CYP2D6-guided opioid therapy improves pain control in CYP2D6 intermediate and poor metabolizers: a pragmatic clinical trial

Genet Med. 2019 Aug;21(8):1842-1850. doi: 10.1038/s41436-018-0431-8. Epub 2019 Jan 23.


Purpose: CYP2D6 bioactivates codeine and tramadol, with intermediate and poor metabolizers (IMs and PMs) expected to have impaired analgesia. This pragmatic proof-of-concept trial tested the effects of CYP2D6-guided opioid prescribing on pain control.

Methods: Participants with chronic pain (94% on an opioid) from seven clinics were enrolled into CYP2D6-guided (n = 235) or usual care (n = 135) arms using a cluster design. CYP2D6 phenotypes were assigned based on genotype and CYP2D6 inhibitor use, with recommendations for opioid prescribing made in the CYP2D6-guided arm. Pain was assessed at baseline and 3 months using PROMIS® measures.

Results: On stepwise multiple linear regression, the primary outcome of composite pain intensity (composite of current pain and worst and average pain in the past week) among IM/PMs initially prescribed tramadol/codeine (n = 45) had greater improvement in the CYP2D6-guided versus usual care arm (-1.01 ± 1.59 vs. -0.40 ± 1.20; adj P = 0.016); 24% of CYP2D6-guided versus 0% of usual care participants reported ≥30% (clinically meaningful) reduction in the composite outcome. In contrast, among normal metabolizers prescribed tramadol or codeine at baseline, there was no difference in the change in composite pain intensity at 3 months between CYP2D6-guided (-0.61 ± 1.39) and usual care (-0.54 ± 1.69) groups (adj P = 0.540).

Conclusion: These data support the potential benefits of CYP2D6-guided pain management.

Keywords: CYP2D6; chronic pain; opioids; pharmacogenetics; precision medicine.

Publication types

  • Clinical Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Analgesics, Opioid / administration & dosage*
  • Analgesics, Opioid / adverse effects
  • Codeine / administration & dosage
  • Codeine / adverse effects
  • Cytochrome P-450 CYP2D6 / genetics*
  • Female
  • Humans
  • Male
  • Middle Aged
  • Pain / drug therapy*
  • Pain / genetics
  • Pain / pathology
  • Pain Management / methods*
  • Pharmacogenetics
  • Polymorphism, Genetic
  • Precision Medicine


  • Analgesics, Opioid
  • Cytochrome P-450 CYP2D6
  • Codeine