Cannabidiol Pharmacotherapy for Comorbid Opioid Addiction and Chronic Pain

项目摘要/摘要 本建议旨在研究大麻二醇(CBD)的镇痛和抗渴求效果。 合并阿片类药物使用障碍(OUD)和慢性疼痛。约70%的慢性疼痛患者患有 奥德。阿片激动剂治疗有效减少阿片类药物使用过量死亡，但不能缓解慢性 疼痛。趋同的临床前研究表明，大麻类药物可降低疼痛敏感性和寻求阿片类药物 行为，这表明他们可以被利用来治疗。然而，大麻类药物的治疗效果 慢性疼痛和慢性疼痛的合并症仍不清楚。鉴于CBD缺乏享乐性质，并建立了 止痛和抗渴求的作用，它对这一群体具有特殊的治疗前景。 定量感觉测试是一种计算机化的疼痛评估方法，用于可靠地 测量抗伤害感觉并预测疼痛治疗反应。QST疼痛生物标记物可以与 行为范式研究CBD缓解疼痛敏感性的双管齐下的效果和提示- 诱导的阿片类药物渴求。这项提案的目标是应用行为药理学、多模式疼痛 研究和临床试验方法研究CBD对合并症患者的安全性和疗效 乌德和慢性疼痛。这将通过以下方式对患者群体产生重大影响：(I)确定 急性给予CBD的安全性(目标1)；(2)确定降低疼痛敏感性所需的CBD剂量 和线索诱导的阿片类药物渴求(目标2)；(3)了解长期联合服用CBD的安全性 阿片类激动剂维持(目标3)；和(4)提供关于CBD止痛效果的初步数据 临床环境中的严重程度/干预和阿片类药物渴求(目标4)。目标1和目标2将通过 人体实验室研究，目标3和4将通过试点临床试验执行。这些研究将 作为新的治疗方法和治疗慢性疼痛的生物标记物的基础。 这项提案将把耶鲁大学和退伍军人事务部康涅狄格州最先进的设施与现有的 与当地阿片类药物治疗方案合作。申请人已经组建了一支著名的专家团队 阿片类药物、大麻类药物和疼痛研究领域的导师。该提案建立在以下基础上的初步工作 大麻素对患有慢性疼痛和慢性疼痛的人类疼痛敏感性的调节。正式的教学论， 研讨会和国家科学会议将支持申请者的培训。具体的培训目标包括 发展(I)成瘾的行为药理学(Ii)多模式疼痛评估，(Iii)的特殊技能 临床试验和高级生物统计学；(Iv)拨款撰写；(V)负责任的研究工作。最后，这一点 应用程序利用申请人作为董事会认证的成瘾精神病学家的坚实的临床基础。这个 来自K23奖项的重要支持将允许申请者的科学发展，导致独立的 及时结合跨学科方法的研究计划，以开发新的治疗方法 乌德和慢性疼痛。

PROJECT SUMMARY/ABSTRACT This proposal seeks to investigate the analgesic and anti-craving efficacy of Cannabidiol (CBD) for comorbid opioid use disorder (OUD) and chronic pain. Chronic pain afflicts approximately 70% of people with OUD. Opioid agonist treatment effectively reduces opioid use overdose deaths, but does not alleviate chronic pain. Convergent preclinical studies have shown that cannabinoids reduce pain sensitivity and opioid-seeking behavior, suggesting they could be leveraged for treatment. Yet, the therapeutic efficacy of cannabinoids for comorbid OUD and chronic pain remains unknown. Given CBD’s lack of hedonic properties and established analgesic and anti-craving effects, it holds particular therapeutic promise for this population. Quantitative Sensory Testing (QST) is a computerized pain assessment method used to reliably measure antinociception and predict the pain treatment response. QST pain biomarkers can be integrated with behavioral paradigms to investigate the two-pronged efficacy of CBD for alleviating pain sensitivity and cue- induced opioid craving. The objective of this proposal is to apply behavioral pharmacology, multimodal pain research and clinical trial methods to study the safety and therapeutic efficacy of CBD for people with comorbid OUD and chronic pain. This will have a significant impact for this patient population, by (i) determining the safety of acute CBD administration (Aim 1); (ii) determining the dose of CBD required to reduce pain sensitivity and cue-induced opioid craving (Aim 2); (iii) understanding the safety of long-term CBD co-administration with opioid agonist maintenance (Aim 3), and (iv) providing preliminary data on the efficacy of CBD to reduce pain severity/interference and opioid craving in the clinical setting (Aim 4). Aims 1 and 2 will be carried out through human laboratory study, and Aims 3 and 4 will be executed through a pilot clinical trial. These studies will serve as the basis for novel treatments and therapeutic biomarkers for comorbid OUD and chronic pain. This proposal will integrate state-of-the-art facilities at Yale and at the VA Connecticut, with established collaborations with local opioid treatment programs. The applicant has assembled a renowned team of expert mentors in the fields of opioid, cannabinoid and pain research. This proposal builds on preliminary work on cannabinoid modulation of pain sensitivity in humans with comorbid OUD and chronic pain. Formal didactics, symposia and national scientific meetings will support the applicant’s training. Specific training goals include developing exceptional skills in (i) behavioral pharmacology of addiction (ii) multimodal assessment of pain, (iii) clinical trials and advanced biostatistics, (iv) grant writing, and (v) responsible conduct of research. Finally, this application leverages the applicant’s robust clinical foundation as a board-certified addiction psychiatrist. The vital support from this K23 award will allow the applicant’s scientific development, leading to an independent research program that timely combines interdisciplinary methods towards developing novel therapeutics for OUD and chronic pain.