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Chronic pain: Methadone vs morphine

Morphine and methadone are both opioids used in pediatric pain management. Morphine is more protein bound in adulthood than during the neonatal period (30% vs 20%). Morphine is metabolized to morphine 3-glucoronide and morphine 6-glucoronide. This occurs through sulfation and gluronidation. The enzymes guiding gluronidation are relatively immature in the neonate so preferentially more drug is metabolized by sulfation than gluronidation in the neonate compared to the adult. These enzyme pathways achieve adult levels by 4-6 months of age.

The clearance and elimination or morphine is also age dependent. In general the clearance of morphine is reduced during the neonatal period and increases with increasing age but there is significant inter-individual variability. Some studies suggest the clearance reaches adult values by 2-3 months of age and other studies suggest clearance doesn’t reach adult levels until 6-12 months of age. The half-life of morphine is prolonged in neonates (6-9 hours) and decreases to adult values (2-4 hours) by 3-12 months of age.

Methadone is a synthetic opioid and it has a significantly longer half-life than morphine. It is also more protein bound than morphine in adults (60-90%). Methadone has not been investigated to the same degree as morphine. A study investigating morphine vs methadone for acute postoperative pain in children found the beta-elimination half-life of methadone to be 19 hours +/- 14 hours (averaged over several age groups). This is shorter than the adult half-life, which is 35 hours +/- 22 hours. Typical pediatric dosing of methadone includes a bolus of 0.1-0.2 mg/kg followed by 0.05 mg/kg every 6-8 hours. Methadone is the only opioid with NMDA antagonism and this may be beneficial in patients with chronic pain. Methadone also blocks the delayed rectifier potassium channel and prolongs QT. It should not be used in patients with known prolonged QT. A 12-lead electrocardiogram will identify patients with prolonged QT prior to the administration of methadone.