Opioids such as tramadol, hydrocodone, and oxycodone are widely used for postoperative pain management and need metabolism by the cytochrome P450 2D6 (CYP2D6) enzyme to form their active compounds. Around 15% of individuals have reduced or absent this enzyme activity and are classified as poor or intermediate metabolizers. This can result in lower levels of active metabolites and potentially inadequate pain relief. Certain medications, such as paroxetine and fluoxetine, further inhibit the activity of the CYP2D6 enzyme through phenoconversion. In contrast, about 3% of individuals are ultra-rapid metabolizers, rising the risk of toxicity. A previous pilot study showed reduced opioid use without worsening pain when CYP2D6-guided prescribing avoided specific opioid medications. Larisa H Cavallari et al. conducted the ADOPT PGx acute pain clinical trial to evaluate this strategy’s impact on post-operative pain control as well as opioid exposure.
This multicenter, open-label, prospective, and randomized clinical study was conducted across eight US health care systems from March 2021 to September 2023. A total of 1,602 patients aged ≥8 years who underwent surgery with expected postoperative pain were enrolled. Patients with chronic opioid users were excluded from this study. Of the 1602, 351 participants (mean age = 62±13 years, female = 68%, male = 32%, Black/African American = 14%, White/European American = 78%) were identified as CYP2D6 intermediate/poor metabolizers and comprised the actionable population. These participants were randomized 1:1 to immediate pharmacogenetic testing with CYP2D6-guided opioid recommendations (n = 176) or control/usual care (n = 175).
The primary outcome was the 10-day Silverman integrated analgesic assessment (SIA) score, which combines opioid use (morphine mg equivalents) and pain intensity. Secondary outcomes were opioid exposure, phenotype-concordant medications, well-being, pain measures, and mobility. Participants were followed for 6 months (till March 2024). These outcomes were analyzed by using statistical methods like the Wilcoxon tests, t-tests, and the Fisher exact or χ2 test.
Total hip (28%) and total knee (50%) arthroplasties were the most common surgeries among the actionable population. Phenotype-concordant prescribing was significantly higher with CYP2D6 guidance compared to the control group (64% vs 27%) with a difference of 37% points (95% confidence interval [CI]: 27-46) and p <0.001. SIA scores were available for 91% of participants in the guided group and 87% in the control group. There was no statistical significant difference was observed in mean 10-day SIA scores between groups (1.4 [95.9] vs -1.4[93.1]) with difference of 2.8 (95% CI: -1.83 to 23.8) and p = 0.80 nor at one month of follow-up period (2.6 [91.8] vs -2.7[98.8]) with difference of 5.2 (95% CI: -15.7 to 26.2) and p = 0.62.
Secondary outcomes, including numeric pain scores (5.2 vs 5.1) and opioid use (13.7 vs 13.2 MME/day), were similar between groups. Additionally, the SIA score did not show any statistically significant differences between groups during the non-oxycodone subgroup (p = 0.35), the non-actionable population (p = 0.28), and adjusted analyses (p = 0.71). Although oxycodone users had a higher SIA score overall, no significant interaction (p = 0.81) was observed. There were no study-related adverse events reported.
This study/s limitations include its pragmatic design with prescriber autonomy, lower than expected concordance, assumptions about CYP2D6 inhibition, missing outcome data, high variability in SIA scores, and evolving multimodal nonopioid pain management practices.
In conclusion, this study found that CYP2D6-guided prescribing significantly changed the postoperative opioid selection but did not improve pain control or reduce opioid use. These findings do not support routine implementation of CYP2D6-guided therapy in modern multimodal postoperative pain management.
Reference: Cavallari LH, Myers RA, Chakraborty H, et al. CYP2D6-Guided Opioid Management and Postoperative Pain Control: A Randomized Clinical Trial. JAMA Netw Open. 2026;9(2):e2558299. doi:10.1001/jamanetworkopen.2025.58299
