Pharmacogenetic analysis of opioid dependence treatment dose and dropout rate

<p><i>Background</i>: Currently, no pharmacogenetic tests for selecting an opioid-dependence pharmacotherapy have been approved by the US Food and Drug Administration. <i>Objectives</i>: Determine the effects of variants in 11 genes on dropout rate and dose in patients receiving methadone or buprenorphine/naloxone (ClinicalTrials.gov Identifier: NCT00315341). <i>Methods</i>: Variants in six pharmacokinetic genes (<i>CYP1A2, CYP2B6, CYP2C19, CYP2C9, CYP2D6, CYP3A4</i>) and five pharmacodynamic genes (<i>HTR2A, OPRM1, ADRA2A, COMT, SLC6A4</i>) were genotyped in samples from a 24-week, randomized, open-label trial of methadone and buprenorphine/naloxone for the treatment of opioid dependence (<i>n</i> = 764; 68.7% male). Genotypes were then used to determine the metabolism phenotype for each pharmacokinetic gene. Phenotypes or genotypes for each gene were analyzed for association with dropout rate and mean dose. <i>Results</i>: Genotype for 5-HTTLPR in the <i>SLC6A4</i> gene was nominally associated with dropout rate when the methadone and buprenorphine/naloxone groups were combined. When the most significant variants associated with dropout rate were analyzed using pairwise analyses, <i>SLC6A4</i> (5-HTTLPR) and <i>COMT</i> (Val158Met; rs4860) had nominally significant associations with dropout rate in methadone patients. None of the genes analyzed in the study was associated with mean dose of methadone or buprenorphine/naloxone. <i>Conclusions</i>: This study suggests that functional polymorphisms related to synaptic dopamine or serotonin levels may predict dropout rates during methadone treatment. Patients with the S/S genotype at 5-HTTLPR in <i>SLC6A4</i> or the Val/Val genotype at Val158Met in <i>COMT</i> may require additional treatment to improve their chances of completing addiction treatment. Replication in other methadone patient populations will be necessary to ensure the validity of these findings.