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EPERC Fast Fact and Concept #75:
Methadone for Pain
Authors: 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. 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. |
Methadone is an effective opioid analgesic for
severe pain. Because of low cost
(a month supply may be US$ 5-10) and
apparent efficacy in complex pain syndromes, it is increasingly used as a
first-line opioid. It is, in effect, a combination drug - part opioid and
part NMDA receptor antagonist. Methods of dose conversion to methadone
from other opioid analgesics that account for this dual action were
discussed in FF# 75. This Fast Fact will describe strategies for beginning
methadone when the patient has not been taking a strong opioid. Note: due
to its complex pharmacology, physicians unfamiliar with methadone are
advised to seek consultation prior to initiating therapy.
Methadone is lipophilic, thus it takes time to develop tissue stores that
maintain serum levels. Note: There is enormous inter-individual variation.
After a single dose there is a short distribution phase (associated with
acute pain relief) with half-life of 2-3 hours and a slow elimination
phase (half-life 15-60 hours). Dosing must account for the accumulation of
drug over days. It is this accumulation that accounts for most therapeutic
misadventures. Liver metabolites are inactive; therefore no dose reduction
is required with renal failure. After steady-state is reached, about
two-thirds of patients will get adequate pain relief maintained with twice
a day (bid) dosing. Note: a number of drugs will alter methadone
metabolism, there needs to be close follow-up and attention to the
addition or subtraction of interacting medications.
There are several approaches to starting methadone for the treatment of
pain. All take into account the long-half life of the drug that leads to
drug accumulation over days. The following discussion presents approaches
based on the literature and the authors? clinical experiences.
Conservative Approach
Begin fixed dose methadone 5 or 10 mg orally bid or tid for 4-7 days.
If incomplete pain relief, increase the dose by 50% and continue for 4-7
days.
Continue increasing dose every 4-7 days until stable pain relief achieved.
Breakthrough pain: use an alternative short acting oral opioid with short
half-life (e.g. morphine 10 mg) every 1 h prn for breakthrough pain and to
provide pain relief during titration phase.
Loading Dose Approach
Load: Start methadone at fixed oral dose (e.g. 5 or 10 mg) q 4h prn only.
Calculate Maintenance: On day 8, calculate the total methadone dosage
taken over last 24 h period and give in divided doses bid or tid. Give 10%
of total daily methadone as prn drug q1h for breakthrough pain. Instruct
the patient to call you if they need to use more than 5 breakthrough doses
per day.
Conversion to Methadone From Another Strong Opioid
Calculate Total Methadone Dose (for conversion information, see FF# 75).
Convert step wise in order to detect if the patient demonstrates a
therapeutic response to a much lower dose of methadone that you had
expected.
Day 1: Replace 1/3 of opioid dose with oral methadone on bid or tid
schedule
Day 2: Replace next 1/3 of opioid dose.
Day 3: Complete change to methadone.
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.
- Bruera E, Sweeney. Methadone use in cancer patients
with pain: a review. J Pall Med 2002; 5:127-138.
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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