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, 12, 1040–1046.

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

To compare the cost of pharmacologic pain management

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

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

• Multisite
• Outpatient setting
• Italy

 The study has clinical applicability for end-of-life and palliative care.

The study was a randomized controlled trial.

• Adverse events (AEs) rated on a 0–3 scale with “0” being not at all and “3” being severe; constipation measured on the number of passages per day
• Pain intensity (PI) scale (0–10)
• Number of daily dose changes to stabilization
• Opioid escalation index (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 rotated to other opioids. There were no significant differences in the number of days to achieve dose stabilization, nor where there significant differences 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. There were no significant differences in quality-of-life scores between groups. 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 compared to fentanyl and morphine but required clinical expertise in dosing due to the need to decrease and then increase the dose in some patients.

• The study had a small sample, with less than 100 patients.
• The study used a convenience sample and was not blinded.

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