Cannabidiol for postoperative Opioid Reduction in primary total Knee arthroplasty – a randomized, 2x2 factorial, double-blind, placebo-controlled clinical trial (The CORK trial)

大麻二酚用于初次全膝关节置换术术后阿片类药物减少 — 一项随机、2x2 析因、双盲、安慰剂对照临床试验（CORK 试验）

• 批准号: 10733651
• 负责人: Kevin Foxman Boehnke
• 金额: $ 127.54万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733651
• 关键词: Acute; Acute Pain; Adverse event; Affect; Age; American; Analgesics; Animals; Anti-Anxiety Agents; Anti-Inflammatory Agents; Anxiety; Arthritis; Cannabidiol; Cannabinoids; Cessation of life; Childhood; Chronic; Client satisfaction; Clinical; Clinical Research; Clinical Trials; Constipation; Controlled Clinical Trials; Development; Dizziness; Dose; Double-Blind Method; Drug Kinetics; Epidiolex; Epilepsy; Flare; General Population; Good Manufacturing Process; Grant; Health Care Costs; Health system; Human; Inflammation; Inflammatory; Interleukin-6; Investigation; Investigational New Drug Application; Knee Osteoarthritis; Literature; Mediating; Medical; Meta-Analysis; Methodology; Modality; Nausea; Operative Surgical Procedures; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Rotation; Outcome; Overdose; Pain; Pain management; Participant; Patients; Perioperative; Persons; Pharmaceutical Preparations; Placebo Control; Placebos; Postoperative Pain; Postoperative Period; Pre-Clinical Model; Property; Randomized; Randomized, Controlled Trials; Reporting; Research; Research Design; Role; Rotator Cuff; Safety; Sample Size; Severities; Site; Sleep; Sleep disturbances; Source; Symptoms; Testing; Tetrahydrocannabinol; Therapeutic Effect; Translating; United States; United States Food and Drug Administration; addiction; anxiety reduction; chronic pain; clinical trial protocol; craving; design; functional improvement; improved; inflammatory marker; knee replacement arthroplasty; multimodality; opioid exposure; opioid sparing; opioid use; opioid use disorder; pain reduction; postoperative recovery; pre-clinical; preclinical study; primary outcome; recruit; repaired; secondary outcome; sex; side effect; systematic review

PROJECT SUMMARY / ABSTRACT Knee osteoarthritis is a very common and debilitating condition, affecting >14 million Americans. Many people with knee osteoarthritis require total knee arthroplasty (TKA) to treat pain and improve function, and opioids remain the primary modality for treatment of pain after TKA. However, opioids carry significant side effects, with ~80% of surgical patients reporting at least one moderate or severe side effect (e.g. nausea, dizziness, constipation). Moreover, perioperative opioid exposure is associated with patients becoming dependent on opioids long after surgical recovery, and new chronic opioid dependence is subsequently associated with increased healthcare costs, the development of opioid use disorder (addiction), overdose, and death. Hence, research into opioid alternatives for postoperative pain is of critical importance. Cannabinoids, including cannabidiol (CBD), are one class of potential opioid-sparing pain medications. While CBD is used by an estimated 14% of the general public, most frequently for chronic pain and related symptoms (including as an opioid substitute), rigorous clinical research on CBD is limited. CBD shows great promise, as it is non- intoxicating, and reduces pain, anxiety and inflammation in animal studies. Previous research has found that CBD reduced opioid craving and anxiety, which further suggests it may decrease opioid use after surgery. It is also well tolerated across numerous medical conditions. Moreover, CBD (Epidiolex), the study drug we will use, is approved by the Food and Drug Administration for treating some seizure disorders, and it is not subject to the same regulatory restrictions as Δ -9-tetrahydrocannabinol (THC). In this study, we will recruit 380 patients undergoing primary total knee arthroplasty (TKA) from two large health systems. In this multi-site, 2x2 factorial, double-blind, randomized controlled trial, participants will receive one of four combinations of placebo or CBD (300 mg/day) for one week prior to surgery together with CBD or placebo for 4 weeks following surgery. Our primary outcome will be post-operative opioid consumption in the 4-week period following surgery. The study design will also allow us to investigate and untangle CBD's pre- and post-surgical effects, including reduction of anxiety, sleep disturbance and inflammation. We will also conduct detailed investigations of the side effects and adverse events, as well as pharmacokinetics of CBD throughout the treatment course. The successful completion of this study will give much needed evidence for the role of CBD as an opioid-sparing medication for pain after surgery. Given that there are more than 50 million surgeries each year in the United States, these findings could have much broader implications beyond TKA and would motivate important new lines of research into the role of CBD.

项目概要/摘要 膝骨关节炎是一种非常常见且令人衰弱的疾病，影响着超过 1400 万美国人。很多人 膝骨关节炎需要全膝关节置换术 (TKA) 来治疗疼痛和改善功能，以及阿片类药物 仍然是 TKA 术后疼痛治疗的主要方式。然而，阿片类药物具有显着的副作用， 约 80% 的手术患者报告至少一种中度或重度副作用（例如恶心、头晕、 便秘）。此外，围术期阿片类药物暴露与患者对阿片类药物的依赖有关 手术恢复后很长时间内阿片类药物，新的慢性阿片类药物依赖随后与 医疗费用增加、阿片类药物使用障碍（成瘾）、用药过量和死亡。因此， 研究阿片类药物替代品治疗术后疼痛至关重要。大麻素， 包括 大麻二酚（CBD）是一类潜在的阿片类止痛药。虽然 CBD 被使用 据估计 14% 的公众，最常见的是慢性疼痛和相关症状（包括作为 阿片类药物替代品），对 CBD 严格的临床研究有限。 CBD 显示出巨大的前景，因为它是非 在动物研究中，它具有令人陶醉的作用，并能减轻疼痛、焦虑和炎症。先前的研究发现 CBD 减少了阿片类药物的渴望和焦虑，这进一步表明它可能会减少手术后阿片类药物的使用。这是 对多种医疗状况也具有良好的耐受性。此外，我们将研究药物 CBD (Epidiolex) 用途，经食品和药物管理局批准用于治疗某些癫痫病，并且不受限制 与相同的监管限制 Δ -9-四氢大麻酚（THC）。在这项研究中，我们将招募 380 名患者 接受来自两个大型卫生系统的初次全膝关节置换术（TKA）。在这个多站点 2x2 阶乘中， 双盲、随机对照试验，参与者将接受安慰剂或 CBD 的四种组合之一 （300 毫克/天）术前 1 周，与 CBD 或安慰剂一起术后 4 周。我们的 主要结局是术后 4 周内阿片类药物的消耗量。研究 设计还将使我们能够研究和理清 CBD 的手术前和手术后效果，包括减少 焦虑、睡眠障碍和炎症。我们也会对副作用进行详细的调查 和不良事件，以及整个治疗过程中 CBD 的药代动力学。成功者 这项研究的完成将为 CBD 作为阿片类药物的作用提供急需的证据 用于手术后的疼痛。鉴于美国每年有超过 5000 万例手术，这些 研究结果可能会产生比全膝关节置换术更广泛的影响，并会激发重要的新路线 研究 CBD 的作用。