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Original Investigation |

Pharmacotherapy for Adults With Alcohol Use Disorders in Outpatient Settings:  A Systematic Review and Meta-analysis

Daniel E. Jonas, MD, MPH1,2; Halle R. Amick, MSPH2; Cynthia Feltner, MD, MPH1,2; Georgiy Bobashev, PhD3; Kathleen Thomas, PhD2; Roberta Wines, MPH2; Mimi M. Kim, PhD4,5; Ellen Shanahan, MA2; C. Elizabeth Gass, MPH1; Cassandra J. Rowe, BA6; James C. Garbutt, MD7,8
[+] Author Affiliations
1Department of Medicine, University of North Carolina, Chapel Hill
2Cecil G. Sheps Center for Health Services Research, University of North Carolina, Chapel Hill
3Research Triangle Institute International, Research Triangle Park, North Carolina
4North Carolina Translational and Clinical Sciences Institute, University of North Carolina, Chapel Hill
5Center on Biobehavioral Health Disparities Research, Duke University, Durham, North Carolina
6Gillings School of Global Public Health, University of North Carolina, Chapel Hill
7Department of Psychiatry, University of North Carolina, Chapel Hill
8Bowles Center for Alcohol Studies, University of North Carolina School of Medicine, Chapel Hill
JAMA. 2014;311(18):1889-1900. doi:10.1001/jama.2014.3628.
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Importance  Alcohol use disorders cause substantial morbidity and early mortality yet remain greatly undertreated. Medications are considerably underused.

Objective  To conduct a systematic review and meta-analysis of the benefits and harms of medications (US FDA-approved and others) for adults with alcohol use disorders.

Data Sources  PubMed, Cochrane Library, PsycINFO, CINAHL, EMBASE, FDA website, and clinical trials registries (January 1, 1970, to March 1, 2014).

Study Selection  Two reviewers selected randomized clinical trials (RCTs) with at least 12 weeks’ duration that reported eligible outcomes and head-to-head prospective cohort studies reporting health outcomes or harms.

Data Extraction and Synthesis  We conducted meta-analyses using random-effects models and calculated numbers needed to treat for benefit (NNTs) or harm (NNHs).

Main Outcomes and Measures  Alcohol consumption, motor vehicle crashes, injuries, quality of life, function, mortality, and harms.

Results  We included 122 RCTs and 1 cohort study (total 22 803 participants). Most assessed acamprosate (27 studies, n = 7519), naltrexone (53 studies, n = 9140), or both. The NNT to prevent return to any drinking for acamprosate was 12 (95% CI, 8 to 26; risk difference [RD], −0.09; 95% CI, −0.14 to −0.04) and was 20 (95% CI, 11 to 500; RD, −0.05; 95% CI, −0.10 to −0.002) for oral naltrexone (50 mg/d). The NNT to prevent return to heavy drinking was 12 (95% CI, 8 to 26; RD −0.09; 95% CI, −0.13 to −0.04) for oral naltrexone (50 mg/d). Meta-analyses of trials comparing acamprosate to naltrexone found no statistically significant difference between them for return to any drinking (RD, 0.02; 95% CI, −0.03 to 0.08) or heavy drinking (RD, 0.01; 95% CI, −0.05 to 0.06). For injectable naltrexone, meta-analyses found no association with return to any drinking (RD, −0.04; 95% CI, −0.10 to 0.03) or heavy drinking (RD, −0.01; 95% CI, −0.14 to 0.13) but found an association with reduction in heavy drinking days (weighted mean difference [WMD], −4.6%; 95% CI, −8.5% to −0.56%). Among medications used off-label, moderate evidence supports an association with improvement in some consumption outcomes for nalmefene (heavy drinking days per month: WMD, −2.0; 95% CI, −3.0 to −1.0; drinks per drinking day: WMD, −1.02; 95% CI, −1.77 to −0.28) and topiramate (% heavy drinking days: WMD, −9.0%; 95% CI, −15.3% to −2.7%; drinks per drinking day: WMD, −1.0; 95% CI, −1.6 to −0.48). For naltrexone and nalmefene, NNHs for withdrawal from trials due to adverse events were 48 (95% CI, 30 to 112) and 12 (95% CI, 7 to 50), respectively; risk was not significantly increased for acamprosate or topiramate.

Conclusions and Relevance  Both acamprosate and oral naltrexone were associated with reduction in return to drinking. When directly compared with one another, no significant differences were found between acamprosate and naltrexone for controlling alcohol consumption. Factors such as dosing frequency, potential adverse events, and availability of treatments may guide medication choice.

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Figure 1.
Disposition of Articles

RCT indicates randomized clinical trial; WHO, World Health Organization.aThe following studies were unavailable in English (this information is from the English-language abstracts): Barrias et al,19 1997 (Portuguese): study of acamprosate; no other details available in English; Huang et al,20 2002 (Chinese): 12-week randomized trial of naltrexone vs placebo; n = 45; Krupitski et al,21 1994 (Russian): study (unspecified design) of baclofen vs sibazon vs amitriptyline vs placebo; n = 90; Ladewig et al,22 1993 (German): 6-month double-blind period of year-long trial of acamprosate vs placebo; number of patients unspecified; Castro et al,23 2009 (Portuguese): 12-week double-blind RCT of naltrexone vs placebo; n = 71; and Roussaux et al,24 1996 (French): double-blind RCT (duration unspecified) of acamprosate vs placebo; n = 127.bThe following non-English studies reported results identical to the results reported in the English-language study publications: Geerlings et al, 1995,25 Kiefer et al, 2003,26 and Sass et al,27 1996.

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Figure 2.
Return to Any Drinking for Selected Medications Compared With Placebo

Weights are from random-effects analysis. Size of data markers reflects study weight. Med indicates medium.

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Figure 3.
Return to Heavy Drinking for Selected Medications Compared With Placebo

Weights are from random-effects analysis. Size of data markers reflects study weight. Med indicates medium.

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