Novel Drug Combinations for Treating Pain in the Elderly

描述(申请人提供)：联合止痛药，包括扑热息痛和阿片类药物，广泛用于老年人(和其他人)的疼痛控制。这在一定程度上是因为这些组合可以产生相加或协同的止痛，并且这些组合产生的不良影响可能比同等剂量的任何一种成分单独产生的副作用要小。即便如此，这些混合物中的对乙酰氨基酚在大剂量摄入后或长期使用后可能会导致肝脏毒性，特别是在老年人或肝功能受损时。阿片类药物的剂量需要增加，以应对因长期使用而产生的耐受性，从而增加老年人不良副作用的发生。我们一直在探索一系列新的和专有的对乙酰氨基酚衍生物，其中先导化合物(SCP-1)对幼年和老年动物都有良好的口服效果，并且几乎没有肝脏毒性。这个第一阶段的SBIR项目探索了SCP-1+可待因在使用幼年和老年动物的急性和慢性疼痛治疗模型中具有与对乙酰氨基酚+可待因组合相当或更好的协同效果，但副作用减少的可行性。它还将确定(在幼年和老年动物中)慢性给药后耐受性和依赖性的发展，以及慢性和急性给药后的肝脏毒性。如果含有可待因的SCP-1被证明比含有可待因的对乙酰氨基酚更有效和/或毒性更小，将在第二阶段SBIR下进行进一步的药物开发，最终将在需要治疗急性或慢性疼痛的老年患者中进行临床试验。

DESCRIPTION (provided by applicant): Combination analgesics, including acetaminophen with opioids, are used extensively for pain management in the elderly (and others). This is, in part, because these combinations can produce analgesia that is additive or synergistic, and the adverse effects produced by the combinations can be less than those produced by equianalgesic doses of either component alone. Even so, the acetaminophen in these combinations can cause hepatotoxicity after ingestion of large doses or from chronic use, particularly in the elderly or when liver function is compromised. The opioid dosages need to be escalated in response to the tolerance that is developed from chronic use, increasing the occurrence of adverse side effects in the elderly. We have been exploring a series of new and proprietary derivatives of acetaminophen, in which the lead compound (SCP-1) has good oral efficacy in both young and aged animals, and produces little, if any, hepatotoxicity. This Phase I SBIR project explores the feasibility that combinations of SCP-1 + codeine can have synergistic effects comparable to or better than acetaminophen + codeine combinations, but with reduced side effects, in models of acute and chronic pain management using young and old animals. It will also determine (in both young and old animals) the development of tolerance and dependence after chronic dosing, as well as hepatotoxicity after chronic and acute dosing. If the SCP-1 with codeine is shown to be more efficacious and/or less toxic than acetaminophen with codeine, further drug development will be proposed under a Phase II SBIR with eventual clinical trials in elderly patients who require management of acute or chronic pain.