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. 2023 Nov 7;330(17):1653–1665. doi: 10.1001/jama.2023.19761

Pharmacotherapy for Alcohol Use Disorder

A Systematic Review and Meta-Analysis

Melissa McPheeters 1,2,✉, Elizabeth A O’Connor 3, Sean Riley 1,4, Sara M Kennedy 1,2, Christiane Voisin 1,4, Kaitlin Kuznacic 5, Cory P Coffey 4, Mark D Edlund 2, Georgiy Bobashev 2, Daniel E Jonas 1,4
PMCID: PMC10630900  PMID: 37934220

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.

Abstract

Importance

Alcohol use disorder affects more than 28.3 million people in the United States and is associated with increased rates of morbidity and mortality.

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 pharmacotherapies for alcohol use disorder.

This systematic review and meta-analysis evaluates efficacy and comparative efficacy of 9 therapies for alcohol use disorder (AUD).

Introduction

Unhealthy 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 National 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 estimated 0.9%, or 265 000 people, received pharmacotherapy for alcohol use disorder.4

This systematic review and meta-analysis evaluated efficacy and comparative efficacy of 9 therapies for alcohol use disorder that are either approved by the US Food and Drug Administration (FDA) (eTable 2 in Supplement 1) or more commonly 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 additional 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 studies published since that may affect the conclusions or understanding 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, disulfiram, or naltrexone) or any of 6 off-label medications (baclofen, gabapentin, varenicline, topiramate, prazosin, and ondansetron) for at least 12 weeks of treatment in an outpatient setting were eligible for inclusion. Twelve weeks of treatment were required because longitudinal studies reported that shorter treatment may yield misleading conclusions 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 any drinking, return to heavy drinking, percentage of drinking 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, studies with the following designs were eligible if they compared 2 drugs of interest: nonrandomized or open-label trials, subgroup analyses from trials, prospective cohort studies, and case-control studies. Nonrandomized and observational studies were included to address harms because RCTs had insufficient 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 reviewers. If the reviewers disagreed, they resolved conflicts by discussion and consensus or by consulting a third, senior member of the team.

Data Extraction, Risk-of-Bias Assessment, and Strength of Evidence

Structured data extraction forms were used to gather relevant 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.8,9,10 The studies were rated as having low, medium, high, or unclear risk of bias.8,9 Questions were included about adequacy of randomization, allocation concealment, similarity of groups at baseline, masking, attrition, validity and reliability of measures, approaches to analyses, and methods of handling missing 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 approach 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.

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 random-effects models.12 We used the DerSimonian and Laird estimator for our primary analyses, with sensitivity analyses using a restricted maximum likelihood model when the pooled effects were statistically significant. For continuous outcomes, 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 calculated to assess statistical heterogeneity.13,14 Potential sources of heterogeneity were examined by analyzing subgroups defined by patient population (eg, US vs non-US studies). Analyses 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 outcomes found a statistically significant result and there was at least moderate strength of evidence for benefit. When quantitative synthesis was not appropriate (eg, <2 similar studies), the data were synthesized qualitatively.

Results

The database search identified 2860 citations, and 2543 citations 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 articles) were new. No observational studies providing data on adverse effects were identified, and therefore all data on adverse events were obtained from RCTs.

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

Figure 1.

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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 included treatment programs, advertisements, referrals, or a combination. Eighty-seven (73.7%) of 118 studies included psychosocial co-interventions. For these studies, effect sizes reflect the benefits of medications added to psychosocial interventions compared with placebo added to psychosocial interventions. Of 23 studies that assessed efficacy of acamprosate, 16 were conducted in Europe and 4 were conducted in the United States. Of 49 studies of naltrexone, 32 were conducted in the United States and 8 were conducted in Europe. Of the 118 included studies, 100 included a co-intervention such as medical management, specific harm reduction, or counseling approaches.

Three medications (ondansetron, varenicline, and prazosin) 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 statistically significant improvement in alcohol consumption outcomes (Table, Figure 2, Figure 3, Figure 4, Figure 5, and Figure 6; eAppendix in Supplement 1).15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66 Compared with placebo, numbers needed to treat to prevent 1 person from returning 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 placebo). Compared with placebo, oral naltrexone (50 mg/d) was associated with a statistically significant improvement in return 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 placebo) 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 association of disulfiram compared with placebo for preventing return 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).

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.

Acamprosate Baclofen Disulfiram Gabapentin Naltrexone Topiramate
50 mg/d, oral 100 mg/d, oral Injection Any dose
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 (95% CI) RR, 0.88 (0.83-0.93) RR, 0.83 (0.70-0.98) RR, 1.03 (0.90-1.17) RR, 0.92 (0.83-1.02) RR, 0.93 (0.87-0.99) RR, 0.97 (0.91-1.03) RR, 0.96 (0.90-1.03) RR, 0.95 (0.92-0.99) Topiramate, 53.8%; placebo, 72.2%
Number needed to treat (95% CI)c 11 (1-32) 18 (4-32)
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 (95% CI) RR, 0.99 (0.94-1.05) RR, 0.92 (0.80-1.06) RR, 0.90 (0.82-0.98) RR, 0.81 (0.72-0.90) RR, 0.93 (0.84-1.01) RR, 1.00 (0.82-1.21) RR, 0.86 (0.80-0.93) Topiramate, 10%; placebo, 14%
Number needed to treat (95% CI)c 11 (5-41)
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 (95% CI)b WMD, −8.3 (−12.2 to −4.4) WMD, −5.55 (−18.79 to 7.69) No significant difference No significant difference WMD, −5.1 (−7.16 to −3.04) WMD, −2.3 (−5.60 to 0.99) WMD, −4.99 (−9.49 to 0.49) WMD, −4.51 (−6.26 to −2.77) WMD, −7.2 (−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 (95% CI)b WMD, −3.4 (−6.45 to 5.86) WMD, −2.16 (−7.34 to 3.02) No significant difference WMD, −4.3 (−7.60 to −0.91) WMD, −3.1 (−5.8 to −0.3) WMD, −4.68 (−8.63 to −0.73) WMD, −3.92 (−5.86 to −1.97) WMD, −6.2 (−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
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 (95% CI)b WMD, 0.6 (−1.43 to 2.64) WMD, 0.85 (−2.23 to 3.93) No significant difference WMD, −0.49 (−0.92 to −0.06) WMD, 1.9 (−1.5 to 5.2) WMD, −0.85 (−1.44 to −0.26) WMD, −2.0 (−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 (95% CI)b Reduced risk
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 (95% CI)b No significant differencej No significant difference Some conflicting resultsk No significant difference
Strength of evidence Insufficient Low (no effect) Insufficient Insufficient Insufficient Low (no effect)
Mortality
No. of studies 8 4 0 0 6 3
No. of participants 2677 660 0 0 1738 507
Results effect size (95% CI)b 7 events (acamprosate) vs 6 events (placebo) 8 baclofen vs 3 placebo 1 event (naltrexone) vs 2 events (placebo) Not reported
Strength of evidence Insufficient Insufficient Insufficient Insufficient Insufficient Insufficient
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Abbreviations: RR, risk ratio; WMD, weighted mean difference.

a

Blank cells indicate data not applicable. Strength of evidence was not rated for naltrexone by dose. Heavy drinking days was defined as ≥4 drinks/d for women and ≥5 drinks/d for men.

b

Negative effect sizes favor intervention over placebo/control.

c

Lack of entry for number needed to treat indicates that the relative risk (95% CI) was not statistically significant, so the investigators did not calculate a number needed to treat or the effect measure was not one that allows direct calculation of number needed to treat (eg, WMD).

d

One study contained 2 treatment groups included in the meta-analysis.79

e

Results were not reported for each treatment group separately, but there were no clinically significant differences across treatment groups.

f

Quality of life and functioning were assessed with the World Health Organization Quality of Life (WHOQOL) and 12-item Short-Form Health Survey (SF-12) version 2 physical and mental health scores.

g

Quality of life and functioning were assessed with the Quality of Life Enjoyment and Satisfaction Questionnaire and the 36-item Short Form Health Survey (SF-36).

h

Each trial used a different measure to assess quality of life and functioning, including the Short Inventory of Problems, SF-36, WHOQOL, SF-12 version 2 physical and mental health scores, Drinker Inventory of Consequences, and SF-12.

i

Quality of life was assessed with the SF-36.

j

Results were not reported for each treatment group separately, but there were no clinically significant differences across treatment groups.

k

One study rated as having unclear risk of bias reported that 1 patient in the placebo group died by “accident.” No other details on the cause or nature of the accident were provided.44 That study also reported 1 injury in the acamprosate group and 2 in the placebo group. Another study, rated as having high risk of bias, reported a “traffic accident” in the acamprosate group.80

Figure 2. Return to Any Drinking, Acamprosate vs Placebo.

Figure 2.

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Figure 3. Return to Any Drinking, Disulfiram vs Placebo.

Figure 3.

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Multiple comparisons within publications are presented separately.

Figure 4. Return to Any Drinking, Naltrexone vs Placebo.

Figure 4.

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

Figure 5. Return to Heavy Drinking, Acamprosate vs Placebo.

Figure 5.

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Heavy drinking is defined as ≥4 drinks/d for women and ≥5 drinks/d for men. Multiple comparisons within publications are presented separately.

Figure 6. Return to Heavy Drinking, Naltrexone vs Placebo.

Figure 6.

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“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 ≥4 drinks/d for women and ≥5 drinks/d for men.

Among medications without an FDA indication for alcohol use disorder treatment, compared with placebo, topiramate was associated with statistically significant improvement 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%), percentage 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 topiramate, 4.0-8.8 with placebo). These findings were associated with moderate strength of evidence. Of 13 double-blind placebo-controlled RCTs that included 1607 participants, 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 imprecision of the effect estimate and inconsistency of results, baclofen data were graded as having low strength of evidence. Compared with placebo, gabapentin was not significantly 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 evidence 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 medications 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 naltrexone; 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 improved 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 standardized measures, and methods for systematically capturing adverse events were often not reported (Figure 7).

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

Figure 7.

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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.

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 common 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). Compared 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, topiramate 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 placebo), taste abnormalities (RR, 3.01; 95% CI, 1.70-5.34; P = .04; range, 15.1%-53.3% with topiramate, 4.8%-31.3% with placebo), 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 associated 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 placebo) 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 acamprosate, 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 directly compared naltrexone, 50 mg/d, with acamprosate did not consistently established superiority of either medication. Studies of naltrexone had moderate strength of evidence for reducing return to any drinking, return to heavy drinking, percentage of drinking days, and percentage of heavy drinking days at the 50-mg/d oral dose compared with placebo. Fewer data were available for the 100-mg/d oral and injectable 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. Acamprosate 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 typically prescribed as 2 tablets administered 3 times daily. Acamprosate is contraindicated for people with severe kidney 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 disorder since the 1950s. However, relatively limited evidence exists to support the efficacy of disulfiram compared with placebo 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.67,68,69,70 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 investigative 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 dysfunction, 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. Evidence 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, osteoporosis, anemia, fetal alcohol spectrum disorders, and several types of cancer.73,74 Excessive alcohol consumption is also associated with higher rates of homicide, suicide, motor vehicle 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 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 medications have similar efficacy for older (eg, aged ≥65 years) or younger (eg, aged in their 20s) people. Of the 70 studies that provided 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 medication 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 medications may have been initiated before discharge. Patients recruited 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 characteristics and differences in the health care systems compared 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. Acamprosate 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 studies enrolling patients who were not yet abstinent reported reduction 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 combined studies of participants with diagnoses of both alcohol dependence and depression and studies of participants without both alcohol dependence and depression. Third, studies may have selectively reported outcomes. Fourth, long-term information about adverse effects was not available. Fifth, for adverse event outcomes, due to small sample sizes and relatively small numbers of events, evidence was often insufficient to determine whether adverse event outcomes were increased. Sixth, in some included studies, less than 100% of participants had alcohol use disorder. Specifically, 3 studies reported that less than 90% of participants had alcohol use disorder.24,77,78

Conclusions

In conjunction with psychosocial interventions, these findings support the use of oral naltrexone, 50 mg/d, and acamprosate as first-line pharmacotherapies for alcohol use disorder.

Educational Objective: To identify the key insights or developments described in this article.

  1. In this meta-analysis of pharmacotherapy for alcohol use disorder, the authors excluded studies evaluating treatment for less than 12 weeks. Why?

    1. Drinking behavior does not change suddenly but tends to “ramp up” and “ramp down,” and shorter time frames limit determination of marginal changes around thresholds for heavy drinking.

    2. Evaluation of health outcomes, including injury, quality of life, and mortality, require a minimum of 6 months to gather sufficient numbers for meaningful comparison.

    3. Studies of treatment for less than 12 weeks may yield misleading results because fluctuations in drinking behavior may be mistaken for efficacy.

  2. Among medications with an US Food and Drug Administration (FDA) indication for alcohol use disorder (acamprosate, disulfiram, and naltrexone), which were associated with a statistically significant reduction in alcohol consumption?

    1. Acamprosate and naltrexone

    2. Disulfiram only

    3. No medication with an FDA indication for treating patients with alcohol use disorder was associated with efficacy.

  3. What conclusions did the authors reach regarding alcohol use treatment and health outcomes including motor vehicle crashes, injury, quality of life, and mortality?

    1. Any treatment for alcohol use disorder, compared with no pharmacologic treatment, was associated with lower risk of traumatic injury and death.

    2. Available trials provided insufficient evidence to assess whether treatment was associated with better health outcomes.

    3. Only acamprosate reduced overall mortality at 12 weeks.

Supplement 1.

eTable 1. Definitions of Unhealthy Alcohol Use (Sometimes Previously Referred to as Alcohol Misuse)

eTable 2. Medications That Are FDA Approved for Treating Adults With Alcohol Dependence

eTable 3. Questions for the Full Technical Report and This Manuscript

eTable 4. Characteristics of Included Studies

eTable 5. Summary of Findings and Strength of Evidence for Efficacy of Medications Used Off-Label or Those Under Investigation

eAppendix. Reference List for Figures 2 Through 5

eReferences

jama-e2319761-s001.pdf (640.3KB, pdf)
Supplement 2.

Data Sharing Statement

jama-e2319761-s002.pdf (36.9KB, pdf)

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Supplementary Materials

Supplement 1.

eTable 1. Definitions of Unhealthy Alcohol Use (Sometimes Previously Referred to as Alcohol Misuse)

eTable 2. Medications That Are FDA Approved for Treating Adults With Alcohol Dependence

eTable 3. Questions for the Full Technical Report and This Manuscript

eTable 4. Characteristics of Included Studies

eTable 5. Summary of Findings and Strength of Evidence for Efficacy of Medications Used Off-Label or Those Under Investigation

eAppendix. Reference List for Figures 2 Through 5

eReferences

jama-e2319761-s001.pdf (640.3KB, pdf)
Supplement 2.

Data Sharing Statement

jama-e2319761-s002.pdf (36.9KB, pdf)

Articles from JAMA are provided here courtesy of American Medical Association

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