Mechanisms of cannabidiol in persons with MS: the role of sleep and pain phenotype

摘要 慢性疼痛影响35%-40%的慢性神经系统疾病患者，包括多发性 硬化症(MS)-一种影响约100万人的中枢神经系统自身免疫性疾病 美国人。不幸的是，神经性疼痛的传统治疗方法的止痛效果是 有限的。大麻二醇(CBD，从大麻中提取)是一种安全、有前途的免费治疗方法， 常与Δ-9-四氢大麻酚(THC)联合用于治疗多发性硬化症(PWMS)患者的疼痛。 然而，CBD-相对于研究得更好的大麻素制剂，其独特的止痛机制 由于THC或THC/CBD组合(具有滥用潜力)-没有被很好地理解，刺激了 需要以CBD单一疗法为重点的机制研究。来自全国范围内研究的初步数据 研究人员进行的PWMS表明，CBD可能通过以下途径独立发挥镇痛作用 改善睡眠，特别是在伴有肿瘤性(集中性)疼痛的PWMS患者。现在正在进行的调查 在这些基础上，早期的发现可以为CBD诱导止痛的机制提供新的见解 效果，并确定最有可能对CBD治疗慢性疼痛有反应的疼痛表型。这 创新的机械学研究建议应用新的多导睡眠图睡眠阶段分析 超越传统的多导睡眠图(PSG)测量，衍生出睡眠宏观结构的新特征 从家庭活动记录中，评估在止痛剂中可能起关键机制作用的睡眠方面 CBD的影响。我们的首要目标是应用这些新的睡眠评估方法，再加上 经过验证的疼痛表型技术，以揭示CBD、睡眠和 PWMS中的止痛，与THC单一治疗、THC/CBD联合治疗或安慰剂相比。有以下情况的人 经历慢性疼痛的MS将接受疼痛表型鉴定，并对肿瘤进行有效的调查测量。 和神经病理性疼痛，并随机接受CBD(Epidiolex®)、THC(屈诺比诺)、THC/CBD联合治疗，或 安慰剂治疗12周。实验室中的PSG和14天的手腕佩戴的肌动图将在基线和12周内收集 后处理。睡眠微结构的变化(目标1；包括睡眠阶段、睡眠时长、睡眠阶段 转移概率和熵)和宏观结构(目标2；包括睡眠规律性、节律性、计时 和持续时间)将在大麻素组和安慰剂组之间进行比较，疼痛表型将是 被评估为CBD相关睡眠变化的预测因子。目标3将评估睡眠指标 微结构和宏观结构作为CBD镇痛反应的中介。这项研究产生的数据 将为CBD研究提供信息，涉及一系列神经和其他慢性疾病，这可能是 应用于开发治疗慢性疼痛的精准医学方法。

Abstract Chronic pain affects 35-40% of people with chronic neurological conditions, including persons with multiple sclerosis (MS) - an autoimmune disease of the central nervous system affecting approximately 1 million Americans. Unfortunately, the analgesic effects of conventional treatments for pain in neurological conditions is limited. Cannabidiol (CBD, derived from cannabis sativa) is a safe, promising complimentary therapy that is frequently used in combination with Δ-9-tetrahydrocannabinol (THC) to treat pain in persons with MS (PwMS). However, the distinct analgesic mechanisms of CBD - relative to better-studied cannabinoid formulations such as THC or THC/CBD combinations (which carry abuse potential) - are not well understood, galvanizing the need for mechanistic research focused on CBD monotherapy. Preliminary data from a nationwide study of PwMS conducted by the investigators suggest that CBD could independently exert analgesic effects through improved sleep, particularly among PwMS with nociplastic (centralized) pain. Investigations that now build upon these early findings could provide novel insight into mechanisms by which CBD induces analgesic effects, and identify pain phenotypes that are most likely to be responsive to CBD for chronic pain. This innovative, mechanistic study proposes to apply novel polysomnographic sleep stage analyses that extend beyond conventional polysomnography (PSG) measures, and new features of sleep macrostructure derived from in-home actigraphy, to assess aspects of sleep that could play key mechanistic roles in the analgesic effects of CBD. Our overarching goal is to apply these novel sleep assessment methods, coupled with validated pain phenotyping techniques, to uncover unique mechanistic associations between CBD, sleep, and analgesia in PwMS, compared to THC monotherapy, THC/CBD combination therapy, or placebo. Persons with MS who experience chronic pain will undergo pain phenotyping with validated survey measures of nociplastic and neuropathic pain, and randomized to CBD (Epidiolex®), THC (dronabinol), THC/CBD combination, or placebo for 12 weeks. In-lab PSG and 14-day wrist-worn actigraphy will be collected at baseline and 12 weeks’ post-treatment. Changes in sleep microstructure (Aim 1; including sleep stage bout length, sleep stage transition probability, and entropy) and macrostructure (Aim 2; including sleep regularity, rhythmicity, timing and duration) will be compared between cannabinoid and placebo groups, and pain phenotype will be assessed as a predictor of CBD-related changes in sleep. Aim 3 will assess the measures of sleep microstructure and macrostructure as mediators of analgesic response to CBD. Data generated from this study will to inform CBD research, across a spectrum of neurological and other chronic conditions, that can be applied to the development of precision-medicine approaches for chronic pain.