Effectiveness of Acamprosate in the Treatment of Alcohol Dependence WILLIAM E

Cochrane for Clinicians Putting Evidence into Practice

Effectiveness of Acamprosate in the Treatment of Alcohol Dependence WILLIAM E. CAYLEY, JR., MD, MDiv, University of Wisconsin Department of Family Medicine, Eau Claire, Wisconsin

The Cochrane Abstract on Clinical Scenario the next page is a sum- receptor agonist that has been prescribed mary of a review from A patient who successfully completed inpa- in Europe for more than 20 years and was the Cochrane Library. It is tient treatment for alcohol dependence is approved by the U.S. Food and Drug Admin- accompanied by an inter- concerned about relapse and requests advice istration in 2004. Although its mechanism pretation that will help clinicians put evidence on measures that can help maintain absti- of action remains unclear, it has been sug- into practice. Dr. Cayley nence from alcohol use. gested that acamprosate may act to reduce presents a clinical scenario processes related to alcohol withdrawal, as and question based on Clinical Question well as reduce the rewarding effects of alco- the Cochrane Abstract, 1 followed by an evidence- Is acamprosate (Campral) effective for main- hol intake. based answer and a taining abstinence from alcohol use? This Cochrane review evaluated the effec- critique of the review. The tiveness and tolerability of acamprosate practice recommenda- Evidence-Based Answer for helping patients dependent on alcohol tions in this activity are available at http://www. When used in conjunction with detoxifi- to maintain abstinence. In all 24 of the cochrane.org/reviews/en/ cation and psychosocial interventions for included trials, acamprosate was prescribed ab004332.html. treating alcohol dependence, acamprosate for at least four weeks in addition to psy- can reduce the risk of any return to drinking chosocial interventions, which varied across and improve cumulative abstinence rates.1 studies. All trials except for one were in This clinical content con- forms to AAFP criteria for (Strength of Recommendation = A, based adult populations, and all trials except for evidence-based continuing on consistent, good-quality patient-oriented one included pretreatment alcohol detoxifi- medical education (EB evidence) cation. The majority of patients included in CME). See CME Quiz on page 537. the trials met diagnostic criteria for alcohol Practice Pointers dependence. The typical acamprosate dos- The series coordinator Alcohol abuse is a major health risk world- age was four to six tablets (333 mg each) for AFP is Kenny Lin, MD, Department of Family wide, causing approximately 3 percent of per day. Medicine, Georgetown deaths globally and contributing significantly Among patients taking acamprosate in University School of Medi- to the risks of stroke, ischemic heart disease, the 24 trials, risk of return to any drink- cine, Washington, DC. hypertension, diabetes mellitus, and liver ing was 86 percent that of patients treated A collection of Cochrane cancer, as well as motor vehicle collisions, with placebo (i.e., 14 percent less risk in for Clinicians published drownings, and homicides.2 Although treat- treatment group compared with placebo). in AFP is available at http://www.aafp.org/afp/ ment of alcoholism is complex and studies Based on statistical weighting of trials, the cochrane. of treatment effectiveness are challenging, a authors calculated a number needed to treat previous Cochrane review found that brief of 9 to prevent one additional patient from interventions can reduce weekly alcohol returning to drinking. Patients treated with consumption, emergency department visits, acamprosate also maintained cumulative and alcohol-related injuries in outpatient abstinence (i.e., total days without alcohol settings.3 Other evidence has shown that use, whether or not the patient had periodic disulfiram (Antabuse) may reduce total days return to drinking) for 11 percent lon- of drinking without improving overall absti- ger than patients taking placebo. The only nence,4 and naltrexone (Revia) is effective for adverse effect of acamprosate that reached reducing overall alcohol use.5 statistical significance compared with pla- Acamprosate is a synthetic glutamate cebo was diarrhea (the authors calculated a

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Cochrane Abstract

Background: Alcohol dependence is among the main were considered in the review. Compared with placebo, health risk factors in most developed and developing acamprosate was shown to significantly reduce the risk countries. Therapeutic success of psychosocial programs of any drinking (risk ratio [RR] = 0.86; 95% confidence for relapse prevention is moderate, but could potentially interval [CI], 0.81 to 0.91; number needed to treat be increased by an adjuvant treatment with the gluta- [NNT] = 9.09; 95% CI, 6.66 to 14.28) and significantly mate antagonist acamprosate. increase the cumulative abstinence duration (mean difference = 10.94 days; 95% CI, 5.08 to 16.81), whereas Objectives: To determine the effectiveness and toler- secondary outcomes (e.g., γ-glutamyltransferase level, ability of acamprosate in comparison with placebo and heavy drinking) did not reach statistical significance. other pharmacologic agents. Diarrhea was the only adverse effect that was more frequently reported for acamprosate treatment than Search Strategy: The authors searched the Cochrane placebo (risk difference = 0.11; 95% CI, 0.09 to 0.13; Drugs and Alcohol Group (CDAG) Specialized Register, NNT = 9.09; 95% CI, 7.69 to 11.11). Effects of industry- PubMed, EMBASE, and CINAHL in January 2009. They sponsored trials (RR = 0.88; 95% CI, 0.80 to 0.97) did also asked manufacturers and researchers about any not significantly differ from those of nonprofit-funded unpublished trials. trials (RR = 0.88; 95% CI, 0.81 to 0.96). In addition, the Selection Criteria: All double-blind, randomized con- linear regression test did not indicate a significant risk of trolled trials that compare the effects of acamprosate with publication bias (P = .861). placebo or active control on drinking-related outcomes. Authors’ Conclusions: Acamprosate appears to be Data Collection and Analysis: Two authors indepen- an effective and safe treatment strategy for supporting dently extracted data. Trial quality was assessed by one continuous abstinence after detoxification in alcohol- author and cross-checked by a second author. Individual dependent patients. Although the sizes of treatment patient data meta-analyses were used to verify the pri- effects appear to be rather moderate in their magnitude, mary effectiveness outcomes. they should be valued against the background of the relapsing nature of alcoholism and the limited therapeu- Main Results: Twenty-four randomized controlled trials tic options currently available for its treatment. with 6,915 participants fulfilled inclusion criteria and

These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the origi- nal reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minor editing changes have been made to the text (http://www.cochrane.org).

weighted number needed to harm of 9), but return to drinking and for cumulative absti- this adverse effect did not affect adherence nence remained statistically significant three to treatment. Overall trial dropout because to 12 months after study conclusion, indicat- of adverse effects or any other cause was ing that benefits of acamprosate may persist actually greater in patients taking placebo. beyond the treatment period. Three of the studies also compared acam- Although treatment of alcohol abuse is prosate versus naltrexone; two studies complicated and can be associated with compared combination treatment of acam- high relapse rates, use of acamprosate in prosate and naltrexone versus placebo; and addition to psychosocial interventions for two studies compared combination treat- patients who have already been detoxified is ment of acamprosate and naltrexone versus associated with reduced return to drinking acamprosate alone. None of these compari- and increased cumulative abstinence during sons demonstrated statistically significant treatment and for up to one year afterward. treatment benefits among interventions. Address correspondence to William E. Cayley, Jr., MD, However, these comparisons showed that MDiv, at [email protected]. Reprints are not available acamprosate carried a higher risk of diar- from the author. rhea, and that the combination of acam- Author disclosure: Nothing to disclose. prosate and naltrexone led to a markedly higher rate of withdrawal because of adverse REFERENCES events compared with placebo or acampro- 1. Rösner S, Hackl-Herrwerth A, Leucht S, Lehert P, Vec- sate alone. chi S, Soyka M. Acamprosate for alcohol dependence. Ten trials reported posttreatment follow- Cochrane Database Syst Rev. 2010;(9):CD004332. up. They found that treatment effects for 2. Guilbert JJ. The world health report 2002 - reducing

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risks, promoting healthy life. Educ Health (Abingdon). interventions or usual care. Trials that did 2003;16(2):230. not include a minimum of six months’ 3. Kaner EF, Beyer F, Dickinson HO, et al. Effectiveness of brief alcohol interventions in primary care populations. follow-up after start of treatment were Cochrane Database Syst Rev. 2007;(2):CD004148. excluded, as were those in which assessment 4. Fuller RK, Branchey L, Brightwell DR, et al. Disulfiram of patients’ stage of change did not alter the treatment of alcoholism. A Veterans Administration cooperative study. JAMA. 1986;256(11):1449-1455. intervention. Forty-one trials met inclusion 5. Anton RF, O’Malley SS, Ciraulo DA, et al.; COMBINE criteria. Four trials involving 3,255 patients Study Research Group. Combined pharmacotherapies directly compared stage-based with non– and behavioral interventions for alcohol dependence: stage-based interventions. Of these, two the COMBINE study: a randomized controlled trial. JAMA. 2006;295(17):2003-2017. trials compared the use of these strategies in self-help materials and two compared these strategies during individual counseling. For stage-based versus standard self-help mate- Cochrane Briefs rials, the combined relative risk (RR) was 0.93 (95% confidence interval [CI], 0.62 Stage-Based Interventions for to 1.39). For stage-based versus counsel- Smoking Cessation ing, the RR was 1.0 (95% CI, 0.82 to 1.22). Thus, there was no clear difference between Clinical Question patient outcomes when the intervention was Should interventions for helping patients determined by stage of change. stop smoking be tailored to their stage of In the remainder of trials, which com- readiness to quit? pared stage-based interventions with usual care or no intervention in a variety of set- Evidence-Based Answer tings (e.g., telephone, lay, or physician inter- Although providing stage-based smoking viewing; computer games), there was a small cessation interventions for those trying to but clear benefit to the intervention. For quit appears to be more effective than not example, in six trials comparing stage-based intervening at all, the evidence does not self-help versus usual care or assessment, support tailoring interventions to a patient’s the RR was 1.32 (95% CI, 1.01 to 1.59). In perceived motivational stage of change. 13 trials comparing individual counseling (Strength of Recommendation = B, based with any control, the RR was 1.24 (95% CI, on inconsistent or limited-quality patient- 1.08 to 1.42). oriented evidence) These data support the use of interventional counseling to help patients stop smok- Practice Pointers ing. Smoking cessation counseling strategies Tobacco use is the cause of more than 400,000 should be used regardless of the patient’s deaths in the United States each year.1 Studies perceived readiness to quit. show that interventional counseling by pri- COREY D. FOGLEMAN, MD mary care physicians has a modest but measur- able impact on cessation rates.2 Some advocate Author disclosure: Nothing to disclose. tailoring motivational counseling to a patient’s SOURCE: Cahill K, Lancaster T, Green N. Stage-based interventions for smoking cessation. Cochrane Database Syst perceived readiness to quit. One stage-based Rev. 2010;(11):CD004492. model of behavioral analysis suggests that smokers begin in the precontemplation stage, REFERENCES from which they progress through the stages of 1. Mokdad AH, Marks JS, Stroup DF, Gerberding JL. Actual contemplation, preparation, action, and finally causes of death in the United States, 2000 [published to maintenance as they quit smoking. corrections appear in JAMA. 2005;293(3):293-294, The authors of this Cochrane Review and JAMA. 2005;293(3):298]. JAMA. 2004;291(10): searched for studies evaluating the effec- 1238-1245. 2. Law M, Tang JL. An analysis of the effectiveness of tiveness of stage-based intervention strat- interventions intended to help people stop smoking. egies compared with non–stage-based Arch Intern Med. 1995;155(18):1933-1941. ■

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