Rationale for combining acamprosate and naltrexone for treating alcohol dependence

Department of Neuropharmacology, The Scripps Research Institute, 10550 North Torrey Pines Road, TPC5, La Jolla, California 92037, USA.
Journal of studies on alcohol. Supplement 08/2005; 15(15):148-56; discussion 140. DOI: 10.15288/jsas.2005.s15.148
Source: PubMed


This article provides an evidence-based review of acamprosate and naltrexone, used alone and in combination. Both medications are gaining increasing availability worldwide by prescription for the treatment of alcohol dependence. There is scientific and clinical interest in examining these drugs in combination, given their high tolerability, moderate effect sizes, different pharmacological profiles and potentially different effects on drinking outcomes.
This article includes a review of the key similarities and differences between acamprosate and naltrexone in the treatment of alcohol dependence; the published double-blind, placebo-controlled trials of acamprosate and naltrexone across a uniform range of outcome criteria to elucidate the differences and similarities in the behavioral effects of these drugs; the two published pharmacokinetic and pharmacodynamic drug interaction studies of acamprosate and naltrexone; and the single-site clinical trial of acamprosate and naltrexone used alone and in combination relative to placebo.
Pharmacokinetic and pharmacodynamic studies report an increase in acamprosate plasma levels with no clinically significant elevation in adverse events when the two drugs are used in combination. Data from dose-response studies for acamprosate alone suggest that the augmentation of acamprosate plasma levels by co-administration of naltrexone may have clinical benefits.
These factors support investigating the efficacy and safety of combining acamprosate and naltrexone for the treatment of alcohol dependence in a large-scale multisite trial, with evaluation of potential predictors of response to each drug alone and in combination relative to placebo.

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    • "The fact that there was no advantage of combined treatment with CBI and naltrexone was unanticipated. In addition, the failure to find an effect of acamprosate either alone or in combination with CBI or naltrexone was particularly unexpected given the positive studies of acamprosate (Mann et al., 2004; Mason et al., 2005) and of the combination of acamprosate and naltrexone (Kiefer et al., 2003; Feeney et al., 2006) conducted in Europe. "
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    ABSTRACT: ObjectiveCOMBINE is the largest study of pharmacotherapy for alcoholism in the United States to date, designed to answer questions about the benefits of combining behavioral and pharmacological interventions. Trajectory-based analyses of daily drinking data allowed identification of distinct drinking trajectories in smaller studies and demonstrated significant naltrexone effects even when primary analyses on summary drinking measures were unsuccessful. The objective of this study was to replicate and refine trajectory estimation and to assess effects of naltrexone, acamprosate and therapy on the probabilities of following particular trajectories in COMBINE. It was hypothesized that different treatments may affect different trajectories of drinking.MethodsWe conducted exploratory analyses of daily indicators of any drinking and heavy drinking using a trajectory-based approach and assessed trajectory membership probabilities and odds ratios for treatment effects.ResultsWe replicated the trajectories (“abstainer”, “sporadic drinker”, “consistent drinker”) established previously in smaller studies. However, greater numbers of trajectories better described the heterogeneity of drinking over time. Naltrexone reduced the chance to follow a “nearly daily” trajectory and Combined Behavioral Intervention (CBI) reduced the chance to be in an “increasing to nearly daily” trajectory of any drinking. The combination of naltrexone and CBI increased the probability of membership in a trajectory in which the frequency of any drinking declined over time. Trajectory membership was associated with different patterns of treatment compliance.ConclusionThe trajectory-analyses identified specific patterns of drinking that were differentially influenced by each treatment and provided support for hypotheses about the mechanisms by which these treatments work.
    Drug and alcohol dependence 12/2009; 107(2-107):221-229. DOI:10.1016/j.drugalcdep.2009.10.017 · 3.42 Impact Factor
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    • "However, the behavioral mechanisms that mediate the effects of NTX on drinking are not well understood. Such knowledge could facilitate the development of other treatment strategies, such as combining medications with complementary mechanisms of action (Mason, 2005). "
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    ABSTRACT: Naltrexone (NTX) has proven to be effective with alcoholics in treatment, with most controlled clinical trials showing beneficial effects on heavy drinking rates. However, little is known about the behavioral mechanisms underlying the effects of NTX on drinking, or about patient characteristics that may moderate NTX's effects on drinking. In this study, ecological momentary assessment (EMA) techniques were used to investigate some of the putative mechanisms of naltrexone's effects on drinking in heavy drinkers who were not seeking treatment for alcohol problems. Polymorphisms in the D4 dopamine receptor (DRD4) gene and the mu-opiate receptor (OPRM1) gene, family history of alcohol problems, age of onset of alcoholism and gender were explored as potential moderators of NTX's effects. After a 1-week placebo lead-in period, heavy drinkers (n = 180), 63% of whom were alcohol-dependent, were randomized to 3 weeks of daily naltrexone (50 mg) or placebo. Throughout the study, participants used EMA on palm-pilot computers to enter, in real time, drink data, urge levels, and subjective effects of alcohol consumption. Naltrexone reduced percentage drinking days in all participants and reduced percent heavy drinking days in DRD4-L individuals; NTX decreased urge levels in participants with younger age of alcoholism onset; NTX increased time between drinks in participants who had more relatives with alcohol problems; and NTX reduced the stimulating effects of alcohol in women. OPRM1 status did not moderate any of NTX's effects. These results confirm earlier findings of NTX's effects on drinking and related subjective effects, and extend them by describing individual difference variables that moderate these effects in the natural environment, using data collected in real time.
    Alcoholism Clinical and Experimental Research 02/2008; 32(1):58-66. DOI:10.1111/j.1530-0277.2007.00545.x · 3.21 Impact Factor
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    • "Six meta-analyses of the efficacy of acamprosate in the treatment of alcohol dependence have been undertaken to date, all of which have concluded that acamprosate is effective in maintaining abstinence in detoxified alcohol dependent individuals.[2944–48] Out of the six, only 3 have been published in a peer-reviewed journal.[294548] "
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    ABSTRACT: Alcohol dependence is a major problem in India. The pharmacological armamentarium for relapse prevention of alcohol has widened with the addition of new drugs. In this article, we review the pharmacology and efficacy of the four most important such drugs: disulfiram, naltrexone, acamprosate and topiramate. The first part of this two-part review series concerns the comparative pharmacology and the second part concerns the efficacy studies. Overall, all four of these drugs have modest but clinically significant usefulness as pharmacoprophylactic agents for relapse prevention or minimization of alcohol dependence. Combinations might be helpful, especially for naltrexone and acamprosate. The issue of supervision and compliance remains important, especially for such drugs as disulfiram and naltrexone. Topiramate is a promising new agent and requires further study. Disulfiram, while very effective in compliant patients, presents challenges in terms of patient selection and side effects. For patients with hepatic impairment, acamprosate is a good choice.
    Indian Journal of Psychiatry 03/2007; 49(1):26-33. DOI:10.4103/0019-5545.31515
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