Clinical trial NCT02026011: Naltrexone for Individuals of East Asian Descent
Official title: Optimizing Naltrexone for Individuals of East Asian Descent
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Alcohol Use Disorder
Keywords: alcohol use disorder
naltrexone
Asian American
pharmacogenetics
OPRM1 gene
Lead sponsor: University of California, Los Angeles
Sponsor class: OTHER
Collaborators: name: National Institute on Alcohol Abuse and Alcoholism (NIAAA)
First posted: 2014-01-01
Enrollment: 87
Sex: ALL
Minimum age (years): 21
Maximum age (years): 65
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: Inclusion Criteria:

* current (i.e., past month) alcohol dependence
* East Asian ethnicity (i.e., Chinese, Korean, or Japanese)
* Prospective genotyping for the A118G SNP of the mu opioid receptor (OPRM1) gene to allow for balanced groups on all three genotypes (AA, AG, GG)

Exclusion Criteria:

* lifetime DSM-IV of drug dependence (other than alcohol or nicotine)
* current use of psychoactive drugs as determined by self-reports and verified using toxicology testing
* lifetime diagnosis of bipolar disorder or any psychotic disorder
* contraindications to an MRI scan (including left handedness)

Primary outcomes:
measure: Subjective Response - Craving for Alcohol
timeFrame: The AUQ was administered across a period of approximately 1.5 hours.
measure: Subjective Response - Stimulation
timeFrame: The BAES Stimulant Subscale was administered at baseline and three levels of breath alcohol concentration: 0.2 g/dl. 0.04, g/dl, and 0.06 g/dl taking place within approximately 1.5 hours
measure: Subjective Response - Sedation
timeFrame: The BAES Sedation Subscale was administered at baseline and three levels of breath alcohol concentration: 0.2 g/dl. 0.04, g/dl, and 0.06 g/dl taking place within approximately 1.5 hours
measure: Neural Response to Alcohol Cues
timeFrame: During the alcohol cue exposure fMRI paradigm which is expected to last 45 minutes
Secondary outcomes:
measure: Alcohol Self-administration - Number of Drinks
timeFrame: Alcohol self-administration period was 1 hour long
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA Addictions Laboratory
state: California
Study officials:
affiliation: University of California, Los Angeles
name: Lara Ray, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ray LA, Bujarski S, Chin PF, Miotto K. Pharmacogenetics of naltrexone in asian americans: a randomized placebo-controlled laboratory study. Neuropsychopharmacology. 2012 Jan;37(2):445-55. doi: 10.1038/npp.2011.192. Epub 2011 Sep 7.