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.