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July 1997
Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations.
Manfredi PL, Borsook D, Chandler SW, Payne R; Pain 1997; 70:99-101.
[ see abstract below ]
and
An update on the clinical use of methadone for cancer pain.
Ripamonti C, Zecca E, Bruera E; Pain 1997; 70: 109-115.
[ see abstract below ]
Two articles in the March and April editions of Pain from prominent centers in this country (Manfredi et al) and around the world (Ripamonti et al) provide a clinical reminder of the availability of additional approaches to a common and distressing clinical problem: patients with cancer whose pain is less than optimally controlled.
Manfredi et al report the management of four patients with cancer-related pain in whom the initial treatment with continuous infusions of i.v. morphine was unsuccessful because of persistent pain and/or oversedation. Each was then treated with continuous i.v. hydromorphone in doses ranging from 6-100 mg/hg. Again sedation limited the amount of opioid to an amount short of satisfactory analgesia, and the medication was changed to a continuous infusion of i.v. methadone.
All four patients reported had long-lasting pain relief without significant side effects at a methadone dose (mg/hr) about 20% of the previous dose of hydromorphone (mg/hr). Traditionally, methadone is thought of as a long-acting opioid, which of course it is. However, in treating severe pain in opioid tolerant patients, the bi-exponential nature of the decay in its plasma level may become apparent: an initial half-life of 2 to 3 hours, followed by a terminal elimination phase of 15 to 60 hours.
This may account for the relatively short analgesic action of single doses and a tendency for methadone to accumulate with repeated doses. Because of this biexponential decline, continuous infusion, particularly initially, may provide smoother analgesia.
As reported last year by Vigano et al (Pain 67:115-9, 1996), patients who survive for long periods with severe pain may require further changes in opioids. After 4 months of good pain relief with methadone, a two-week rotation to hydromorphone was needed to alleviate the increasing pain, sedation and myoclonus that developed on the methadone. Upon returning to methadone therapy, the patient s sensitivity to its effects had been regained and it was again a useful analgesic.
In their review article, Ripamonti et al take a broader view of the use of methadone for cancer pain. They outline the pharmacology of methadone and review recent reported experience with its oral and rectal administration. They cite the following unique characteristics as reasons that methadone is
a particularly good drug for this purpose:
- Lack of active metabolites
- Long (and unpredictable) half-life
- High lipid solubility
- Excellent absorption after oral or rectal administration
- Very low cost
The availability of non-parenteral routes and low cost make methadone particularly useful in populations who do not have access to technical and financial resources.
Both papers emphasize the importance of thoughtful and well-monitored conversion from other opioids to methadone. Opioid dose equivalence in opioid-naive patients is far better characterized in the literature than is dose equivalence in patients who have been treated chronically with these medications. Currently, controversy exists as to the appropriate conversion factors.
Because of the substantial inter- and intra-patient variability in absorption (41 to 99% absorbed after oral administration), elimination (beta half-life of 15 to as long as 120 h), opioid receptors and pain mechanisms, strict adherence to formulas is not likely to be successful.
Many patients, especially adolescents with high opioid requirements and their families, worry that they will become "addicted" or that health care workers consider them to be "drug addicts" because of their high needs. Due to the large amount of "just say no" advertising in the media and the confusion between physical dependence and addition that remains, even in physicians in major medical centers, this concern is understandable even in the face of consistent explanations and reassurance that it is not the case.
Because methadone has received far more attention in the lay press as a maintenance drug for opioid addicts, I have found that this concern is reinforced in some patients when they are told that a change to methadone analgesia is being considered. If the possibility of this perception is addressed explicitly when methadone use is initially presented, one potential obstacle to its successful use can be avoided.
Return to the Current Literature Review Front Page, or read the abstracts:
ABSTRACTS
Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations.
Methadone is a very effective second-line opioid for treatment of cancer pain. However, the starting doses of methadone indicated on opioid conversion charts may over-estimate the dose of intravenous (i.v.) methadone needed. In this report, we describe four patients with cancer-related pain treated with continuous i.v. morphine and hydromorphone. Because of persistent pain and opioid side effects limiting increases in opioid dose, each patient was switched to i.v. methadone.
All four patients had excellent pain relief without significant side effects at a dose that, according to the available conversion charts, was approximately 3% of the calculated equi-analgesic dose of hydromorphone. When converting from continuous i.v. hydromorphone to continuous i.v. methadone, much lower doses than those suggested by the opioid conversion charts should be used as starting doses.
An update on the clinical use of methadone for cancer pain.
Methadone is a synthetic opioid agonist considered a second choice drug in the management of cancer pain. Methadone has a number of unique characteristics including excellent oral and rectal absorption, no known active metabolites, high potency, low cost, and longer administration intervals, as well as an incomplete cross-tolerance with respect to other mu-opioid receptor agonist drugs. For those reasons, methadone has the potential of playing a major role in the treatment of cancer pain.
However, its use is limited by the remarkably long and unpredictable half-life, large inter-individual variations in pharmacokinetics, the potential for delayed toxicity, and above all by the limited knowledge of correct administration intervals and the equianalgesic ratio with other opioids when administered chronically.
Recent findings suggest that standard equianalgesic tables are unreliable for methadone titration in patients tolerant to high doses of opioid agonists and that switchovers should take place slowly and should be personalized. Future research has to better define the variation in both bioavailability and elimination of methadone in different patient populations, the interaction between methadone and the most commonly used drugs in cancer patients, the type and activity of potential methadone metabolites, and the equianalgesic doses between methadone and the most commonly used opioids.
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