Mercadante, S., Porzio, G., Ferrera, P., Fulfaro, F., Aielli, F., Verna, L., . . . Mangione, S. (2008). Sustained-release oral morphine versus transdermal fentanyl and oral methadone in cancer pain management. European Journal of Pain (London, England), 12(8), 1040–1046.

To compare, in patients with advanced cancer, the analgesic efficacy, adverse effects, and effect on quality of life of morphine, fentanyl, and methadone

Patients were randomized to morphine, fentanyl, or methadone. Morphine was offered as breakthrough pain medication at one-sixth the equianalgesic 24-hour dose. Adjuvant medications were allowed. If the patient experienced poor opioid response or uncontrolled adverse events, he or she switched to another opioid. Data were collected at four weekly intervals.

• The sample was composed of 108 patients, 36 in the morphine group (22 patients in this group completed the study), 36 in the fentanyl group (25 completed the study), and 36 in the methadone group (23 completed the study).
• In the morphine group, mean patient age was 59 years; in the fentanyl group, 57 years; and in the methadone group, 61 years.
• In the morphine group, 10 patients were female; in the fentanyl group, 14 were female; and in the methadone group, 12 were female. In the morphine group, 12 patients were male; in the fentanyl group, 11 were male; and in the methadone group, 11 were male.
• Patients had advanced cancer with pain and required first-line opioids for pain control. Patients were excluded from the study if they had liver or renal disease, cognitive impairment, or expected survival of less than three months; if they were undergoing radiation therapy or a new course of chemotherapy; or if they had prevalent incident pain, mixed pain, or nociceptive and neuropathic pain. Breast cancer was the most frequent diagnosis.

• Multisite
• Outpatient
• Multiple sites in Italy

Randomized controlled trial

• Scale (0 = not at all, 3 = severe), to measure adverse events 
• Number of passages per day, to measure constipation
• Scale, 0–10, to measure pain intensity (PI)
• Number of daily dose changes to stabilization
• Opioid escalation index, or OEI (OMD – OSD/OSD per day x 100, where OMD represents doses administered at four weeks after study initiation and OSD represents the opioid starting dose at study initiation)
• Spitzer Quality of Life Index
• Costs of opioid therapy

• A similar number of patients in each group switched to other opioids.
• No significant differences existed in number of days to achieve dose stabilization.
• No significant differences existed in the number of dose changes needed during titration.
• No differences existed in the PI of the three groups.
• OEI% was highest in the fentanyl group and significantly lower in the methadone group; 14 patients on methadone did not have a dose change, but 8 required a decrease in the dose and then a subsequent increase.
• Authors observed no significant intergroup difference in quality-of-life scores.
• Methadone was less expensive.

All three opioids were effective in controlling cancer pain in some patients. Adverse event profiles were similar. Methadone was less expensive than fentanyl or morphine but required clinical expertise in dosing. (The doses of some patients had to decrease and then increase.)

• The study had a small sample, with fewer than 100 patients.
• The sample was a convenience sample; it was not blinded.

Long-acting morphine, fentanyl, and methadone are effective in controlling the pain of advanced cancer. Methadone is an option for patients for whom cost is a concern. Prescribing methadone requires clinical expertise.