PROJECT SUMMARY: The multicenter PRECISE Analgesia (Prospective Randomized Evaluation of Analgesia for Cardiac and Idiopathic Scoliosis Spine Fusion Elective Surgery in Children) trials will a) implement and in- vestigate the efficacy and safety of multidose methadone-based standardized enhanced recovery after surgery (ERAS) protocol, and b) develop personalized ERAS protocols including precision methadone and oxycodone dosing and personalized analgesia for the safe and effective opioid-sparing management of surgical pain after posterior spine fusion (PSF) and cardiac surgery (CS) in children. PSF and CS are both extremely painful sur- geries in children requiring long hospital stays and high opioid use associated with adverse effects (AEs), high incidence of opioid dependence (OD), and chronic post-surgical pain (CPSP). Post-discharge prescribed oxyco- done is used for >1-2 weeks, and opioid dependence occurs within 5 days in children. 20-50% of children develop CPSP, largely due to severe uncontrolled acute surgical pain, contributing to life-long risks for opioid use/misuse and the ongoing opioid epidemic. There is an urgent need for safe, effective opioid-sparing analgesia as well as proactive risk predictions and personalized analgesia to provide best-in-class immediate surgical pain relief while minimizing the risk of opioid-induced respiratory depression (RD), sedation, postoperative nausea and vomiting (PONV), CPSP and persistent opioid use/misuse. Recently, we showed that a methadone- based standardized ERAS protocol shortened hospital stays (2-4 days), reduced prescribed opioid use (5-7 vs. 7-18 days), and the risks of CPSP. Despite this improvement, with standardized methadone ERAS, 30-40% of children still experi- enced uncontrolled severe pain, PONV, and sedation from methadone and oxycodone. Our preliminary data show that CYP2B6 and ORM1 genotypes and alpha acid glycoprotein (AAG) contribute to the variation in phar- macokinetics (PK), analgesia, and adverse outcomes. Our preliminary data in children undergoing CS with car- dio-pulmonary bypass (CPB) reveal opioid-sparing and safe postoperative analgesia with methadone. We will now study the effect of CPB on intraoperative methadone dosing with robust PK modeling to enable precision methadone dosing for the first time in children. Our expert multidisciplinary team will enroll a total of 1000 children to conduct two parallel randomized clinical trials for PSF (500 children 12-<18 yrs from 4 clinical sites) and CS (500 children 1 month-10 yrs from 5 clinical sites). Specifically, we will 1. Conduct two randomized clinical trials in PSF and CS to compare acute pain relief, opioid-sparing efficacy, and safety of standardized periopera- tive multidose methadone-based ERAS vs. standard-of-care non-methadone-based analgesia. 2. Develop pre- cision methadone dosing based on age, CYP2B6 and ORM1 variants, AAG, and CPB, and 3. Identify patient profiles that predict benefit from the assigned analgesia protocol to optimize clinical outcomes. Overall Impact: Implementation of evidence-based standardized methadone-based ERAS pain management and individualized risk prediction will maximize acute surgical pain relief while minimizing opioid use and AEs in millions of children.

Project Narrative Each year, >5 million American children undergo surgeries including major and painful cardiac surgeries and spine fusion surgeries. More than 50% of these children experience uncontrolled severe acute surgical pain, significant opioid-related adverse outcomes including respiratory depression, persistent opioid use/misuse, opi- oid dependence, overdoses, and deaths, and chronic persistent surgical pain. Implementation of evidence-based standardized perioperative methadone-based multimodal acute surgical pain management in this clinical trial, and proactive and personalized risk identification will maximize acute surgical pain relief while minimizing opioid use, serious opioid-related adverse outcomes, and transition of acute surgical pain to chronic surgical pain in millions of children undergoing major and painful surgeries each year.