Cannabidiol Pharmacotherapy for Comorbid Opioid Addiction and Chronic Pain

项目总结/摘要 该提案旨在研究大麻二酚（CBD）的镇痛和抗渴望功效， 共病阿片类药物使用障碍（OUD）和慢性疼痛。慢性疼痛折磨着大约70%的人， OUD。阿片类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 痛苦汇聚的临床前研究表明，大麻素降低疼痛敏感性和阿片类药物寻求 行为，这表明它们可以用于治疗。然而，大麻素的治疗效果 OUD和慢性疼痛的共病仍然未知。由于CBD缺乏享乐属性， 止痛和抗渴望的效果，它持有特别的治疗承诺，为这一群体。 定量感觉测试（QST）是一种计算机化的疼痛评估方法， 测量抗伤害感受并预测疼痛治疗反应。QST疼痛生物标志物可以与 行为模式，以调查CBD的双管齐下的疗效，减轻疼痛敏感性和线索， 诱导阿片类药物成瘾这项提案的目的是应用行为药理学，多模式疼痛 研究和临床试验方法，以研究CBD对共病患者的安全性和治疗效果 OUD和慢性疼痛。这将对该患者群体产生重大影响，通过（i）确定 急性CBD给药的安全性（目标1）;（ii）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望（目标2）;（iii）了解长期CBD与 阿片类激动剂维持（目标3），以及（iv）提供CBD减轻疼痛疗效的初步数据 严重性/干扰和阿片类药物渴求在临床环境（目标4）。目标1和2将通过以下方式实现： 人类实验室研究，以及目标3和4将通过初步临床试验执行。这些研究将 作为OUD和慢性疼痛共病的新型治疗和治疗生物标志物的基础。 该提案将整合耶鲁大学和弗吉尼亚州康涅狄格州的最先进的设施， 与当地阿片类药物治疗计划合作。申请人组建了一个著名的专家团队， 阿片类药物、大麻素和疼痛研究领域的导师。这项建议的基础是以下方面的初步工作： 大麻素调节OUD和慢性疼痛共病患者的疼痛敏感性。正式的教学法， 专题讨论会和国家科学会议将支持申请者的培训。具体培训目标包括 发展特殊技能（i）成瘾的行为药理学（ii）疼痛的多模式评估，（iii） 临床试验和先进的生物统计学，（iv）赠款写作，和（v）负责任的研究行为。最后 申请利用申请人作为董事会认证的成瘾精神病学家的强大临床基础。的 这项K23奖的重要支持将使申请人的科学发展，导致一个独立的 研究计划，及时结合跨学科的方法，开发新的治疗方法， OUD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.