Proof of Concept Trial of Cannabis Derivatives in Neuropathic Pain.

摘要 慢性疼痛是美国退伍军人的一个重大负担，是退伍军人特别关注的问题。 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 糖尿病患者，CDNP对退伍军人的致残性比平民更大。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， CDNP患者由于依从性差和副作用。持续的阿片类药物危机导致了重大的 对控制疼痛的安全有效的替代品感兴趣，并且非常需要研究 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的临床医生对大麻及其主要成分表示了极大的兴趣。 成分（δ-9-四氢大麻酚，THC;大麻二酚，CBD）用于疼痛管理，但现存的 描述大麻对疼痛的潜在风险和益处的研究很薄弱。本研究代表了 这是第一次研究大麻素对患有CDNP的退伍军人的潜在益处和风险的重大努力。 通过国家认可的大麻研究专家（D 'Souza博士），退伍军人 慢性疼痛研究专家（McGeary博士），海因斯合作研究计划协调中心，以及 阿尔伯克基合作研究项目临床研究药学协调中心。这 研究合作的发展是为了有意义地扩展现有的研究， 随机、双盲、安慰剂对照、平行组设计。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 在缓解退伍军人CDNP患者疼痛方面优于安慰剂，但优于上级。此外，这将权衡安全性和 干预措施对已确定疗效的耐受性。调查人员将与5名VAMC合作， 招募320名成年退伍军人样本，他们符合高影响CDNP的诊断标准， CDNP治疗，目前不是大麻使用者，不符合大麻诊断标准 使用Disorder。入组的退伍军人将被随机分配到四个研究组之一：1）5 mg 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 2-1周滴定期（以最大限度地减少副作用并提高耐受性），随后为4周目标治疗期 治疗剂量和随后的2周减量滴定（以尽量减少大麻戒断症状）。的 本研究的主要结果是疼痛数字评定量表（NRS）的平均变化， 每天完成三次标准化疼痛日记，产生平均每日疼痛评分。二次 结果包括疼痛质量、功能/残疾、健康相关生活质量、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 使用尿生物标志物、每周药丸计数和每日手机辅助远程 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。 将使用3水平分层混合效应线性回归模型分析数据。如果成功， 拟议的研究将为在美国使用大麻治疗CDNP提供最高质量的概念验证数据。 老兵这些数据将为疼痛退伍军人的大麻研究提供有意义的指导 并且很有可能也会使平民受益。

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.