Development of SCP-1/opioid combinations for pain

描述（由申请人提供）：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。具有不同作用机制的镇痛剂的组合增强镇痛功效，同时减少单个组分的剂量依赖性不良反应。对乙酰氨基酚是一种相对安全、常用的非处方镇痛和解热药物;然而，摄入大剂量可导致肝毒性。此外，随着含阿片类药物的组合的重复给药而发展的镇痛耐受性通过增加对乙酰氨基酚/阿片类药物剂量来补偿。这反过来又增加了对乙酰氨基酚诱导的肝脏并发症的风险。显然，医生和患者更喜欢副作用最少的止痛药组合，并提供更安全和更有效的疼痛治疗。该SBIR项目的研究将优化阿片类药物和非阿片类药物与SCP-1的组合。 SCP-1是圣查尔斯制药公司一系列新的对乙酰氨基酚专利衍生物中的主要化合物。SCP-1具有高镇痛活性，但无解热活性和肝毒性。在I期，我们将使用等效线分析来证明在组合中创建最佳剂量的可行性，以获得与对乙酰氨基酚和阿片类药物组合相同或更高疗效和更好安全性特征的协同效应。我们将确定显示最佳镇痛起效和持续时间的组合，并通过使用GPT/GOT血浆活性和肝脏和肾脏中的谷胱甘肽含量来定义其安全性特征。在第二阶段，我们将进一步表征这些SCP-1/阿片类药物组合，寻找那些不是退烧药的组合，因此与手术后疼痛的治疗相关。此外，还将评估SCP-1组合在其他疼痛模型（如慢性压迫性损伤和疱疹性疼痛）中的镇痛作用，我们将使用选定的组合进行一些临床前研究。

DESCRIPTION (provided by applicant): Combinations of acetaminophen with opioids (i.e., hydrocodone, codeine) are frequently prescribed for acute and chronic pain management. Combinations of analgesics with different mechanisms of action enhance analgesic efficacy while reducing the dose-dependent adverse effects of the individual components. Acetaminophen is a relatively safe, commonly used over-the-counter analgesic and antipyretic drug; however, ingestion of large doses can cause hepatotoxicity. Moreover, the analgesic tolerance, which evolves with repeated administration of opioid-containing combinations, is compensated by increasing the acetaminophen/opioid doses. This, in turn, increases the risk of acetaminophen-induced hepatic complications. Clearly physicians and patients will prefer analgesic combinations that have the fewest side effects and that provide a safer and more efficacious treatment for pain. The research in this SBIR project will optimize combinations of opioids and non-opioids with SCP-1. SCP-1 is the lead compound from St. Charles Pharmaceuticals's series of new proprietary derivatives of acetaminophen. SCP-1 has high analgesic activity but is free from antipyretic activity and hepatotoxicity. During phase I, we will use isobolographic analysis to demonstrate the feasibility of creating optimal doses within the combinations to obtain the synergistic effects with equal or higher efficacy and better safety profile than acetaminophen and opioid combination. We will determine the combinations that display the best onset and duration of analgesia and define their safety profiles by using GPT/GOT plasma activity and glutathione content in the liver and kidney. During Phase II, we will further characterize these SCP-1/opioid combinations looking for those combinations that are not antipyretics and are thus relevant to the treatment of post-surgical pain. Also the lead SCP-1 combinations will be evaluated for analgesia in other pain models such as chronic constriction injury and herpetic pain and we will undertake some of the preclinical studies using the selected combinations.