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.

项目总结/摘要 膝关节骨关节炎是一种非常常见和衰弱的疾病，影响超过1400万美国人。很多人 膝关节骨关节炎需要全膝关节置换术（TKA）来治疗疼痛和改善功能， 仍然是治疗TKA术后疼痛的主要方式。然而，阿片类药物具有显著的副作用， 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，围手术期阿片类药物暴露与患者依赖 手术恢复后长期使用阿片类药物，随后出现新的慢性阿片类药物依赖， 增加的医疗费用，阿片类药物使用障碍（成瘾）的发展，过量和死亡。因此，我们认为， 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镇痛药物。虽然CBD是由一个 估计有14%的普通公众，最常见的是慢性疼痛和相关症状（包括作为一种 阿片类替代品），对CBD的严格临床研究有限。CBD显示出巨大的希望，因为它是非- 在动物研究中，它具有麻醉作用，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。是 在许多医疗条件下也耐受良好。此外，CBD（Epidiolex），我们将 使用，由食品和药物管理局批准用于治疗一些癫痫发作疾病，并且它不受 同样的监管限制， Δ -9-四氢大麻酚（THC）。在这项研究中，我们将招募380名患者， 来自两个大型医疗系统的初次全膝关节置换术（TKA）。在这个多点的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 mg/天）与手术后4周的CBD或安慰剂一起施用。我们 主要结果是术后4周内阿片类药物的消耗量。研究 设计也将使我们能够调查和解开CBD的术前和术后影响，包括减少 焦虑、睡眠障碍和炎症。我们还将对副作用进行详细调查 和不良事件，以及CBD在整个治疗过程中的药代动力学。成功 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 治疗术后疼痛考虑到美国每年有超过5000万例手术， 研究结果可能具有比TKA更广泛的意义，并将激发重要的新产品线， 研究CBD的作用。