DESCRIPTION (provided by applicant): Pain is one of the most devastating, persistent and incapacitating symptoms in patients with cancer. More than eighty percent of patients with advanced cancer develop pain before death. The great majority of these patients will require opioid analgesics for appropriate pain control. Morphine is recommended as a first line opioid by the World Health Organization Cancer Pain Relief Guidelines. However, the active metabolites of morphine can accumulate and result in opioid induced neurotoxicity, and repeated administration will lead to the need for higher dose or opioid rotation. In addition, the price of morphine can be prohibitively expensive for developing countries, and therefore, most patients with cancer elsewhere in the world die without having ever received a single dose of strong opioid analgesic. Methadone has demonstrated its excellent oral bioavailability, rapid onset of analgesic action, a long life associated with prolonged analgesic effect requiring infrequent administration, lack of known active metabolites. Further, methadone is not opioid derivative, and is much less expensive. Our pilot randomized controlled trial demonstrates similar levels of pain relief in patients receiving methadone or morphine in a 4-week long trial. This leads us to hypothesize that over time the maintenance of pain control in patients receiving methadone due to its absence of NMDA production and opioid metabolite accumulation will result in less frequent opioid induced toxicity, dose escalation and treatment failure, and therefore, improved quality of life. Our long term goal of this study is to provide superior analgesic control for patients with advanced cancer. In this randomized, double blind, parallel study, we aim to determine the clinical efficacy (measuring pain intensity, toxicity, dose escalation, treatment failure and quality of life), to perform economic evaluation (comparing the costs and clinical benefits). 250 patients will be enrolled in the study, half of the patients will receive slow release morphine every 12 hours plus rescue opioid dose, and half will receive methadone every 12 hours plus rescue opioid dose for a total of 12 weeks. All patients will be titrated up to their optimal opioid dose level. Validated instruments will be used to assess pain, symptoms, toxicities and quality of life. Cost-effectiveness analysis will be performed using resource utilization, and medical and non-medical costs. Relevance to Public Health: In this study, we will test if methadone is better than morphine in cancer pain control, quality of life, and is more cost-effective.