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

摘要 慢性疼痛影响35-40%患有慢性神经系统疾病的人，包括患有多种神经系统疾病的人。 硬化症（MS）-中枢神经系统的自身免疫性疾病，影响约100万 美国人不幸的是，传统治疗方法对神经系统疾病疼痛的镇痛作用是 有限公司大麻二酚（CBD，来自大麻）是一种安全，有前途的免费治疗， 经常与Δ-9-四氢大麻酚（THC）组合用于治疗MS患者（PwMS）的疼痛。 然而，CBD的独特镇痛机制-相对于更好地研究的大麻素制剂， 作为THC或THC/CBD组合（具有滥用潜力）-没有得到很好的理解， 需要对CBD单一疗法进行机制研究。一项全国性研究的初步数据显示， 研究人员进行的PwMS表明，CBD可以通过以下方式独立发挥镇痛作用： 改善睡眠，特别是在PwMS与伤害性（集中）疼痛。现在的调查 这些早期发现可以为CBD诱导镇痛的机制提供新的见解 影响，并确定最有可能对CBD慢性疼痛有反应的疼痛表型。这 创新的，机械的研究提出了应用新的多导睡眠图睡眠阶段分析， 超越了传统的多导睡眠图（PSG）的措施，和睡眠宏观结构的新特点， 从家庭活动记录仪中，评估睡眠的各个方面，这些方面可能在止痛剂中发挥关键的机械作用。 CBD的影响。我们的首要目标是应用这些新的睡眠评估方法， 有效的疼痛表型分析技术，以揭示CBD，睡眠和 与THC单一疗法、THC/CBD组合疗法或安慰剂相比，PwMS中的镇痛。人 经历慢性疼痛的MS将通过经验证的伤害性调查措施进行疼痛表型分析。 和神经性疼痛，并随机分配至CBD（Epidiolex®）、THC（屈大麻酚）、THC/CBD组合，或 安慰剂12周。将在基线和12周时收集实验室PSG和14天腕戴式体动记录仪。 后处理。睡眠微结构的变化（目的1;包括睡眠阶段长度，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，时间 和持续时间）将在大麻素组和安慰剂组之间进行比较，并且将对疼痛表型进行评估。 评估为睡眠中CBD相关变化的预测因子。目标3将评估睡眠指标 微观结构和宏观结构作为CBD镇痛反应的介质。本研究生成的数据 将告知CBD研究，在神经系统和其他慢性疾病的范围内， 应用于慢性疼痛的精确医学方法的发展。

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.