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

ABSTRACT: 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.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.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.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.

SUBMITTER: Arias AJ

PROVIDER: S-EPMC2950972 | biostudies-literature | 2008 Jul

REPOSITORIES: biostudies-literature

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

Arias Albert J AJ Armeli Stephen S Gelernter Joel J Covault Jonathan J Kallio Antero A Karhuvaara Sakari S Koivisto Tiina T Mäkelä Rauno R Kranzler Henry R HR

Alcoholism, clinical and experimental research 20080701 7

<h4>Background</h4>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.<h4>Methods</h4>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 t ...[more]

PMID: 18537939

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Project description:Background and aimsCannabis is commonly used among people who drink alcohol, but evidence suggests a nuanced relationship between alcohol consumption and cannabis use. In particular, among individuals undergoing alcohol treatment the impact of cannabis on alcohol intake may depend upon cannabis use frequency. We aimed to test the effects of within-day cannabis use on total drinks consumed and likelihood of binge drinking on a given day among all participants and compare these relationships between males and females and between individuals who reported infrequent and frequent cannabis use.DesignThis observational study is a substudy of a larger randomized controlled trial (RCT). Individuals were included from the RCT if they reported any cannabis use and were divided into groups based on cannabis use patterns. Alcohol use was compared within and between groups.SettingIndividuals were recruited from 2016 to 2020 from community and university settings in Denver and Boulder, CO, USA.ParticipantsOf the 182 individuals enrolled in the RCT, 96 cannabis-using subjects were included in these analyses.MeasurementsSubjects completed a time-line follow-back (TLFB) at baseline, 4, 8 (end of treatment) and 20 weeks. Daily data on alcohol and cannabis use from the TLFB at all time-points were analyzed.FindingsAcross the sample (n = 96), individuals drank approximately 29% fewer drinks [95% confidence interval (CI) = 18-39%, P < 0.001] and were 2.06 times (95% CI =1.37-3.08, P < 0.001) less likely to have a binge-drinking episode on days that cannabis was used compared with days that cannabis was not used. These patterns were observed in males, females and the infrequent and frequent cannabis use groups. Findings were inconclusive regarding differences in the association between cannabis use and alcohol outcomes when comparing males and females and when comparing infrequent and frequent cannabis use groups.ConclusionsHeavy drinkers engaged in treatment to reduce their alcohol consumption who also use cannabis appear to increase their cannabis use on days when they reduce their alcohol consumption.

Project description:Background: Alcohol-associated liver disease (ALD) is the most common disorder of prolonged drinking. Mechanisms underlying cirrhosis in such patients remain unclear. MicroRNAs play regulatory role in several diseases, are affected by alcohol and may be important players in alcohol use disorders, such as cirrhosis. Methods: We investigated serum samples from heavy chronic alcohol users (80 g/day (male) and 50 g/day (female) for ≥10 years) that were available from our previously reported GenomALC study. A subset of GenomALC drinkers with liver cirrhosis (cases, n = 24) and those without significant liver disease (drinking controls, n = 23) were included. Global microRNA profiling was performed using high-throughput real-time quantitative PCR to identify the microRNA signatures associated with cirrhosis. Ingenuity Pathway Analysis (IPA) software was utilized to identify target mRNAs of significantly altered microRNAs, and molecular pathways were analysed. Identified microRNAs were analysed for correlation with traditional liver disease biomarkers and risk gene variants previously reported from GenomALC genome-wide association study. Results: The expression of 21 microRNAs was significantly downregulated in cases compared to drinking controls (p < 0.05, ∆∆Ct > 1.5-fold). Seven microRNAs (miR-16, miR-19a, miR-27a, miR-29b, miR-101, miR-130a, and miR-191) had a highly significant correlation (p < 0.001) with INR, bilirubin and MELD score. Three microRNAs (miR-27a, miR-130a and miR-191) significantly predicted cases with AUC-ROC 0.8, 0.78 and 0.85, respectively (p < 0.020); however, INR performed best (0.97, p < 0.001). A different set of six microRNAs (miR-19a, miR-26a, miR-101, miR-151-3p, miR-221, and miR-301) showed positive correlation (ranging from 0.32 to 0.51, p < 0.05) with rs10433937:HSD17B13 gene variant, associated with the risk of cirrhosis. IPA analysis revealed mRNA targets of the significantly altered microRNAs associated with cell death/necrosis, fibrosis and increased steatosis, particularly triglyceride metabolism. Conclusions: MicroRNA signatures in drinkers distinguished those with liver cirrhosis from drinkers without liver disease. We identified mRNA targets in liver functions that were enriched for disease pathogenesis pathways.

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

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

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