OPRM1 rs1799971 Polymorphism Predicts Differential Response to Extended-Release Naltrexone in Alcohol Use Disorder: The Interplay of Genetics and Motivation

Abstract

Alcohol use disorder (AUD) remains a major contributor to the global burden of disease. Extended-release naltrexone (XR-NTX), a μ-opioid receptor antagonist, is a key pharmacological option for maintaining abstinence, though individual treatment response varies substantially. Genetic variability in the μ-opioid receptor gene (OPRM1), particularly rs1799971, may underpin this heterogeneity. Study objective was to evaluate the association between OPRM1 rs1799971 polymorphism and clinical outcomes of XR-NTX therapy in patients with AUD while examining interactions with motivational profiles. In this prospective study, 100 patients with AUD in remission received six monthly intramuscular injections of XR-NTX (380 mg). Genotyping for OPRM1 rs1799971 was performed using real-time allele-specific PCR. Primary outcomes included craving dynamics (PACS), relapse rates, abstinence duration, and treatment adherence over 180 days. Motivation was assessed through structured interviews. The A/A genotype was associated with longer abstinence (150.6 ± 36.2 days), lower relapse rates (29.2%), greater craving reduction, and higher treatment completion (86.2%) compared to A/G and G/G (A/A vs. A/G: p = 0.005; A/A vs. G/G: p = 0.021). The G allele significantly increased relapse risk (OR = 2.93; 95% CI: 1.48-5.79). Intrinsic motivation was associated with better outcomes. A significant genotype-motivation interaction was observed (p = 0.038). No genotype-related differences in adverse event frequency were observed. OPRM1 rs1799971 polymorphism significantly influences the efficacy of XR-NTX in AUD. Carriers of the A/A genotype derive greater therapeutic benefit, while G allele carriers may require intensified clinical support. Pre-therapeutic OPRM1 genotyping could optimize XR-NTX personalization, with G-allele carriers warranting intensified psychosocial support.

Keywords: AUD; OPRM1 polymorphism; extended-release naltrexone; personalized medicine; pharmacogenetics; rs1799971.