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We have previously shown associations between 4 genetic variants in opioid and stress-related genes (OPRM1, NPYR1/NPYR5, NR3C1, and CRHBP) and prolonged abstinence from heroin without methadone maintenance treatment (MMT). We currently assessed the associations between these variants and MMT patients’ characteristics.A non-selective group of 351 patients who stayed at least 1 year in their first admission to MMT were genotyped and their characteristics and substance in urine on admission and after 1 year were studied.The proportions of patients with both cocaine and benzodiazepine abuse were reduced significantly after 1 year in MMT; however, cocaine abuse cessation was significantly associated with the non-carriers of the CRHBP (corticotrophin releasing hormone binding protein) SNP rs1500 minor C allele (GG genotype) (P = 0.0009, PBonferroni = 0.0221). More carriers of the 2 C alleles (CC genotype) than carriers of the GC and GG genotypes abused cocaine on admission (32.3% vs 19.7%, respectively, P = 0.0414, recessive model), and more of the C allele carriers (GC and CC genotypes) than non-carriers (GG genotype) abused cocaine after 1 year in MMT (25.7% vs 15.8%, respectively, P = 0.0334, dominant model). Abusers of benzodiazepine were more prevalent among carriers of the C allele compared with non-carriers on admission (60.6% vs 45.9%, respectively, P = 0.0080, dominant model), as well as after 1 year in MMT (50.9% vs 39.1%, respectively, P = 0.0362).Reduction in cocaine abuse among MMT patients may be mediated by a genetic effect in a stress-related gene (CRHBP SNP rs1500 minor C allele). Evaluations of larger samples, additional SNPs, and different populations are needed to support these findings.