68 Opioid Tolerance and Pharmacogenetics in Pediatric Burn Patients

Abstract Introduction Opioids are the predominant analgesic for pediatric burn patients. Burned children are frequently critically ill and require prolonged hospitalization with multiple surgical interventions. Pain associated with burns is severe, and failure to appropriately manage burn pain acutely can lead to long term negative consequences for these children. Prolonged opioid use, however, can lead to tolerance. While tolerance is anecdotally observed to develop at different rates in individual patients, the impact of genetic variability on the rate of development of tolerance is not known. This prospective study assesses the impact of genetic variability on opiate requirement in burned children. Methods A pilot study of pediatric burn patients was performed. Whole exome sequencing was used to evaluate genes involved in the metabolism and response to opioids. Oral morphine equivalents by weight (OME/kg) were calculated by day. Tolerance was determined by evaluating the rate of decline of OME/kg following the final major surgical procedure. Patients in the lowest third for rate of decline of opioid use were compared to other patients. Results Nine pediatric burn patients with median total body surface area of burn of 22% (IQR 12–36) and median age 7 years (IQR 5–13) were analyzed. Significant variability in the rate of decline of OME was observed, ranging from a decline 0.0971 OMEs/kg/day to an incline of 0.0057 OME/kg/day. Patients with a rate of decline in the lower third had a high frequency of missense mutations with predicted functional impact in the mu opioid receptor: 67% had a variant predicted to have functional impact, compared to 50% of patients in the upper two thirds. Two patients overall had missense mutations with predicted functional impact in the delta opioid receptor, with one having more rapidly developed tolerance. Conclusions The rate at which pediatric burn patients develop tolerance is variable. Variants in the mu opioid receptor may contribute to the rate at which patients develop tolerance. The function of many variants identified in this study is unknown, and their contribution to the development of tolerance requires further studies. Large scale studies to evaluate the rate of variants in the population and their relationship to tolerance development are critical to formulate personalized pain management for burned children.