Planning Grant for a Clinical Trial Of Cannabidiol For Postoperative Opioid Reduction in Primary Total Knee Arthroplasty

摘要 膝关节骨关节炎（KOA）是一种常见且使人衰弱的疾病，影响超过1400万美国人。许多KOA 患者需要全膝关节置换术（TKA）来恢复足够的功能。术后，疼痛控制 通过多模式镇痛，包括阿片类药物。然而，阿片类药物具有显著的副作用， 高达6.5%的人在手术后出现新的持续使用，导致美国阿片类药物危机。 因此，开发替代阿片类镇痛药对于预防阿片类药物依赖至关重要 手术后。一类潜在的阿片样物质保留镇痛剂是大麻二酚（CBD），大麻二酚是一种活性化合物， 大麻CBD是非中毒性的，在许多医疗条件下耐受性良好， 抗炎、镇痛和抗焦虑作用。在最近的临床试验中，CBD 由于膝关节OA和其他疾病引起的慢性疼痛的疼痛和功能。此外，小型临床试验表明， 急性施用CBD可以减少阿片类药物的渴望和焦虑-后者与更严重的 手术结果和手术后更大的疼痛。综上所述，这些证据表明，CBD可能 在手术环境中避免使用阿片类药物。然而，虽然CBD被公众广泛用于疼痛， 关节炎和焦虑，没有在手术后环境中进行CBD的研究。拟定研究 是计划进行严格的双盲随机对照试验（RCT）的第一步，以评估 CBD在手术后保留阿片类药物。我们将利用最近FDA批准的Epidiolex（附表V， CBD药物），以确保研究药物的标准化，并提高我们发现的普遍性。主 目的是制定一项临床试验计划，以检查术后给予的CBD是否是阿片类药物- 保留TKA后，并利用我们机构的能力准备和提交后续U 01 申请运行此试验。我们的总体假设是，CBD通过抗阿片类药物发挥阿片类药物节省作用。 炎症、镇痛和抗焦虑机制。为了发展我们的计划，我们提出两个目标。1：设计a 临床试验方案，评估口服CBD是否减少TKA后阿片类药物的消耗。2：完成 以下里程碑为我们成功的U 01应用做好准备：1）制定操作手册 程序; 2）设计和测试我们的研究数据库; 3）开发和测试招聘程序; 4）获得 试验用新药许可证; 5）启动IRB申请，制定知情同意文件;以及6） 制定数据安全和监控计划。拟议的发展计划将是迈向 阐明CBD在手术后环境中的作用。虽然我们拟定的研究将在TKA中进行， 结果将对术后适当使用CBD产生广泛的影响， 各种选择性手术我们的研究结果将有助于如何最好地利用非阿片类药物的持续辩论 镇痛药用于疼痛管理-在阿片类药物持续流行的背景下，这是一个至关重要的领域。

Abstract Knee osteoarthritis (KOA) is a common and debilitating condition, affecting >14 million Americans. Many KOA patients require total knee arthroplasty (TKA) to restore adequate function. Postoperatively, pain control is delivered through multimodal analgesia, including opioids. However, opioids carry significant side effects, and up to 6.5% of people develop new persistent use following surgery, contributing to the US opioid crisis. Therefore, developing alternative opioid sparing analgesics is critical for preventing opioid dependence following surgery. One class of potential opioid-sparing analgesic is cannabidiol (CBD), an active compound in Cannabis sativa. CBD is non-intoxicating and well tolerated across numerous medical conditions, and exerts anti-inflammatory, analgesic, and anxiolytic effects in preclinical studies. In recent clinical trials, CBD improved pain and function in chronic pain due to knee OA and other conditions. Further, small clinical trials have shown that acutely administered CBD reduces opioid craving and anxiety – the latter being associated with worse surgical outcomes and greater pain following surgery. Taken together, this evidence suggests that CBD may be opioid sparing in surgical settings. However, while CBD is widely used by the general public for pain, arthritis, and anxiety, no studies with CBD have been conducted in post-surgical settings. The proposed study represents the first step in planning a rigorous, double-blind, randomized controlled trial (RCT) to assess if CBD is opioid-sparing following surgery. We will leverage the recent FDA approval of Epidiolex (Schedule V, CBD drug) to ensure study drug standardization and improve generalizability of our findings. The primary objective is to develop a clinical trial plan to examine whether post-operatively administered CBD is opioid- sparing following TKA, and to harness the capacity at our institution to prepare and submit a subsequent U01 application to run this trial. Our overarching hypothesis is that CBD exerts opioid-sparing effects through anti- inflammatory, analgesic, and anxiolytic mechanisms. To develop our plan, we propose two aims. 1: Design a clinical trial protocol that assesses whether oral CBD reduces opioid consumption following TKA. 2: Complete the following milestones to prepare us for a successful U01 application: 1) Develop a manual of operating procedures; 2) Design and test our study database; 3) Develop and test recruitment procedures; 4) Obtain an Investigational New Drug License; 5) Initiate a IRB application, develop informed consent document; and 6) Develop a Data Safety and Monitoring Plan. The proposed development plan would be the first step towards elucidating CBD effects in a post-surgical setting. While our proposed study will be performed in TKA, the results will have broad implications regarding appropriate CBD use in the postoperative period for a wide variety of elective surgeries. Our results will contribute to the ongoing debate of how to best utilize non-opioid analgesics for pain management – an area of critical importance in the context of the ongoing opioid epidemic.