Pharmacogenetics of Naltrexone in Asian Americans: A Randomized Placebo-Controlled Laboratory Study

Abstract

Recent clinical and laboratory studies have shown that the effects of naltrexone for alcoholism may be moderated by the Asn40Asp single-nucleotide polymorphism (SNP) of the m-opioid receptor gene (OPRM1). Allele frequencies for this polymorphism, however, have been shown to vary substantially as a function of ethnic background, such that individuals of Asian descent are more likely to carry the minor (Asp40) allele. The objective of this study is to test the naltrexone pharmacogenetic effects of the Asn40Asp SNP in a sample of Asian Americans. This study consists of a double-blinded, randomized, placebo-controlled laboratory trial of naltrexone. Participants (n ¼ 35, 10 females; 13 Asn40Asn and 22 Asp40 carriers) were non-treatment-seeking heavy drinkers recruited from the community. After taking naltrexone or placebo, participants completed an intravenous alcohol administration session. The primary outcome measures were subjective intoxication and alcohol craving. Results suggested that Asp40 carriers experienced greater alcohol-induced sedation, subjective intoxication, and lower alcohol craving on naltrexone, as compared to placebo, and to Asn40 homozygotes. There results were maintained when controlling for ALDH2 (rs671) and ADH1B (rs1229984) markers and when examining the three levels of OPRM1 genotype, thereby supporting an OPRM1 gene dose response. These findings provide a much-needed extension of previous studies of naltrexone pharmacogenetics to individuals of Asian descent, an ethnic group more likely to express the minor allele putatively associated with improved biobehavioral and clinical response to this medication. These findings help further delineate the biobehavioral mechanisms of naltrexone and its pharmacogenetics.

Genetic and Environmental Predictors of Alcohol Use in Asian American Young Adults

“…To ensure a wide distribution of alcohol use and problems, participants were recruited into two groups. The first group consisted of heavy drinkers (n = 49) who were recruited for a laboratory trial of naltrexone in non-treatment-seeking Asian American heavy drinkers (Ray et al, 2012). Inclusion criteria included (a) Chinese, Korean, or Japanese descent; (b) age between 21 and 35 years; (c) currently taking no psychoactive medications; (d) having no major psychiatric disorder; and (e) current heavy alcohol use as identified by the Alcohol Use Disorders Identification Test (AUDIT), with a cutoff score of 8 or above (Allen et al, 1997).…”

Opportunities for the Development of Neuroimmune Therapies in Addiction

“…Such findings on safety and mechanisms are vital to deciding whether to invest resources for efficacy testing for a putative addiction medication. Our team has used human laboratory paradigms to test several medications for addiction, including naltrexone (Ray, Bujarski, Chin, & Miotto, 2012;Ray & Hutchison, 2007), topiramate (Miranda et al, 2008;Ray et al, 2009), quetiapine (Moallem & Ray, 2012;Ray, Chin, Heydari, & Miotto, 2011), and varenicline (Ray et al, 2014(Ray et al, , 2013. Given the new opportunities presented by recent discoveries on the role of neuroinflammation in addiction as well as new advancements in the technology of medication development, including the refinement of powerful human laboratory models, the stage is set for the discovery of novel treatments for substance use disorders.…”

Pharmacogenomics of alcohol addiction: Personalizing pharmacologic treatment of alcohol dependence

“…Carriers of 118G allele reported experiencing decreased euphoria during naltrexone treatment aft er seeing and drinking alcohol [40]. Results of a double-blinded, randomized, placebo-controlled laboratory trial on naltrexone that included 35 non-treatment seeking Asian Americans heavy drinkers have also showed that 118G carriers experience greater alcohol-induced sedation and subjective intoxication, and lower alcohol craving compared to 118AA [41]. OPRM1 118G allele was also associated with increased percentage of non-hazardous drinking in a study that included 112 European problem drinkers treated with naltrexone 100mg/day for 12 weeks [42].…”