Effects of opioid receptor gene variation on targeted nalmefene treatment in heavy drinkers.

BACKGROUND: Recent studies examining the moderating effects of polymorphic variation in opioid receptor genes have yielded conflicting results. We examined opioid receptor gene polymorphisms as moderators of the therapeutic effects of the opioid antagonist nalmefene. METHODS: Participants (n = 272) were subjects who consented to the pharmacogenetic analysis of a multi-site, randomized, placebo-controlled trial of targeted nalmefene for the reduction of heavy drinking. We genotyped two single nucleotide polymorphisms (SNPs) in OPRM1 (including A118G, a commonly studied SNP that encodes an Asn40Asp amino acid substitution), two SNPs in OPRD1, and one SNP in OPRK1, which encode the mu-, delta-, and kappa-opioid receptors, respectively. Regression analysis served to examine the moderating effects of these SNPs on medication response. RESULTS: As previously described by Karhuvaara et al. (2007), nalmefene significantly reduced the number of heavy drinking and very heavy drinking days per week, compared with placebo. There were no main or moderating effects of the genotypes examined on these outcomes. CONCLUSIONS: Our finding that the therapeutic effects of targeted nalmefene were not moderated by polymorphic variation in opioid receptor genes is consistent with two recent reports showing that variation in opioid receptor genes does not moderate the response to naltrexone. However, these findings contrast with those from two other studies, in which the Asn40Asp polymorphism in OPRM1 moderated the naltrexone treatment response. Additional research is needed to clarify the role of variation in opioid receptor genes on the response to opioid antagonist treatment of alcoholism.

Targeted nalmefene with simple medical management in the treatment of heavy drinkers: a randomized double-blind placebo-controlled multicenter study.

BACKGROUND: Clinical studies with opioid antagonists for treatment of problem drinking have mainly been conducted in specialized alcohol treatment centers, included structured psychosocial treatment, and have focused on maintaining abstinence after a period of abstinence from alcohol. METHODS: This multisite, randomized double-blind study investigated targeted nalmefene in reducing heavy drinking. Specialized alcohol treatment centers and private general practices enrolled 403 subjects (328 men, 75 women). Subjects were instructed to take nalmefene 10 to 40 mg (n=242) or placebo (n=161) when they believed drinking to be imminent. After 28 weeks, 57 subjects from the nalmefene group continued into a 24-week randomized withdrawal extension. Concomitant psychosocial intervention was minimal and no treatment goals were imposed. Alcohol consumption was recorded using the time-line follow-back method. Biochemical indicators of alcohol use were also measured. RESULTS: The mean monthly number of heavy drinking days (HDDs) during the 12-week period before inclusion was 15.5 (SD 6.9) in the nalmefene group and 16.2 (SD 6.9) in the placebo group. During treatment, the mean numbers of HDDs were 8.6 to 9.3 in the nalmefene group and 10.6 to 12.0 in the placebo group (p=0.0065). The levels of serum alanine aminotransferase and gamma-glutamyl transferase decreased in the nalmefene group compared with the placebo group (p=0.0088 and 0.0023). During the randomized withdrawal period, subjects randomized to placebo apparently returned to heavier drinking. Subjects receiving nalmefene reported more nausea, insomnia, fatigue, dizziness, and malaise than subjects on placebo. CONCLUSIONS: Nalmefene appears to be effective and safe in reducing heavy drinking, even when accompanied by minimal psychosocial support.