{
  "abstract": "Background Perioperative pain management in paediatric patients presents unique challenges due to differences in physiology, pain perception, and pharmacokinetics compared to adults. Inadequate pain control can have both immediate and long-term consequences, including delayed recovery, increased risk of chronic pain, and psychological distress. Traditional opioid analgesics, while effective, are associated with significant side effects and risks, such as respiratory depression, opioid-induced hyperalgesia, and the potential for tolerance and dependence. Methadone, a synthetic opioid with a distinctive pharmacological profile, offers a promising alternative or adjunct in this context. Its use in paediatric perioperative settings has been limited but is gaining traction as new evidence emerges. Pharmacological properties of methadone: Methadone distinguishes itself from other opioids through its dual mechanism of action. As a potent μ-opioid receptor agonist, it provides robust analgesia. Simultaneously, its antagonism of the NMDA receptor contributes to reduced central sensitization, inhibition of opioid-induced hyperalgesia, and potential prevention of chronic post-surgical pain. Methadone’s long and variable half-life (ranging from 8 to 59 hours in children, depending on age and individual metabolism) supports sustained analgesic effects, which can be particularly beneficial for procedures associated with significant or prolonged pain. Pharmacokinetically, methadone is highly lipophilic, resulting in extensive tissue distribution and a large volume of distribution. It is metabolized in the liver, primarily by CYP3A4, CYP2B6, and CYP2D6 enzymes, with considerable inter-individual variability. This variability underpins the need for individualized dosing and careful monitoring, especially in paediatric populations, where developmental differences further complicate pharmacokinetics. Rationale for perioperative use in children: The rationale for methadone use in paediatric perioperative care is grounded in its ability to provide prolonged analgesia from a single intraoperative dose, potentially reducing the need for repeated opioid administration and minimizing fluctuations in pain control. Methadone’s NMDA antagonism may also decrease the risk of developing opioid tolerance and opioid-induced hyperalgesia, both of which are significant concerns in children undergoing repeated or extensive surgical interventions. Moreover, the efficacy of methadone in treating neuropathic pain makes it a valuable option for surgeries involving nerve injury or where neuropathic pain components are anticipated, such as spinal fusion, major orthopaedic procedures, or thoracotomies. Clinical evidence: Although the paediatric literature on perioperative methadone is not as extensive as in adults, a growing body of studies supports its utility. Several prospective randomized controlled trials and retrospective cohort studies have evaluated the efficacy and safety of intraoperative methadone in children: - In spinal fusion surgery, single intraoperative doses of methadone (0.2–0.3 mg/kg) have been associated with lower postoperative pain scores, reduced opioid consumption, and decreased need for rescue analgesia compared to morphine or fentanyl. - Studies in paediatric cardiac and abdominal surgery have reported similar findings, with methadone providing prolonged analgesia and improved patient comfort, often with no increase in adverse events when appropriately monitored. - Case series and smaller trials suggest that methadone’s benefits extend to patients with opioid tolerance, where it can help overcome tolerance-related challenges and provide effective pain control Despite these positive findings, the evidence base remains limited by small sample sizes, heterogeneous dosing regimens, and variability in outcome measures. Larger, multicentre trials are needed to confirm these results and develop standardized protocols. Safety profile and risk mitigation: The main safety concerns with methadone in paediatric perioperative care are: - Respiratory depression: the long half-life of methadone increases the risk of delayed respiratory depression, necessitating extended monitoring postoperatively, especially in children with risk factors such as obesity, sleep-disordered breathing, or concurrent sedative use. - QT Interval prolongation: methadone can prolong the QT interval, predisposing to torsades de pointes and other arrhythmias. Baseline and postoperative ECG monitoring are recommended in children with known cardiac disease, electrolyte imbalances, or those on other QT-prolonging drugs. Drug accumulation and interactions: Owing to its hepatic metabolism, the clearance of methadone may be affected by drug interactions (e.g., CYP inhibitors/inducers) and liver dysfunction. Individualized dosing and awareness of potential interactions are critical. Other side effects: Nausea, vomiting, constipation, and pruritus are common to all opioids, including methadone. These are generally managed with standard supportive measures. Overall, when administered by experienced clinicians in a monitored setting, the safety profile of methadone 22is comparable to other opioids, with the added benefit of less frequent dosing. Practical application and dosing strategies: methadone is typically administered as a single intravenous dose at induction of anaesthesia, with suggested doses ranging from 0.1 to 0.3 mg/kg (maximum doses vary by protocol and institutional practice). Lower doses are advisable in younger children or those with risk factors for adverse effects. The timing of administration is usually at induction or early in the procedure to allow for titration and observation of initial effects. Postoperative pain management should continue to incorporate multimodal strategies, including acetaminophen, NSAIDs, and regional anaesthesia where appropriate. The prolonged action of methadone may reduce or eliminate the need for patient-controlled analgesia (PCA) or frequent nurse-administered opioid boluses, streamlining postoperative care and potentially facilitating earlier mobilization and discharge. Patient selection and monitoring: Not all paediatric patients are ideal candidates for perioperative methadone. Careful preoperative assessment is essential, with particular attention to: - Cardiac history and baseline ECG - Respiratory comorbidities (e.g., sleep apnea) - Hepatic and renal function - Concomitant medications (especially those affecting QT interval or methadone metabolism) - Continuous cardiorespiratory monitoring is recommended for at least 24 hours postoperatively in patients receiving methadone, with prompt recognition and management of any adverse effects. Current guidelines and expert consensus: There are currently no universally accepted guidelines for perioperative methadone use in paediatric patients. However, expert panels and institutional protocols increasingly recognize its value in selected cases, particularly for: - Major surgeries with expected severe or prolonged pain - Patients with opioid tolerance or chronic pain syndromes - Cases where conventional opioids have failed or produced unacceptable side effects - Education of the entire perioperative team—including anaesthesiologists, surgeons, nurses, and pharmacists—is vital to ensure safe and effective use. Future directions and research needs: Key areas for future research include: - Large, multicentre randomized controlled trials to establish optimal dosing, efficacy, and safety across diverse paediatric populations and surgical procedures - Pharmacogenomic studies to identify predictors of methadone metabolism and response, enabling personalized medicine approaches - Long-term outcome studies to assess the impact of perioperative methadone on chronic pain development, opioid use patterns, and quality of life - Comparative effectiveness research evaluating methadone against other long-acting opioids and multimodal analgesic strategies Additionally, the development of standardized protocols and consensus guidelines will facilitate broader and safer adoption of methadone in paediatric perioperative care. Conclusions methadone is an underutilized but promising option for perioperative pain management in paediatric patients. Its unique pharmacological profile—combining potent opioid analgesia with NMDA antagonism—offers several potential advantages over conventional opioids, including prolonged pain relief, reduced opioid requirements, and mitigation of opioid-induced hyperalgesia and tolerance. While safety concerns exist, particularly regarding respiratory depression and QT prolongation, these can be managed with careful patient selection, individualized dosing, and vigilant postoperative monitoring. As evidence continues to accumulate, methadone may assume a more prominent role in paediatric anaesthesia, particularly for children undergoing major surgery, those with opioid tolerance, or in cases refractory to standard analgesic regimens. Ongoing research and the development of clear guidelines will be essential to maximize the benefits and minimize the risks associated with its use.References Thigpen JC, Odle BL, Harirforoosh S. 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  "authors": [
    {
      "affiliations": [
        "Anaesthesia, Intensive Care and Pain Medicine, AORN S.Anna e S. Sebastiano – Caserta, Caserta, Italy"
      ],
      "name": "Pasquale De Negri"
    },
    {
      "affiliations": [
        "Anaesthesia, Intensive Care and Pain Medicine, AORN S.Anna e S. Sebastiano – Caserta, Caserta, Italy"
      ],
      "name": "Clara De Negri"
    }
  ],
  "title": "FT06 Methadone for perioperative pain management in paediatric patients",
  "uid": "72aafb1b-8473-5771-b985-bcae4e77478b"
}