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 膝骨关节炎 (KOA) 是一种常见且令人衰弱的疾病，影响超过 1400 万美国人。许多KOA 患者需要进行全膝关节置换术（TKA）才能恢复足够的功能。术后，疼痛控制是 通过多模式镇痛（包括阿片类药物）提供。然而，阿片类药物具有显着的副作用，并且 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，开发替代阿片类药物的镇痛药对于预防阿片类药物依赖至关重要 手术后。一类潜在的阿片类镇痛药是大麻二酚（CBD），它是一种活性化合物 大麻。 CBD 是无毒的，并且在多种疾病中具有良好的耐受性，并且可以发挥作用 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 改善了 膝关节骨关节炎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 强烈施用 CBD 可以减少阿片类药物的渴望和焦虑——后者与更糟糕的情况有关 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 在手术环境中应节约使用阿片类药物。然而，虽然 CBD 被公众广泛用于治疗疼痛， 关节炎和焦虑症，尚未在术后环境中进行 CBD 的研究。拟议的研究 代表了规划严格、双盲、随机对照试验 (RCT) 的第一步，以评估是否 手术后 CBD 可以节省阿片类药物。我们将利用 FDA 最近批准的 Epidiolex（附表 V、 CBD 药物），以确保研究药物标准化并提高我们研究结果的普遍性。初级 目标是制定一项临床试验计划，以检查术后施用的 CBD 是否是阿片类药物 节省后续 TKA，并利用我们机构的能力准备和提交后续 U01 申请运行此试验。我们的首要假设是 CBD 通过抗阿片类药物发挥节省阿片类药物的作用 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：设计一个 评估口服 CBD 是否会减少 TKA 后阿片类药物消耗的临床试验方案。 2：完成 以下里程碑帮助我们为成功的 U01 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）制定并测试招聘程序； 4) 获得 新药研究许可证； 5) 发起IRB申请，制定知情同意文件；和 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 在术后环境中的作用。虽然我们提出的研究将在 TKA 中进行， 结果将对术后期间适当使用 CBD 产生广泛影响 各种择期手术。我们的结果将有助于关于如何最好地利用非阿片类药物的持续辩论 用于疼痛管理的镇痛药——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。