Papers of the Week

Response to analgesic therapy is influenced by several factors including genetics and drug-drug interactions. Pharmacogenetic (PGx) variants in the CYP2D6 gene modify response to opioids by altering drug metabolism. We sought to determine the potential impact of PGx testing on the care of Veterans with noncancer pain prescribed opioids metabolized by CYP2D6 (codeine, hydrocodone, or tramadol). A retrospective analysis was performed within the Veterans Health Administration (VHA) evaluating prescription records for pain medications metabolized by CYP2D6 and interacting drugs from 2012-2017. Among 2,436,654 VHA pharmacy users with at least one opioid prescription, 34% met the definition of chronic use (longer than 90 days with more than 10 prescriptions or 120 days- supply). Opioids were commonly co-prescribed with antidepressants interacting with CYP2D6 (28%). An estimated 21.6% (n=526,905) of these patients are at elevated risk of an undesirable response to their opioid medication based on predicted phenotypes and drug-drug interactions: 3.5% are predicted CYP2D6 ultrarapid metabolizers and at increased risk for toxicity, 5.4% are poor metabolizer at higher risk for nonresponse, and 12.8% are normal or intermediate metabolizers co-prescribed a CYP2D6 inhibitor leading to phenoconversion into poor metabolizer. Despite the high rate of co-prescription of opioids and interacting drugs, CYP2D6 testing was infrequent in the sample (0.02%) and chart review suggest that test results were used to optimize antidepressant treatments rather than pain medications. Using pharmacogenetic testing combined with consideration of phenoconversion may allow for an enhanced precision medicine approach to pain management in Veterans.