbers needed
to treat were calculated when pooled RRs for binary out-
comes found a statistically significant result and there was at
least moderate strength of evidence for benefit. When quan-
titative synthesis was not appropriate (eg, <2 similar studies),
the data were synthesized qualitatively.
Results
The database search identified 2860 citations, and 2543 cita-
tions were excluded during title and abstract review. Of 317 full-
text articles included after title and abstract review, 267 were
excluded, leaving 156 articles that described results of 118 RCTs
(Figure 1). Of these, 81 RCTs (106 articles) were included in the
2014 systematic review on this topic,5 and 37 RCTs (50 ar-
ticles) were new. No observational studies providing data on
adverse effects were identified, and therefore all data on ad-
verse events were obtained from RCTs.
Characteristics of the 37 RCTs that were new since 2104
are shown in eTable 4 in Supplement 1. Sample sizes ranged
from 12 to 921. Treatment duration ranged from 12 to 52 weeks.
All participants met criteria for alcohol dependence in 103 of
118 of the clinical trials. Recruitment methods varied and in-
cluded treatment programs, advertisements, referrals, or a
combination. Eighty-seven (73.7%) of 118 studies included psy-
chosocial co-interventions. For these studies, effect sizes re-
flect the benefits of medications added to psychosocial inter-
ventions compared with placebo added to psychosocial
interventions. Of 23 studies that assessed efficacy of acam-
prosate, 16 were conducted in Europe and 4 were conducted
in the United States. Of 49 studies of naltrexone, 32 were con-
ducted in the United States and 8 were conducted in Europe.

jama.com (Reprinted) JAMA November 7, 2023 Volume 330, Number 17 1655

© 2023 American Medical Association. All rights reserved.

 1656
Table. Summary of Findings and Strength of Evidence From Trials Assessing Efficacy of Medications With at Least Low Strength of Evidence for Benefit for Alcohol Use Disordera

Naltrexone
Acamprosate Baclofen Disulfiram Gabapentin 50 mg/d, oral 100 mg/d, oral Injection Any dose Topiramate
Return to any drinking
No. of studies 20 8 3 3 16 3 2 25 1
No. of participants 6380 995 622 522 2347 946 939 4604 106
Results effect size RR, 0.88 RR, 0.83 RR, 1.03 RR, 0.92 RR, 0.93 RR, 0.97 RR, 0.96 RR, 0.95 Topiramate, 53.8%;
(95% CI) (0.83-0.93) (0.70-0.98) (0.90-1.17) (0.83-1.02) (0.87-0.99) (0.91-1.03) (0.90-1.03) (0.92-0.99) placebo, 72.2%
Research Original Investigation

Number needed 11 (1-32) 18 (4-32)

to treat (95% CI)c
Strength of evidence Moderate Low Low (no effect) Low Moderate Low (no effect) Low (no effect) Moderate Insufficient
Return to heavy drinking
No. of studies 7 4 0 3 23 2 2 27 1
No. of participants 2496 483 0 522 3170 858 615 4645 170
Results effect size RR, 0.99 RR, 0.92 RR, 0.90 RR, 0.81 RR, 0.93 RR, 1.00 RR, 0.86 Topiramate, 10%;
(95% CI) (0.94-1.05) (0.80-1.06) (0.82-0.98) (0.72-0.90) (0.84-1.01) (0.82-1.21) (0.80-0.93) placebo, 14%
Number needed to treat 11 (5-41)
(95% CI)c

JAMA November 7, 2023 Volume 330, Number 17 (Reprinted)

Strength of evidence Moderate (no effect) Low (no effect) Insufficient Low Moderate Low (no effect) Low (no effect) Moderate Insufficient
Percentage of drinking days
No. of studies 14 5 2 1 15 3 2 24d 8
No. of participants 4916 714 290 112 1992 1023 467 4021 1080
Results effect size WMD, −8.3 WMD, −5.55 No significant No significant WMD, −5.1 WMD, −2.3 WMD, −4.99 WMD, −4.51 WMD, −7.2
(95% CI)b (−12.2 to −4.4) (−18.79 to 7.69) difference difference (−7.16 to −3.04) (−5.60 to 0.99) (−9.49 to 0.49) (−6.26 to −2.77) (−14.3 to −0.1)
Strength of evidence Moderate Low (no effect) Insufficient Insufficient Moderate Low Low Moderate Moderate
Percentage of heavy drinking days
No. of studies 2 9 0 3 7 2 3 13 9
No. of participants 123 1112 0 600 624 423 956 2167 1210
Results effect size WMD, −3.4 WMD, −2.16 No significant WMD, −4.3 WMD, −3.1 WMD, −4.68 WMD, −3.92 WMD, −6.2
(95% CI)b (−6.45 to 5.86) (−7.34 to 3.02) difference (−7.60 to −0.91) (−5.8 to −0.3) (−8.63 to −0.73) (−5.86 to −1.97) (−10.9 to −1.4)
Strength of evidence Insufficient Low (no effect) Insufficient Low (no effect) Moderate Low Low Moderate Moderate
Drinks per drinking day

© 2023 American Medical Association. All rights reserved.

No. of studies 2 2 0 2 9 1 0 16 7
No. of participants 139 146 0 428 1018 240 0 2011 922
Results effect size WMD, 0.6 WMD, 0.85 No significant WMD, −0.49 WMD, 1.9 WMD, −0.85 WMD, −2.0
(95% CI)b (−1.43 to 2.64) (−2.23 to 3.93) difference (−0.92 to −0.06) (−1.5 to 5.2) (−1.44 to −0.26) (−3.1 to −1.0)
Strength of evidence Insufficient Low (no effect) Insufficient Low (no effect) Low Insufficient Insufficient Low Moderate
Motor vehicle crashes or injuries
No. of studies 0e 0 0 0 0 2
No. of participants 0 0 0 0 0 541
Results effect size Reduced risk
(95% CI)b

(continued)

jama.com
Pharmacotherapy for Alcohol Use Disorder
 Table. Summary of Findings and Strength of Evidence From Trials Assessing Efficacy of Medications With at Least Low Strength of Evidence for Benefit for Alcohol Use Disordera (continued)

Naltrexone

jama.com
Acamprosate Baclofen Disulfiram Gabapentin 50 mg/d, oral 100 mg/d, oral Injection Any dose Topiramate
Strength of evidence Insufficient Insufficient Insufficient Insufficient Insufficient Low
Quality of life or function
No. of studies 1 2 0 0 5 2
No. of participants 612f 384g 0 0 1844h 118i
Results effect size No significant No significant Some conflicting No significant
(95% CI)b differencej difference resultsk difference
Strength of evidence Insufficient Low (no effect) Insufficient Insufficient Insufficient Low (no effect)
Pharmacotherapy for Alcohol Use Disorder

Mortality
No. of studies 8 4 0 0 6 3
No. of participants 2677 660 0 0 1738 507
Results effect size 7 events (acamprosate) 8 baclofen 1 event (naltrexone) Not reported
(95% CI)b vs 6 events (placebo) vs 3 placebo vs 2 events (placebo)
Strength of evidence Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient
g
Abbreviations: RR, risk ratio; WMD, weighted mean difference. Quality of life and functioning were assessed with the Quality of Life Enjoyment and Satisfaction Questionnaire
a and the 36-item Short Form Health Survey (SF-36).
Blank cells indicate data not applicable. Strength of evidence was not rated for naltrexone by dose. Heavy drinking
h
days was defined as ⱖ4 drinks/d for women and ⱖ5 drinks/d for men. Each trial used a different measure to assess quality of life and functioning, including the Short Inventory of
b Problems, SF-36, WHOQOL, SF-12 version 2 physical and mental health scores, Drinker Inventory of
Negative effect sizes favor intervention over placebo/control.
c
Consequences, and SF-12.
Lack of entry for number needed to treat indicates that the relative risk (95% CI) was not statistically significant,
i
so the investigators did not calculate a number needed to treat or the effect measure was not one that allows Quality of life was assessed with the SF-36.
j
direct calculation of number needed to treat (eg, WMD). Results were not reported for each treatment group separately, but there were no clinically significant
d differences across treatment groups.
One study contained 2 treatment groups included in the meta-analysis.79
k
e One study rated as having unclear risk of bias reported that 1 patient in the placebo group died by “accident.”
Results were not reported for each treatment group separately, but there were no clinically significant
differences across treatment groups. No other details on the cause or nature of the accident were provided.44 That study also reported 1 injury
f
in the acamprosate group and 2 in the placebo group. Another study, rated as having high risk of bias,
Quality of life and functioning were assessed with the World Health Organization Quality of Life (WHOQOL) and
reported a “traffic accident” in the acamprosate group.80
12-item Short-Form Health Survey (SF-12) version 2 physical and mental health scores.

© 2023 American Medical Association. All rights reserved.

(Reprinted) JAMA November 7, 2023 Volume 330, Number 17
Original Investigation Research

1657
 Research Original Investigation Pharmacotherapy for Alcohol Use Disorder

Figure 2. Return to Any Drinking, Acamprosate vs Placebo

Duration, No./total No. (%) Risk ratio Favors Favors

Source wk Acamprosate Placebo (95% CI) acamprosate placebo
Lhuintre et al,43 1985 13 22/42 (52.4) 31/43 (72.1) 0.73 (0.52-1.02)
Lhuintre et al,44 1990 12 208/279 (74.6) 245/291 (84.2) 0.89 (0.81-0.96)
Pelc et al,56 1992 26 42/55 (76.4) 45/47 (95.7) 0.80 (0.68-0.93)
Paille et al,55 1995 51 294/361 (81.4) 157/177 (88.7) 0.92 (0.85-0.99)
Whitworth et al,65 1996 52 183/224 (81.7) 208/224 (92.9) 0.88 (0.82-0.95)
Sass et al,61 1996 48 75/136 (55.1) 102/136 (75.0) 0.74 (0.61-0.88)
Poldrugo,60 1997 26 63/122 (51.6) 84/124 (67.7) 0.76 (0.62-0.94)
Pelc et al,57 1997 13 74/126 (58.7) 53/62 (85.5) 0.69 (0.57-0.82)
Geerlings et al,32 1997 26 96/128 (75.0) 116/134 (86.6) 0.87 (0.77-0.98)
Besson et al,24 1998 51 41/55 (74.5) 47/55 (85.5) 0.87 (0.72-1.05)
Tempesta et al,62 2000 26 87/164 (53.0) 115/166 (69.3) 0.77 (0.64-0.91)
Chick et al,26 2000 24 254/289 (87.9) 260/292 (89.0) 0.99 (0.93-1.05)
Gual and Lehert,33 2001 26 92/141 (65.2) 109/147 (74.1) 0.88 (0.75-1.03)
Kiefer et al,37 2003 12 30/40 (75.0) 37/40 (92.5) 0.81 (0.66-0.99)
Baltieri and De Andrade,21 2004 12 15/40 (37.5) 21/35 (60.0) 0.63 (0.39-1.01)
Anton et al,17 2005 16 244/303 (80.5) 254/309 (82.2) 0.98 (0.91-1.06)
Morley et al,48 2006 12 44/55 (80.0) 50/61 (82.0) 0.98 (0.82-1.16)
Mason et al,46 2006 24 328/341 (96.2) 240/260 (92.3) 1.04 (1.00-1.09)
Berger et al,23 2013 12 48/51 (94.1) 40/49 (81.6) 1.15 (0.99-1.34)
Higuchi et al,35 2015 24 86/163 (52.8) 105/164 (64.0) 0.82 (0.68-0.99)
Heterogeneity: τ2 = 0.01, I2 = 77.64%, H2 = 4.47 0.88 (0.83-0.93)
Test of Θi = Θj: Q(19) = 84.97, P <.001
Overall 0.88 (0.83-0.93)
Heterogeneity: τ2 = 0.01, I2 = 77.64%, H2 = 4.47
Test of group differences: Qb(0) = 0.00
0.2 1 4
Risk ratio (95% CI)

Figure 3. Return to Any Drinking, Disulfiram vs Placebo

Duration, No./total No. (%) Risk ratio Favors Favors

Source wk Disulfiram Placebo (95% CI) disulfiram placebo
Fuller et al,28 1986 52 34/43 (79.1) 37/42 (88.1) 0.90 (0.74-1.09)
Fuller et al,28 1986 52 34/43 (79.1) 32/43 (74.4) 1.06 (0.84-1.34)
Fuller and Roth ,29 1979 52 164/202 (81.2) 167/199 (83.9) 0.97 (0.88-1.06)
Fuller and Roth ,29 1979 52 164/202 (81.2) 158/204 (77.5) 1.05 (0.95-1.16)
Petrakis et al,58 2005 12 15/66 (22.7) 22/64 (34.4) 0.66 (0.38-1.16)
Heterogeneity: τ2 = 0.00, I2 = 18.41%, H2 = 1.23 0.99 (0.92-1.06)
Test of Θi = Θj: Q(4) = 4.90, P = .30
Overall 0.99 (0.92-1.06)
Heterogeneity: τ2 = 0.00, I2 = 18.41%, H2 = 1.23
Test of group differences: Qb(0) = 0.00
0.2 1 4
Risk ratio (95% CI)

Multiple comparisons within publications are presented separately.

Of the 118 included studies, 100 included a co-intervention such
as medical management, specific harm reduction, or counsel-
ing approaches.
Three medications (ondansetron, varenicline, and prazo-
sin) had either low strength of evidence suggesting benefit or
insufficient evidence and are not further discussed (eTable 5
in Supplement 1).
Alcohol Consumption Outcomes
Among the medications with an FDA indication for alcohol use
disorder, acamprosate and naltrexone were associated with sta-
tistically significant improvement in alcohol consumption out-
comes (Table, Figure 2, Figure 3, Figure 4, Figure 5, and
Figure 6; eAppendix in Supplement 1).15-66 Compared with pla-
cebo, numbers needed to treat to prevent 1 person from re-
turning to any drinking were 11 (95% CI, 1-32; 20 trials;
n = 6380) for acamprosate and 18 (95% CI, 4-32; 16 trials;
n = 2347) for oral naltrexone (50 mg/d), respectively. There was
no significant difference in return to heavy drinking between
acamprosate and placebo (RR, 0.99; 95% CI, 0.94-1.05; P = .69;
range, 41.9%-81.5% with acamprosate, 45.8%-82.9% with pla-
cebo). Compared with placebo, oral naltrexone (50 mg/d) was

1658 JAMA November 7, 2023 Volume 330, Number 17 (Reprinted) jama.com

© 2023 American Medical Association. All rights reserved.

Pharmacotherapy for Alcohol Use Disorder Original Investigation Research

Figure 4. Return to Any Drinking, Naltrexone vs Placebo

Duration, No./total No. (%) Risk ratio Favors Favors

Source wk Naltrexone Placebo (95% CI) naltrexone placebo
Naltrexone, 50 mg/d oral
O’Malley et al,50 1992 12 27/52 (51.9) 38/52 (73.1) 0.72 (0.53-0.98)
Volpicelli et al,63 1995 12 21/54 (38.9) 21/45 (46.7) 0.83 (0.53-1.32)
Volpicelli et al,64 1997 12 27/48 (56.3) 32/49 (65.3) 0.86 (0.62-1.19)
Oslin et al,54 1997 12 6/21 (28.6) 8/23 (34.8) 0.82 (0.34-1.98)
Anton et al,18 1999 12 36/68 (52.9) 42/63 (66.7) 0.79 (0.60-1.06)
Chick et al,27 2000 12 70/85 (82.4) 64/79 (81.0) 1.02 (0.88-1.18)
Lee et al,42 2001 12 19/35 (54.3) 11/18 (61.1) 0.89 (0.55-1.43)
Krystal et al,40 2001 12 255/418 (61.0) 140/209 (67.0) 0.91 (0.81-1.03)
Morris et al,49 2001 12 43/55 (78.2) 49/56 (87.5) 0.89 (0.75-1.06)
Gastpar et al,31 2002 12 41/84 (48.8) 45/87 (51.7) 0.94 (0.70-1.27)
Ahmadi and Ahmadi,15 2002 36 32/58 (55.2) 43/58 (74.1) 0.74 (0.56-0.98)
Guardia et al,34 2002 12 53/101 (52.5) 54/101 (53.5) 0.98 (0.76-1.27)
Kiefer et al,37 2003 12 26/40 (65.0) 37/40 (92.5) 0.70 (0.55-0.90)
Balldin et al,20 2003 24 55/56 (98.2) 59/62 (95.2) 1.03 (0.97-1.10)
Killeen et al,38 2004 12 30/51 (58.8) 21/36 (58.3) 1.01 (0.70-1.44)
Petrakis et al,58 2005 12 21/59 (35.6) 22/64 (34.4) 1.04 (0.64-1.68)
Morley et al,48 2006 12 44/53 (83.0) 50/61 (82.0) 1.01 (0.86-1.20)
O’Malley et al,52 2007 12 49/57 (86.0) 38/50 (76.0) 1.13 (0.94-1.36)
O’Malley et al,51 2008 16 22/34 (64.7) 30/34 (88.2) 0.73 (0.56-0.97)
Baltieri et al,22 2008 12 35/49 (71.4) 39/54 (72.2) 0.99 (0.78-1.26)
Heterogeneity: τ2 = 0.01, I2 = 35.07%, H2 = 1.54 0.93 (0.87-0.99)
Test of Θi = Θj: Q(19) = 29.26, P = .06
Naltrexone, 100 mg/d oral
Anton et al,19 2006 16 241/309 (78.0) 254/309 (82.2) 0.95 (0.88-1.03)
Oslin et al,53 2008 24 95/120 (79.2) 96/120 (80.0) 0.99 (0.87-1.12)
Pettinati et al,59 2010 14 39/49 (79.6) 30/39 (76.9) 1.03 (0.83-1.29)
Heterogeneity: τ2 = 0.00, I2 = 0.00%, H2 = 1.00 0.97 (0.91-1.03)
Test of Θi = Θj: Q(2) = 0.70, P = .70
Naltrexone, injection
Kranzler et al,39 2004 12 130/158 (82.3) 141/157 (89.8) 0.92 (0.84-1.00)
Garbutt et al,30 2005 24 388/415 (93.5) 198/209 (94.7) 0.99 (0.95-1.03)
Heterogeneity: τ2 = 0.00, I2 = 54.45%, H2 = 2.20 0.96 (0.90-1.03)
Test of Θi = Θj: Q(1) = 2.20, P = .14
Overall 0.95 (0.92-0.99)
Heterogeneity: τ2 = 0.00, I2 = 25.82%, H2 = 1.35
Test of group differences: Qb(2) = 0.99, P = .61
0.2 1 4
Risk ratio (95% CI)

“Overall” refers to pooled estimate for all forms of naltrexone (50 mg/d oral, 100 mg/d oral, and injection).

associated with a statistically significant improvement in re-
turn to heavy drinking (RR, 0.81; 95% CI, 0.72-0.90; P < .001;
range, 14.3%-94.6% with naltrexone, 29.7%-93.5% with pla-
cebo) with a number needed to treat of 11 (95% CI, 5-41; 19 trials;
n = 2875). Compared with placebo, injectable naltrexone was
not associated with lower rates of return to any drinking (RR,
0.96; 95% CI, 0.90-1.03; P = .14; 2 trials; n = 939; range, 82.3%-
93.5% with naltrexone, 89.8%-94.7% with placebo) or return
to heavy drinking (RR, 1.00; 95% CI, 0.82-1.21; P = .09; 2 trials;
n = 615; range, 59.2%-77.2% with naltrexone, 52.7%-84.1% with
placebo). Compared with placebo, injectable naltrexone was
associated with greater reduction in percentage of drinking
days (WMD, −4.99; 95% CI, −9.49 to −0.49; P = .23; 2 trials;
n = 467) and percentage of heavy drinking days (WMD, −4.7;
95% CI, −8.6 to −0.73; P = .80; 3 trials; n = 956). Data from 3
RCTs that included 622 participants did not show an associa-
tion of disulfiram compared with placebo for preventing re-
turn to any drinking (RR, 1.03; 95% CI, 0.90-1.17; P = .28; range,
22.7%-81.2% with disulfiram, 34.4%-88.1% with placebo)
(Table).
Among medications without an FDA indication for alco-
hol use disorder treatment, compared with placebo, topira-
mate was associated with statistically significant improve-
ment in the weighted mean of absolute percentage of
drinking days (WMD, −7.2; 95% CI, −14.3 to −0.1; P = .14;
range, 5.5%-62.4% with topiramate, 6.4%-70.9%), percent-
age of heavy drinking days (WMD, −6.2; 95% CI, −10.9
to −1.4; P = .32; range, 2.3%-43.8% with topiramate, 5.3%-
51.8% with placebo), and number of drinks per drinking day
(WMD, −2.0; 95% CI, −3.1 to −1.0; P = .19; range, 1.2-6.5 with

jama.com (Reprinted) JAMA November 7, 2023 Volume 330, Number 17 1659

© 2023 American Medical Association. All rights reserved.

 Research Original Investigation Pharmacotherapy for Alcohol Use Disorder

Figure 5. Return to Heavy Drinking, Acamprosate vs Placebo

Duration, No./total No. (%) Risk ratio Favors Favors

Source wk Acamprosate Placebo (95% CI) acamprosate placebo
Chick et al,26 2000 24 246/289 (85.1) 242/292 (82.9) 1.03 (0.96-1.10)
Kiefer et al,37 2003 12 25/40 (62.5) 30/40 (75.0) 0.83 (0.62-1.12)
Kiefer et al,37 2003 12 20/40 (50.0) 25/40 (62.5) 0.80 (0.54-1.18)
Morley et al,48 2006 12 40/55 (72.7) 43/61 (70.5) 1.03 (0.82-1.30)
Morley et al,48 2006 12 40/55 (72.7) 39/53 (73.6) 0.99 (0.79-1.24)
Anton et al,19 2006 16 211/303 (69.6) 226/309 (73.1) 0.95 (0.86-1.05)
Anton et al,19 2006 16 211/303 (69.6) 207/309 (67.0) 1.04 (0.93-1.16)
Mason et al,46 2006 24 143/341 (41.9) 119/260 (45.8) 0.92 (0.76-1.10)
Wölwer et al,66 2011 24 65/124 (52.4) 65/125 (52.0) 1.01 (0.79-1.28)
Mann et al,45 2013 12 89/172 (51.7) 41/85 (48.2) 1.07 (0.82-1.40)
Mann et al,45 2013 12 89/172 (51.7) 86/169 (50.9) 1.02 (0.83-1.25)
Heterogeneity: τ2 = 0.00, I2 = 0.00%, H2 = 1.00 1.00 (0.96-1.04)
Test of Θi = Θj: Q(10) = 5.90, P = .82
Overall 1.00 (0.96-1.04)
Heterogeneity: τ2 = 0.00, I2 = 0.00%, H2 = 1.00
Test of group differences: Qb(0) = 0.00
0.2 1 4
Risk ratio (95% CI)

Heavy drinking is defined as ⱖ4 drinks/d for women and ⱖ5 drinks/d for men. Multiple comparisons within publications are presented separately.

topiramate, 4.0-8.8 with placebo). These findings were asso-
ciated with moderate strength of evidence. Of 13 double-
blind placebo-controlled RCTs that included 1607 partici-
pants, compared with placebo, baclofen was associated with
significantly lower rates of return to any drinking (RR, 0.83;
95% CI, 0.70-0.98; P < .001; range, 28.6%-92.4% with
baclofen, 53.2%-89.9% with placebo). Because of impreci-
sion of the effect estimate and inconsistency of results,
baclofen data were graded as having low strength of evi-
dence. Compared with placebo, gabapentin was not signifi-
cantly associated with lower rates of return to any drinking
(RR, 0.92; 95% CI, 0.83-1.02: P = .08; range, 79.5-86.1 with
gabapentin, 88.2-95.9 with placebo) or with significant
reduction in return to heavy drinking (RR, 0.90; 95% CI,
0.82-0.98; P = .75; range, 63.4-75.9 with gabapentin, 77.6-
87.0 with placebo), but both results had low strength of evi-
dence and only 3 clinical trials reported these outcomes.
A meta-analysis of 4 RCTs including 1141 participants that
directly compared acamprosate with naltrexone19,37,45,48 found
no statistically significant difference between the 2 medica-
tions for improvement in alcohol use outcomes consisting of
return to any drinking (RR, 1.03; 95% CI, 0.96-1.10; P = .57;
range, 75.0-80.5 with acamprosate, 65.0-83.0 with naltrex-
one; 3 trials; n = 800) or return to heavy drinking (RR, 1.02;
95% CI, 0.93-1.11; P = .65; range, 50.0-72.7 with acamprosate,
50.9-73.6 with naltrexone; 4 trials; n = 1141).
Health Outcomes
There was insufficient evidence from RCTs to assess whether
treatment with most medications was associated with im-
proved health outcomes. Outcomes such as motor vehicle
crashes, injuries, quality of life, function, and mortality were
infrequently reported in the included studies (Table).
Adverse Effects
Adverse event data were often not collected using standard-
ized measures, and methods for systematically capturing ad-
verse events were often not reported (Figure 7).
Among medications with at least some (low) strength of
evidence for benefit in any outcome, compared with placebo,
dizziness was the most common mild adverse effect across
medications and was reported with naltrexone (RR, 1.99; 95%
CI, 1.47-2.69; P = .37; range, 2.9%-34.8% with naltrexone, 0.0%-
20.6% with placebo), baclofen (RR, 1.89; 95% CI, 1.40-2.55;
P = .40; range, 4.8%-30.2% with baclofen, 0.0%-22.8% with
placebo), topiramate (RR, 2.29; 95% CI, 1.39-3.78; P = .65; range,
0.0%-28.0% with topiramate, 1.9%-10.7% with placebo), and
gabapentin (RR, 1.70; 95% CI, 1.24-2.32; P = .83; range, 6.5%-
7.8% with gabapentin, 3.8%-6.0% with placebo). Compared
with placebo, any gastrointestinal distress was more com-
mon for acamprosate (diarrhea: RR, 1.58; 95% CI, 1.27-1.97;
P = .03; range, 3.0%-63.7% with acamprosate, 1.6%-64.9% with
placebo) and naltrexone (nausea: RR, 1.73; 95% CI, 1.51-1.98;
P = .19; range, 2.5%-57.6% with naltrexone, 0.0%-47.1% with
placebo; vomiting: RR, 1.53; 95% CI, 1.23-1.91; P = .79; range,
0.0%-25.6% with naltrexone, 0.0%-23.4% with placebo). Com-
pared with placebo, baclofen was associated with higher rates
of drowsiness (RR, 1.46; 95% CI, 1.15-1.86; P = .28; range, 6.3%-
50.0% with baclofen, 9.4%-32.6% with placebo), numbness
(RR, 7.78; 95% CI, 1.42-42.56; P = .48; range, 7.1%-12.6% with
baclofen, 0.0%-1.1% with placebo), and sleepiness (RR, 1.81;
95% CI, 1.11-2.97; P = .77; range, 2.4%-36.2% with baclofen,
0.0%-17.7% with placebo). Compared with placebo, topira-
mate was associated with higher risks of many adverse events,
including paresthesias (RR, 3.08; 95% CI, 2.11-4.49; P = .06;
range, 0.0%-57.3% with topiramate, 1.9%-29.4% with pla-
cebo), taste abnormalities (RR, 3.01; 95% CI, 1.70-5.34; P = .04;

1660 JAMA November 7, 2023 Volume 330, Number 17 (Reprinted) jama.com

© 2023 American Medical Association. All rights reserved.

Pharmacotherapy for Alcohol Use Disorder Original Investigation Research

Figure 6. Return to Heavy Drinking, Naltrexone vs Placebo

Duration, No./total No. (%) Risk ratio Favors Favors

Source wk Naltrexone Placebo (95% CI) naltrexone placebo
Naltrexone, 50 mg/d oral
O’Malley et al,50 1992 12 24/52 (46.2) 34/52 (65.4) 0.71 (0.50-1.01)
Volpicelli et al,63 1995 12 10/54 (18.5) 17/45 (37.8) 0.49 (0.25-0.96)
Volpicelli et al,64 1997 12 17/48 (35.4) 26/49 (53.1) 0.67 (0.42-1.06)
Oslin et al,54 1997 12 3/21 (14.3) 8/23 (34.8) 0.41 (0.13-1.35)
Anton et al,18 1999 12 26/68 (38.2) 38/63 (60.3) 0.63 (0.44-0.91)
Chick et al,27 2000 24 57/85 (67.1) 53/79 (67.1) 1.00 (0.81-1.24)
Krystal et al,40 2001 12 183/418 (43.8) 105/209 (50.2) 0.87 (0.73-1.04)
Monti et al,47 2001 12 16/64 (25.0) 19/64 (29.7) 0.84 (0.48-1.49)
Morris et al,49 2001 12 28/55 (50.9) 43/56 (76.8) 0.66 (0.49-0.89)
Latt et al,41 2002 12 19/56 (33.9) 27/51 (52.9) 0.64 (0.41-1.00)
Guardia et al,34 2002 12 8/101 (7.9) 19/101 (18.8) 0.42 (0.19-0.92)
Ahmadi and Ahmadi,15 2002 12 12/58 (20.7) 33/58 (56.9) 0.36 (0.21-0.63)
Gastpar et al,31 2002 12 34/84 (40.5) 36/87 (41.4) 0.98 (0.68-1.40)
Kiefer et al,37 2003 12 20/40 (50.0) 30/40 (75.0) 0.67 (0.47-0.95)
Balldin et al,20 2003 24 53/56 (94.6) 58/62 (93.5) 1.01 (0.92-1.11)
Killeen et al,38 2004 12 21/51 (41.2) 12/36 (33.3) 1.24 (0.70-2.18)
Anton et al,17 2005 12 33/80 (41.3) 46/80 (57.5) 0.71 (0.51-0.98)
Huang et al,36 2005 14 4/20 (20.0) 3/20 (15.0) 1.33 (0.34-5.21)
Morley et al,48 2006 12 39/53 (73.6) 43/61 (70.5) 1.04 (0.83-1.31)
O’Malley et al,52 2007 12 39/57 (68.4) 32/50 (64.0) 1.07 (0.81-1.40)
O’Malley et al,51 2008 16 22/34 (64.7) 28/34 (82.4) 0.79 (0.59-1.05)
Brown et al,25 2009 12 4/20 (20.0) 10/23 (43.5) 0.46 (0.17-1.24)
Mann et al,45 2013 12 86/169 (50.9) 41/85 (48.2) 1.05 (0.81-1.38)
Heterogeneity: τ2 = 0.03, I2 = 58.72%, H2 = 2.42 0.81 (0.72-0.90)
Test of Θi = Θj: Q(22) = 53.29, P <.001
Naltrexone, 100 mg/d oral
Anton et al,19 2006 16 207/309 (67.0) 226/309 (73.1) 0.92 (0.83-1.02)
Oslin et al,53 2008 24 73/120 (60.8) 76/120 (63.3) 0.96 (0.79-1.17)
Heterogeneity: τ2 = 0.00, I2 = 0.00%, H2 = 1.00 0.93 (0.84-1.01)
Test of Θi = Θj: Q(1) = 0.17, P = .68
Naltrexone, injection
Kranzler et al,39 2004 12 122/158 (77.2) 132/157 (84.1) 0.92 (0.82-1.02)
ALK21−014,16 2011 12 90/152 (59.2) 78/148 (52.7) 1.12 (0.92-1.37)
Heterogeneity: τ2 = 0.01, I2 = 66.35%, H2 = 2.97 1.00 (0.82-1.21)
Test of Θi = Θj: Q(1) = 2.97, P = .08
Overall 0.86 (0.80-0.93)
Heterogeneity: τ2 = 0.02, I2 = 54.99%, H2 = 2.22
Test of group differences: Qb(2) = 5.00, P = .08
0.1 1 6
Risk ratio (95% CI)

“Overall” refers to pooled estimate for all forms of naltrexone (50 mg/d oral, 100 mg/d oral, and injection). Heavy drinking is defined as ⱖ4 drinks/d for women
and ⱖ5 drinks/d for men.

range, 15.1%-53.3% with topiramate, 4.8%-31.3% with pla-
cebo), and cognitive dysfunction (RR, 2.37; 95% CI, 1.58-3.55;
P = .48; range, 12.6%-23.9% with topiramate, 5.4%-11.3% with
placebo). Compared with placebo, gabapentin was associ-
ated with cognitive dysfunction (RR, 2.76; 95% CI, 1.51-5.06;
P = .37; range, 5.9%-25.5% with gabapentin, 5.7%-17% with pla-
cebo) and dizziness (RR, 1.70; 95% CI, 1.24-2.32; P = .83; range,
21.2%-56.8% with gabapentin, 13.7%-32.6% with placebo). In
direct comparisons of acamprosate and oral naltrexone in RCTs,
patients treated with acamprosate had lower rates of nausea
(RR, 0.56; 95% CI, 0.35-0.88; P = .11; range, 3.8%-23.8% with
acamprosate, 2.5%-55.6% with naltrexone) and vomiting (RR,
0.60; 95% CI, 0.39-0.93; P = .88; range, 8.9%-11.1% with acam-
prosate, 14.6%-22.2% with naltrexone) compared with those
treated with naltrexone.
Discussion
In this systematic review and meta-analysis that included 118
clinical trials, the highest strength of evidence for treatment
of alcohol use disorder was available for acamprosate and
oral naltrexone (50 mg/d). Randomized clinical trials that di-
rectly compared naltrexone, 50 mg/d, with acamprosate
did not consistently established superiority of either medica-
tion. Studies of naltrexone had moderate strength of evidence

jama.com (Reprinted) JAMA November 7, 2023 Volume 330, Number 17 1661

© 2023 American Medical Association. All rights reserved.

 Research Original Investigation Pharmacotherapy for Alcohol Use Disorder

Figure 7. Summary of Strength-of-Evidence Assessments for Harms Outcomes

Adverse event Acamprosate Baclofen Disulfiram Gabapentin Naltrexone Topiramate Varenicline

Anxiety IE IE
Cognitive dysfunction IE IE IE IE
Diarrhea IE
Dizziness IE
Drowsiness NA IE NA NA NA NA
Fatigue NA NA NA NA NA NA
Headache IE
Insomnia IE
Nausea IE
Numbness IE IE NA
Rash IE IE IE
Sleepiness NA NA NA NA NA NA
Study withdrawals due to adverse event IE
Suicide attempts or suicidal ideation IE IE IE IE IE IE
Taste abnormalities IE IE IE IE IE
Vision changes IE IE IE IE
Vomiting IE IE

Moderate strength of evidence for adverse event Low strength of evidence for adverse event
Moderate strength of evidence for no adverse event Low strength of evidence for no adverse event

IE indicates insufficient evidence; NA, not assessed. This figure includes all drugs with a rating of at least low strength of evidence for adverse events for at least 1
outcome. All doses of naltrexone were assessed together.

for reducing return to any drinking, return to heavy drinking,
percentage of drinking days, and percentage of heavy drink-
ing days at the 50-mg/d oral dose compared with placebo.
Fewer data were available for the 100-mg/d oral and inject-
able doses. Studies of acamprosate showed moderate strength
of evidence for significant reduction in return to any drinking
and reduction in drinking days compared with placebo. Acam-
prosate was not associated with benefit for return to heavy
drinking (moderate strength of evidence).
Oral naltrexone is more convenient than acamprosate,
requiring a single daily dose, whereas acamprosate is typi-
cally prescribed as 2 tablets administered 3 times daily.
Acamprosate is contraindicated for people with severe kid-
ney impairment and requires dose adjustments for moderate
kidney impairment. Oral naltrexone is contraindicated for
patients with acute hepatitis or liver failure and for those
using opioids or who have anticipated need for opioids.
Naltrexone can precipitate severe withdrawal for patients
dependent on opioid medications.
Disulfiram has been FDA approved for alcohol use disor-
der since the 1950s. However, relatively limited evidence ex-
ists to support the efficacy of disulfiram compared with pla-
cebo for preventing return to any drinking or other alcohol
consumption outcomes. Four RCTs of disulfiram have been
published that were not eligible for this review because of their
trial designs and comparisons.67-70 These small trials (with 15
or fewer disulfiram-treated patients in each) had limitations
that included a small sample size and inability to distinguish
between benefits from disulfiram and benefits of counseling
or benefits from therapeutic relationships with the investiga-
tive team.71,72
Among medications without FDA approval for alcohol
use disorder, studies of topiramate compared with placebo
had moderate strength of evidence for significant reductions
in percentage of drinking days, percentage of heavy drinking
days, and drinks per drinking days. However, topiramate was
associated with adverse effects that included cognitive dys-
function, dizziness, numbness and/or tingling, and taste
abnormalities. Studies of baclofen and gabapentin had low
strength of evidence for benefit in at least 1 outcome. Evi-
dence was largely insufficient or low for benefit on health
outcomes, including quality of life, motor vehicle crashes,
and mortality.
Alcohol use disorder is associated with numerous health
problems, including but not limited to hypertension, heart
disease, stroke, cognitive impairment, sleep problems,
depression, anxiety, peripheral neuropathy, gastritis and
gastric ulcers, liver disease including cirrhosis, pancreatitis, os-
teoporosis, anemia, fetal alcohol spectrum disorders, and sev-
eral types of cancer.73,74 Excessive alcohol consumption is also
associated with higher rates of homicide, suicide, motor ve-
hicle crashes and deaths, sexual violence, domestic violence,
and drownings.75
Applicability of Findings
Using DSM-5 criteria, most participants in the included studies
likely had moderate to severe alcohol use disorder. Thus,
applicability of the findings to people with mild alcohol use

1662 JAMA November 7, 2023 Volume 330, Number 17 (Reprinted) jama.com

© 2023 American Medical Association. All rights reserved.

Pharmacotherapy for Alcohol Use Disorder Original Investigation Research

disorder is uncertain. The mean age of participants was typically
between 40 and 49 years, with only 21 studies enrolling younger
or older populations. Thus, it is uncertain whether the medi-
cations have similar efficacy for older (eg, aged ≥65 years) or
younger (eg, aged in their 20s) people. Of the 70 studies that pro-
vided data on race and sex, most (n = 63) included a majority
of White male participants, and none specified sex other than
male or female. Because 100 of 118 clinical trials studied drug
therapy combined with a nonmedication treatment (such as
counseling), results reflect benefits from a combination of medi-
cation and cotherapy compared with placebo and cotherapy.
Of the 5 studies of acamprosate that were conducted in the
United States, most reported no significant benefit either for
return to any drinking or return to heavy drinking. Clinical trials
conducted in the United States recruited patients largely
through advertisements, while 15 of 22 clinical trials in other
countries recruited participants from inpatient settings, where
patients may have undergone alcohol withdrawal and medi-
cations may have been initiated before discharge. Patients re-
cruited in the clinical trials conducted in the United States may
have represented a more general population with a larger range
of alcohol use at baseline. Thus, the lack of efficacy in US-based
trials for acamprosate may reflect differences in patient char-
acteristics and differences in the health care systems com-
pared with clinical trials from other countries.
Most studies required patients to abstain for at least a few
days before initiating medication, and the medications were
generally recommended for maintenance of abstinence. Acam-
prosate and injectable naltrexone are FDA approved only for
use in patients who have established abstinence, although the
duration of required abstinence is not established. Three stud-
ies enrolling patients who were not yet abstinent reported re-
duction in heavy drinking with naltrexone compared with
placebo30,76 or acamprosate compared with placebo.33
Limitations
This review has several limitations. First, clinical trials with
less than 12 weeks of follow-up from the time of medication
initiation were excluded. Second, the meta-analysis com-
bined studies of participants with diagnoses of both alcohol
dependence and depression and studies of participants with-
out both alcohol dependence and depression. Third, studies
may have selectively reported outcomes. Fourth, long-term in-
formation about adverse effects was not available. Fifth, for
adverse event outcomes, due to small sample sizes and rela-
tively small numbers of events, evidence was often insuffi-
cient to determine whether adverse event outcomes were in-
creased. Sixth, in some included studies, less than 100% of
participants had alcohol use disorder. Specifically, 3 studies re-
ported that less than 90% of participants had alcohol use
disorder.24,77,78
Conclusions
In conjunction with psychosocial interventions, these find-
ings support the use of oral naltrexone, 50 mg/d, and acampro-
sate as first-line pharmacotherapies for alcohol use disorder.

ARTICLE INFORMATION
Accepted for Publication: September 12, 2023.
Author Contributions: Dr McPheeters had full
access to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: McPheeters, O’Connor, Edlund,
Bobashev, Jonas.
Acquisition, analysis, or interpretation of data:
McPheeters, O’Connor, Riley, Kennedy, Voisin,
Kuznacic, Coffey, Bobashev, Jonas.
Drafting of the manuscript: McPheeters, O’Connor,
Riley, Kennedy, Kuznacic, Coffey, Jonas.
Critical review of the manuscript for important
intellectual content: McPheeters, O’Connor, Voisin,
Edlund, Bobashev, Jonas.
Statistical analysis: McPheeters, O’Connor, Riley,
Jonas.
Obtained funding: McPheeters, Jonas.
Administrative, technical, or material support:
Kennedy, Voisin, Bobashev, Jonas.
Supervision: McPheeters, Jonas.
Conflict of Interest Disclosures: None reported.
Funding/Support: This project was funded under
contract 75Q80120D00007, task order
75Q80122F32004 from the Agency for Healthcare
Research and Quality (AHRQ) of the US
Department of Health and Human Services.
Role of the Funder/Sponsor: This topic was
nominated by the AHRQ program official for
EvidenceNow: Managing Unhealthy Alcohol Use
Initiative and selected by AHRQ for systematic
review by an evidence-based practice center.
A representative from AHRQ served as a
contracting officer’s representative and provide
technical assistance during the conduct of the full
evidence report and provided comments on draft
versions of the full evidence report. AHRQ did not
directly participate in the literature search,
determination of study eligibility criteria, data
analysis or interpretation, or preparation, review, or
approval of the manuscript for publication.
Disclaimer: The authors of this article are
responsible for its content. Statements in the article
do not necessarily represent the official views of or
imply endorsement by AHRQ or the US Department
of Health and Human Services. AHRQ retains a
license to display, reproduce, and distribute the
data and the report from which this manuscript was
derived under the terms of the agency’s contract
with the author.
Data Sharing Statement: See Supplement 2.
Additional Contributions: We gratefully
acknowledge the following individuals for their
contributions to this project, none of whom
received compensation: from AHRQ: Meghan
Wagner, PharmD, AHRQ Task Order Officer
Elisabeth Kato, MD, MRP, and Cleo Alford, MPS,
MSc; from the American Psychiatric Association:
Laura Fochtmann, MD, and Jennifer Medicus; from
the American Society of Addiction Medicine: Anna
Pagano, PhD, and Ray Denny, PhD; from RTI
International–University of North Carolina
at Chapel Hill Evidence-Based Practice Center (for
administrative support, review, and/or editing):
Roberta Wines, MPH, Carol Woodell, BSPH,
Nila Sathe, MA, MLIS, Sharon Barrell, MA, Mary
Gendron, and Teyonna Downing.
REFERENCES
1. Centers for Disease Control and Prevention.
Deaths from excessive alcohol use in the United
States. Accessed January 23, 2023, https://www.
cdc.gov/alcohol/features/excessive-alcohol-deaths.
html
2. Substance Abuse and Mental Health Services
Administration. Key Substance Use and Mental
Health Indicators in the United States: Results From
the 2020 National Survey on Drug Use and Health.
Published 2021. Accessed May 3, 2023. https://
www.samhsa.gov/data/
3. Substance Abuse and Mental Health Services
Administration. National Survey on Drug Use and
Health, detailed tables. Accessed July 25, 2022.
https://www.samhsa.gov/data/report/2020-nsduh-
detailed-tables
4. Substance Abuse and Mental Health Services
Administration. Key Substance Use and Mental
Health Indicators in the United States: Results From
the 2021 National Survey on Drug Use and Health.
Published 2022. Accessed May 3, 2023. https://
www.samhsa.gov/data/sites/default/files/reports/
rpt39443/2021NSDUHFFRRev010323.pdf
5. Jonas DE, Amick HR, Feltner C, et al.
Pharmacotherapy for Adults with Alcohol-Use
Disorders in Outpatient Settings. Published May 13,
2014. Accessed May 3, 2023. https://
effectivehealthcare.ahrq.gov/products/alcohol-
misuse-drug-therapy/research

jama.com (Reprinted) JAMA November 7, 2023 Volume 330, Number 17 1663

© 2023 American Medical Association. All rights reserved.

 Research Original Investigation
6. Jonas DE, Amick HR, Feltner C, et al.
Pharmacotherapy for adults with alcohol use
disorders in outpatient settings: a systematic
review and meta-analysis. JAMA. 2014;311(18):
1889-1900. doi:10.1001/jama.2014.3628
7. McGowan J, Sampson M, Salzwedel DM, Cogo E,
Foerster V, Lefebvre C. PRESS: Peer Review of
Electronic Search Strategies: 2015 guideline
statement. J Clin Epidemiol. 2016;75:40-46. doi:10.
1016/j.jclinepi.2016.01.021
8. Methods guide for effectiveness and
comparative effectiveness reviews. Accessed May
3, 2023. https://www.ncbi.nlm.nih.gov/books/
NBK47095/
9. Viswanathan M, Ansari MT, Berkman ND, et al.
Assessing the Risk of Bias of Individual Studies in
Systematic Reviews of Health Care Interventions.
Published 2012. Accessed May 3, 2023. https://
www.effectivehealthcare.ahrq.gov/
10. Sterne JAC, Savović J, Page MJ, et al. RoB 2:
a revised tool for assessing risk of bias in
randomised trials. BMJ. 2019;366:l4898. doi:10.
1136/bmj.l4898
11. Owens DK, Lohr KN, Atkins D, et al. Grading the
strength of a body of evidence when comparing
medical interventions—Agency for Healthcare
Research and Quality and the Effective Health-Care
Program. J Clin Epidemiol. 2010;63(5):513-523.
doi:10.1016/j.jclinepi.2009.03.009
12. Sutton AJ, Abrams KR, Jones DR, Sheldon TA,
Song F. Methods for Meta-Analysis in Medical
Research. Wiley; 2000.
13. Higgins JP, Thompson SG. Quantifying
heterogeneity in a meta-analysis. Stat Med. 2002;
21(11):1539-1558. doi:10.1002/sim.1186
14. Higgins JP, Thompson SG, Deeks JJ, Altman DG.
Measuring inconsistency in meta-analyses. BMJ.
2003;327(7414):557-560. doi:10.1136/bmj.327.7414.
557
15. Ahmadi J, Ahmadi N. A double blind,
placebo-controlled study of naltrexone in the
treatment of alcohol dependence. Ger J Psychiatry.
2002;5(4):85-89.
16. ClinicalTrials.gov. ALK21-014: efficacy and
safety of Medisorb naltrexone (Vivitrol) after
enforced abstinence. Accessed October 6, 2023.
https://www.clinicaltrials.gov/study/NCT00501631
17. Anton RF, Moak DH, Latham P, et al. Naltrexone
combined with either cognitive behavioral or
motivational enhancement therapy for alcohol
dependence. J Clin Psychopharmacol. 2005;25(4):
349-357. doi:10.1097/01.jcp.0000172071.81258.04
18. Anton RF, Moak DH, Waid LR, Latham PK,
Malcolm RJ, Dias JK. Naltrexone and cognitive
behavioral therapy for the treatment of outpatient
alcoholics: results of a placebo-controlled trial. Am J
Psychiatry. 1999;156(11):1758-1764. doi:10.1176/ajp.
156.11.1758
19. Anton RF, O’Malley SS, Ciraulo DA, et al;
COMBINE Study Research Group. Combined
pharmacotherapies and behavioral interventions
for alcohol dependence: the COMBINE study:
a randomized controlled trial. JAMA. 2006;295(17):
2003-2017. doi:10.1001/jama.295.17.2003
20. Balldin J, Berglund M, Borg S, et al. A 6-month
controlled naltrexone study: combined effect with
cognitive behavioral therapy in outpatient
treatment of alcohol dependence. Alcohol Clin Exp
1664 JAMA November 7, 2023 Volume 330, Number 17 (Reprinted)
© 2023 American Medical Association. All rights reserved.
Res. 2003;27(7):1142-1149. doi:10.1097/01.ALC.
0000075548.83053.A9
21. Baltieri DA, De Andrade AG. Acamprosate in
alcohol dependence: a randomized controlled
efficacy study in a standard clinical setting. J Stud
Alcohol. 2004;65(1):136-139. doi:10.15288/jsa.2004.
65.136
22. Baltieri DA, Daró FR, Ribeiro PL, de Andrade AG.
Comparing topiramate with naltrexone in the
treatment of alcohol dependence. Addiction. 2008;
103(12):2035-2044. doi:10.1111/j.1360-0443.2008.
02355.x
23. Berger L, Fisher M, Brondino M, et al. Efficacy
of acamprosate for alcohol dependence in a family
medicine setting in the United States:
a randomized, double-blind, placebo-controlled
study. Alcohol Clin Exp Res. 2013;37(4):668-674.
doi:10.1111/acer.12010
24. Besson J, Aeby F, Kasas A, Lehert P,
Potgieter A. Combined efficacy of acamprosate
and disulfiram in the treatment of alcoholism:
a controlled study. Alcohol Clin Exp Res. 1998;22(3):
573-579. doi:10.1111/j.1530-0277.1998.tb04295.x
25. Brown ES, Carmody TJ, Schmitz JM, et al.
A randomized, double-blind, placebo-controlled
pilot study of naltrexone in outpatients with bipolar
disorder and alcohol dependence. Alcohol Clin Exp
Res. 2009;33(11):1863-1869. doi:10.1111/j.1530-
0277.2009.01024.x
26. Chick J, Anton R, Checinski K, et al.
A multicentre, randomized, double-blind,
placebo-controlled trial of naltrexone in the
treatment of alcohol dependence or abuse. Alcohol
Alcohol. 2000;35(6):587-593. doi:10.1093/alcalc/
35.6.587
27. Chick J, Howlett H, Morgan MY, Ritson B.
United Kingdom Multicentre Acamprosate Study
(UKMAS): a 6-month prospective study of
acamprosate versus placebo in preventing relapse
after withdrawal from alcohol. Alcohol Alcohol.
2000;35(2):176-187. doi:10.1093/alcalc/35.2.176
28. Fuller RK, Branchey L, Brightwell DR, et al.
Disulfiram treatment of alcoholism: a Veterans
Administration Cooperative Study. JAMA. 1986;256
(11):1449-1455. doi:10.1001/jama.1986.
03380110055026
29. Fuller RK, Roth HP. Disulfiram for the treatment
of alcoholism: an evaluation in 128 men. Ann Intern
Med. 1979;90(6):901-904. doi:10.7326/0003-
4819-90-6-901
30. Garbutt JC, Kranzler HR, O’Malley SS, et al;
Vivitrex Study Group. Efficacy and tolerability of
long-acting injectable naltrexone for alcohol
dependence: a randomized controlled trial. JAMA.
2005;293(13):1617-1625. doi:10.1001/jama.293.13.1617
31. Gastpar M, Bonnet U, Böning J, et al. Lack of
efficacy of naltrexone in the prevention of alcohol
relapse: results from a German multicenter study.
J Clin Psychopharmacol. 2002;22(6):592-598. doi:
10.1097/00004714-200212000-00009
32. Geerlings PJ, Ansoms C, Van Den Brink W.
Acamprosate and prevention of relapse in
alcoholics: results of a randomized,
placebo-controlled, double-blind study in
out-patient alcoholics in the Netherlands, Belgium
and Luxembourg. Eur Addict Res. 1997;3(3):129-137.
doi:10.1159/000259166
33. Gual A, Lehert P. Acamprosate during and after
acute alcohol withdrawal: a double-blind
Pharmacotherapy for Alcohol Use Disorder
placebo-controlled study in Spain. Alcohol Alcohol.
2001;36(5):413-418. doi:10.1093/alcalc/36.5.413
34. Guardia J, Caso C, Arias F, et al. A double-blind,
placebo-controlled study of naltrexone in the
treatment of alcohol-dependence disorder: results
from a multicenter clinical trial. Alcohol Clin Exp Res.
2002;26(9):1381-1387. doi:10.1111/j.1530-0277.2002.
tb02682.x
35. Higuchi S; Japanese Acamprosate Study Group.
Efficacy of acamprosate for the treatment of
alcohol dependence long after recovery from
withdrawal syndrome: a randomized, double-blind,
placebo-controlled study conducted in Japan
(Sunrise Study). J Clin Psychiatry. 2015;76(2):181-188.
doi:10.4088/JCP.13m08940
36. Huang MC, Chen CH, Yu JM, Chen CC.
A double-blind, placebo-controlled study of
naltrexone in the treatment of alcohol dependence
in Taiwan. Addict Biol. 2005;10(3):289-292. doi:
10.1080/13556210500223504
37. Kiefer F, Jahn H, Tarnaske T, et al. Comparing
and combining naltrexone and acamprosate in
relapse prevention of alcoholism: a double-blind,
placebo-controlled study. Arch Gen Psychiatry.
2003;60(1):92-99. doi:10.1001/archpsyc.60.1.92
38. Killeen TK, Brady KT, Gold PB, et al.
Effectiveness of naltrexone in a community
treatment program. Alcohol Clin Exp Res. 2004;28
(11):1710-1717. doi:10.1097/01.ALC.0000145688.
30448.2C
39. Kranzler HR, Wesson DR, Billot L; Drug Abuse
Sciences Naltrexone Depot Study Group.
Naltrexone depot for treatment of alcohol
dependence: a multicenter, randomized,
placebo-controlled clinical trial. Alcohol Clin Exp Res.
2004;28(7):1051-1059. doi:10.1097/01.ALC.
0000130804.08397.29
40. Krystal JH, Cramer JA, Krol WF, Kirk GF,
Rosenheck RA; Veterans Affairs Naltrexone
Cooperative Study 425 Group. Naltrexone in the
treatment of alcohol dependence. N Engl J Med.
2001;345(24):1734-1739. doi:10.1056/NEJMoa011127
41. Latt NC, Jurd S, Houseman J, Wutzke SE.
Naltrexone in alcohol dependence: a randomised
controlled trial of effectiveness in a standard clinical
setting. Med J Aust. 2002;176(11):530-534. doi:10.
5694/j.1326-5377.2002.tb04550.x
42. Lee A, Tan S, Lim D, et al. Naltrexone in the
treatment of male alcoholics—an effectiveness
study in Singapore. Drug Alcohol Rev. 2001;20(2):
193-199. doi:10.1080/09595230120058579
43. Lhuintre JP, Daoust M, Moore ND, et al. Ability
of calcium bis acetyl homotaurine, a GABA agonist,
to prevent relapse in weaned alcoholics. Lancet.
1985;1(8436):1014-1016. doi:10.1016/S0140-6736
(85)91615-0
44. Lhuintre JP, Moore N, Tran G, et al.
Acamprosate appears to decrease alcohol intake in
weaned alcoholics. Alcohol Alcohol. 1990;25(6):
613-622. doi:10.1093/oxfordjournals.alcalc.a045057
45. Mann K, Lemenager T, Hoffmann S, et al;
PREDICT Study Team. Results of a double-blind,
placebo-controlled pharmacotherapy trial in
alcoholism conducted in Germany and comparison
with the US COMBINE study. Addict Biol. 2013;18
(6):937-946. doi:10.1111/adb.12012
46. Mason BJ, Goodman AM, Chabac S, Lehert P.
Effect of oral acamprosate on abstinence in patients
with alcohol dependence in a double-blind,
jama.com
Pharmacotherapy for Alcohol Use Disorder
placebo-controlled trial: the role of patient
motivation. J Psychiatr Res. 2006;40(5):383-393.
doi:10.1016/j.jpsychires.2006.02.002
47. Monti PM, Rohsenow DJ, Swift RM, et al.
Naltrexone and cue exposure with coping and
communication skills training for alcoholics:
treatment process and 1-year outcomes. Alcohol
Clin Exp Res. 2001;25(11):1634-1647. doi:10.1111/j.
1530-0277.2001.tb02170.x
48. Morley KC, Teesson M, Reid SC, et al.
Naltrexone versus acamprosate in the treatment of
alcohol dependence: a multi-centre, randomized,
double-blind, placebo-controlled trial. Addiction.
2006;101(10):1451-1462. doi:10.1111/j.1360-0443.
2006.01555.x
49. Morris PL, Hopwood M, Whelan G, Gardiner J,
Drummond E. Naltrexone for alcohol dependence:
a randomized controlled trial. Addiction. 2001;96
(11):1565-1573. doi:10.1046/j.1360-0443.2001.
961115654.x
50. O’Malley SS, Jaffe AJ, Chang G, Schottenfeld
RS, Meyer RE, Rounsaville B. Naltrexone and coping
skills therapy for alcohol dependence: a controlled
study. Arch Gen Psychiatry. 1992;49(11):881-887.
doi:10.1001/archpsyc.1992.01820110045007
51. O’Malley SS, Robin RW, Levenson AL, et al.
Naltrexone alone and with sertraline for the
treatment of alcohol dependence in Alaska natives
and non-natives residing in rural settings:
a randomized controlled trial. Alcohol Clin Exp Res.
2008;32(7):1271-1283. doi:10.1111/j.1530-0277.2008.
00682.x
52. O’Malley SS, Sinha R, Grilo CM, et al. Naltrexone
and cognitive behavioral coping skills therapy for
the treatment of alcohol drinking and eating
disorder features in alcohol-dependent women:
a randomized controlled trial. Alcohol Clin Exp Res.
2007;31(4):625-634. doi:10.1111/j.1530-0277.2007.
00347.x
53. Oslin DW, Lynch KG, Pettinati HM, et al.
A placebo-controlled randomized clinical trial of
naltrexone in the context of different levels of
psychosocial intervention. Alcohol Clin Exp Res.
2008;32(7):1299-1308. doi:10.1111/j.1530-0277.2008.
00698.x
54. Oslin D, Liberto JG, O’Brien J, Krois S,
Norbeck J. Naltrexone as an adjunctive treatment
for older patients with alcohol dependence. Am J
Geriatr Psychiatry. 1997;5(4):324-332. doi:10.1097/
00019442-199700540-0000
55. Paille FM, Guelfi JD, Perkins AC, Royer RJ, Steru
L, Parot P. Double-blind randomized multicentre
trial of acamprosate in maintaining abstinence from
alcohol. Alcohol Alcohol. 1995;30(2):239-247.
56. Pelc I, Le Bon O, Verbanck P, Lehert P,
Opsomer L. Calciumacetylhomotaurinate for
maintaining abstinence in weaned alcoholic
patients: a placebo-controlled double-blind
multi-centre study. In: Naranjo CA, Sellers EM, eds.
jama.com
© 2023 American Medical Association. All rights reserved.
Novel Pharmacological Interventions for Alcoholism.
Springer-Verlag; 1992.
57. Pelc I, Verbanck P, Le Bon O, Gavrilovic M, Lion
K, Lehert P. Efficacy and safety of acamprosate in
the treatment of detoxified alcohol-dependent
patients: a 90-day placebo-controlled dose-finding
study. Br J Psychiatry. 1997;171:73-77. doi:10.1192/
bjp.171.1.73
58. Petrakis IL, Poling J, Levinson C, Nich C, Carroll
K, Rounsaville B; VA New England VISN I MIRECC
Study Group. Naltrexone and disulfiram in patients
with alcohol dependence and comorbid psychiatric
disorders. Biol Psychiatry. 2005;57(10):1128-1137.
doi:10.1016/j.biopsych.2005.02.016
59. Pettinati HM, Oslin DW, Kampman KM, et al.
A double-blind, placebo-controlled trial combining
sertraline and naltrexone for treating co-occurring
depression and alcohol dependence. Am J Psychiatry.
2010;167(6):668-675. doi:10.1176/appi.ajp.2009.
08060852
60. Poldrugo F. Acamprosate treatment in a
long-term community-based alcohol rehabilitation
programme. Addiction. 1997;92(11):1537-1546.
doi:10.1111/j.1360-0443.1997.tb02873.x
61. Sass H, Soyka M, Mann K, Zieglgänsberger W.
Relapse prevention by acamprosate: results from a
placebo-controlled study on alcohol dependence.
Arch Gen Psychiatry. 1996;53(8):673-680. doi:10.
1001/archpsyc.1996.01830080023006
62. Tempesta E, Janiri L, Bignamini A, Chabac S,
Potgieter A. Acamprosate and relapse prevention in
the treatment of alcohol dependence:
a placebo-controlled study. Alcohol Alcohol. 2000;
35(2):202-209. doi:10.1093/alcalc/35.2.202
63. Volpicelli JR, Clay KL, Watson NT, O’Brien CP.
Naltrexone in the treatment of alcoholism:
predicting response to naltrexone. J Clin Psychiatry.
1995;56(suppl 7):39-44.
64. Volpicelli JR, Rhines KC, Rhines JS, Volpicelli
LA, Alterman AI, O’Brien CP. Naltrexone and alcohol
dependence: role of subject compliance. Arch Gen
Psychiatry. 1997;54(8):737-742. doi:10.1001/
archpsyc.1997.01830200071010
65. Whitworth AB, Fischer F, Lesch OM, et al.
Comparison of acamprosate and placebo in
long-term treatment of alcohol dependence. Lancet.
1996;347(9013):1438-1442. doi:10.1016/S0140-6736
(96)91682-7
66. Wölwer W, Frommann N, Jänner M, et al. The
effects of combined acamprosate and integrative
behaviour therapy in the outpatient treatment of
alcohol dependence: a randomized controlled trial.
Drug Alcohol Depend. 2011;118(2-3):417-422. doi:10.
1016/j.drugalcdep.2011.05.001
67. Azrin NH, Sisson RW, Meyers R, Godley M.
Alcoholism treatment by disulfiram and community
reinforcement therapy. J Behav Ther Exp Psychiatry.
1982;13(2):105-112. doi:10.1016/0005-7916(82)
90050-7
(Reprinted) JAMA November 7, 2023 Volume 330, Number 17
Original Investigation Research
68. Azrin NH. Improvements in the
community-reinforcement approach to alcoholism.
Behav Res Ther. 1976;14(5):339-348. doi:10.1016/
0005-7967(76)90021-8
69. Liebson IA, Tommasello A, Bigelow GE.
A behavioral treatment of alcoholic methadone
patients. Ann Intern Med. 1978;89(3):342-344. doi:
10.7326/0003-4819-89-3-342
70. Gerrein JR, Rosenberg CM, Manohar V.
Disulfiram maintenance in outpatient treatment of
alcoholism. Arch Gen Psychiatry. 1973;28(6):798-
802. doi:10.1001/archpsyc.1973.01750360034004
71. Saitz R. Medications for alcohol use disorders.
JAMA. 2014;312(13):1349. doi:10.1001/jama.2014.
10152
72. Jonas DE, Feltner C, Garbutt JC. Medications
for alcohol use disorders—reply. JAMA. 2014;312
(13):1351. doi:10.1001/jama.2014.10170
73. Corrao G, Bagnardi V, Zambon A, La Vecchia C.
A meta-analysis of alcohol consumption and the
risk of 15 diseases. Prev Med. 2004;38(5):613-619.
doi:10.1016/j.ypmed.2003.11.027
74. Schuckit MA. Alcohol-use disorders. Lancet.
2009;373(9662):492-501. doi:10.1016/S0140-6736
(09)60009-X
75. Cherpitel CJ, Ye Y. Alcohol-attributable fraction
for injury in the U.S. general population: data from
the 2005 National Alcohol Survey. J Stud Alcohol
Drugs. 2008;69(4):535-538. doi:10.15288/jsad.
2008.69.535
76. Kranzler HR, Armeli S, Tennen H, et al. Targeted
naltrexone for early problem drinkers. J Clin
Psychopharmacol. 2003;23(3):294-304. doi:10.1097/
01.jcp.0000084030.22282.6d
77. Cook RL, Zhou Z, Miguez MJ, et al. Reduction in
drinking was associated with improved clinical
outcomes in women with HIV infection and
unhealthy alcohol use: results from a randomized
clinical trial of oral naltrexone versus placebo.
Alcohol Clin Exp Res. 2019;43(8):1790-1800. doi:10.
1111/acer.14130
78. Edelman EJ, Moore BA, Holt SR, et al. Efficacy
of extended-release naltrexone on HIV-related and
drinking outcomes among HIV-positive patients:
a randomized-controlled trial. AIDS Behav. 2019;23
(1):211-221. doi:10.1007/s10461-018-2241-z
79. Foa EB, Yusko DA, McLean CP, et al. Concurrent
naltrexone and prolonged exposure therapy for
patients with comorbid alcohol dependence and
PTSD: a randomized clinical trial. JAMA. 2013;310
(5):488-495. doi:10.1001/jama.2013.8268
80. Laaksonen E, Koski-Jännes A, Salaspuro M,
Ahtinen H, Alho H. A randomized, multicentre,
open-label, comparative trial of disulfiram,
naltrexone and acamprosate in the treatment of
alcohol dependence. Alcohol Alcohol. 2008;43(1):
53-61. doi:10.1093/alcalc/agm136
1665