Satisfaction With Methadone and Opioid Receptor Genes Polymorphisms in Treatment-Refractory Heroin-Dependent Patients

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Patient satisfaction with methadone as a medication to treat heroin addiction may be associated with polymorphisms of the opioid receptor genes mu (OPRM1), delta (OPRD1), and kappa (OPRK1), in as much as opioid receptors mediate the primary effects of methadone. The Scale to Assess Satisfaction with Medications for Addiction Treatment–Methadone for Heroin Addiction (SASMAT-METHER)1 is suitable to measure satisfaction with methadone. The SASMAT-METHER is a self-reported 17-item scale comprising 3 subscales: Personal Functioning and Well-Being, Anti-Addictive Effect on Heroin, and Anti-Addictive Effect on Other Substances. Given that all opioid receptors mediate distinct mental and physical functions,2 satisfaction with the compatibility of methadone with personal functioning and well-being could be associated with OPRM1, OPRD1, and OPRK1 polymorphisms. Variants of OPRK1 are particularly likely to be associated with methadone satisfaction because kappa receptors mediate aversivelike effects of opioid agonists.3 Likewise, given that the effects of opioid agents on the reinforcement of heroin and even nonopioid substances have been found to be mediated by all opioid receptors,4 it also seems probable that satisfaction with the anti-addictive effects of methadone on heroin or nonopioid substances would be associated with OPRM1, OPRD1, and OPRK1 polymorphisms. To investigate these questions, we conducted the present candidate-gene study in which we examined possible associations between satisfaction with methadone and variants of opioid receptor genes in patients considered methadone maintenance treatment (MMT) nonresponders.
A total of 216 unrelated methadone-maintained, heroin-dependent Spanish patients of European descent were included in this study. All participants were nonresponsive to MMT, defined as continued compulsive use of heroin and/or nonopioid substances requiring inpatient detoxification treatment. Patients with mental disorders that could hinder clinical assessments (eg, neurocognitive disorders) were excluded. Written informed consent was obtained from all participants. The study protocol was approved by the institutional review board of Sant Pau Hospital.
We analyzed 30 single-nucleotide polymorphisms (SNPs) from OPRM1, OPRD1, and OPRK1 genes (Supplementary Table 1, Supplemental Digital Content 1, http://links.lww.com/JCP/A431). Some SNPs were tag SNPs (r2 cutoff > 0.8 and a minor allele frequency > 10% in European population) selected with the HapMap genome browser (http://www.hapmap.org) and the Haploview software v.4.2; the remaining SNPs were those most commonly studied in previous association studies. Genotype determination was carried out in genomic DNA with real-time polymerase chain reaction using a 48.48 dynamic array on the BioMark system (Fluidigm, San Francisco, Calif). For each SNP, deviations from Hardy-Weinberg equilibrium were assessed using an exact test.5 Adjustment of methadone dose desired by patients was assessed using the Visual Analogue Scale of Methadone Dose.6 Linear regressions were used to test bivariate associations between SASMAT-METHER scores and genetic variables. Subsequently, further association analyses were performed for each SNP using generalized linear models adjusted for covariates. Days of heroin use during the last month and patients' desire for downward adjustment of the methadone dose were selected as covariates because both have been found to be independently associated with satisfaction with methadone in MMT nonresponders.6 In this study, both variables also showed significant associations with SASMAT-METHER. Furthermore, dominant, recessive, and codominant genetic models were tested. Tests of significance were 2-tailed and were considered significant if P < 0.05. Association analyses were performed using the IBM SPSS Statistical Software (v22.0).
Participants were predominantly men (75.9%), with a mean (SD) age of 40.8 (6.5) years. Heroin consumption started at a mean (SD) age of 21.2 (6.8) years. The main route of heroin administration was intravenous (67.6%), followed by intranasal (19.9%) and intrapulmonary (12.5%). Most patients also reported a history of use of alcohol (67.1%), benzodiazepines (56%), cannabis (86.1%), cocaine (90.7%), and tobacco (98.1%).
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