CYP2D6 ‐Guided Opioid Therapy for Chronic Pain: A Multi‐Center Pragmatic Randomized Controlled Trial

The analgesic effectiveness of several opioids depends on CYP2D6-mediated metabolism to more active opioid receptor agonists. CYP2D6 activity is impacted by genetic variability and medications that inhibit CYP2D6. We conducted a pragmatic, multi-center, randomized, controlled trial to determine whether CYP2D6-guided opioid prescribing improves chronic pain. Participants were adults recruited from primary care or pain specialty clinics with at least 3 months of chronic pain treated or considered for treatment with tramadol, hydrocodone, or codeine. Participants were randomized to the usual care or CYP2D6-guided arm, in which CYP2D6 pharmacogenetic testing was performed. Healthcare professionals were recommended to avoid tramadol, hydrocodone, or codeine in patients with CYP2D6 intermediate or poor or ultra-rapid (for safety) metabolizer phenotypes based on either genotype or drug interactions. The primary outcome was the change in composite pain intensity scores from baseline to 3 months. Of 1048 enrolled participants, 282 had an actionable CYP2D6 phenotype. In this group, CYP2D6-guided recommendations did not improve the change in composite pain intensity scores from baseline to 3 months compared with usual care (mean [SD] -0.8 [2.4] vs. -0.7 [2.3]) or improve drug-gene concordance (26.8% vs. 27.1%) in the CYP2D6-guided versus usual care arm, respectively. In an exploratory analysis, participants whose therapy changed to align with their CYP2D6 phenotype had significantly improved pain scores. In conclusion, incorporating CYP2D6-guided recommendations for opioid therapy into routine practice did not change prescribing sufficiently to assess its impact on chronic pain control, suggesting that EHR-integrated CYP2D6 guidance is insufficient to change opioid prescribing for chronic pain.

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Publication Details

Journal
Clinical Pharmacology & Therapeutics
Published
2026-10-15
DOI
https://doi.org/10.1002/cpt.70505
Primary Topic
Pharmacogenetics and Drug Metabolism
Type
article
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0.00

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article

CYP2D6 ‐Guided Opioid Therapy for Chronic Pain: A Multi‐Center Pragmatic Randomized Controlled Trial

Todd C. Skaar, Jordan F. Baye, Khoa A. Nguyen, Rachel A. Myers et al.
Clinical Pharmacology & Therapeutics
Pharmacogenetics and Drug Metabolism
article

CYP2D6 ‐Guided Opioid Therapy for Chronic Pain: A Multi‐Center Pragmatic Randomized Controlled Trial

Todd C. Skaar, Jordan F. Baye, Khoa A. Nguyen, Rachel A. Myers, Paul Richard Dexter, Elizabeth C. Harris, Erica N. Elwood, John Thomas Callaghan, Deepak Voora, Azita Sadeghpour, Saskia Shuman, Carol R. Horowitz, Hrishikesh Chakraborty, Michael T. Eadon, Kerri L. Cavanaugh, Emily J. Cicali, Larisa H. Cavallari, Lindsay J. Hines, Roger Benton Fillingim, Emma M. Tillman, Marc B. Rosenman, Julie Ann Johnson, Josh F. Peterson, Lori A. Orlando, Michelle A. Ramos, Christina M. Wyatt, Rajbir Singh, the IGNITE Pragmatic Trials Network
article en

Abstract

The analgesic effectiveness of several opioids depends on CYP2D6-mediated metabolism to more active opioid receptor agonists. CYP2D6 activity is impacted by genetic variability and medications that inhibit CYP2D6. We conducted a pragmatic, multi-center, randomized, controlled trial to determine whether CYP2D6-guided opioid prescribing improves chronic pain. Participants were adults recruited from primary care or pain specialty clinics with at least 3 months of chronic pain treated or considered for treatment with tramadol, hydrocodone, or codeine. Participants were randomized to the usual care or CYP2D6-guided arm, in which CYP2D6 pharmacogenetic testing was performed. Healthcare professionals were recommended to avoid tramadol, hydrocodone, or codeine in patients with CYP2D6 intermediate or poor or ultra-rapid (for safety) metabolizer phenotypes based on either genotype or drug interactions. The primary outcome was the change in composite pain intensity scores from baseline to 3 months. Of 1048 enrolled participants, 282 had an actionable CYP2D6 phenotype. In this group, CYP2D6-guided recommendations did not improve the change in composite pain intensity scores from baseline to 3 months compared with usual care (mean [SD] -0.8 [2.4] vs. -0.7 [2.3]) or improve drug-gene concordance (26.8% vs. 27.1%) in the CYP2D6-guided versus usual care arm, respectively. In an exploratory analysis, participants whose therapy changed to align with their CYP2D6 phenotype had significantly improved pain scores. In conclusion, incorporating CYP2D6-guided recommendations for opioid therapy into routine practice did not change prescribing sufficiently to assess its impact on chronic pain control, suggesting that EHR-integrated CYP2D6 guidance is insufficient to change opioid prescribing for chronic pain.

Clinical Pharmacology & Therapeutics
Northwestern University (US), Meharry Medical College (US), Lurie Children's Hospital (US), Sanford Health (US), Regenstrief Institute (US), Duke University (US), South Dakota State University (US), University of North Dakota (US), University of Florida Health (US), Sidney & Lois Eskenazi Hospital (US), Institute for Family Health (US), University of Florida (US), VA Tennessee Valley Healthcare System (US), Duke Medical Center (US), Eskenazi Health Foundation (US), Indiana University Indianapolis (US), Indiana University School of Medicine, The Ohio State University (US), Vanderbilt University Medical Center (US), Icahn School of Medicine at Mount Sinai (US)
National Institutes of Health, National Human Genome Research Institute
Good health and well-being
Openalex Percentile: Top 11%
Pharmacogenetics and Drug Metabolism
DOIOpen Access PDFOpenAlex
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