Introduction     Methadone, a potent opioid agonist, has many characteristics that make it useful for the treatment of pain when round-the-clock opioid analgesia is indicated.  Although available for decades, its use has gained renewed interest due to its low cost, inactive metabolites, and many routes of administration.  This Fast Fact will introduce methadone’s pharmacology and clinical use as an analgesic.   

Pharmacology  Unlike morphine, methadone is a racemic mix; one stereoisomer acts as a NMDA receptor antagonist, the other is a mu-opioid receptor agonist. The NMDA mechanism plays an important role in the prevention of opioid tolerance, potentiation of opioid effects. and is the theoretical basis for its use in neuropathic pain syndromes, although this latter impression is largely anecdotal. 

Methadone is highly lipophilic with rapid GI absorption and onset of action.  It has a large initial volume of distribution with slow tissue release.  Oral bioavailability is high, ~ 80%.  Unlike morphine there are no active metabolites and biotransformation to an active drug is not required. The major route of metabolism is hepatic with significant fecal excretion; renal excretion can be enhanced by urine acidification (pH <6.0).   Unlike morphine, no dose adjustment is needed in patients with renal failure since there are no active metabolites.  It is also much less expensive than other opioids, including morphine. 

Prescribing     Methadone is available in tablet, liquid and injectable forms; oral preparations can be used rectally.  Parenteral routes include IV bolus dosing or continuous infusion.  Any clinician with a Schedule II DEA license can prescribe methadone for pain; a special license is only required to prescribe methadone for the treatment of addiction. However, because of its unique pharmacology and potential to prolong the QTc interval, many suggest that its use should be limited to those with significant expertise and experience in managing methadone (e.g., palliative care, pain management, or oncology clinicians). In some jurisdictions, it is necessary to apply the words “for pain” on the prescription. It can be dosed anywhere from once a day to 3 times a day.  Usual doses when initiating methadone are 2.5 to 5 mg by mouth once to twice a day.   

Cautions     Unlike morphine, hydromorphone, or oxycodone, methadone has an extended terminal half-life of up to 190 hours.  This half-life does not match the observed duration of analgesia (6-12 hours) after steady state is reached.  This long half-life can lead to increased risk for sedation and respiratory depression, especially in the elderly or with rapid dose adjustments. Rapid titration guidelines for other opioids do not apply to methadone. Given recent reports that high-dose methadone may be associated with development of QT interval prolongation and Torsades de Pointes, EKG monitoring may be appropriate when changes in dosage are made (depending upon life expectancy and goals of care).   

Pediatrics    With close monitoring by an experienced prescriber, methadone has been used safely in children, although the safety, effectiveness, and the pharmacokinetics of methadone in patients below the age of 18 years have not been established by the Food and Drug Administration. 

Potency     An important property of methadone is that its apparent potency, compared to other opioids, varies with the patient’s current exposure to other opioids. This makes conversions from one opioid to methadone more dangerous and less reliable.  Below for is one suggested dosing guide for opioid tolerant patients (Reference 1).  However, there is a lot of variability in published methadone conversions.  Therefore, when rotating one opioid to methadone, it is vital that clinicians consult with an experienced clinician (e.g., palliative care or pain specialist) and a clinical pharmacist.  

Daily oral morphine dose equivalents         Conversion ratio of oral morphine to oral methadone 

      <100 mg                                                                          3:1 (i.e. 3 mg morphine = 1 mg methadone) 

      101-300 mg                                                                     5:1 

      301-600 mg                                                                   10:1 

      601-800 mg                                                                   12:1 

      801-1000 mg                                                                 15:1 

      >1001 mg                                                                       20:1 

Due to incomplete cross-tolerance, the initial methadone dose is typically 50-75% the equianalgesic dose.   

Key Points 

• Compared to morphine, methadone is inexpensive, safe in renal failure, will provide a longer duration of action, and has a theoretic advantage in complex pain.
• Because of its long and variable elimination half-life methadone is not an ideal opioid when rapid dose adjustments are needed. Do not increase oral methadone more frequently than every 4 days.
• Dose conversion to: from other opioids and methadone is complex and particularly more dangerous than other opioids. Consult a pharmacist and a pain or palliative care specialist.
• Patient and family education is essential as they may misinterpret prescription of methadone to mean that their clinicians believe the patient has an opioid use disorder.    

References 

1. Ayonrinde OT, Bridge DT.  The rediscovery of methadone for cancer pain management.  Med  J Austral.  2000; 173:536-40.
2. Bruera E, Sweeney C.  Methadone use in cancer patients with pain: a review. J Pall Med. 2002; 5(1):127-38.
3. Bruera E, Palmer J, Bosnjak S, et al.  Methadone versus Morphine as a first-line strong opioid for cancer pain:  A randomized double-blind study.  J Clin Oncol. 2004; 22:185-192.
4. Davies D, DeVlaming D, Haines C.  Methadone Analgesia for Children with Advanced Cancer.  Pediatr Blood Cancer 2008; 51:393-397.
5. Fine PG, Portenoy RK, on Evidence AH. Establishing “best practices” for opioid rotation: conclusions of an expert panel. Journal of pain and symptom management. 2009 Sep 1;38(3):418-25.
6. Iribarne C, Dreano Y, Bardou LG, et al. Interaction of methadone with substrates of human hepatic cytochrome P450 3A4. Toxicology. 1997; 117:13-23.
7. Krantz MJ, Lewkowiez L, Hays H, et al.  Torsade de Pointes associated with very-high-dose methadone.  Ann Intern Med. 2002; 137:501-4.
8. Kreutzwiser, D., Tawfic, Q.A. Methadone for Pain Management: A Pharmacotherapeutic Review. CNS Drugs 2020; 34:827–839.
9. McLean S, Twomey F.  Methods of rotation from another strong opioid to methadone for the management of cancer pain:  A systematic review of the available evidence.  Journal of pain and symptom management.  2015; doi:10.1016/j.jpainsymman.2015.02.029.
10. Morley JS, Makin MK.  The use of methadone in cancer pain poorly responsive to other opioids.  Pain Rev. 1998; 5:51-8.
11. Rowbotham MC. The debate over opioids and neuropathic pain. In: Kalso E, McQuay HJ, Wiesenfeld-Hallin Z, eds. Opioid Sensitivity of Chronic Noncancer Pain. (Progress in Pain Research and Management, Vol 14). Seattle, WA: IASP Press; 1999: pp 307-317.
12. Roxane Laboraties.  (2015).  Dolophine (methadone hydrochloride): Highlights of prescribing information.
13. Webster LR, Fine PG.  Review and critique of opioid rotation practices and associated risks of toxicity.  Pain Medicine.  2012; 13: 562-570.

Version History:  This Fast Fact was originally edited by David E Weissman MD. 2nd Edition published July 2006; 3rd Edition June 2015; 4th Edition May 2025.
Conflicts of Interest: None to report.