Proof of Concept Trial of Cannabis Derivatives in Neuropathic Pain.

摘要 慢性疼痛对美国退伍军人来说是一个沉重的负担，对患有 糖尿病。糖尿病退伍军人患慢性糖尿病周围神经病变(CDNP)的风险高于平民 对于糖尿病，CDNP对退伍军人的残疾程度比对平民更大。CDNP的一线治疗， 包括加强血糖控制、运动和药物治疗，显示出不一致的结果 因依从性差和副作用而患CDNP的个人。持续的阿片类药物危机导致了重大的 对安全有效的止痛替代品的兴趣，而且有很大的研究需要 疼痛控制的理想选择，可能会改善治疗依从性和结果。退伍军人 团体和退伍军人事务部临床医生对大麻及其主要成分表示了极大的兴趣 用于止痛的成分(β-9-四氢大麻酚，THC；大麻二酚，CBD)，但现有的 描述大麻治疗疼痛的潜在风险和好处的研究很薄弱。本研究代表了 研究大麻类药物对患有CDNP的退伍军人的潜在益处和风险的第一项重大努力 通过全国公认的大麻研究专家(D‘Souza博士)、退伍军人 慢性疼痛研究专家(McGeary博士)，Hines合作研究项目协调中心，以及 阿尔伯克基合作研究项目临床研究药房协调中心。这 开发研究协作是为了使用四臂对现有研究进行有意义的扩展， 随机、双盲、安慰剂对照、平行分组设计。这项随机试验是作为一项 概念验证研究以确定大麻成分(THC、CBD)或其组合(THC+CBD)是否 CDNP退伍军人在减轻疼痛方面优于安慰剂。此外，这将权衡安全性和 干预措施相对于已确定的疗效的耐受性。调查人员将与5家VAMC合作 招募320名符合高影响力CDNP诊断标准的成年退伍军人，病情稳定 接受CDNP治疗(S)，不是目前吸食大麻的人，不符合大麻的诊断标准 使用无序。入伍的退伍军人将被随机分配到四个学习臂中的一个：1)5毫克THC P.O Bid；2) 400 mg CBD P.O Bid；3)5 mg THC+5 mg CBD P.O Bid；或4)安慰剂P.O Bid。参与者将完成一份 2周的滴定阶段(以最大限度地减少副作用和提高耐受性)，然后是4周的目标 治疗剂量和随后两周的滴定(以减少大麻戒断症状)。这个 这项研究的主要结果是疼痛数字分级量表(NRS)的平均变化 标准化的疼痛日记每天完成三次，产生平均每天的疼痛评分。次要的 结果包括疼痛质量、功能/残疾、与健康相关的生活质量、感知 改善和治疗满意度、情绪功能和安全性。调查人员将评估 使用尿液生物标记物、每周药片计数和每日手机远程辅助治疗依从性 结果依从性(Caroma)联系人，还将评估药物依从性和疼痛日记条目。 数据将使用三级分层混合效应线性回归模型进行分析。如果成功，则 拟议的研究将为美国使用大麻治疗CDNP提供最高质量的概念证据数据。 退伍军人。这些数据将为退伍军人疼痛的进一步研究提供有意义的指导 而且很有可能也会让CDNP的平民受益。

ABSTRACT Chronic pain is a significant burden to United States Veterans and is a particular concern for Veterans with diabetes. Diabetic Veterans have a higher risk of chronic diabetic peripheral neuropathy (CDNP) than civilians with diabetes, and CDNP is more disabling for Veterans than it is for civilians. Frontline treatment for CDNP, including enhanced glycemic control, exercise, and pharmacotherapies, show inconsistent outcomes for individuals with CDNP due to poor adherence and side effects. The ongoing opioid crisis has led to significant interest in safe and effective alternatives for pain control, and there is a significant need for research on desirable options for pain control that are likely to improve treatment adherence and outcomes. Veterans groups and Veterans Affairs clinicians have expressed significant interest in cannabis and its principal constituents (delta-9-tetrathydrocannabinol, THC; cannabidiol, CBD) for pain management, but the extant research describing the potential risks and benefits of cannabis for pain is weak. The present study represents the first significant effort to examine the potential benefits and risks of cannabinoids for Veterans with CDNP through a collaboration between a nationally-recognized cannabis research expert (Dr. D’Souza), a Veteran chronic pain research expert (Dr. McGeary), the Hines Cooperative Studies Program Coordinating Center, and the Albuquerque Cooperative Studies Program Clinical Research Pharmacy Coordinating Center. This research collaboration was developed to meaningfully expand on the extant research using a 4-arm, randomized, double-blind, placebo-controlled, parallel group design. This randomized trial was developed as a proof of concept study to determine if cannabis constituents (THC, CBD) or their combination (THC+CBD) are superior to placebo in reducing pain in Veterans with CDNP. Additionally, this will weigh the safety and tolerability of the interventions against the identified efficacy. The investigators will work with 5 VAMCs to recruit a sample of 320 adult Veterans who meet diagnostic criteria for high-impact CDNP, are on stable treatment(s) for CDNP, are not current cannabis users and who do not meet diagnostic criteria for Cannabis Use Disorder. Enrolled Veterans will be randomly assigned to one of four study arms: 1) 5 mg THC P.O BID; 2) 400 mg CBD P.O BID; 3) 5mg THC + 5 mg CBD P.O BID; or 4) placebo P.O BID. Participants will complete a 2-week titration phase (to minimize side effects and improve tolerability) followed by 4 weeks on the target treatment dose and a subsequent 2-week down titration (to minimize cannabis withdrawal symptoms). The primary outcome of this research is mean change in Numeric Rating Scale of pain (NRS) based on a standardized pain diary completed three times daily producing an average daily pain score. Secondary outcomes include measures of pain quality, functioning/disability, health-related quality of life, perceived improvement and treatment satisfaction, emotional functioning, and safety. The investigators will assess treatment adherence using urinary biomarkers, weekly pill counts, and daily cell phone assisted remote outcomes adherence (CAROMA) contacts that will also assess medication adherence and pain diary entries. Data will be analyzed using a 3-level hierarchical mixed-effects linear regression model. If successful, the proposed study will offer the highest quality proof of concept data for the use of cannabis to treat CDNP in U.S. Veterans. These data will provide meaningful guidance on additional studies of cannabis for Veterans with pain and have a high likelihood of also benefiting civilians with CDNP.