Personalized Perioperative Opioid Strategies in Children: Focus on Methadone, Pharmacogenomics and Prevention of Persistent Postoperative Opioid Use

Persistent postoperative opioid use (PPOU) is an emerging challenge in pediatric perioperative care, with rates as high as 4.7% in opioid-naive adolescents. Despite advances in multimodal analgesia, current protocols often fail to prevent long-term opioid exposure, particularly after high-risk surgeries such as spinal fusions. While multiple strategies exist to reduce PPOU in children, including regional anesthesia and non-opioid analgesics, this review specifically focuses on methadone and pharmacogenomic-guided opioid prescribing as promising approaches. Methadone, a long-acting opioid with mu-opioid agonism, NMDA antagonism, and monoamine reuptake inhibition, has shown encouraging outcomes in adult and emerging pediatric studies but remains underutilized due to concerns over safety, variability, and familiarity. This narrative review explores the intersection of methadone pharmacology, pharmacogenomic (PGx)-guided opioid prescribing, and their potential to reduce PPOU and optimize perioperative pain control in children. We examine methadone's unique pharmacokinetic profile, extended half-life, and ability to reduce central sensitization and opioid tolerance. Data from pediatric trials in cardiac, spinal, and major abdominal surgeries are reviewed, highlighting methadone's potential to lower total opioid use, stabilize postoperative pain trajectories, and improve recovery. The review also discusses the role of PGx testing, particularly CYP2D6, CYP3A4, UGT2B7, and OPRM1 variants, in tailoring methadone dosing to individual metabolic profiles, reducing adverse effects, and improving analgesic efficacy. There are no well accepted generalizable perioperative methadone dose, number of doses and dosing intervals due to limited large multicenter studies in children. We outline challenges, including QTc prolongation, dosing variability, lack of pediatric-specific PGx guidelines, and ethical considerations around genetic testing in minors. The review calls for multidisciplinary perioperative teams, expanded PGx implementation, and real-world data from registries and AI-integrated models to support precision opioid strategies. Preventing PPOU in children is critical. Integration of methadone-based multimodal analgesia in high-risk painful in-patient procedures and future integration of PGx represent positive steps toward personalized, effective, and safer pain management in pediatric surgical patients, an urgent need as opioid stewardship becomes a clinical and public health imperative.