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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. An important property of methadone is that its apparent
potency, compared to other opioids, varies with the patient's current
exposure to other opioids. Suggested Dosing Guide for Opioid Tolerant
Patients:
Daily oral morphine dose
equivalents
followed by the
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, it is recommended that the initial dose is
50-75% of the equianalgesic dose.
Summary
| Compared to morphine, methadone is inexpensive, may provide improved
analgesia in neuropathic pain and will provide a longer duration of
action. Dosing intervals at the start of treatment are q 4-6 hours, and
may be increased over time to q 6-12 hours. |
| Methadone is not indicated in poorly controlled pain where rapid
dose adjustments are needed; do not increase oral methadone more
frequently than every 4 days. |
| Dose conversion to and from other opioids and methadone is complex;
consultation with pain management specialists familiar with methadone
use is recommended. |
| Patient and family education is essential as they may misinterpret
prescription of methadone to mean that their physician believes that
they already are an addict. |
References
- Ayonrinde OT, Bridge DT. The rediscovery of methadone
for cancer pain management. Med J Austral. 2000;173:536-40.
- Bruera E, Sweeney C. Methadone use in cancer patients
with pain: A review. J Pall Med. 2002:5(1):127-38.
- Iribarne C, Dreano Y, Bardou LG, et al. Interaction
of methadone with substrates of human hepatic cytochrome P450 3A4.
Toxicology 1997; 117:13-23
- Morley JS, Makin MK. The use of methadone in cancer
pain poorly responsive to other opioids. Pain Rev 1998;5:51-8.
- 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
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