Methadone is an important analgesic in cancer pain management as underscored by these developments:
(1) a systematic review of 35 years of evidence has confirmed that methadone is safe and effective as an analgesic for cancer pain (see abstract);
(2) in the last 5 years, there is evidence of an increase in the number of methadone prescriptions for cancer pain in the US and among palliative care physicians in the UK; and
(3) in the last 10 years, case reports, surveys and reviews have demonstrated the unique and favorable analgesic properties of methadone in treating cancer-related pain (see abstracts);
Professor Eduardo Bruera, an internationally respected expert in clinical oncology and palliative medicine, reviews the clinical merits of methadone, the advantages and challenges of switching from other opioids to methadone, and the appropriateness of using methadone as a first-line opioid for cancer pain.

--Sophie M. Colleau, PhD

An interview with Professor Eduardo Bruera *

* Eduardo Bruera is Professor of Medicine, Chair of the Department of Palliative Care & Rehabilitation Medicine, and Clinical Medical Director of the Palliative Care & Rehabilitation Medicine Center, the University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA.

Q: What type of pain is most responsive to methadone?
A: Methadone is indicated for the relief of moderate to severe cancer pain, including nociceptive and neuropathic pain. Methadone is an attractive option when pain fails to respond to other opioids, when patients develop toxicity with other opioids or tolerate other opioids poorly.

Q: Are the analgesic mechanisms of methadone different from other opioids?
A: Methadone shares properties of other opioids and has a few unique properties. Along with morphine, fentanyl and hydromorphone, methadone is a Mu receptor agonist. Methadone is also uniquely a Delta receptor agonist, and an antagonist at the NMDA receptors. These characteristics may explain why patients treated with methadone require a lesser escalation in dosage compared with patients given morphine.

Q: What are the advantages of methadone as an analgesic for the prescriber?
Methadone is available in tablet, liquid, powder and injectable forms for oral, rectal, sublingual or intravenous use. Unlike codeine, morphine, hydromorphone or oxycodone, methadone has no active metabolites and is therefore a good choice for patients at risk for toxicity from metabolite accumulation. Methadone has excellent oral and rectal absorption, and can be safely administered in patients with renal failure. In addition, methadone's long duration of analgesia with chronic use allows less frequent dosing than with other opioids, so it is especially useful when a patient requires continuous opioid analgesia without frequent dose adjustments.

Q: What are the advantages of methadone for patients and healthcare organizations?
A: Methadone is synthetic and easily manufactured. It is one-tenth the cost of other opioids making methadone attractive for cancer pain patients in any setting where access to pain medicines is based on the ability of a person to pay for them.

Q: Are there any data on how often clinicians use methadone in palliative medicine today?
A: In a study of opioid prescribing at MD Anderson Cancer Center, we found that the number of outpatient methadone prescriptions increased 12-fold over a 3 year period. In the UK, 89% of palliative medicine physicians surveyed reported using methadone for pain management [see abstract]. However, worldwide, the clinical use of methadone as an analgesic remains very limited.

Q: What are the barriers to using methadone for pain management?
A: There are three major barriers to the use of methadone as an opioid analgesic. The first barrier is that many clinicians do not really understand the pharmacokinetics of this drug and are confused about dosage. Indeed, prescribing methadone requires more care and attention than prescribing morphine and a good understanding of its properties is required for safe use. However, with proper education and tools, such as conversion protocols [see conversion protocols], clinicians can use methadone successfully for pain management.

Q: What is the second barrier?
The second barrier is the stigma attached to methadone in the mind of some physicians who have not distinguished methadone's role in pain management from its role as a maintenance therapy for opioid dependence. In fact, methadone has been used as an analgesic since 1946, before its use in the treatment of opioid addiction began.

Q: What is the third barrier?
A: I believe that the low cost of methadone [see table] is a double-edged sword: one the one hand methadone represents a significant cost saving for cancer patients requiring high-dose opioids. On the other hand, the availability of methadone as a generic drug creates no incentive for the pharmaceutical industry or for health institutions to invest in clinical trials, marketing or professional education.

Q: What is the WHO's position about methadone?
A: Methadone is recommended as an alternative to morphine in the WHO guidelines for cancer pain management (1996). In March 2005, the Expert Committee on the Selection and Use of Essential Medicines added methadone to the list of essential drugs, in recognition of methadone's role in substance dependence programs.

Q: What impact does the inclusion of methadone to the Essential Medicines List have for the treatment of cancer pain?
A: The addition of methadone may gradually improve the present situation of the great majority of patients with advanced cancer who die without ever having received a single dose of strong opioid analgesic, particularly in the developing world.

Q: Is methadone an option as first-line treatment when chronic opioid therapy is initiated?
A: Because it has a long half-life and can be dosed at convenient intervals, methadone is an option along extended-release preparations when starting patients on opioids. However, there are few data on which to base the initial dosing of methadone for cancer pain in patients not already receiving a strong opioid.

Q: In a randomized, double-blind study, you compared methadone to morphine as a first-line opioid for cancer pain. What did you find?
A: We found that morphine and methadone were well tolerated by seriously ill cancer patients and that methadone resulted in good pain control, but was not superior to morphine [see abstract]. However, the study limitations do not allow definitive conclusions that methadone could not be a useful first-line opioid.

Q: Is methadone as safe as morphine?
A: A recent Cochrane Review suggests that methadone and morphine have similar efficacy and side effects in cancer pain patients [see abstract].

Q: When is it appropriate to switch a patient to methadone?
A: Methadone is a good choice when pain remains poorly controlled or when the side effects of other opioids prevent dosage escalation.

Q: What are the challenges when switching a patient to methadone for pain control?
A: There are two primary challenges:the first is the tremendous interpatient pharmacokinetic variability. The second is understanding equianalgesic potency and opioid dose-conversion tables.

Q: Can you comment on the pharmacokinetics of methadone?
A: The pharmacokinetic properties of methadone govern both the advantages and the difficulties of using this opioid for pain control in seriously ill patients. Methadone's half-life is highly variable, ranging between 12 and 150 hours. In most patients, the half-life is approximately one day. In addition, irrespective of the dose or route of administration, it takes from 5 days to a week or more in some patients to reach steady-state plasma levels, so methadone does not take effect immediately. Once steady state is reached, the duration of analgesia is 6 to 12 hours.

Q: What do you need to watch for?
A: Since methadone's half-life is so much longer than the duration of analgesia, there is a risk of drug accumulation which can increase the potential for sedation and respiratory depression. This requires close monitoring of the patient after the treatment is started or the dose is increased.

Q: What accounts for the variability in individual responses to opioids and to methadone in particular?
A: Differences in responses to opioids are due in part to genetic differences in sensitivity that can be profound; because of these interindividual variations, dosing methadone requires subtle titration to reach the optimal dose for the patient. Beyond the initial titration however, frequent dosage changes are not necessary with methadone.

Q: Is methadone more or less potent than morphine?
A: Methadone is more potent than many older opioid conversion charts estimate. On average it is 10 times more potent than morphine. Let me clarify that more potent does not mean more effective; potency is the equivalent dose required to obtain the same effect.

Q: Why is equianalgesic conversion of methadone particularly challenging?
A: Methadone's equianalgesic dose-ratio compared to other opioids changes according to the dose of the previous opioid: the higher the dose, the higher the ratio. For example, when morphine at lower doses is switched to methadone (e.g. 30-60 mg/day orally), the potency may be 3 to 5 times; when switched from higher doses (e.g., >300 mg morphine/day orally), the potency may be 12 times or even higher.

Q: Is there a uniformly accepted conversion ratio to switch to methadone from another opioid?
A: Conversion protocols from other opioids to methadone have been published by well-established groups in the US, the UK, Italy, Germany, China and Canada [see conversion protocols]. All protocols agree that dosing should be based on the degree of prior opioid use. Before calculating the initial dose, it is paramount to consider the clinical scenario, including the reasons for the opioid rotation and the patient characteristics such as age, renal and liver function, mental status and pulmonary function.

Q: Is close monitoring of patients always needed?
A: We know that patients who receive methadone must be carefully monitored for rising blood levels to avoid overmedication with repeated dosing, so daily nursing visits to assess the patient are required until the methadone dose is stable.

Q: What are the most common forms of administration?
A: The oral route using tablets or a liquid formulation is effective and well tolerated. Rectal administration of methadone which requires compounding of suppositories, can produce rapid relief of pain due to its rapid absorption which is usually complete within 30 minutes. The rectal route is appropriate in patients with nausea, vomiting, dysphagia, or bowel obstruction. Subcutaneous administration is best managed by frequent site rotation to avoid inflammation of the skin at the injection site, and by diluting the methadone to lower concentrations in solution [see abstract]. Continuous epidural methadone has been used for cancer pain with good results, although the epidural route may not be needed since methadone is absorbed rapidly.

Q: Since polypharmacy is commonplace with cancer patients, what is the impact of adding methadone to the mix?
A: Many medications either increase or decrease serum methadone levels. The probability of drug interaction is higher with methadone than with morphine or other opioids. Analgesics with opioid-antagonist properties (e.g., buprenorphine, butorphanol, nalbuphine) should not be used with methadone because they can displace methadone from Mu-opioid receptors.

Q: What side effects are associated with methadone?
A: The side effects of methadone are similar to other Mu agonists and include nausea, vomiting, dizziness, clouding of consciousness, and pruritus. Methadone is less sedating than morphine.

Q: Can methadone be safely used in the elderly with cancer pain?
A: Methadone should be used with caution to treat pain in the elderly because of delayed clearances, psychogenic pain and intolerance of low doses of opioids.

Q: What recommendations do you have for a physician new to methadone prescribing?
A: Dose conversion between opioids and methadone is complex, but improves with experience. No conversion ratio can be effective for every patient, so frequent observation and personalized titration are required. When administered in proper doses and intervals, methadone is a very safe drug for both inpatients and outpatients.

References mentioned
Esphani N, Palmer LJ, Shen L et al. Patterns of outpatient opioid prescribing at a comprehensive cancer center: the dramatic increase in methadone prescribing for cancer pain over a 3-year period. Proc Am Soc Clin Oncol 2003; 22:790 (abstr 3177).

Manfredi P, Houde R. Prescribing methadone, a unique analgesic. J Support Oncol 2003; 1: 216-220.

Ripamonti C, Bianchi M. The use of methadone in cancer pain. Hematol Oncol Clin N Am 2002; 16: 543-555.

WHO. Cancer pain relief: with a guide to opioid availability. --2nd edition. WHO: 1996.

Average monthly wholesale cost of methadone vs. other opioids in the US
Methadone ...........................................5 mg orally three times daily (90 pills).....$8.24 Sustained-release morphine-generic..........30mg orally twice daily (60 pills).......$101.50 Sustained-release morphine-brand ...........30 mg orally twice daily (60 pills)......$113.50 Sustained-release oxycodone-brand...........20 mg orally twice daily (60 pills)......$176.50 Transdermal fentanyl-brand.......................25mcg per hour (10 patches)...........$154.00

Source: Toombs JD, Kral LA. Methadone treatment for pain states. Am Fam Physician 2005; 71: 1353-1358.