Morphine versus Methadone as First Line Strong Opioid for Cancer Pain

描述（由申请人提供）：疼痛是癌症患者中最具破坏性、持续性和失能性的症状之一。超过80%的晚期癌症患者在死亡前会出现疼痛。这些患者中的绝大多数将需要阿片类镇痛药来适当控制疼痛。吗啡是世界卫生组织癌症疼痛缓解指南推荐的一线阿片类药物。然而，吗啡的活性代谢产物可蓄积并导致阿片诱导的神经毒性，并且重复给药将导致需要更高剂量或阿片轮换。此外，吗啡的价格对发展中国家来说可能高得令人望而却步，因此，世界其他地方的大多数癌症患者在死亡时从未接受过一剂强效阿片类镇痛药。美沙酮具有良好的口服生物利用度，镇痛作用起效快，使用寿命长，镇痛效果延长，不需要频繁给药，缺乏已知的活性代谢物。此外，美沙酮不是阿片衍生物，并且便宜得多。我们的试点随机对照试验表明，在为期4周的试验中，接受美沙酮或吗啡的患者的疼痛缓解水平相似。这使我们假设，随着时间的推移，由于缺乏NMDA产生和阿片代谢物积累，接受美沙酮的患者的疼痛控制的维持将导致阿片类药物诱导的毒性、剂量递增和治疗失败的频率降低，因此，生活质量改善。本研究的长期目标是为晚期癌症患者提供上级镇痛控制。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），进行经济学评价（比较成本和临床获益）。250名患者将入组研究，其中一半患者将每12小时接受一次缓释吗啡加阿片类药物补救剂量，另一半患者将每12小时接受一次美沙酮加阿片类药物补救剂量，共12周。所有患者将滴定至其最佳阿片类药物剂量水平。将使用经验证的工具评估疼痛、症状、毒性和生活质量。将使用资源利用以及医疗和非医疗成本进行成本效益分析。与公共卫生的相关性：在这项研究中，我们将测试美沙酮是否比吗啡在癌症疼痛控制，生活质量方面更好，并且更具成本效益。

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.