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A polymorphism in the OPRM1 3′-untranslated region is associated with methadone efficacy in treating opioid dependence

The Pharmacogenomics Journal volume 18, pages 173–179 (2018)Cite this article

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Abstract

The μ-opioid receptor (MOR) is the primary target of methadone and buprenorphine. The primary neuronal transcript of the OPRM1 gene, MOR-1, contains a ~13 kb 3′ untranslated region with five common haplotypes in European-Americans. We analyzed the effects of these haplotypes on the percentage of opioid positive urine tests in European-Americans (n=582) during a 24-week, randomized, open-label trial of methadone or buprenorphine/naloxone (Suboxone) for the treatment of opioid dependence. A single haplotype, tagged by rs10485058, was significantly associated with patient urinalysis data in the methadone treatment group. Methadone patients with the A/A genotype at rs10485058 were less likely to have opioid-positive urine drug screens than those in the combined A/G and G/G genotypes group (relative risk=0.76, 95% confidence intervals=0.73–0.80, P=0.0064). Genotype at rs10485058 also predicted self-reported relapse rates in an independent population of Australian patients of European descent (n=1215) who were receiving opioid substitution therapy (P=0.003). In silico analysis predicted that miR-95-3p would interact with the G, but not the A allele of rs10485058. Luciferase assays indicated miR-95-3p decreased reporter activity of constructs containing the G, but not the A allele of rs10485058, suggesting a potential mechanism for the observed pharmacogenetic effect. These findings suggest that selection of a medication for opioid dependence based on rs10485058 genotype might improve outcomes in this ethnic group.

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Acknowledgements

Main START study funding came from the National Institute on Drug Abuse through the Clinical Trials Network (CTN) through a series of grants provided to each participating node: the Pacific Northwest Node (U10 DA01714), the Oregon Hawaii Node (U10 DA013036), the California/Arizona Node (U10 DA015815), the New England Node (U10 DA13038), the Delaware Valley Node (U10 DA13043), the Pacific Region Node (U10 DA13045), and the New York Node (U10 DA013046). Suboxone for the START trial was provided by Reckitt-Benckiser Pharmaceuticals (now Indivior Inc.). Dr. Berrettini was supported by the Delaware Valley Node (U10 DA13043) and by R21 DA036808. Dr. Crist was supported by NIDA grant K01 DA036751 and pilot project funding through the Veterans Integrated Service Network (VISN) 4 Mental Illness Research, Education, and Clinical Center (MIRECC). Funding support for the Comorbidity and Trauma Study (CATS) was provided by the National Institute on Drug Abuse (R01 DA17305); GWAS genotyping services at the Center for Inherited Disease Research (CIDR) at The Johns Hopkins University were supported by the National Institutes of Health (contract N01-HG-65403). We thank Elisia Clark, Emre Karatas, Alison Lai, and Wint Thu Saung for contributions to the genotyping of the START population.

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  1. R C Crist and G A Doyle: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Psychiatry, Center for Neurobiology and Behavior, University of Pennsylvania School of Medicine, PA, Pennsylvania, USA

    R C Crist, G A Doyle & W H Berrettini

  2. Department of Psychiatry, Washington University School of Medicine, MO, St Louis, USA

    E C Nelson

  3. National Drug and Alcohol Research Centre, UNSW Australia, Sydney, New South Wales, Australia

    L Degenhardt

  4. QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

    N G Martin

  5. The University of Queensland, Herston, Queensland, Australia

    G W Montgomery

  6. Veteran's Affairs Puget Sound Health Care System, Seattle, WA, USA

    A J Saxon

  7. University of California, Los Angeles, Integrated Substance Abuse Programs, Los Angeles, CA, USA

    W Ling

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Correspondence to R C Crist.

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Competing interests

Dr Degenhardt has received educational grants from Mundipharma International and Indivior Dr Saxon receives funding from MedicaSafe and has received compensation from UpToDate, Indivior and Alkermes. Dr Ling is a consultant for Indivior, US WorldMed and Cerecor and also has research support from the Patient-Centered Outcomes Research Institute, Indivior, Alkermes and Brauburn Pharmaceuticals. The remaining authors declare no conflict of interest.

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Crist, R., Doyle, G., Nelson, E. et al. A polymorphism in the OPRM1 3′-untranslated region is associated with methadone efficacy in treating opioid dependence. Pharmacogenomics J 18, 173–179 (2018). https://doi.org/10.1038/tpj.2016.89

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