Opioid and Dopamine Genes Interact to Predict Naltrexone Response in a Randomized Alcohol Use Disorder Clinical Trial

Abstract

Background: While the opiate antagonist, naltrexone, is approved for treating alcohol use disorder (AUD), not everyone who receives the medication benefits from it. This study evaluated whether the OPRM1 SNP rs1799971 interacts with the dopamine transporter gene DAT1/SLC6A3 VNTR rs28363170 or the catechol-O-methyltransferase (COMT) gene SNP rs4680 in predicting naltrexone response. Methods: Individuals who met DSM-IV alcohol dependence were randomly assigned to naltrexone (50 mg/d) or placebo based on their OPRM1 genotype (75 G-allele carriers and 77 A-allele homozygotes) and also genotyped for DAT1 VNTR (9 vs. 10 repeats) or COMT SNP (val/val vs. met carriers). Heavy drinking days (%HDD) were evaluated over 16 weeks and at the end of treatment. Effect sizes (d) for naltrexone response were calculated based on genotypes. Results: Naltrexone, relative to placebo, significantly reduced %HDD among OPRM1 G carriers who also had DAT1 10/10 (p = 0.021, d = 0.72) or COMT val/val genotypes (p = 0.05, d = 0.80), and to a lesser degree in those OPRM1 A homozygotes who were also DAT1 9-repeat carriers (p = 0.09, d = 0.70) or COMT met carriers (p = 0.03, d = 0.63). All other genotype combinations showed no differential response to naltrexone. Diarrhea/abdominal pain was more prominent in OPRM1 A homozygotes who were also DAT 9 or COMT met carriers. Conclusions: These results suggest that individuals with AUD with a more opioid-responsive genotype (OPRM1 G carriers) respond better to naltrexone if they have genotypes indicating normal/less dopamine tone (DAT1 10,10 or COMT val,val), while those with a less responsive opioid-responsive genotype (OPRM1 A homozygotes) respond better to naltrexone if they have genotypes indicating greater dopamine tone (DAT1 9-repeat or COMT met carriers). These results could lead to more personalized AUD treatments.

Epigenetic moderators of naltrexone efficacy in reducing heavy drinking in Alcohol Use Disorder: a randomized trial

“…We initially reported that, among non-treatment-seeking AUD individuals, naltrexone, relative to placebo, reduced alcohol self-administration and cue-elicited ventral striatal activation most among OPRM1 G-allele carriers who were also SLC6A3 10R homozygotes ( 5 , 6 ). We subsequently replicated and extended this finding in a randomized controlled trial (RCT) among treatment-seeking AUD patients, in which naltrexone, relative to placebo, most effectively reduced heavy drinking among OPRM1 G-allele carriers who were also SLC6A3 10R or COMT val-allele homozygotes ( 7 ). Taken together, these data suggested that a combination of genetically predisposed enhanced MOR function and reduced striatal or cortical synaptic dopamine accumulation was associated with superior naltrexone response.…”

“…Detailed methods for the parent RCT ( ClinicalTrials.gov identifier: NCT00920829 ) have been reported previously ( 7 , 27 ). The Medical University of South Carolina Institutional Review Board approved all procedures, and all participants provided informed consent before participation.…”

“…Participants were required to be ages 18–70; report heavy drinking (at least 4/5 standard drinks per day for women/men) on at least 50% of days in the 90 days before assessment; and meet DSM-IV ( Diagnostic and Statistical Manual of Mental Disorders, revised 4 th edition ) diagnostic criteria for Alcohol Dependence, as assessed by the Structured Clinical Interview for DSM-IV ( 28 ). Participants were also required to self-identify as Caucasian or Asian, secondary to low rs1799971 G-allele frequency among individuals of African descent; we previously reported that analysis of population allele frequencies for 50 SNPs included on the methylation assay used here indicated a high degree of correspondence between self-reported and SNP-identified ancestry ( 7 ). Participants who reported cocaine or marijuana use in the 90 days before assessment were included, as long as they did not meet DSM-IV criteria for dependence on either substance or any other except nicotine and had a negative urine drug screen upon medication randomization.…”

“…Naltrexone is believed to reduce drinking through opioid-mediated effects on alcohol-induced dopamine release ( 3 , 4 ), so genes associated with opioid signaling and dopamine reuptake and inactivation are logical targets. We previously reported epistatic interactions between functional polymorphisms in the μ-opioid receptor (MOR), dopamine transporter (DAT), and catechol-O-methyltransferase (COMT) genes ( OPRM1, SLC6A3 , and COMT) that predicted naltrexone response ( 5 – 7 ). We focused on single nucleotide polymorphisms (SNPs) in OPRM1 (rs1799971) and COMT (rs4680) and a variable number tandem repeat (VNTR) polymorphism in the SLC6A3 3’ untranslated region (rs28363170).…”

Agreement between DSM-IV and DSM-5 measures of substance use disorders in a sample of adult substance users

“…Since its publication, the DSM-5 SUD diagnostic criteria have been widely adopted by clinicians and researchers to assess risk factors and consequences of substance use, and to identify participants for inclusion in clinical trials of treatment effectiveness. Nevertheless, a wide variety of researchers continue to rely on DSM-IV diagnoses because data from many studies, including large clinical trials [18,[22][23][24][25][26] and U.S yearly national general population surveys are based on DSM-IV diagnoses of SUD [27].…”