Sinclair Method Studies

Clinical and biological moderators of response to naltrexone in alcohol dependence: a systematic review of the evidence.

Aim

The goal of this systematic review was to identify moderators of naltrexone efficacy in the treatment of alcohol dependence.

Methods

We searched Pubmed, CINHAL, Embase, PsycINFO and the Cochrane Library from 1990 to April 2012 and reference lists of pertinent review articles, which yielded 622 trial, pooled analysis and review articles. Using pre-established eligibility criteria, two reviewers independently determined whether abstracts contained evidence of demographic or biological characteristics, i.e. moderators, influencing naltrexone response in alcohol dependence. We assessed each publication for risk of bias and evaluated the strength of the body of evidence for each moderator.

Results

Twenty-eight publications (on 20 studies) met criteria for data synthesis. These included 26 publications from 12 randomized, placebo-controlled trials, three non-randomized, non-placebo studies and one randomized, non-placebo study. In addition, there were two publications from pooled analyses of four randomized, placebo-controlled trials. Family history of alcohol problems and the Asn40Asp polymorphism of the μ-opioid receptor gene showed a positive association with efficacy in four of five and three of five studies, respectively. Other moderators reported to be associated with efficacy included male sex (two of five studies), pre-treatment drinking (two of two studies) and high craving (two of five studies). However, the overall risk of bias in the published literature is high.

Conclusions

The identification of naltrexone-responsive alcohol-dependent patients is still in development. Studies to date point to two potential moderators—family history and presence of the OPRM1 Asn40Asp polymorphism—as having the strongest evidence. However, the data to date is still insufficient to recommend that any moderator be used in determining clinical treatment.

Can We Predict Who Benefits from Naltrexone in the Treatment of Alcohol Dependence?

Naltrexone, an opioid antagonist, was approved by the U.S. Food and Drug Administration in 1994 to treat alcohol dependence. It has subsequently been widely investigated as a treatment for alcohol dependence and heavy drinking using a variety of study designs. The most comprehensive meta-analysis of naltrexone’s efficacy showed that it exerts a modest effect on multiple drinking outcomes, the greatest effect being a 17% reduction in the risk of relapse to heavy drinking compared to placebo (1). Multiple studies, beginning shortly after the medication’s approval and continuing to the present, have sought to identify and validate moderators of naltrexone’s efficacy. These studies selected certain clinical or genetic features to identify alcohol-dependent individuals who were most likely to show a robust treatment response.In this issue of the journal, Garbutt et al. (2) systematically review 622 studies in an effort to discern factors that moderate the therapeutic response to the use of naltrexone in alcohol treatment. The authors focused on moderating variables for which at least two published studies were identified. The moderators considered included a family history of alcohol dependence; pretreatment craving for alcohol; the Asn40Asp single nucleotide polymorphism (rs1799971) in OPRM1, which encodes the mu-opioid receptor; sex; pretreatment drinking patterns; psychopathology; alcoholism subtype; and sweetliking/disliking. The review applied established criteria to assess the strength of the evidence by rating the studies on risk of bias, directness of the link between the intervention and an important health outcome, consistency of the findings, and precision of the estimated effect.Full Article

Predictors for the Efficacy of Naltrexone Treatment in Alcohol Dependence: Sweet Preference E. Laaksonen J. Lahti J.D. Sinclair P. Heinälä H. Alho Alcohol and Alcoholism, Volume 46, Issue 3, 1 May 2011, Pages 308–311. Published: 25 January 2011.

Aims: To analyse the possible associations between sweet preference and the efficacy of naltrexone treatment of alcohol dependence. Methods: The preference for different concentrations of sucrose was evaluated in 78 participants diagnosed with alcohol dependence after treatment for 32 weeks with naltrexone or placebo without prior detoxification. Results: A significant difference between naltrexone and placebo groups was found in the association between the preference for higher sucrose concentrations and relapses to heavy drinking. Higher sweet preference was significantly related to successful treatment measures in the naltrexone group but not in the placebo group. Conclusion: Sweet preference has a strong correlation to treatment outcomes with naltrexone, and sweet preference might be used as a predictor for better treatment results in alcoholics. Our study offers one possible new explanation of the clinical observation that naltrexone is not effective for every patient.Full Article

Shantrel S. Canidate, Giselle D. Carnaby, Christa L. Cook, Robert L. Cook, A Systematic Review of Naltrexone for Attenuating Alcohol Consumption in Women with Alcohol Use Disorders, Alcoholism: Clinical and Experimental Research, 2017, 41, 3, 466.

Several clinical trials have evaluated naltrexone as a treatment for alcohol use disorders (AUDs), but few have focused on women. The aim of this review was to systematically review and summarize the evidence regarding the impact of naltrexone compared to placebo for attenuating alcohol consumption in women with an AUD. A systematic review was conducted using PubMed, Cochrane, Web of Science, CINAHL, and Alcohol Studies Database to identify relevant peer-reviewed randomized controlled trials (RCTs) published between January 1990 and August 2016. Seven published trials have evaluated the impact of naltrexone on drinking outcomes in women distinct from men; 903 alcohol-dependent or heavy drinking women were randomized to receive once daily oral or depot (injectable) naltrexone or placebo with/without behavioral intervention. Two studies examining the quantity of drinks per day observed trends toward reduction in drinking quantity among women who received naltrexone versus placebo. The 4 studies examining the frequency of drinking had mixed results, with 1 study showing a trend that favored naltrexone, 2 showing a trend that favored placebo, and 1 that showed no difference. Two of the 3 studies examining time to relapse observed trends that tended to favor naltrexone for time to any drinking and time to heavy drinking among women who received naltrexone versus placebo. While the growing body of evidence suggests a variety of approaches to treat AUD, the impact of naltrexone to combat AUD in women is understudied. Taken together, the results suggest that naltrexone may lead to modest reductions in quantity of drinking and time to relapse, but not on the frequency of drinking in women. Future research should incorporate sophisticated study designs that examine gender differences and treatment effectiveness among those diagnosed with an AUD and present data separately for men and women.

Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. Raymond F. Anton, MD; Stephanie S. O’Malley, PhD; Domenic A. Ciraulo, MD; et al. JAMA. 2006 May 3;295(17):2003-17.

Context Alcohol dependence treatment may include medications, behavioral therapies, or both. It is unknown how combining these treatments may impact their effectiveness, especially in the context of primary care and other nonspecialty settings.Objectives To evaluate the efficacy of medication, behavioral therapies, and their combinations for treatment of alcohol dependence and to evaluate placebo effect on overall outcome.Design, Setting, and Participants Randomized controlled trial conducted January 2001-January 2004 among 1383 recently alcohol-abstinent volunteers (median age, 44 years) from 11 US academic sites with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnoses of primary alcohol dependence.Interventions Eight groups of patients received medical management with 16 weeks of naltrexone (100 mg/d) or acamprosate (3 g/d), both, and/or both placebos, with or without a combined behavioral intervention (CBI). A ninth group received CBI only (no pills). Patients were also evaluated for up to 1 year after treatment.

Main Outcome Measures Percent days abstinent from alcohol and time to first heavy drinking day.

Results All groups showed substantial reduction in drinking. During treatment, patients receiving naltrexone plus medical management (n = 302), CBI plus medical management and placebos (n = 305), or both naltrexone and CBI plus medical management (n = 309) had higher percent days abstinent (80.6, 79.2, and 77.1, respectively) than the 75.1 in those receiving placebos and medical management only (n = 305), a significant naltrexone × behavioral intervention interaction (P = .009). Naltrexone also reduced risk of a heavy drinking day (hazard ratio, 0.72; 97.5% CI, 0.53-0.98; P = .02) over time, most evident in those receiving medical management but not CBI. Acamprosate showed no significant effect on drinking vs placebo, either by itself or with any combination of naltrexone, CBI, or both. During treatment, those receiving CBI without pills or medical management (n = 157) had lower percent days abstinent (66.6) than those receiving placebo plus medical management alone (n = 153) or placebo plus medical management and CBI (n = 156) (73.8 and 79.8, respectively; P<.001). One year after treatment, these between-group effects were similar but no longer significant.

Conclusions Patients receiving medical management with naltrexone, CBI, or both fared better on drinking outcomes, whereas acamprosate showed no evidence of efficacy, with or without CBI. No combination produced better efficacy than naltrexone or CBI alone in the presence of medical management. Placebo pills and meeting with a health care professional had a positive effect above that of CBI during treatment. Naltrexone with medical management could be delivered in health care settings, thus serving alcohol-dependent patients who might otherwise not receive treatment.