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

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 OPRM1SNP rs1799971 interacts with the dopamine transporter gene DAT1/SLC6A3VNTR rs28363170 or the catechol‐O‐methyltransferase (COMT) gene SNP rs4680 in predicting naltrexone response. Individuals who met DSM‐IV alcohol dependence were randomly assigned to naltrexone (50 mg/d) or placebo based on their OPRM1genotype (75 G‐allele carriers and 77 A‐allele homozygotes) and also genotyped for DAT1VNTR (9 vs. 10 repeats) or COMTSNP (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. Naltrexone, relative to placebo, significantly reduced %HDD among OPRM1G carriers who also had DAT110/10 (p= 0.021, d= 0.72) or COMTval/val genotypes (p= 0.05, d= 0.80), and to a lesser degree in those OPRM1A homozygotes who were also DAT19‐repeat carriers (p= 0.09, d= 0.70) or COMTmet carriers (p= 0.03, d= 0.63). All other genotype combinations showed no differential response to naltrexone. Diarrhea/abdominal pain was more prominent in OPRM1A homozygotes who were also DAT9 or COMTmet carriers. These results suggest that individuals with AUD with a more opioid‐responsive genotype (OPRM1G carriers) respond better to naltrexone if they have genotypes indicating normal/less dopamine tone (DAT110,10 or COMTval,val), while those with a less responsive opioid‐responsive genotype (OPRM1A homozygotes) respond better to naltrexone if they have genotypes indicating greater dopamine tone (DAT19‐repeat or COMTmet carriers). These results could lead to more personalized AUD treatments. Measuring individual genetic variation could improve AUD naltrexone treatment. When mu opioid receptor gene (OPRM1 A118G) “high brain opioid function” G allele carriers also have “normal or low dopamine brain function” gene polymorphisms i.e. dopamine transporter (DAT 10R) or catechol‐o‐methyl transferase (COMT 158 Val/Val), they respond better to naltrexone. However, OPRM1 AA common variant “normal brain opioid function” individuals respond better to naltrexone if they also have DAT 9R or COMT met alleles indicating “greater brain dopamine” functionality.