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

摘要 膝骨性关节炎(KOA)是一种常见的使人虚弱的疾病，影响着1400万美国人。许多KOA 患者需要全膝关节置换术(TKA)以恢复足够的功能。术后，疼痛控制是 通过多种方式的止痛，包括阿片类药物。然而，阿片类药物有显著的副作用，而且 高达6.5%的人在手术后出现新的持续使用，这导致了美国的阿片类药物危机。 因此，开发替代阿片类药物是预防阿片依赖的关键。 在手术后。一类潜在的非阿片类止痛药是大麻二酚(CBD)，它是一种 大麻。CBD不会让人醉酒，在多种医疗条件下都能很好地耐受，并能 临床前研究中的抗炎、止痛和缓解焦虑作用。在最近的临床试验中，CBD有所改善 疼痛和功能的慢性疼痛由膝盖骨关节炎和其他情况。此外，小规模的临床试验表明 准确地服用CBD可以减少阿片类药物的渴求和焦虑--后者与更糟糕的病情有关 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 在手术环境中要节约使用阿片类药物。然而，尽管CBD被普通公众广泛用于止痛， 对于关节炎和焦虑症，还没有在手术后环境下进行的关于CBD的研究。建议进行的研究 代表了计划严格的双盲随机对照试验(RCT)的第一步，以评估 CBD是手术后阿片类药物的节约型。我们将利用FDA最近批准的Epidiolex(附表V， CBD药物)，以确保研究药物的标准化，并提高我们研究结果的推广性。初级阶段 目的是制定一项临床试验计划，以检查术后应用CBD是否为阿片类药物。 保留在TKA之后，并利用我们机构的能力来准备和提交后续的U01 申请运行这项试验。我们的主要假设是，CBD通过抗阿片类药物发挥节制阿片的作用。 炎症、止痛和缓解焦虑的机制。为了制定我们的计划，我们提出了两个目标。1：设计 评估口服CBD是否减少TKA后阿片类药物消耗的临床试验方案。2：完成 以下里程碑为我们成功应用U01做好准备：1)开发一本操作手册 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 研究新药许可证；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实现以下目标的第一步 阐明CBD在手术后环境中的作用。虽然我们建议的研究将在将军澳进行，但 结果将对广泛的术后期间适当使用CBD有广泛的影响。 各种选择性手术。我们的结果将有助于正在进行的关于如何最好地利用非阿片类药物的辩论 止痛药用于疼痛管理--在目前阿片类药物流行的背景下，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.