Cannabinoid Effects on Sleep and Pain Mechanisms in Osteoarthritis of the Knee

大麻素对膝骨关节炎睡眠和疼痛机制的影响

基本信息

批准号：
10650850
负责人：
Kevin Foxman Boehnke
金额：
$ 14.25万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-15 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10650850
关键词：
Adverse effects Affect American Analgesics Anti-Inflammatory Agents Antiinflammatory Effect Award Cannabidiol Cannabinoids Cannabis sativa plant Central Nervous System Chronic Clinical Trials Communication Complement Conduct Clinical Trials Degenerative polyarthritis Double-Blind Method Environment Equipment Faculty Fatigue Functional Magnetic Resonance Imaging Functional disorder Goals Individual Inflammation Intervention Knee Osteoarthritis Laboratories Lead Magnetic Resonance Imaging Measures Mediating Mediation Mentors Mentorship Methods Michigan N-octanoylglucosylamine National Center for Complementary and Integrative Health Nociception Operative Surgical Procedures Opioid Pain Pain Research Pain management Parents Participant Patient Outcomes Assessments Patient Self-Report Peripheral Pharmaceutical Preparations Phenotype Pittsburgh Sleep Quality Index Placebos Psychometrics Psychophysics Public Health Randomized Reporting Research Research Design Research Personnel Resources Role Running Science Sensory Sleep Sleep disturbances Testing Tetrahydrocannabinol Tissues Training Treatment outcome Universities Wrist abuse liability actigraphy analog central pain chronic pain chronic painful condition clinical pain clinical trial analysis design disability experience functional improvement improved improvement on sleep joint injury men neuroimaging non-opioid analgesic opioid epidemic osteoarthritis pain pain processing pain reduction pain symptom painful neuropathy response secondary outcome side effect skills sleep quality synergism tenure track treatment response

项目摘要

Abstract Chronic pain due to knee osteoarthritis (OA) is a large contributor to disability, affecting millions of Americans. Sleep disturbances contribute to worsened pain symptoms in knee OA. However, treatment outcomes for knee OA remain poor. This is because pain is not monolithic, and differences in underlying pain mechanisms affect treatment response. While knee OA pain can be due to tissue and joint damage (nociceptive pain), it can also be augmented and maintained by central nervous system (CNS) dysfunction - i.e., nociplastic pain. Different underlying mechanisms may explain inconsistent clinical trial results with cannabinoids - the active compounds in Cannabis sativa. While clinical trials suggest that cannabinoids may be useful analgesics and sleep-aids, these trials were done with Δ⁹-tetrahydrocannabinol (THC) and THC analogs, which have abuse potential. However, a recent study showed that cannabidiol (CBD) reduced pain and increased function in men with knee OA. CBD is non-intoxicating, exerts analgesic and anti-inflammatory effects, and also shows promise for improving sleep. The proposed studies will examine how CBD and/or THC affect sleep in knee OA, and the degree to which associated changes in sleep affect pain. Our overarching hypothesis is that CBD+THC will improve sleep the most, followed by THC, and then CBD, and that improvements in sleep will partially mediate improvements in pain. To test this hypothesis, we propose three aims that will provide me with the additional training necessary to unify chronic pain, sleep, and cannabinoid mechanisms as an independent researcher: 1) Acquire training in clinical trial conduct and cutting edge pain-phenotyping methods by helping lead a randomized, double-blinded, 2x2 factorial design study that assesses whether pain centralization predicts differential analgesic responsiveness to CBD and THC in knee OA (parent study R01AT010381); 2) In an ancillary trial within Aim 1, investigate cannabinoid effects on sleep through self-report and objective measures; 3) Assess if cannabinoid sleep effects mediate changes in pain and explore interactions between sleep and pain phenotype. Given that pain centralization occurs in many chronic pain conditions, our approach in knee OA may have broad implications for developing non-opioid analgesics. This award will take place at the University of Michigan (UM) under Drs. Daniel Clauw, Richard Harris, Steven Harte, Alexander Tsodikov, Helen Burgess, and David Williams, who are world-renowned experts in chronic pain, neuroimaging, psychophysics, clinical trial analyses, sleep, and pain psychometrics, respectively. UM is an ideal environment for this award because of the available resources, including faculty who are committed to clinical pain research and mentoring, research-devoted magnetic resonance imaging (MRI) scanners and state-of-the-art pain testing equipment, and ample laboratory and office space at the Chronic Pain and Fatigue Research Center. Upon completing this award, I will be well suited to make the transition to an independent, tenure-track faculty.

抽象的由于膝盖骨关节炎（OA）引起的慢性疼痛是影响数百万美国人的重要原因。睡眠灾害会导致膝盖OA的疼痛症状恶化。但是，膝盖的治疗结果 OA仍然很差。这是因为疼痛不是整体的，并且潜在的疼痛机制的差异会影响治疗反应。虽然膝关节疼痛可能是由于组织和关节损伤（伤害感受性疼痛），但也可以通过中枢神经系统（CNS）功能障碍（即鼻骨疼痛）增强和维护。不同的潜在的机制可能解释了与大麻素的不一致的临床试验结果 - 活性化合物在大麻中。虽然临床试验表明大麻素可能是有用的镇痛药和睡眠辅助药，但这些试验是用具有滥用潜力的Δ⁹四氢大麻酚（THC）和THC类似物进行的。但是，最近的一项研究表明，大麻二酚（CBD）减轻了膝盖男性的疼痛和功能增加 OA。 CBD无毒性，发挥镇痛作用和抗炎作用，也显示出对改善睡眠。拟议的研究将研究CBD和/或THC如何影响膝盖OA的睡眠，以及相关睡眠变化的程度会影响疼痛。我们的总体假设是CBD+THC将改善睡眠最多，其次是THC，然后是CBD，而睡眠的改善将部分介导疼痛的改善。为了检验这一假设，我们提出了三个目标，将为我提供其他将慢性疼痛，睡眠和大麻素机制统一为独立研究人员所必需的训练：1）通过帮助领导A，获得临床试验和尖端疼痛型方法的培训随机，双盲，2x2阶乘设计研究，评估疼痛集中是否预测膝关节OA中对CBD和THC的差异镇痛反应能力（家长研究R01AT010381）； 2） AIM 1中的辅助试验，通过自我报告和客观措施研究大麻素对睡眠的影响； 3）评估大麻素睡眠效应是否介导疼痛的变化并探索睡眠与睡眠之间的相互作用疼痛表型。鉴于疼痛集中化发生在许多慢性疼痛条件下，我们的膝盖方法 OA可能对发展非阿片类镇痛药具有广泛的影响。该奖项将在密歇根大学（UM）Drs。 Daniel Clauw，Richard Harris，Steven Harte，Alexander Tsodikov，海伦·伯吉斯（Helen Burgess）和戴维·威廉姆斯（David Williams）是世界知名的慢性疼痛，神经影像学专家心理物理学，临床试验分析，睡眠和疼痛精神计量学分别。嗯是理想的环境该奖项是因为有可用的资源，包括致力于临床疼痛研究的教师以及心理，研究介绍的磁共振成像（MRI）扫描仪和最先进的疼痛测试慢性疼痛和疲劳研究中心的设备以及足够的实验室和办公空间。之上完成此奖项，我将非常适合过渡到独立的终身教师。