Pharmacogenetics of Opioid Agonist Therapy

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Abstract Methadone (MET) and buprenorphine/naloxone (BUP) are two distinct FDA-approved agonist medications for treatment of opioid addiction. There are prominent pharmacologic differences between BUP and MET. MET is a full mu agonist, while BUP is a partial mu agonist~ BUP has kappa antagonist properties, while MET is devoid of kappa antagonism. At present it is not possible to use clinical or biomarker predictors to determine who will most likely benefit from one medication versus the other. Recent research has suggested that a common variation in the delta opioid receptor gene (OPRD1), single nucleotide polymorphism (SNP) rs678849, may predict response (urine drug screen for illicit opioids) among African-Americans (AAs) to these medications. AA opioid addicts with a CC genotype at rs678849 have a greater probability of gaining substantial therapeutic benefit from MET, while those with alternative genotypes (C/T + TT) have a greater probability to responding well to BUP (relative risk = 2.8~ p = 2.2 x 10-5). The current project represents an attempt to confirm the original finding in an independent population. Individuals of AA ethnicity, age at least 18, being treated with methadone (n = 150) or buprenorphine/naloxone (n = 150) for opioid addiction at treatment centers in New Haven and the Philadelphia Veterans Administration Medical Center, will be invited to participate. Participation involves review of medical records (to determine eligibility and response to treatment), a brief semi-structured interview and a single small (5 ml) venous blood sample. Blood will be used for DNA extraction and the rs678849 SNP will be genotyped. Genotype x treatment interaction analysis is planned, including as co-variates age, gender, age-at-onset of opioid addiction, co-morbid disorders~ urine drug screen results for opioids during the most recent 20 weeks is the sole endpoint. This phenotype will be analyzed also using generalized estimating equation methods, with the urine drug screen results treated as repeated measures. If the original observation is confirmed, this research may lead to a simple and inexpensive test for optimal agonist treatment of opioid addiction among African- Americans.