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

大麻二酚用于初次全膝关节置换术术后阿片类药物减少的临床试验规划拨款

• 批准号: 10294554
• 负责人: Kevin Foxman Boehnke
• 金额: $ 20.59万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-02 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294554
• 关键词: Absence of pain sensation; Acute; Acute Pain; Affect; American; Analgesics; Anti Inflammatory Analgesics; Anti-Anxiety Agents; Anti-Inflammatory Agents; Antiinflammatory Effect; Anxiety; Area; Arthritis; Award; C-reactive protein; Cannabidiol; Cannabinoids; Cannabis sativa plant; Child; Chronic; Clinic; Clinical Research; Clinical Trials; Clinical trial protocol document; Consent Forms; Data; Databases; Dependence; Development Plans; Dose; Double-Blind Method; Ensure; Epidiolex; Exposure to; FDA approved; Formulation; General Population; Grant; Hospitalization; Human; Individual; Institution; Institutional Review Boards; Interleukin-6; Intravenous; Investigational Drugs; Kidney Transplantation; Knee; Knee Osteoarthritis; Licensing; Manuals; Medical; Meta-Analysis; Methodology; Monitor; Narcotics; Operative Surgical Procedures; Opiate Addiction; Opioid; Opioid Analgesics; Oral; Pain; Pain management; Participant; Patients; Pharmaceutical Preparations; Placebos; Postoperative Pain; Postoperative Period; Procedures; Protocols documentation; Randomized; Randomized Controlled Trials; Research; Research Personnel; Risk; Running; Safety; Sample Size; Schedule; Seizures; Sleep; Standardization; Surgeon; Symptoms; Testing; Tetrahydrocannabinol; Translating; addiction; chronic pain; craving; design; disability; improved; improved functioning; inflammatory marker; knee replacement arthroplasty; men; multimodality; non-opioid analgesic; opioid epidemic; opioid exposure; opioid sparing; opioid use; osteoarthritis pain; pain reduction; preclinical study; prescription opioid; prevent; protocol development; recruit; side effect; surgery outcome; systematic review

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.

抽象的 膝盖骨关节炎（KOA）是一种常见且令人衰弱的疾病，影响了1400万美国人。许多KOA 患者需要全膝关节置换术（TKA）才能恢复足够的功能。术后，疼痛控制是 通过包括阿片类药物在内的多模式镇痛。但是，阿片类药物具有重大副作用，并且 多达6.5％的人在手术后发展出新的持续使用，这导致了美国阿片类药物危机。 因此，开发替代的Ooid保留镇痛药对于预防OID依赖性至关重要 手术后。一类潜在的阿片类镇痛镇痛是大麻二醇（CBD），一种活性化合物 大麻sativa。 CBD在众多医疗条件下无毒性且耐受性良好，并且执行 临床前研究中的抗炎，镇痛和抗焦虑作用。在最近的临床试验中，CBD改进了 膝盖OA和其他疾病引起的慢性疼痛疼痛和功能。此外，已经显示了小型临床试验 急性管理的CBD降低了Oioid的渴望和动画 - 后者与更糟 手术后的手术结局和更大的疼痛。综上所述，这些证据表明CBD可能 在外科手术环境中保留阿片类药物。但是，尽管CBD被公众广泛用于痛苦，但 关节炎和动画，在手术后的环境中没有对CBD进行研究。拟议的研究 代表计划严格，双盲，随机对照试验（RCT）的第一步，以评估是否是否 手术后，CBD正在占阿片类药物。我们将利用Epidiolex最近的FDA批准（附表V， CBD药物），以确保研究药物标准化并提高我们发现的普遍性。主要 目的是制定临床试验计划，以检查术后给药的CBD是否是阿片类药物 在TKA之后保留，并利用我们机构准备并提交后续U01的能力 申请进行此试验。我们的总体假设是，CBD通过抗 - 炎症，镇痛和抗焦虑机制。为了制定我们的计划，我们提出了两个目标。 1：设计 临床试验方案评估口服CBD是否会减少TKA后的OOID消耗。 2：完成 以下里程碑，为我们准备成功的U01应用程序：1）制定操作手册 程序； 2）设计和测试我们的研究数据库； 3）制定和测试招聘程序； 4）获得一个 调查新药许可； 5）启动IRB申请，开发了知情同意文件；和6） 制定数据安全和监视计划。拟议的发展计划将是迈向的第一步 在手术后环境中阐明CBD效应。虽然我们提出的研究将在TKA中进行，但 结果将对术后适当使用的适当使用具有广泛的影响 各种选修手术。我们的结果将有助于如何最好地利用非阿片类药物进行持续的辩论 用于疼痛管理的镇痛学 - 在正在进行的阿片类药物流行的背景下至关重要的领域。