Naltrexone for Individuals of East Asian Descent
Condition: Alcohol Use Disorder
MeSH terms: Alcoholism; Alcohol Drinking
Study type: Interventional
Phase: Phase 2

Summary: 
      This study will elucidate the pharmacogenetic effects of the Asn40Asp SNP of the OPRM1 gene
      on biobehavioral and neural markers of response to naltrexone in individuals of East Asian
      descent, an ethnic group most likely to express the positive predictive allele.
    

Detailed description: 
      Recent pharmacogenetic studies have advanced the gene coding for µ-opioid receptors (OPRM1)
      gene as a potential moderator of responses to naltrexone. The most widely studied
      polymorphism of the OPRM1 gene is the Asn40Asp single nucleotide polymorphism (SNP), a
      functional mutation thought to affect receptor activity such that the Asp40 variant binds
      β-endorphin three times stronger than the Asn40 allele. Recent studies have found that Asp40
      carriers have a stronger striatal dopamine response to intravenous alcohol administration and
      report stronger feelings of alcohol reward. Findings from the COMBINE Study demonstrated that
      if treated with Medication Management alone and naltrexone, 87.1% of Asp40 carriers had a
      good clinical outcome, compared with only 54.8% of Asn40 homozygotes. While these findings
      are promising, studies have also highlighted allele frequency imbalance as a function of
      ethnicity such that the Asp40 allele frequency is approximately 20% in Caucasians, 5% in
      individuals of African Ancestry, and as high as 50% among individuals of East Asian descent.
      Therefore, to the extent to which this SNP moderates behavioral and clinical responses to
      NTX, ethnicity must be carefully considered in order to extend the findings from primarily
      Caucasian samples to ethnic minorities, such as Asian Americans. Preliminary work by our team
      has found that among individuals of East Asian descent, Asp40 carriers show greater
      NTX-induced blunting of alcohol craving as well as potentiation of the aversive effects of
      alcohol. This pilot study also found support for a gene dose-response, such that Asp40Asp
      individuals showed greater NTX responsivity than those with the Asn40Asp genotype. This study
      seeks to build upon these preliminary findings by testing heavy drinkers of East Asian
      descent across three OPRM1 genotypes (Asn40Asn, n = 30; Asn40Asp, n = 30, and Asp40Asp, n =
      30). Participants will complete two double-blinded, counterbalanced alcohol infusion and
      self-administration sessions, one after taking NTX (50 mg/day) and one after taking matched
      placebo for five days. In each medication condition, participants will complete a functional
      neuroimaging task examining cue-induced craving for alcohol. This study will elucidate the
      pharmacogenetic effects of the Asn40Asp SNP of the OPRM1 gene on biobehavioral and neural
      markers of response to naltrexone in individuals of Asian descent, an ethnic group most
      likely to express the positive predictive allele (Asp40). The long-term objective of this
      research is to optimize alcoholism pharmacotherapy and to address health disparities by
      advancing pharmacogenetic studies in ethnic minority groups.
    

Intervention name(s): Naltrexone; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): Naltrexone is an opioid receptor antagonist with highest affinity for mu opioid receptors; Sugar pill, matched to the active study medication in capsule size and color
Other intervention name(s): Revia; Depade; Vivitrol; Sugar pill
Intervention MeSH terms: Naltrexone
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: alcohol use disorder; naltrexone; Asian American; pharmacogenetics; OPRM1 gene