Fast Fact and Concept #75: Methadone for Pain

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Title: Fast Fact and Concept #75: Methadone for Pain

Author(s): G Gazelle; PG Fine

Methadone, a potent opioid agonist, has many characteristics that make it useful for the treatment of pain when continuous opioid analgesia is indicated. Although available for decades, its use has gained renewed interest due to its low cost and potential activity in neuropathic pain syndromes. Unlike morphine, methadone is a racemic mix; one stereoisomer acts as a NMDA receptor antagonist, the other is a mu-agonist opioid. The NMDA mechanism plays an important role in the prevention of opioid tolerance, potentiation of opioid effects, and efficacy for neuropathic pain syndromes, although this latter impression is largely anecdotal.

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. In some jurisdictions, it is necessary to apply the words "for pain" on the prescription. 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; 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. Methadone is available in tablet, liquid and injectable forms; oral preparations can be used rectally. Parenteral routes include IV bolus dosing or continuous infusion.

Unlike morphine, hydromorphone or oxycodone, methadone has an extended terminal half-life, 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 methodone MAY be associated with development of Torsades, depending upon life expectancy and goals of care, EKG monitoring may be appropriate when changes in dosage are made. An important property of methadone is that its apparent potency, compared to other opioids, varies with the patient's current exposure to other opioids.

The chart below indicates the
Daily Oral Morphine Dose Equivalents
followed by the
Conversion Ratio of Oral Morphine to Oral Methadone

Due to incomplete cross-tolerance, it is recommended that the initial dose is 50-75% of the equianalgesic dose.


Also see:
Fast Fact #36, Calculating Opioid Dose Conversions
Fast Fact #86, Methadone: Starting dose information

  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. Iribarne C, Dreano Y, Bardou LG, et al. Interaction of methadone with substrates of human hepatic cytochrome P450 3A4. Toxicology 1997; 117:13-23
  4. Morley JS, Makin MK. The use of methadone in cancer pain poorly responsive to other opioids. Pain Rev 1998;5:51-8.
  5. 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, 1999, Seattle, IASP Press, pp 307-317.

Copyright and Referencing Information: Users are free to download and distribute Fast Facts for educational purposes only. Citation for referencing. Fast Facts and Concepts #75 Methadone for the treatment of pain. G Gazelle and PG Fine. September 2002. End-of-Life Physician Education Resource Center www.eperc.mcw.edu

Fast Facts and Concepts was originally developed as an end-of-life teaching tool by Eric Warm, MD, U. Cincinnati, Department of Medicine. See: Warm, E. Improving EOL care--internal medicine curriculum project. J Pall Med 1999; 2: 339-340.

Disclaimer: Fast Facts provide educational information, this information is not medical advice. Health care providers should exercise their own independent clinical judgment. Some Fast Fact information cites the use of a product in dosage, for an indication, or in a manner other than that recommended in the product labeling. Accordingly, the official prescribing information should be consulted before any such product is used.

Creation Date: 9/2002

Format: Handouts

Purpose: Instructional Aid, Self-Study Guide, Teaching

Training: Fellows, 3rd/4th Year Medical Students, PGY1 (Interns), PGY2-6, Physicians in Practice
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Non-Physician: Nurses

ACGME Competencies: Medical Knowledge, Patient Care

Keyword(s): Addiction, Chronic non-malignant pain, Controlled substance regulations, Pain, Pain assessment, Pain treatment

The Fast Facts series is distributed for educational use only and does not constitute medical advice. For the most current version of Fast Facts visit the EPERC web site at www.eperc.mcw.edu. This mirror version is provided subject to copyright restrictions for educational use within the Inter-Instutional Collaborating Network on End-of-Life Care (IICN).