IMPROVING OF CARE BY REVERSAL OF OPIOID CONSTIPATION

吗啡和其他阿片类药物是晚期癌症患者广泛使用的止痛药，便秘是阿片类止痛药最常见的治疗相关副作用。阿片类药物诱导的便秘的常规措施往往是不够的，便秘成为阿片类药物使用和阿片类药物剂量在这些患者的限制因素。 大量接受慢性阿片类药物治疗疼痛的临终关怀患者宁愿忍受疼痛，也不愿面对阿片类药物引起的严重失能性便秘。 因此，阿片类药物诱导的便秘（继发于治疗的症状）对这些晚期患者的生活质量具有显著的负面影响。姑息治疗和临终关怀管理的做法没有得到足够的重视，在过去，需要加强临终病人的姑息治疗已成为显而易见的，在这个国家。 在这个拟议的项目中，一种新的外周阿片受体拮抗剂，甲基纳洛酮，在治疗慢性阿片类药物诱导的便秘的疗效进行了评估。 具体目标1和2研究将利用临床药理学方法（II/III期试验）来评估静脉内和口服甲基纳洛酮在美沙酮成瘾者和晚期恶性疾病患者中逆转慢性阿片类药物诱导的肠道动力变化和便秘的疗效和剂量反应。 这些试验将是随机、双盲、安慰剂对照研究。 在这些研究中，将使用乳果糖氢呼吸试验测量口-盲肠通过时间，并将评价阳性乳酸反应和阿片类镇痛作用。 此外，还将记录便秘、大便频率和粘稠度以及"总体健康状况"的主观视觉模拟量表（VAS）评分。还将收集药代动力学数据。 在这些研究中，将研究人类阿片类药物胃肠道药理学的潜在机制，这是一个以前尚未解决的问题，因为由于阿片类药物系统的生理学差异，将以前动物实验的数据转化为人类可能存在问题。甲基纳洛酮，第一个选择性外周阿片受体拮抗剂，临床应用将是姑息治疗的一个重大进展。 该项目的成功完成将导致一些未来的研究，其中甲基纳洛酮的其他应用，以及阿片类药物的作用机制及其在人类中的拮抗作用，可以探索。

Morphine and other opioids are widely used analgesics in advanced cancer patients, and constipation is the most common treatment-associated side effect of opioid pain medications. Conventional measures for opioid-induced constipation are often insufficient, and constipation becomes a limiting factor in opioid use and opioid dose in these patients. A significant number of hospice patients receiving chronic opioids for pain would rather endure their pain than face the severe incapacitating constipation that opioids cause. Thus, opioid-induced constipation, a symptom secondary to the treatment, has a significant negative impact on the quality of life of these terminal patients. Palliative care and end of life management practices have received insufficient attention in the past, and the need to enhance palliative care of dying patients has become apparent in this country. In this proposed project, the efficacy of a novel peripheral opioid receptor antagonist, methylnaltrexone, in the treatment of chronic opioid-induced constipation, will be evaluated. Specific Aim 1 and 2 studies will utilize a clinical pharmacology approach (Phase II/III trials) to evaluate the efficacy and dose-response of intravenous and oral methylnaltrexone in reversing chronic opioid-induced gut motility changes and constipation in methadone addicts and patients with advanced malignant conditions. These trials will be randomized, double-blind, placebo-controlled studies. In these studies, the oral-cecal transit time will be measured using the lactulose hydrogen breath test, and positive laxation response and opioid analgesic effect will be evaluated. In addition, subjective visual analog scale (VAS) scores for constipation, stool frequency and consistency, and "overall well being" will be recorded. Pharmacokinetic data will also be collected. In these studies, mechanisms underlying opioid gastrointestinal pharmacology in humans, an issue that has not been addressed before, will be investigated, since translation of data from previous animal experiments to humans may be problematic due to differences in the physiology of the opioid systems. Bringing methylnaltrexone, the first selective peripheral opioid receptor antagonist, to clinical application will be a significant advance in palliative care. Successful completion of this project will lead to a number of future studies in which other applications of methylnaltrexone, as well as its mechanisms of action of both opioids and their antagonism in humans, can be explored.