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© 2002 American Society for Clinical Oncology
Opioid Rotation to Methadone: Proceed With CautionUniversity of Alberta, Edmonton, Alberta, Canada To the Editor:We appreciate Indelicato and Portenoy’s1 thoughtful and practical summary of the role of opioid rotation in cancer pain management. Their comments on the limitations of equianalgesic tables and the need for individualization of dose and ongoing monitoring are particularly important. We wish to highlight further the need for caution when switching to methadone. Indelicato and Portenoy1 refer to the greater than expected potency of methadone, and they recommend reducing the calculated equianalgesic dose by 75% to 90%. In our experience, potentially life-threatening respiratory depression may occur despite the use of a conservative dose calculation. We previously reported a case of an 80-year-old man with intractable brachial plexus neuropathy secondary to Pancoast tumor who required rotation from hydromorphone to methadone.2 The patient’s physician attempted a gradual conversion at home over a period of 5 days from hydromorphone 60 mg orally per day to methadone 30 mg orally per day. However, on the 5th day the patient was discovered by his spouse to be unresponsive to verbal stimulation, with depressed respiratory rate and apneic spells of up to 30 seconds. The spouse immediately contacted the physician, who went to the patient’s home and administered naloxone 0.4 mg subcutaneously. The patient’s level of consciousness and respiratory rate subsequently improved. If a patient is being considered for a rotation to methadone, we would strongly suggest involving a physician who is experienced in the use of this opioid. Also, provision should be made for adequate monitoring during the rotation and for emergency access to medical support and naloxone. If these conditions cannot be met in the patient’s home, then we would advise performing the rotation in an inpatient setting. REFERENCES
1.
Indelicato RA, Portenoy RK: Opioid rotation in the management of refractory cancer pain. J Clin Oncol 20: 348-352, 2002 2. Oneschuk D, Bruera E: Respiratory depression during methadone rotation in a patient with advanced cancer. J Palliat Care 16: 50-54, 2000[Medline]
ResponseBeth Israel Medical Center, New York, NY In Reply to Daniell and Watanabe et al:We thank Dr Daniell and Dr Watanabe et al for their comments on our article.1 We strongly agree with the latter authors’ call for caution when switching to methadone from some other mu agonist opioid. As we discussed in our article,1 the d-isomer of methadone, which makes up half of the racemic methadone available in the United States, blocks the N-methyl-D-aspartate receptor. This action, which may produce independent analgesic effects and reverse analgesic tolerance, presumably explains the observation that methadone may be far more potent than suggested on published equianalgesic dose tables. Unexpectedly high potency and a long elimination half-life combine to increase the challenge in using methadone safely and effectively. However, with cautious dosing and appropriate monitoring, the drug can indeed be useful, and we would encourage oncologists to learn the guidelines for methadone administration that we1 and others2,3 have suggested. Dr Daniell’s comments highlight the potential for molecular biology and pharmacogenomic research to alter clinical practice. The observation that some patients—fewer than 10%—may be poorly responsive to codeine because of relatively limited activity at the cytochrome P-450 isoenzyme 2D6 (CYP 2D6) is well accepted.4 This understanding should be incorporated into the assessment of patient outcomes when codeine is used. We would encourage caution, however, in extrapolating biochemical data to the clinical setting when referring to other opioids. Although it is true that oxycodone and hydrocodone are metabolized to active opioid compounds, it has not been demonstrated that this effect has clinical relevance. A study of oxycodone in humans, which evaluated psychomotor and subjective effects,5 and several animal studies of hydrocodone6,7 did not confirm that the actions of these drugs are dependent on conversion to their active metabolites. Until we have better clinical data, it would be premature to conclude that change in the functioning of the CYP 2D6 isozyme induced by other drugs is a significant factor in the response to these opioids. REFERENCES 1. Indelicato RA, Portenoy RK: Opioid rotation in the management of refractory cancer pain. J Clin Oncol 20: 348-352, 2002 2. Mancini I, Lossignol DA, Body JJ: Opioid switch to oral methadone in cancer pain. Curr Opin Oncol 12: 308-313, 2000[CrossRef][Medline] 3. Ripamonti C, Groff L, Brunelli C, et al: Switching from morphine to oral methadone in treating cancer pain: What is the equianalgesic ratio? J Clin Oncol 16: 3216-3221, 1998[Abstract] 4. Poulsen L, Brosen K, Arendt-Nielsen L, et al: Codeine and morphine in extensive and poor metabolizers of sparteine: Pharmacokinetics, analgesic effects and side effects. Eur J Clin Pharmacol 51: 289-295, 1996[CrossRef][Medline] 5. Heiskanen T, Olkkola KT, Kalso E: Effects of blocking CYP2D6 on the pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacol Ther 64: 603-611, 1998[CrossRef][Medline]
6.
Tomkins DM, Otton SV, Hoharchi N, et al: Effect of cytochrome P450 2D1 inhibition on hydrocodone metabolism and its behavioral consequences in rats. J Pharmacol Exp Ther 280: 1374-1382, 1997 7. Lelas S, Wegert S, Otton SV, et al: Inhibitors of cytochrome P450 differentially modify discriminative-stimulus and antinociceptive effects of hydrocodone and hydromorphone in rhesus monkeys. Drug Alcohol Depend 54: 239-249, 1999[CrossRef][Medline]
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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