Methadone Versus Morphine As a First-Line Strong Opioid for Cancer Pain: A Randomized, Double-Blind Study Eduardo Bruera, J. Lynn Palmer, Snezana Bosnjak, Maria Antonieta Rico, Jairo Moyano, Catherine Sweeney, Florian Strasser, Jie Willey, Mariela Bertolino, Clarissa Mathias, Odette Spruyt, and Michael J. Fisch A B S T R A C T Purpose To compare the effectiveness and side effects of methadone and morphine as first-line treatment with opioids for cancer pain. Patients and Methods Patients in international palliative care clinics with pain requiring initiation of strong opioids were randomly assigned to receive methadone (7.5 mg orally every 12 hours and 5 mg every 4 hours as needed) or morphine (15 mg sustained release every 12 hours and 5 mg every 4 hours as needed). The study duration was 4 weeks. Results A total of 103 patients were randomly assigned to treatment (49 in the methadone group and 54 in the morphine group). The groups had similar baseline scores for pain, sedation, nausea, confusion, and constipation. Patients receiving methadone had more opioid-related drop-outs (11 of 49; 22%) than those receiving morphine (three of 54; 6%; P = .019). The opioid escalation index at days 14 and 28 was similar between the two groups. More than three fourths of patients in each group reported a 20% or more reduction in pain intensity by day 8. The proportion of patients with a 20% or more improvement in pain at 4 weeks in the methadone group was 0.49 (95% CI, 0.34 to 0.64) and was similar in the morphine group (0.56; 95% CI, 0.41 to 0.70). The rates of patient-reported global benefit were nearly identical to the pain response rates and did not differ between the treatment groups. Conclusion Methadone did not produce superior analgesic efficiency or overall tolerability at 4 weeks compared with morphine as a first-line strong opioid for the treatment of cancer pain. J Clin Oncol 22:185-192. © 2004 by American Society of Clinical Oncology INTRODUCTION Cancer is among the most feared chronic illnesses [1], and more than two thirds of patients with metastatic cancer experience pain [2]. The great majority of these patients require opioid analgesics for appropriate pain control [3]. Morphine has been shown to be an effective analgesic, and it is recom- mended as a first-line opioid in the WHO Cancer Pain Relief Guidelines [4]. However, only level C evidence supports this recom- mendation, reflecting the paucity of good- quality clinical studies in cancer pain [5]. Morphine undergoes hepatic metabo- lism and renal elimination [6]. Some of its active metabolites can accumulate in situa- tions such as chronic treatment, dose esca- lation, dehydration, or renal failure [6,7]. Opioid metabolite accumulation has been considered one of the major causes of opi- oid-induced neurotoxicity [7,8]. Other opi- oid agonists such as hydromorphone, oxyc- odone, or codeine also result in opioid metabolite accumulation [7,9]. Although its manufacture is simple, the price of mor- phine ranges according to the international price of the poppy, and even the immediate- From the Department of Palliative Care and Rehabilitation Medicine, the Univer- sity of Texas M.D. Anderson Cancer Center, Houston, TX; Institute for On- cology and Radiology of Serbia, Bel- grade, Yugoslavia-Serbia; Instituto Na- cional del Cancer, Santiago, Chile; Departamento de Anestesia, Clinica de Dolor, Fundacion Santafe de Bogota, Bogota, Colombia; Unidad de Cuidados Paliativos Hospital Enrique Tornu-Funda- cion FEMEBA, Buenos Aires, Argentina; Nucleo de Oncolgia da Bahia, Bahia, Brazil; and Peter Mac Callum Cancer Institute, Department of Pain and Pallia- tive Care, East Melbourne, Australia. Submitted March 27, 2003; accepted October 24, 2003. Supported in part by the Brown Foun- dation, Houston, TX, and the Tobacco Settlement Foundation. Florian Strasser is supported by a grant from Swiss Cancer Research (BIL grant KFS 950- 09-1999). Authors’ disclosures of potential con- flicts of interest are found at the end of this article. Address reprint requests to Eduardo Bruera, MD, Department of Palliative Care & Rehabilitation Medicine (Unit 0008), the University of Texas M.D. Anderson Cancer Center, 1515 Hol- combe Blvd, Houston, TX 77030-0049; e-mail: Ebruera@mail.mdanderson.org. © 2004 by American Society of Clinical Oncology 0732-183X/04/2201-185/$20.00 DOI: 10.1200/JCO.2004.03.172 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T VOLUME 22  NUMBER 1  JANUARY 1 2004 185 Downloaded from ascopubs.org by 44.197.201.37 on June 13, 2022 from 044.197.201.037 Copyright © 2022 American Society of Clinical Oncology. All rights reserved.