Cannabinoid interactions with central and peripheral pain mechanisms in osteoarthritis of the knee

大麻素与膝骨关节炎中枢和外周疼痛机制的相互作用

• 批准号: 10225303
• 负责人: RICHARD E HARRIS
• 金额: $ 76.02万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10225303
• 关键词: Absence of pain sensation; Address; Adverse effects; Adverse event; Affect; American; Analgesics; Anti-Inflammatory Agents; Antiinflammatory Effect; Area; Brain; C-reactive protein; Cannabidiol; Cannabinoids; Cannabis sativa plant; Clinical; Clinical Trials; Data; Degenerative polyarthritis; Diagnostic radiologic examination; Dose; Double-Blind Method; Dronabinol; Epidiolex; Exposure to; Functional disorder; Harm Reduction; Hydroxyl Radical; Individual; Inflammation; Insula of Reil; Interleukin-6; Intervention; Knee; Knee Osteoarthritis; Link; Magnetic Resonance Imaging; Measures; Methods; Neuraxis; Neurobiology; Nociception; Operative Surgical Procedures; Opioid; Outcome; Pain; Pain management; Participant; Patient Outcomes Assessments; Patients; Peripheral; Pharmaceutical Preparations; Phenotype; Placebos; Preparation; Randomized; Reporting; Research Design; Running; Sensory; Series; Symptoms; Testing; Tetrahydrocannabinol; Tissues; Work; base; central pain; chronic pain; chronic painful condition; clinically relevant; design; disability; improved functioning; indexing; inflammatory marker; joint injury; knee pain; marijuana use; men; neurochemistry; neuroimaging; non-opioid analgesic; opioid epidemic; osteoarthritis pain; pain processing; pain reduction; pain symptom; painful neuropathy; peripheral pain; precision medicine; response; secondary analysis; side effect; translational model; treatment response

Abstract Chronic pain due to knee osteoarthritis (OA) is a large contributor to disability, affecting over >14 million Americans. However, treatment is difficult and outcomes are 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., centralized or nociplastic pain. Variable CNS contributions explain why some people have severe radiographic knee damage yet report no pain, while others have “normal” radiographs yet report severe pain. Our group and others have shown that this centralized phenotype occurs in nearly all chronic pain conditions. Further, we have demonstrated the clinical relevance of matching pain mechanisms with therapies, showing that a greater degree of pain centralization lowers responsiveness to interventions (e.g., opioids and surgeries) directed toward reducing nociceptive pain in knee OA. Differences in underlying mechanisms may explain inconsistent clinical trial results with cannabinoids - the active compounds in Cannabis sativa. Clinical trials suggest that cannabinoids can be effective analgesics, but this has been shown primarily with Δ[9]-tetrahydrocannabinol (THC) dominant preparations, 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, and exerts analgesic and anti-inflammatory effects. The proposed studies are the first attempt to understand how CBD and THC affect different chronic pain mechanisms by examining the effects of these compounds on knee OA in individuals with varying degrees of pain centralization. Our overarching hypothesis is that CBD will decrease peripheral inflammation, THC will modify CNS pain processing, and combined CBD+THC will do both. To test this hypothesis, we propose three specific aims. Aim 1: In a randomized, double-blinded, 2x2 factorial design study, longitudinally assess peripheral and CNS effects of CBD and THC on inflammation (interleukin 6) and neurobiological correlates of centralized pain (i.e., default mode network to insula connectivity) using a phenotyping battery of patient reported outcomes, experimental sensitivity testing, and neuroimaging that we have successfully applied to other drugs and pain conditions. Aim 2: Examine effects of THC and CBD and their metabolites on additional indices of brain connectivity and neurochemistry as well as inflammatory markers. Aim 3 (exploratory): Assess whether pain centralization predicts differential analgesic responsiveness to CBD and THC. Given that pain centralization occurs on a spectrum in many chronic pain conditions, our approach in knee OA will act as a translational model that can be applied to nearly all other pain conditions and will have broad implications for developing non-opioid analgesics for pain management.

抽象的 膝骨关节炎 (OA) 引起的慢性疼痛是造成残疾的一个重要因素，影响超过 1400 万美国人，但治疗很困难且结果不佳，这是因为疼痛不是单一的，并且潜在疼痛机制的差异会影响治疗反应。虽然膝骨关节炎疼痛可能是由于组织和关节损伤（伤害性疼痛）引起的，但中枢神经系统 (CNS) 功能障碍也可能会加剧和维持这种疼痛，即中枢性疼痛或伤害性疼痛的变化可以解释其原因。有些人有严重的X光膝关节损伤但报告没有疼痛，而另一些人的X光片“正常”但报告严重疼痛，我们的小组和其他人已经表明这种集中表型发生在几乎所有慢性疼痛病症中。将疼痛机制与治疗相匹配，表明更大程度的疼痛集中会降低对旨在减少膝骨关节炎伤害性疼痛的干预措施（例如阿片类药物和手术）的反应性。潜在机制的差异可能解释了大麻素临床试验结果的不一致。临床试验表明大麻素可以是有效的镇痛剂，但这主要是通过 Δ[9]-四氢大麻酚 (THC) 制剂来证明的，这些制剂具有滥用的可能性。 ） CBD 可以减轻男性膝盖骨关节炎的疼痛并增强其功能，并且具有镇痛和抗炎作用。通过检查这些化合物对不同程度的疼痛集中个体的膝关节骨关节炎的影响，我们的总体假设是 CBD 会减少外周炎症，THC 会改变 CNS 疼痛处理，而 CBD+THC 的组合会影响不同的慢性疼痛机制。为了检验这一假设，我们提出了三个具体目标 1：在一项随机、双盲、2x2 析因设计研究中，纵向评估 CBD 和 THC 对炎症（白细胞介素 6）和中枢神经系统的影响。使用患者报告结果的表型分析、实验敏感性测试和神经影像学来研究中枢性疼痛（即默认模式网络与岛叶连接）的神经生物学相关性，我们已成功地将其应用于其他药物和疼痛状况。目标 2：检查 THC 和疼痛状况的影响。 CBD 及其代谢物对大脑连接和神经化学以及炎症标志物的其他指标的影响 目标 3（探索性）：评估疼痛集中化是否可以预测不同的镇痛反应。鉴于许多慢性疼痛病症中疼痛集中化，我们在膝关节 OA 方面的方法将作为一种转化模型，可应用于几乎所有其他疼痛病症，并将对开发非阿片类药物产生广泛影响。用于疼痛管理的镇痛药。