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Opioid and Dopamine Genes Interact to Predict Naltrexone Response in a Randomized Alcohol Use Disorder Clinical Trial
Author(s) -
Anton Raymond F.,
Voronin Konstantin E.,
Book Sarah W.,
Latham Patricia K.,
Randall Patrick K.,
Glen Willam Bailey,
Hoffman Michaela,
Schacht Joseph P.
Publication year - 2020
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/acer.14431
Subject(s) - naltrexone , rs4680 , catechol o methyl transferase , alcohol dependence , medicine , alcohol use disorder , genotype , placebo , pharmacology , snp , opioid , single nucleotide polymorphism , alcohol , biology , genetics , gene , biochemistry , receptor , alternative medicine , pathology
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.