Nalmefene and naltrexone reduce alcohol intake via selective efficacy in subpopulations distinguished by behavioral...

The relative efficacies of nalmefene versus naltrexone for alcohol use disorder is the subject of intense and ongoing debate. The two pan-opioid receptor ligands differ primarily in actions at the kappa opioid receptor, where naltrexone acts as an antagonist and nalmefene acts as a partial agonist. Parallel clinical trials for nalmefene or naltrexone have produced widely disparate outcomes and a marked lack of consensus regarding which of the compounds should be used for the treatment of alcohol use disorder.

Here we leveraged a mouse model (n = 56 male C57BL/6 J) to directly compare the efficacy of nalmefene and naltrexone within-subject. After acquiring operant responding for ethanol, each subject underwent four treatment block conditions: nalmefene (0.1 mg/kg i.p.), naltrexone (1.0 mg/kg i.p.), the selective kappa opioid receptor agonist U50,488 (1.0 mg/kg i.p.) and placebo (saline 10 ml/kg i.p.). Each treatment block consisted of an ethanol self-administration session followed by two subsequent sessions of punished (quinine adulterated) ethanol self-administration sessions with treatment given 30 min prior to each session.

We show that nalmefene and naltrexone have similar efficacy in reducing ethanol consumption, whereas U50,488 increases ethanol consumption. Despite similar effects in aggregate analyses, nalmefene- and naltrexone-induced reductions in drinking are driven by fully separate subpopulations which do not show any beneficial response to the non-preferred compound and display markedly different behavioral phenotypes prior to treatment. A predictive model based on circulating biogenic amines allows for high accuracy classification of nalmefene- versus naltrexone-responders.

Together, these results provide a roadmap for improving alcohol use disorder treatment outcomes via precision application of existing compounds.