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OPRM1, OPRK1, and COMT genetic polymorphisms associated with opioid effects on experimental pain: a randomized, double-blind, placebo-controlled study

The Pharmacogenomics Journal volume 20, pages 471–481 (2020)Cite this article

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Abstract

Genetic polymorphisms have been shown to affect opioid requirement for pain relief. However, true genetic effect is often difficult to assess due to underlying pain conditions and placebo effects. The goal of this study was to understand how common polymorphisms affect opioid effects while controlling for these factors. A randomized, double-blind, placebo-controlled study was implemented to assess how opioid effects are modulated by COMT (rs6269, rs4633, rs4848, rs4680), OPRM1 (A118G), and OPRK1 (rs1051660, rs702764, rs16918875). One hundred and eight healthy subjects underwent experimental pain testing before and after morphine, butorphanol, and placebo (saline). Association analysis was performed between polymorphisms/haplotypes and opioid response, while correcting for race, gender, placebo effects, and multiple comparisons. Pressure pain was significantly associated with rs6269 and rs4633 following butorphanol. The AA genotype of rs4680 or A_T_C_A/ A_T_C_A (rs6269_rs4633_ rs4818_rs4680) diplotype of COMT, combined with the AG genotype of OPRM1 A118G, showed significantly increased pressure pain threshold from butorphanol. Opioid effects on pressure, ischemic, heat pain, and side effects were nominally associated with several SNPs and haplotypes. Effects were often present in one opioid but not the other. This indicates that these polymorphisms affect pain relief from opioids, and that their effects are opioid and pain modality specific.

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Fig. 1: Timeline representing the temporal structure of procedures during each experimental session.
Fig. 2: COMT SNPs were associated with decreased response to opioids in pressure pain threshold.
Fig. 3
Fig. 4
Fig. 5: A118G of OPRM1 was associated with higher pressure pain threshold from morphine in the masseter.
Fig. 6: Joint effect of COMT and OPRM1 polymorphisms on opioid response.
Fig. 7: OPRK1 SNPs associated with altered heat pain tolerance and threshold from opioids.

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Acknowledgements

This work was supported by NIH/NINDS grant R01NS041670.

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Authors and Affiliations

  1. Department of Anesthesiology, Perioperative and Pain Medicine, Division of Pain Medicine, Stanford University, Redwood City, CA, USA

    Kwo Wei David Ho

  2. Department of Neurology, University of Florida, Gainesville, FL, USA

    Kwo Wei David Ho

  3. Department of Molecular Genetics & Microbiology, and UF Genetics Institute, University of Florida, Gainesville, FL, USA

    Margaret R. Wallace

  4. Department of Medicine, University of Florida, Gainesville, FL, USA

    Roland Staud

  5. Department of Community Dentistry and Behavioral Science, University of Florida, Gainesville, FL, USA

    Roger B. Fillingim

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Ho, K.W.D., Wallace, M.R., Staud, R. et al. OPRM1, OPRK1, and COMT genetic polymorphisms associated with opioid effects on experimental pain: a randomized, double-blind, placebo-controlled study. Pharmacogenomics J 20, 471–481 (2020). https://doi.org/10.1038/s41397-019-0131-z

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