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

摘要 膝关节骨关节炎(OA)引起的慢性疼痛是导致残疾的一大因素，影响着数百万美国人。 睡眠障碍会加重膝骨性关节炎的疼痛症状。然而，膝部的治疗结果 办公自动化仍然很穷。这是因为疼痛不是一成不变的，潜在疼痛机制的不同会影响 治疗反应。虽然膝骨性关节炎疼痛可能是由于组织和关节损伤(伤害性疼痛)，但它也可以 中枢神经系统(CNS)功能障碍--即伤害性疼痛--可以增强和维持这种功能。不同 潜在的机制可能解释与大麻类活性化合物临床试验结果不一致的原因 在大麻属植物中。虽然临床试验表明大麻素可能是有用的镇痛剂和睡眠辅助剂， 这些试验是用Δ⁹-四氢大麻酚及其类似物进行的，它们有滥用的可能性。 然而，最近的一项研究表明，大麻二醇(CBD)可以减轻膝盖男性的疼痛并增强其功能 骨关节炎。CBD是非醉人的，具有止痛和消炎作用，也显示出 改善睡眠。拟议的研究将检验CBD和/或THC如何影响膝骨性关节炎患者的睡眠，以及 与睡眠相关的变化对疼痛的影响程度。我们的主要假设是CBD+THC将 改善睡眠最多，其次是THC，然后是CBD，睡眠改善将在一定程度上起到调节作用 疼痛的改善。为了验证这一假设，我们提出了三个目标，它们将为我提供额外的 作为独立研究人员，对统一慢性疼痛、睡眠和大麻素机制所需的培训：1) 获得临床试验指导和前沿疼痛表型方法方面的培训 评估疼痛集中度是否预测疼痛的随机、双盲、2x2析因设计研究 膝骨性关节炎患者对CBD和THC的不同止痛反应(父母研究R01AT010381)； 目标1内的辅助试验，通过自我报告和客观措施调查大麻素对睡眠的影响； 3)评估大麻素睡眠效应是否调节疼痛的变化，并探索睡眠和 疼痛表型。考虑到疼痛集中发生在许多慢性疼痛情况下，我们在膝盖上的方法 OA可能对开发非阿片类止痛药具有广泛的影响。颁奖典礼将在 密歇根大学(UM)由Daniel Clauw，Richard Harris，Steven Harte，Alexander Tsodikov博士领导， 海伦·伯吉斯和大卫·威廉姆斯，他们是世界著名的慢性疼痛、神经成像、 心理物理学、临床试验分析、睡眠和疼痛心理计量学。UM是一个理想的环境 因为有可用的资源，包括致力于临床疼痛研究的教员 和指导，致力于研究的磁共振成像(MRI)扫描仪和最先进的疼痛测试 设备，以及在慢性疼痛和疲劳研究中心充足的实验室和办公空间。vt.在.的基础上 完成这一奖项后，我将非常适合过渡到一名独立的终身教职教师。

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.