An Intronic Variant in OPRD1 Predicts Treatment Outcome for Opioid Dependence in African-Americans

Abstract

Although buprenorphine and methadone are both effective treatments for opioid dependence, their efficacy can vary significantly among patients. Genetic differences may explain some of the variability in treatment outcome. Understanding the interactions between genetic background and pharmacotherapy may result in more informed treatment decisions. This study is a pharmacogenetic analysis of the effects of genetic variants in OPRD1, the gene encoding the δ-opioid receptor, on the prevalence of opioid-positive urine tests in African-Americans (n=77) or European-Americans (n=566) undergoing treatment for opioid dependence. Patients were randomly assigned to treatment with either methadone or buprenorphine/naloxone (Suboxone) over a 24-week open-label clinical trial, in which illicit opioid use was measured by weekly urinalysis. In African-Americans, the intronic SNP rs678849 predicted treatment outcome for both medications. Methadone patients with the CC genotype were less likely to have opioid-positive urine tests than those in the combined CT and TT genotypes group (relative risk (RR)=0.52, 95% confidence interval (CI)=0.44-0.60, p=0.001). In the buprenorphine treatment group, however, individuals with the CC genotype were more likely to have positive opioid drug screens than individuals in the combined CT and TT genotypes group (RR=2.17, 95% CI=1.95-2.68, p=0.008). These findings indicate that the genotype at rs678849 predicts African-American patient response to two common treatments for opioid dependence, suggesting that matching patients to treatment type based on the genotype at this locus may improve overall treatment efficacy. This observation requires confirmation in an independent population.

The Genetics, Neurogenetics and Pharmacogenetics of Addiction

“…Response rates vary dramatically and the use of none of these is without risks [126]. One recent study of African-Americans found that for a variant, rs678849, in the gene encoding the delta opioid receptor ( OPRD1 ), CC individuals had more positive urine tests (24 weeks post-treatment) if treated with buprenorphine but less positive tests when treated with methadone [127]. Another recent study implicates a functional variant (rs2760118) in the gene encoding the succinic semialdehyde dehydrogenase enzyme ( ALDH5A1 ) in response to methadone maintenance with T allele carriers more likely to be non-responders [128].…”

Medication-assisted therapy for opioid addiction

“…Due to resource limitations, decisions on whether to analyze the blood genetic elements will be reviewed and analyzed case by case. Recently, some CTN trials have produced interesting genetic findings [10]. …”

Precision medicine and pharmacogenetics: what does oncology have that addiction medicine does not?

“…In cardiovascular medicine, diverse approaches have identified clinically relevant (though not currently applicable) pharmacokinetic gene-medication pairs, including CYP2C19 /clopidogrel and CYP2C9 /warfarin, and pharmacodynamic pairs, including VKORC1 /warfarin and ADRB1 /bucindolol (20, 36). In addiction medicine, gene-medication pairs identified using a candidate gene approach include a non-synonymous substitution (rs1799971) in OPRM1 (which encodes the mu-opioid receptor) and naltrexone for treating alcohol dependence (37), a variant (rs2832407) in GRIK1 (which encodes the GluK1 subunit of the kainate receptor) and topiramate treatment of heavy drinking (38), two variants (5′-HTTLPR and rs1042173) in SLC6A4 (which encodes the serotonin transporter) and ondansetron (39), and a variant (rs678849) in OPRD1 (which encodes the delta-opioid receptor) and buprenorphine or methadone treatment of opioid dependence (40). However, these gene-medication pairs have either failed to replicate in a prospective study design ( OPRM1 /naltrexone (41) or have not yet been evaluated prospectively ( GRIK1 -topiramate, SLC6A4 /ondansetron, OPRD1 /opioid agonists).…”