Effects of naltrexone on alcohol sensitivity and genetic moderators of medication response - A double-blind placebo-controlled study

Context: Clinical trials have suggested a modest effect of naltrexone as a pharmacotherapy for alcoholism, and a recent study has suggested that the effects may be moderated by variations in the mu- opioid receptor gene (OPRM1). However, the mechanism by which naltrexone may be differentially effective as a function of the OPRM1 genotype is unclear. Objectives: (1) To replicate and expand on the association between the A118G single nucleotide polymorphism ( SNP) of the OPRM1 gene and alcohol sensitivity, (2) to examine the effects of naltrexone on alcohol sensitivity, and (3) to test the A118G SNP of the OPRM1 gene as a moderator of the effects of naltrexone on alcohol sensitivity. Design: A within-subject, double-blind, placebo-controlled laboratory trial of naltrexone. Setting: Participants were recruited from the community. Participants: Non-treatment-seeking heavy drinkers were enrolled in the study. Prospective genotyping was conducted to oversample for the genetic variant of interest. Intervention: After taking naltrexone (50 mg) or placebo, participants completed an intravenous alcohol challenge session in which they were assessed at baseline and at each of the 3 target breath alcohol concentrations: 0.02, 0.04, and 0.06 mg/L. Main Outcome Measures: The Biphasic Alcohol Effects Scale, the Alcohol Urge Questionnaire, the Profile of Mood States, and the Alcohol Rating Scale were administered. Results: Individuals with at least 1 copy of the G allele reported lower alcohol craving and higher alcohol-induced "high" across rising breath alcohol concentrations. Naltrexone was found to blunt alcohol's effects on stimulation, positive mood, craving, and enjoyment. The effects of naltrexone on blunting alcohol-induced high were stronger among individuals with the G allele. Conclusion: This study advances the knowledge of mechanisms of action of naltrexone and genetic moderators of response to this pharmacotherapy.