The multicenter PRECISE Analgesia (Prospective Randomized Evaluation of Analgesia for Idiopathic Scoliosis Spine Fusion Elective Surgery in Children) trials will a) implement and investigate 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 c) personalized analgesia for the safe and effective opioid-sparing management of surgical pain after posterior spine fusion (PSF) in children.

SPECIFIC AIMS. The multicenter PRECISE Analgesia (Prospective Randomized Evaluation of Analgesia for Idiopathic Scoliosis Spine Fusion Elective Surgery in Children) trials will a) implement and investigate 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 c) personalized analgesia for the safe and effective opioid-sparing management of surgical pain after posterior spine fusion (PSF) in children.

The long-term goal is to proactively improve the safety and efficacy of surgical pain control while reducing opioid AEs and the opioid epidemic burden in all children undergoing inpatient surgeries. The central hypothesis is that a standardized, multidose, methadone-based ERAS protocol will reduce acute surgical pain, overall opioid use, RD, PONV, and CPSP compared with standard-of-care short-acting opioid-based analgesia in children undergoing PSF (Aim 1). Investigators will use PK and genetic variations along with clinical factors to develop optimal intra- and post-operative methadone dosing in children to enable precision analgesia in the future (Aim 2). Finally, Investigators will identify patient profiles with genetic, epigenetic, PK, clinical, and psychological factors to predict benefit from assigned analgesia for optimal clinical outcomes (Aim 3). The expert multidisciplinary and multicenter team will enroll a total of 1000 children to conduct a randomized clinical trial for PSF (500 children 10-<18 yrs from 4 clinical sites). In this study, specifically, Investigators will:

Aim 1. Conduct a randomized clinical trial in PSF to compare acute pain relief, opioid-sparing efficacy, and safety of standardized perioperative multidose methadone-based ERAS vs. standard-of-care non-methadone-based analgesia. Acute surgical pain, opioid needs (morphine equivalents), RD, PONV, and CPSP will be lower in methadone-based analgesia compared to short-acting opioid-based analgesia.

Aim 2. Develop precision methadone dosing based on age, CYP2B6 and ORM1 variants, and AAG. Age, CYP2B6 and ORM1 variants, AAG levels, and will explain methadone's PK variability and dose adjustments that correlate with optimal clinical outcomes among 500 children receiving methadone.

Aim 3. Identify patient profiles that predict benefits from the assigned analgesia protocol to optimize clinical outcomes. Personalized risk prediction models will be developed and validated including genetic variants (i.e., CYP2B6, CYP2D6, ABCB1, OPRM1, and FAAH), and psychological and clinical factors to predict benefit with the assigned treatments (methadone or non-methadone) for pre-specified clinical endpoints (i.e., lower acute surgical pain, RD, PONV, OD, and CPSP) in PSF.

Overall Impact: Develop actionable evidence for the efficacy of standardized, multidose, methadone-based ERAS protocols and will harness genetic, clinical, and psychological factors contributing to variability in methadone and oxycodone PK, acute surgical pain, transition to CPSP, opioid-induced PONV, RD, and dependence to develop personalized analgesia strategy and dosing for children undergoing PSF. 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.

Inclusion Criteria:

1. Age 10 - < 18 years
2. American Society of Anesthesiologists (ASA) Physical Status 1 or 2
3. Undergoing PSF for idiopathic scoliosis
4. Participant or legal guardian can speak and read English or Spanish

Exclusion Criteria:

1. Pregnant patients
2. Methadone allergy
3. Preoperative prolonged QTc more than 460 msec (-30 days to 0 day)
4. Subjects undergoing concomitant treatment with known cytochrome P450 inhibitors included in methadone labeling (i.e. macrolides (e.g. erythromycin), azole-antifungal agents (e.g. ketoconazole, voriconazole), protease inhibitors (e.g. ritonavir), fluconazole, SSRIs (e.g. sertraline, fluvoxamine)
5. Preoperative opioid use within 30 days before surgery
6. History of severe sleep apnea, defined as a prior sleep study demonstrating an apnea-hypopnea index (AHI) greater than 10.
7. Significant liver, kidney, neurological disease, developmental delay, or any other co-existing medical condition per discretion of the clinical investigator

Identifiable data and specimens will be shared with the sponsor of the study. The investigators and study team will comply with all the NIH's Public Access and Data Sharing requirements including Release of Publications and Sharing of Underlying Primary Data. Release of Publications: The investigators will publish their results in open access journals for broad and free availability immediately without any embargo period. Electronic copies of publications will be deposited within four weeks of acceptance by a journal in PubMed Central with proper metadata to be made discoverable and accessible upon publication.

Time frame is within 5-years of study completion.

Online collaborative tools to facilitate data sharing such as SharePoint or Xythos