Naltrexone aversion and treatment efficacy are greatest in humans and rats that actively consume high levels of alcohol.

The opioid antagonist naltrexone is the standard pharmacotherapy for alcoholism, although compliance is often low. The mechanism by which naltrexone reduces drinking is yet unclear. Here we show that in active alcoholics the magnitude of naltrexone treatment efficacy is correlated with the level of naltrexone-induced aversive side effects. This correlation is not observed when subjects are sober, but emerges following alcohol administration, when subjects are intoxicated. In contrast, there is no correlation following placebo administration. To clarify these results, naltrexone was administered to ethanol-consuming rats prior to quantification of naltrexone aversion. Ethanol consumption preceding naltrexone treatment was again correlated with subsequent naltrexone-induced aversion, and this aversion correlated with subsequent decrease in ethanol consumption. In contrast, when naltrexone was given to ethanol-free rats, aversion was not predictive of ethanol consumption. We conclude that naltrexone treatment efficacy is greater during active ethanol consumption and may be partly due to aversive side effects.