Anaes · Anaesthetic adjuncts

Methadone

Also known as Synthetic diphenylpropylamine opioid · Long-acting mu agonist with NMDA antagonism · Racemic dual-mechanism opioid

Methadone is a synthetic DIPHENYLPROPYLAMINE opioid — chemically distinct from both the phenanthrenes (morphine) and the phenylpiperidines (fentanyl). It is supplied as a RACEMIC mixture: the R-enantiomer is a full mu-opioid agonist responsible for analgesia, while the S-enantiomer is a non-competitive NMDA antagonist that confers methadone's unique anti-hyperalgesic and anti-tolerance properties. Methadone also weakly inhibits serotonin and norepinephrine reuptake. Its pharmacokinetics are extraordinary and exam-critical: excellent and reliable oral bioavailability (40 to 100 per cent, mean about 80), high plasma protein binding to alpha-1-acid glycoprotein (85 to 90 per cent), a large volume of distribution (3 to 5 L/kg), hepatic metabolism by CYP3A4 and CYP2B6 (NOT CYP2D6) to inactive metabolites, slow clearance (1 to 7 mL/kg/min), and an EXTREMELY LONG and HIGHLY VARIABLE elimination half-life of 8 to 59 hours (mean about 24). This half-life far exceeds the analgesic duration of 4 to 8 hours, so repeated dosing produces ACCUMULATION and DELAYED RESPIRATORY DEPRESSION — the cardinal danger. Methadone blocks the hERG potassium channel, causing QT prolongation and a dose-dependent risk of TORSADES DE POINTES that demands ECG monitoring. Its three roles are opioid maintenance therapy for opioid use disorder (where the long half-life is an asset permitting once-daily dosing), chronic and cancer pain (especially neuropathic or opioid-tolerant, where NMDA antagonism is an advantage), and an emerging perioperative role as a single intraoperative dose of 0.1 to 0.2 mg/kg that provides 24 to 48 hours of analgesia and reduces PCA opioid consumption (Murphy cardiac-surgery trials). Built on the Kreutzwiser pharmacotherapeutic review (2020), the Murphy intraoperative-methadone cardiac-surgery trials (2015, 2020), the Mercadante opioid-conversion systematic review (2011), the El Sherbini hERG/sudden-cardiac-death review (2024), the Miller and Palix methadone maintenance studies (2026), and the Nunez-Rodriguez and Evaldsson perioperative respiratory-depression protocols (2025, 2026).