862 Challenges and Lessons Learned from Opioid Pharmacogenetic Studies in Burn Patients

Abstract

Abstract Introduction ”One-size fits all” opioid dosing often results in a lack of efficacy or toxic consequences. Patients are heterogeneous; their drug sensitivity varies, potentially impacting therapeutic outcomes. Implementation of pharmacogenetic testing in the clinical setting is needed to improve precision dosing, especially in the critically ill (e.g. burns). However, due to the lack of comprehensive data addressing the functional impact of genetic variants, universal implementation of genetic screening is not yet possible. While animal models provide valuable data, they do not capture the vast heterogeneity and comorbidities of patients. Clinical pharmacogenetic studies are needed to advance our understanding of genetic variability and clinical impacts on opioid efficacy. The purpose of this report is to describe the challenges of clinical opioid pharmacogenetic studies in burn patients. Methods We performed two studies: 1) a pilot study evaluating CYP gene haplotypes in 13 adult burn patients receiving fentanyl using remnant samples and 2) a pediatric burn patient fentanyl pharmacogenetic study. In the pediatric study, we initially screened with a customized 18 gene panel (opioid pathway specific), and later expanded to whole exome analysis. Results We identified 3 adult slow-metabolizers, one with a CYP3A4 and two with CYP2D6 haplotypes and an average of 80+ variants identified in the 18 genes in preliminary analysis of pediatric patients. Multiple challenges were identified in conducting clinical observational studies. Although remnant samples can be hypothesis-generating, clinical data linkage is limited, decreasing the ability for covariate analysis to investigate clinical factors contributing to altered fentanyl metabolism. The use of a commercial haplotype panel, while convenient, only identifies known haplotypes and doesn’t identify all variants in patients. Research protocols must be tailored to clinical workflow. Repeated dosing of fentanyl, which is standard of care but may not be detailed in medical record charting, predisposes research analysis to inaccuracies. Sparse blood sampling, errors in blood draw methodology and loss of vascular access, particularly in pediatrics, can render data sets unanalyzable. Conclusions While we have faced many challenges, overall, these studies have produced valuable data to enable better future clinical research design. Educating bedside nurses on study goals, teaching investigators about clinical workflow, and trouble-shooting proper sample collection and charting are essential elements of a successful study. Finally, minimizing sample volume and optimizing sample time points allows for better study adherence and more accurate analysis. Applicability of Research to Practice Lessons learned from these studies will aid in the optimization of study design of future burns pharmacogenetic clinical studies.