Novel drug combinations for the management of pain

描述（由申请人提供）：由于潜在的不良和危险的副作用，一些镇痛化合物的治疗用途通常受到限制。然而，具有不同作用机制的镇痛剂的组合可以增强镇痛功效（协同作用），同时减少单个组分的剂量依赖性不良反应。因此，开发具有协同作用的组合镇痛剂将有效地减少每种化合物的剂量，从而减少不良反应，同时保持镇痛效力。 对乙酰氨基酚与阿片类药物的组合（即，氢可酮、可待因）经常被处方用于急性和慢性疼痛管理。然而，尽管对乙酰氨基酚组合对中度至重度疼痛具有更大的功效，并且是市场上最受欢迎的处方止痛药，但人们已经认识到，即使在治疗剂量下，对乙酰氨基酚（以及含有对乙酰氨基酚的组合）也可能导致肝毒性。因此，具有与对乙酰氨基酚相似的镇痛特性，但具有很少或没有肝毒性的药物将是这些组合中对乙酰氨基酚的有价值的替代品。第一阶段支持开发一种无毒的对乙酰氨基酚类似物（SCP-1），我们探索了将这种化合物与其他阿片类和非阿片类镇痛药联合使用的可行性。我们的目标是确定两种SCP-1组合（一种阿片类药物和一种非阿片类药物），它们显示出协同镇痛特性，并将成为II期进一步药物开发的基础。基于其上级协同镇痛特性，SCP-1+可待因和SCP-1+可乐定组合被鉴定为进一步开发的候选物。在II期支持下，我们将进一步评估和筛选不同SCP-1：可待因和SCP-1：可乐定组合比例（即制剂）的镇痛特征和不良副作用。这些结果将是进行II期关键早期临床前GLP安全性研究的基础，这些研究将用于我们向FDA提交的IND申请。在III期，我们将进行I期人体临床试验，以评估正常人类志愿者的耐受性和口服生物利用度，并进行II期人体临床试验，以评估术后疼痛患者的联合用药。

DESCRIPTION (provided by applicant): The therapeutic use of some analgesic compounds is often limited because of potentially adverse and dangerous side effects. However, combinations of analgesics with different mechanisms of action could enhance analgesic efficacy (synergy) while reducing the dose-dependent adverse effects of the individual components. The development of combination analgesics that are synergistic, therefore, would effectively reduce the dose of each compound, thus reducing the adverse effects while maintaining analgesic potency. Combinations of acetaminophen with opioids (i.e., hydrocodone, codeine) are frequently prescribed for acute and chronic pain management. However, although acetaminophen combinations have greater efficacy for moderate to severe pain and are some of the most popular prescription analgesics on the market, it has been recognized that even at therapeutic doses acetaminophen (and combinations containing acetaminophen) can cause liver toxicity. Thus, a drug with a similar analgesic profile to acetaminophen, but with little or no hepatotoxicity, would be a valuable substitute for acetaminophen in these combinations. Phase I supported the development of a non-toxic acetaminophen analog (SCP-1) in which we explored the feasibility of using this compound in combination with other opioid and nonopioid analgesics. Our goal was to identify two SCP-1 combinations (one opioid and one nonopioid) that displayed synergistic analgesic properties, and would be the basis for further drug development in Phase II. Based on their superior synergistic analgesic profile, SCP-1+codeine and SCP-1+clonidine combinations were identified as candidates for further development. Under Phase II support we will evaluate and screen further the analgesic profiles and adverse side-effects of different SCP-1 : codeine and SCP-1 : clonidine combination ratios (i.e. formulations). These results will be the basis for conducting key early stage pre-clinical GLP safety studies under Phase II that will be used in our IND applications to the FDA. In Phase III we will conduct Phase I human clinical trials to evaluate tolerability and oral bioavailability in normal human volunteers, and Phase II human clinical trials to evaluate the combinations in postoperative pain patients.