Naltrexone vs Placebo for the Treatment of Alcohol Dependence

Abstract

IMPORTANCE Alcohol use disorder is one of the leading causes of disability worldwide. While effective pharmacological treatments exist, they are efficacious only in certain individuals, contributing to their limited use. Secondary analysis of clinical trial data suggests that a functional polymorphism (rs1799971, Asn40Asp) of the μ-opioid receptor gene (OPRM1) is associated with the risk of relapse to heavy drinking following treatment with the opioid antagonist naltrexone. OBJECTIVE To prospectively examine whether rs1799971 is predictive of naltrexone treatment response. DESIGN, SETTING, AND PARTICIPANTS We conducted a 12-week, double-blind, randomized clinical trial of naltrexone vs placebo in individuals with alcohol dependence (intent-to-treat analysis). Participants were randomly assigned to study treatment based on the presence of 1 or 2 copies of the Asp40 allele compared with those homozygous for the Asn40 allele (2 × 2 cell design). Recruitment occurred between January 2009 and September 2013. All participants were seen in an outpatient clinical setting. A convenience sample of participants (n = 221) was recruited from 5 sites. All participants met DSM-IV criteria for alcohol dependence, with no concurrent psychotic or manic symptoms, no use of concurrent psychotropic medications, and no current dependence on illicit substances. INTERVENTIONS The study drug was naltrexone (50 mg) given once daily or corresponding placebo. MAIN OUTCOMES AND MEASURES The primary study outcome measure was relapse to heavy drinking measured using the timeline follow-back method. RESULTS There was no evidence of a genotype × treatment interaction on the primary outcome of heavy drinking (P = .32). In the Asn40 group, the observed effect of naltrexone was similar to that in previous trials (odds ratio, 0.69; 95% CI, 0.41-1.18; P = .17), with a very small naltrexone effect in the Asp40 group (odds ratio, 1.10; 95% CI, 0.52-2.31; P = .80), contrary to the pattern expected a priori. A significant reduction in heavy drinking occurred across all groups (P = .001). Other drinking outcomes, and all secondary outcomes, demonstrated similar time effects, with no genotype × treatment interaction. CONCLUSIONS AND RELEVANCE The results of this study do not support the hypothesis that the Asp40 allele moderates the response to naltrexone treatment. It is premature to use the Asn40Asp polymorphism as a biomarker to predict the response to naltrexone treatment of alcohol dependence. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00831272

Cost-Effectiveness Analysis of Genotype-Guided Treatment Allocation in Patients with Alcohol Use Disorders Using Naltrexone or Acamprosate, Using a Modeling Approach

“…Prescription of naltrexone, instead of acamprosate, for all AUD carriers of a G-allele could improve the overall treatment effectiveness, by preventing more relapses and therefore reducing costs associated with AUD. However, a recent study did not support previous findings on OPRM1 genotype-guided treatment allocation in AUD patients [22].…”

“…In our base-case analysis, assuming an effect of the OPRM1 genotype, we showed that OPRM1 screening can be cost-effective. However, these results need to be interpreted very carefully as recent evidence did not confirm prior data on OPRM1 pharmacogenetics in AUD [22]. On average, the genotype strategy is slightly more expensive, but also slightly more effective compared to no genotyping strategy.…”

“…Eventually, we performed a threshold analyses for the risk of relapse in G-allele carriers using naltrexone, as the study of Oslin et al [22] showed no-effect of OPRM1 genotyping. With this threshold analysis, the minimal added effectiveness of genotype-based treatment allocation at which screening is cost-effective was determined.…”

The American Psychiatric Association Practice Guideline for the Pharmacological Treatment of Patients With Alcohol Use Disorder

“…In the German PREDICT study (total N=426), modeled after the COMBINE study, there was no difference among naltrexone, acamprosate, and placebo groups on the time to first heavy drinking (Mann et al 2013). In a 12-week, low-risk-of-bias trial, subjects (N=221) were randomly assigned to 50 mg/day oral naltrexone or placebo in blocks on the basis of their OPRM1 genotype (Oslin et al 2015). There was no difference in the odds of heavy drinking with naltrexone as compared with placebo for either genotype, although significant reductions in heavy drinking occurred in all treatment groups.…”

“…Since the AHRQ review, additional studies have not found a relationship between genotype and naltrexone response. As described above, one study randomly assigned subjects (N=221) to 50 mg/day oral naltrexone or to placebo with stratification on the basis of their OPRM1 genotype (Oslin et al 2015). In this 12-week trial, there was no difference in the odds of heavy drinking with naltrexone as compared with placebo for either genotype.…”