Utilize CYP2D6-Guided Opioid Therapy for Adults with Cancer Pain

Background

More than half of patients with cancer will require opioid analgesic therapy during their treatment to manage moderate to severe pain. Opioids are a first line agent for moderate to severe pain in the oncology patient population. However, roughly one-third of patients with cancer do not achieve adequate pain control. This prompted researchers to further investigate the pharmacogenomic mechanism behind the variable response to opioids and if pharmacogenomics can be used to leverage the variable response patients experience with opioids.

The CYP2D6 enzyme is responsible for converting codeine, tramadol, hydrocodone, and oxycodone into their respective therapeutically active metabolites. The 2020 Clinical Pharmacogenetic Implementation Consortium guideline on the impact of CYP2D6 phenotype and opioid dosing provides specific recommendations for codeine, tramadol, and hydrocodone. However, the guideline cites conflicting clinical data from studies assessing the efficacy and adverse event rates with oxycodone across different CYP2D6 metabolizing phenotypes. The latest guideline does not provide oxycodone dosing recommendations based on phenotype, noting that more and larger studies are needed.

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Methods

The researchers designed a multi-site, prospective, unblinded, hybrid implementation effectiveness trial conducted at the University of Florida Health Cancer Center and Moffit Cancer Center in Tampa, Florida. The only inclusion criteria were that the patients had to be receiving treatment for cancer and had suboptimal pain control. Patients were randomized into 1 of 2 study arms. One arm used CYP2D6 genotyping to guide drug therapy dosing and selection, while the other group represented the “usual care arm,” in which patients underwent pharmacogenomic testing, but the result was not used to guide pain therapy.

Patients in the CYP2D6 genotyping-guided care group had their predicted phenotype converted into a clinical phenotype, taking into account any CYP2D6 inhibitors they were taking. If found to be taking any CYP2D6 strong inhibitors, the patient’s clinical phenotype was classified as a poor metabolizer. Patients taking moderate or weak CYP2D6 inhibitors had their CYP2D6 activity score reduced by 50% to determine their clinical phenotype.

Patients had their pain assessed using the Brief Pain Inventory-Short Form (BPI-SF) questionnaire at baseline and at weeks 2, 4, 6, and 8. The researchers tracked all opioid and non-opioid medications at baseline and throughout the 8-week study period and identified whether correlation existed between pain scoring, opioids used, and CYP2D6 clinical phenotype. The turnaround time was tracked for the buccal cell-derived DNA samples used for genotyping. Documentation in physician notes was used to determine if CYP2D6 genotyping results led to changes in drug therapy.

Results

The study enrolled 87 participants, 75% of whom had metastatic disease. At baseline, 71% of enrolled participants were managing pain with oxycodone, while 40% of study participants were using more than 1 opioid agent. Of those enrolled, 85 patients completed the study, with 38 randomized to the genotyping-guided pain care arm and the other 47 to the usual care arm. The median turnaround time on genotyping was 10 days and 5 out of 38 (13%) of the genotyped-guided care patients required retesting due to failure on genotyping the first sample. After genotyping and taking CYP2D6 inhibitors into account, clinical phenotyping showed that 11 out of 38 (29%) patients had a non-normal and clinically actionable result (poor, intermediate, or ultrarapid clinical phenotype), meaning potentially altered opioid metabolism and either inadequate pain control or increased risk of side effects at standard dosing.

Genotyping results were only referenced in 9 of 38 (24%) of the notes for patients with CYP2D6 genotyping. Only 2 out of 11 (18%) had a drug therapy change in concordance with CYP2D6-guided recommendations. When compared to baseline pain scores, both treatment arms saw reduction in the patient-reported pain scoring at week 8, but there was no statistically significant difference between groups. The researchers also found no difference in baseline pain scoring when looking across the different CYP2D6 phenotypes for patients taking oxycodone.

Discussion and Conclusions

There are several key takeaways from this study. First, it emphasizes the importance of having providers and pharmacists trained in interpreting and utilizing pharmacogenomic results, as very few cancer patients with clinically actionable CYP2D6 phenotypes had changes made to their pain medication regimen. The researchers noted the importance of having efficient clinical decision support and how automated clinical decision support at the point of prescribing would likely help increase provider utilization of pharmacogenomic results.

Additionally, this study provides more clinical data on the lack of a clear association between CYP2D6 phenotype and clinical response to oxycodone, despite CYP2D6 activating oxycodone to the more therapeutically active compound oxymorphone. In addition, the study showed that using buccal swabs to obtain DNA for genotyping led to delays in CYP2D6 results being obtained and utilized, as retesting had to be done for several patients. Other studies have shown DNA obtained from blood samples for pharmacogenomic testing is less likely to require retesting compared to saliva or buccal cell derived samples.

Reference

Mosley SA, Cicali E, Del Cueto A, et al. CYP2D6- guided opioid therapy for adults with cancer pain: A randomized implementation clinical trial. Pharmacotherapy. 2023;43:1286-1296. doi:10.1002/phar.2875