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

大麻二酚对多发性硬化症患者的作用机制：睡眠和疼痛表型的作用

• 批准号: 10468081
• 负责人: Tiffany Joy Braley
• 金额: $ 69.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-15 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10468081
• 关键词: Absence of pain sensation; Affect; Aftercare; American; Analgesics; Autoimmune Diseases; CNS autoimmune disease; Cannabidiol; Cannabinoids; Cannabis sativa plant; Chronic; Combined Modality Therapy; Coupled; Data; Development; Dronabinol; Electroencephalogram; Entropy; Epidiolex; Exhibits; Formulation; Frequencies; Goals; Heart; Home; Individual; Intervention; Investigation; Knowledge; Length; Measures; Mediator of activation protein; Methods; Modeling; Multiple Sclerosis; National Center for Complementary and Integrative Health; Neuraxis; Neurologic; Numeric Rating Scale; Pain; Pain intensity; Pain management; Patient Self-Report; Patients; Periodicity; Persons; Phenotype; Placebos; Play; Polysomnography; Population; Positioning Attribute; Probability; REM Sleep; Randomized; Research; Research Personnel; Respondent; Role; Signal Transduction; Sleep; Sleep Disorders; Sleep Stages; Sleep disturbances; Surveys; Techniques; Tetrahydrocannabinol; Therapeutic; Time; Wrist; abuse liability; actigraphy; central pain; chronic pain; chronic pain management; conventional therapy; experience; improved; innovation; insight; non rapid eye movement; novel; pain processing; painful neuropathy; placebo group; precision medicine; response; sensory system; sleep health; sleep onset; sleep pattern; sleep physiology; treatment group

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.

抽象的 慢性疼痛影响 35-40% 患有慢性神经系统疾病的人，包括患有多种疾病的人 硬化症 (MS) - 一种中枢神经系统自身免疫性疾病，影响约 100 万人 不幸的是，传统疗法对神经系统疼痛的镇痛作用是有限的。 大麻二酚（CBD，源自大麻）是一种安全、有前途的补充疗法。 经常与 Δ-9-四氢大麻酚 (THC) 联合使用来治疗多发性硬化症 (PwMS) 患者的疼痛。 然而，CBD 独特的镇痛机制 - 相对于经过更好研究的大麻素制剂，例如 由于 THC 或 THC/CBD 组合（具有滥用潜力） - 尚未得到充分理解，从而激发了 需要针对 CBD 单一疗法进行机制研究来自全国性研究的初步数据。 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，尤其是伴有伤害性（集中性）疼痛的 PwMS。 这些早期发现可以为 CBD 诱导镇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。 创新的机械研究建议应用新颖的多导睡眠阶段分析，以扩展 超越传统的多导睡眠图（PSG）测量，并衍生出睡眠宏观结构的新特征 从家庭体动记录仪中，评估睡眠的各个方面，这些方面可能在镇痛中发挥关键的机械作用 我们的首要目标是应用这些新颖的睡眠评估方法，再加上 经过验证的疼痛表型分析技术，揭示 CBD、睡眠和疼痛之间的独特机制关联 与 THC 单一疗法、THC/CBD 联合疗法或安慰剂相比，PwMS 的镇痛效果。 经历慢性疼痛的多发性硬化症患者将接受经过验证的伤害塑料调查措施的疼痛表型分析 和神经性疼痛，并随机分配至 CBD (Epidiolex®)、THC（屈大麻酚）、THC/CBD 组合，或 将在基线和 12 周后收集 12 周的实验室内 PSG 和 14 天腕戴式体动记录仪。 治疗后睡眠微观结构的变化（目标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、时间安排） 和持续时间）将在大麻素组和安慰剂组之间进行比较，并且疼痛表型将 作为 CBD 相关睡眠变化的预测指标，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。 将为 CBD 研究提供信息，涵盖一系列神经系统疾病和其他慢性疾病，这可以 应用于开发慢性疼痛的精准医学方法。