Project Summary: Perioperative opioid adverse effects--from common but less-serious post-operative nausea and vomiting to the more serious respiratory depression and death—are current but preventable challenges in managing surgical pain. Severe surgical pain is still poorly managed, yet clinicians must also avoid unpredictable and life-threatening opioid adverse effects as well as long-term opioid use/misuse. This application innovatively proposes to translate evidence into a proactive clinical practice to optimize post- surgical pain control and decrease opioid-related adverse effects. Current evidence shows that opioid me- tabolism, opioids’ analgesic and adverse effects are influenced by genetic variations. The FDA warns against the use of codeine and tramadol in children (due to postoperative anoxic brain injuries and deaths) and in nursing mothers (due to serious breathing problems and infantile death). Preoperative genotyping and personalized analgesia are not practiced despite evidence, regulatory warnings, CPIC guidelines, cost- effectiveness and insurance coverage for CYP2D6 testing due to translational bottlenecks, lack of infra- structure and knowledge gaps in how to personalize opioid use and dose precisely for optimal outcomes. Thus, there is an urgent and unmet critical need for a perioperative precision analgesia infrastructure to overcome the translational barriers and to improve safety and effectiveness of opioids in children and nurs- ing mothers. Personalizing analgesia based on genetic risks will reduce opioid use, adverse-effects, and accelerate value-based care opportunities. However, these opportunities are constrained by lack of trans- lational platforms and major gaps in our understanding of how to personalize and precisely dose opioids. In this collaborative CTSA project, we propose to overcome the translational barriers by developing an inno- vative perioperative precision analgesia platform (PPAP) to reduce serious adverse outcomes of opioids, and improve safety of opioids in: 1) children undergoing painful surgery, and 2) nursing mothers and their infants. We have robust evidence and implementation expertise on genetic risk factors including CYP2D6 and other genetic variations for opioids’ analgesic efficacy and opioid-related serious adverse effects, meth- ods of implementation of genotypes with clinical decision support in electronic health records, genotype- based perioperative opioid use and innovative digital tools for electronic patient reported outcomes at all participating CTSA hubs. This application with innovative preoperative genotyping, integrated personalized decision support aims to enhance understanding of opioid metabolism, personalized opioid selection, pre- cision dosing, and clinical outcomes in neonates, children, and nursing mothers, and to disseminate findings to other CTSA hubs. A unified CTSA-wide PPAP will enable genetic risk predictions and personalized in- terventions to maximize pain relief while minimizing opioid use and adverse effects in millions of children and nursing mothers undergoing surgery each year.

Project Narrative The proposed precision perioperative analgesia platform and two case studies in children undergoing major surgery as well as nursing mothers following cesarean delivery in five CTSA hubs have transformative public health relevance. This collaborative CTSA application will overcome barriers in translating precision medicine evidence to perioperative practice settings as well as achieve the best-in-class post-surgical pain and opioid- related outcomes in millions of children undergoing painful surgeries and women undergoing cesarean delivery every year, by proactively identifying patients at risk for opioid-related serious adverse effects, risk of persistent surgical pain and opioid dependence, and personalizing opioid use with precision dosing.