PROJECT SUMMARY/ABSTRACT Safe and effective analgesia after surgery is a paramount yet unmet medical need in children, and poorly treated pediatric pain remains a persistent and significant public health concern. For moderate to severe acute postoperative pain, opioids remain the mainstay and most efficacious systemic pharmacologic therapy. However, adequate age-specific pediatric pain treatment is limited by insufficient understanding of the dose-dependent clinical effects of even widely available opioid analgesics. Every day, anesthesiologists and surgeons who care for children are forced to navigate these knowledge gaps – to ensure adequate pain relief while balancing concerns for opioid side effects and harms, patient and parental satisfaction, adherence to practice guidelines, and compliance with legislative statutes that restrict opioid prescribing. The challenge to determine the optimal analgesic regimen after pediatric surgery is particularly critical for the 500,000 children who undergo tonsillectomy annually. Tonsillectomy is the most common painful elective procedure in children, yet analgesic management after surgery remains inadequate, insufficient, and without consensus. Specifically, opioid prescribing practices after tonsillectomy are highly variable, largely dependent on individual surgeons, and susceptible to both over- and under-prescribing in an era when opioids have become a major public health concern. We must do better. A recent paradigm shift in perioperative opioid use in adult surgical patients – the use of long-acting (methadone) over short-acting opioids – has successfully diminished acute and chronic postoperative pain and enabled less post-discharge opioid prescribing. Methadone, and its superior pharmacologic properties, fulfills the therapeutic goal to better match the duration of analgesia to duration of pain. Nonetheless, despite well-established benefits as a highly effective perioperative analgesic in adults, methadone use to treat surgical pain in children has been limited to major inpatient procedures and hampered by the lack of robust clinical data. Our proposal will address the urgent need to determine the optimal age- specific, weight-based dose of intraoperative methadone for outpatient tonsillectomy in children in order to improve analgesic outcomes and decrease the need for postoperative take-home opioids. We propose a single center, randomized, double-blind, parallel-group, dose-finding trial of single-dose intraoperative intravenous (IV) methadone compared with short-acting opioids in 396 children in three age-matched cohorts. We will 1) determine the optimal age-specific intraoperative dose of IV methadone in pediatric tonsillectomy that results in less postoperative pain and opioid use compared with short-acting opioids, and 2) assess the impact of long- versus short-acting intraoperative opioid on post-tonsillectomy recovery outcomes. After study completion, we expect to have enriched the understan...