Implications of OPRM1 and CYP2B6 variants on treatment outcomes in methadone-maintained patients in Ontario: Exploring sex differences

Abstract

Genetic variants in the OPRM1 and CYP2B6 genes, respectively coding for an opioid receptor and methadone metabolizers, have been linked to negative treatment outcomes in patients undergoing methadone maintenance treatment, with little consensus on their effect. This study aims to test the associations between pre-selected SNPs of OPRM1 and CYP2B6 and outcomes of continued opioid use, relapse, and methadone dose. It also aims to observe differences in associations within the sexes. 1,172 participants treated with methadone (nMale = 666, nFemale = 506) were included in this study. SNPs rs73568641 and rs7451325 from OPRM1 and all the tested CYP2B6 SNPs were detected to be in high linkage disequilibrium. Though no associations were found to be significant, noteworthy differences were observed in associations of OPRM1 rs73568641 and CYP2B6 rs3745274 with treatment outcomes between males and females. Further research is needed to determine if sex-specific differences are present.

Pharmacogenetics of Biochemically Verified Abstinence in an Opioid Agonist Therapy Randomized Clinical Trial of Methadone and Buprenorphine/Naloxone

“…The OPRM1 rs1799971 variant was previously examined in the context of methadone maintenance treatment in the START and GENOA trials, both of which used biochemically verified urine screens, however, neither trial looked at genetic effects on abstinence. 37,40 In the end points examined by these trials, there was no evidence of an association of rs1799971 with relapse, continued opioid use, or dose in the GENOA trial, or with dropout or dose in the trial. In the OPTIMA trial, we were able to analyze dropout as an exploratory measure, where we also found no difference by rs1799971 genotype, consistent with the START trial (Table S7); dropout may be influenced more by non-genetic factors, such as dose, number of comorbidities, and administration of other medications.…”

“…Variation in metabolic enzymes can result in a difference in plasma concentrations of a treatment drug; if important to outcomes, this could manifest as a different effective dose and/or a different response. 36,40 For example, an individual with lower plasma methadone, due to variants associated with faster methadone metabolism, may have worse treatment outcomes, and physicians may increase methadone dosage to adjust for this. As dose is tailored to each individual response, 32 this may partly explain why variants related to metabolism had no effect on non-treatment OFUS.…”

“…Exploratory analyses for dropout and continued non‐treatment opioid use were also conducted, as these were end points in pharmacogenetic analyses in the Starting Treatment With Agonist Replacement Therapies (START) and Genetics of Opioid Addiction (GENOA) trials involving methadone OAT 37,40 . Dropout was defined here as a failure to provide a urine sample at visit 12 (i.e., week 24) based on the START trial 37 .…”

“…Exploratory analyses for dropout and continued non-treatment opioid use were also conducted, as these were end points in pharmacogenetic analyses in the Starting Treatment With Agonist Replacement Therapies (START) and Genetics of Opioid Addiction (GENOA) trials involving methadone OAT. 37,40 Dropout was defined here as a failure to provide a urine sample at visit 12 (i.e., week 24) based on the START trial. 37 Continued non-treatment opioid use was defined here as failing one or more non-treatment OFUS throughout all 12 study visits based on the GENOA trial 40 ; in one analysis, missed visits were coded as non-abstinent (i.e., a non-OFUS), similar to the OPTIMA trial, and in a separate analysis, missed visits were excluded, similar to the GENOA trial.…”

“…37,40 Dropout was defined here as a failure to provide a urine sample at visit 12 (i.e., week 24) based on the START trial. 37 Continued non-treatment opioid use was defined here as failing one or more non-treatment OFUS throughout all 12 study visits based on the GENOA trial 40 ; in one analysis, missed visits were coded as non-abstinent (i.e., a non-OFUS), similar to the OPTIMA trial, and in a separate analysis, missed visits were excluded, similar to the GENOA trial. 40 Additional end points of the trials (i.e., relapse (GENOA) and dose (GENOA and START)) were not analyzed due to the shorter treatment window and limited dose data collected in the OPTIMA trial, respectively.…”