CANCER PAIN: PHARMACOKINETIC CORRELATES OF ANALGESIA

这项建议的主要目的是为了更好地了解 临床药理学的理论和实践方面 阿片类镇痛药在人体内的应用 这样的知识将允许 制定科学的准则， 治疗急性和慢性疼痛的药物。 我们以前的 研究表明， 临床镇痛药的药代动力学药效学模型 问题研究 研究的主要领域将是衡量活跃的 吗啡的代谢物，特别是吗啡-6-葡糖苷酸， 葡糖苷酸，经口服、胃肠外和鞘内途径， 评估其对镇痛和副作用的贡献， 吗啡 使用我们的药代动力学-药效学模型，我们将 研究药物和心理因素， 患者控制的镇痛药（PCA）和重复口服给药， 固定或prn时间表。 同样，我们希望定量地 定义药效学效应耐受性的发展 阿片类药物治疗疼痛 阿片 通过新途径给药的镇痛剂具有特殊的优点 癌症病人的痛苦。 我们计划继续研究 药代动力学方面的舌下，皮下，和 鞘内给药，并使用绵羊模型进一步 评估脑脊液药物的药代动力学 分布 我们开发了一种评估疼痛的方法 我们将研究这种方法的敏感性， 儿童镇痛药的相对效力。 比较 对海洛因和氢吗啡酮的研究旨在评估 这些药物中的每一种在急性和慢性 癌症疼痛管理 这些研究将在 急性和慢性癌症疼痛患者， 研究人类疼痛的合适实验组。

The major objectives of this proposal are to better understand the theoretical and practical aspects of the clinical pharmacology of opioid analgesics in human. Such knowledge will allow for the development of scientifically based guidelines for the use of these drugs in the management of acute and chronic pain. Our previous studies have demonstrated the necessity and utility of pharmacokinetic pharmacodynamic models in clinical analgesic studies. The major areas for study will be to measure the active metabolites of morphine, specifically morphine-6-glucuronide,- glucuronide, following oral, parenteral and intrathecal routes to assess its contribution to the analgesic and side effects of morphine. Using our pharmacokinetic-pharmacodynamic model, we will study the pharmacological and psychological factors that relate to patient controlled analgesiac (PCA) and repetitive oral dosing on a fixed or prn schedule. Similarly, we hope to quantitatively define the development of tolerance to the pharmacodynamic effects of opioids during repetitive losing for pain management. Opioid analgesics administered by novel routes offer special advantages to the cancer patient with pain. We plan to continue to study the pharmacokinetic aspects of sublingual, subcutaneous, and intrathecal administration and to use a sheep model to further assess the pharmacokinetics of cerebrospinal fluid drug distribution. We have developed a methodology to assess pain in children and we will study the sensitivity of this method to define the relative potency of analgesics in children. Comparative studies of heroin and hydromorphone have been designed to assess the relative merits of each of these drugs in acute and chronic cancer pain management. These studies will be performed in patients with acute and chronic pain of cancer who represent an appropriate experimental group for the study of pain in humans.