Bruera E, Palmer JL, Bosnjak S, Rico MA, Moyano J, Sweeney C, Strasser F, Willey J, Bertolino M, Mathias C, Spruyt O, Fisch MJ

J Clinical Oncology 2004; 22: 185-192

This is a first randomised, double-blind parallel study of strong opioids carried out with the aim to compare oral methadone with oral sustained-release morphine as first-line treatments of cancer patients in the outpatient setting. Specifically, the study examined the doses, schedule and side effects over 4 weeks, and whether methadone could produce superior analgesia compared to sustained-release morphine, at the same time producing similar side effects?

Seven international palliative care groups in Argentina, Yugoslavia, Brazil, Columbia, Chile, Australia and Spain conducted the study.  The Department of PC and Rehabilitation Medicine at the University of Texas' M.D. Anderson Cancer Center coordinated the study but did not enrol patients.

Patients with advanced cancer, that were strong-opioid naïve and who had normal cognitive function, poor pain control, normal renal function,  and a life expectancy of at least 4 weeks were enrolled--all patients gave informed consent. 103 patients were randomly assigned to receive either oral methadone 7.5 mg every 12 hrs plus 5 mg every 4 hrs p.r.n for breakthrough pain (BTP) or slow-release morphine 15 mg twice daily and immediate-release morphine 5 mg every 4 hrs p.r.n. for BTP. The doses of the drugs under study were increased by 30% if the patient needed more than 2 BT doses/day and reduced by 30% if the patient felt sedated (reported sedation). Only laxatives and antiemetics were allowed during the study. Patients were assessed daily for pain, nausea, sedation, confusion, and constipation during the first week (Numerical Scale 0-10) and on days 8, 15, 22, 29. Additionally, every week the overall benefit according to the patient, and the investigator, was assessed  (verbal rating scale 1-7). Opioid escalation indices were calculated at the end of the study.

Forty-nine patients received methadone and 54 patients received oral morphine. During the study many patients on methadone or morphine had withdrawn from the study. However, by day 8, 12% of patients receiving methadone withdrew because of side effects (sedation and nausea) compared to 0% of patients on morphine (p= .01). On day 29, 22% of patients on methadone had withdrawn compared to 6% of patients on morphine (p = 0.19) due to side effects (sedation, vomiting, myoclonus).

The proportion of patients with improvement of pain was similar between the two groups as was the opioid escalation index at days 14 and 28. The median daily methadone dose was 17.5 (range 7.5 to 40 mg) on day 14, and 20 mg (range 7.5 to 55 mg) on day 28. The median morphine dose was 40 (15 to 100 mg) on day 14, and 45 mg (15 to 150 mg) on day 28.  The rate at which patients in the two treatment groups reported overall benefit was very similar to the pain response rate.

Why I chose this article

This is the first randomised double-blind study conducted out patients with cancer-related pain, comparing the efficacy, and tolerability, of methadone and sustained-release morphine administered orally as first-line strong opioid therapy.

The fact that more patients treated with methadone, compared to sustained-release morphine, withdrew from the study due to side effects should make us want to study this drug further- even during the titration phase in strong opioid naive patients.