Introduced in the 1940s, Methadone is one of the longest acting μ-opioid receptor analgesics and is unique among clinically used opioids due to its racemic formulation. It has found wide clinical use as a long-acting analgesic, especially in advanced cancer pain, as well as in the treatment of Opioid Use Disorder (OUD).

Mechanism of Action

  • (l) isomer is a potent μ-receptor agonist.
  • (d) isomer acts to block NMDA receptors plus serotonin and NE reuptake. 
  • It has antinociceptive properties not found in other opioids.
Clinical Use: 


  • Pain associated with advancing cancer or terminal illness
  • Chronic pain unrelieved by other analgesic – behavioral strategies
  • Opioid Withdrawal
  • Medication Assisted Therapy (MAT) in the treatment of OUD​

Clinical Recommendations

Large patient variability in Bioavailability, Binding and Metabolism (half-life 13 - 100 hr) Prescribe with caution. Seek consultation early if unfamiliar. Following initial dose(s) (loading period) maintenance dose may be lower. Close monitoring and dose adjustments are required.


Analgesia: (oral, iv) Peak effect 2 hr after oral: Peak effect 15-20 min after iv administration. Administered every 8 hr. Convert from 24 hr oral morphine requirements, consider 50% reduction as starting dose. Limit initial 24 hr oral dosing not to exceed 60mg / day when methadone naïve. Any provider can prescribe methadone for analgesia.

MOUD (oral) Maintain once-daily requirement (30-100+mg daily), Provider licensure for outpatient induction and maintenance for OUD.

Special Considerations: 

Side Effects

  • Sedation 
  • Respiratory Depression
  • Confusion – Altered Mental Status
  • Nausea / Vomiting
  • Constipation
  • Urinary Retention
  • Arrhythmia


  • Prolonged QTc 
  • Hepatic failure 
  • OSA / Central Sleep Apnea / COPD

Davis MP, Walsh D: Methadone for relief of cancer pain: A review of pharmacokinetics, pharmacodynamics, drug interactions and protocols of administration. Support Care Cancer 2001;9:73.

Toombs, JD and Kral, LA: Methadone treatment for pain states. Am Fam Physician 2005 1;71(7):1353-8.