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Drug repurposing for opioid use disorders: integration of computational prediction, clinical corroboration, and mechanism of action analyses


Morbidity and mortality from opioid use disorders (OUD) and other substance use disorders (SUD) is a major public health crisis, yet there are few medications to treat them. There is an urgency to accelerate SUD medication development. We present an integrated drug repurposing strategy that combines computational prediction, clinical corroboration using electronic health records (EHRs) of over 72.9 million patients and mechanisms of action analysis. Among top-ranked repurposed candidate drugs, tramadol, olanzapine, mirtazapine, bupropion, and atomoxetine were associated with increased odds of OUD remission (adjusted odds ratio: 1.51 [1.38–1.66], 1.90 [1.66–2.18], 1.38 [1.31–1.46], 1.37 [1.29–1.46], 1.48 [1.25–1.76], p value < 0.001, respectively). Genetic and functional analyses showed these five candidate drugs directly target multiple OUD-associated genes including BDNF, CYP2D6, OPRD1, OPRK1, OPRM1, HTR1B, POMC, SLC6A4 and OUD-associated pathways, including opioid signaling, G-protein activation, serotonin receptors, and GPCR signaling. In summary, we developed an integrated drug repurposing approach and identified five repurposed candidate drugs that might be of value for treating OUD patients, including those suffering from comorbid conditions.

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Fig. 1: Flowcharts of the integrate SUD repurposing system.
Fig. 2: Odds ratios of remission from opioid dependence and the corresponding 95% CI of 10 of top 20-ranked drugs.

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We acknowledge support from Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health under the NIH Director’s New Innovator Award number DP2HD084068, NIH National Institute on Aging R01 AG057557, R01 AG061388, R56 AG062272, National Institute on Drug Addiction UG1DA049435, American Cancer Society Research Scholar Grant RSG-16-049-01—MPC, and The Clinical and Translational Science Collaborative (CTSC) of Cleveland 1UL1TR002548-01.

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RX conceived, designed, and supervised the study. MZ performed drug prediction and clinical evaluation. QW performed the mechanism of action study. RX, QW, MZ, and NDV drafted the manuscript. NDV, CLZ, and AR critically contributed to data interpretation and result discussion. All authors approved the manuscript.

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Correspondence to Rong Xu.

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Zhou, M., Wang, Q., Zheng, C. et al. Drug repurposing for opioid use disorders: integration of computational prediction, clinical corroboration, and mechanism of action analyses. Mol Psychiatry 26, 5286–5296 (2021).

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