Morphine versus Methadone as First Line Strong Opioid for Cancer Pain

描述（由申请人提供）：疼痛是癌症患者最具破坏性、持续性和致残的症状之一。超过80%的晚期癌症患者在死前都会出现疼痛。这些患者中的绝大多数将需要阿片类镇痛药来适当地控制疼痛。世界卫生组织癌症疼痛缓解指南推荐吗啡作为一线阿片类药物。然而，吗啡的活性代谢物可积累并导致阿片类药物诱导的神经毒性，反复给药将导致需要更高剂量或阿片类药物轮换。此外，对于发展中国家来说，吗啡的价格可能贵得令人望而却步，因此，世界其他地方的大多数癌症患者在没有接受过一剂强效阿片类镇痛药的情况下死亡。美沙酮已被证明具有良好的口服生物利用度，镇痛作用起效快，使用寿命长，无需频繁给药即可延长镇痛效果，缺乏已知的活性代谢产物。此外，美沙酮不是阿片类衍生物，价格便宜得多。我们的试点随机对照试验表明，在4周的试验中，接受美沙酮或吗啡治疗的患者疼痛缓解程度相似。这导致我们假设，由于美沙酮缺乏NMDA的产生和阿片样物质代谢物的积累，随着时间的推移，接受美沙酮治疗的患者维持疼痛控制将导致阿片样物质引起的毒性减少，剂量增加和治疗失败，从而改善生活质量。我们这项研究的长期目标是为晚期癌症患者提供更好的镇痛控制。在这项随机、双盲、平行研究中，我们旨在确定临床疗效（测量疼痛强度、毒性、剂量递增、治疗失败和生活质量），进行经济评估（比较成本和临床收益）。250例患者将被纳入研究，其中一半患者每12小时接受缓释吗啡加阿片类药物抢救剂量，一半患者每12小时接受美沙酮加阿片类药物抢救剂量，共12周。所有患者将滴定至最佳阿片类药物剂量水平。经过验证的仪器将用于评估疼痛、症状、毒性和生活质量。将利用资源利用情况以及医疗和非医疗费用进行成本效益分析。与公众健康相关：在这项研究中，我们将测试美沙酮在癌症疼痛控制、生活质量和成本效益方面是否优于吗啡。

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.