Cannabidiol Pharmacotherapy for Comorbid Opioid Addiction and Chronic Pain

大麻二酚药物治疗阿片类药物成瘾和慢性疼痛

• 批准号: 10605357
• 负责人: Joao Paulo De Aquino
• 金额: $ 19.17万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605357
• 关键词: Acceleration; Acute; Adverse effects; Adverse event; Analgesics; Animals; Behavior; Behavioral Paradigm; Biological Markers; Biometry; Board Certification; Brief Pain Inventory; Cannabidiol; Cannabinoids; Clinical; Clinical Trials; Collaborations; Connecticut; Cue-induced relapse; Cues; DSM-V; Data; Development; Dose; Enrollment; Foundations; Goals; Grant; Heroin; Hour; Human; Institution; Laboratory Study; Link; Maintenance; Measures; Mentored Patient-Oriented Research Career Development Award; Mentors; Methadone; Methods; Morbidity - disease rate; National Institute of Drug Abuse; Opiate Addiction; Opioid; Opioid agonist; Oral; Outcome; Outcome Study; Pain; Pain Measurement; Pain Research; Pain management; Participant; Patient Self-Report; Patients; Persons; Pharmaceutical Preparations; Pharmacotherapy; Placebo Control; Placebos; Population; Positioning Attribute; Property; Psychiatrist; Questionnaires; Randomized; Relapse; Research; Research Training; Resources; Safety; Self Administration; Sensory; Severities; Sex Differences; Techniques; Testing; Therapeutic; Time; Training; Treatment Efficacy; Urine; Verbal Learning; Visual; Vulnerable Populations; Work; Writing; abuse liability; addiction; antinociception; behavioral pharmacology; career; chronic pain; clinical training; cognitive testing; comorbidity; computerized; craving; drug testing; endogenous cannabinoid system; hedonic; indexing; meetings; mortality; multimodality; new therapeutic target; non-cancer chronic pain; novel; novel therapeutics; opioid agonist therapy; opioid treatment program; opioid use; opioid use disorder; overdose death; pain reduction; pain sensitivity; patient population; performance tests; preclinical study; programs; response; responsible research conduct; safety assessment; safety study; skills; symposium; therapeutic biomarker; treatment response

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.

项目概要/摘要 该提案旨在研究大麻二酚 (CBD) 的镇痛和抗渴功效 共病阿片类药物使用障碍（OUD）和慢性疼痛。大约 70% 的患者患有慢性疼痛 沉香木。阿片类药物激动剂治疗可有效减少阿片类药物使用过量死亡，但不能缓解慢性 疼痛。临床前研究表明，大麻素可降低疼痛敏感性和阿片类药物寻求 行为，表明它们可以用于治疗。然而，大麻素的治疗功效 OUD 和慢性疼痛的共病仍然未知。鉴于 CBD 缺乏享乐属性且已建立 由于具有镇痛和抗渴求作用，它对这一人群具有特殊的治疗前景。 定量感官测试 (QST) 是一种计算机化疼痛评估方法，用于可靠地 测量镇痛作用并预测疼痛治疗反应。 QST 疼痛生物标志物可与 行为范式研究 CBD 对缓解疼痛敏感性和提示的双管齐下功效 诱发阿片类药物的渴望。该提案的目标是应用行为药理学、多模式疼痛 研究 CBD 对合并症患者的安全性和治疗效果的研究和临床试验方法 OUD 和慢性疼痛。通过 (i) 确定 紧急 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 和提示诱发的阿片类药物渴望（目标 2）； (iii) 了解长期 CBD 联合用药的安全性 阿片类激动剂维持治疗（目标 3），以及 (iv) 提供有关 CBD 减轻疼痛功效的初步数据 临床环境中的严重性/干扰和阿片类药物渴望（目标 4）。目标 1 和 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来执行。这些研究将 作为 OUD 共病和慢性疼痛的新疗法和治疗生物标志物的基础。 该提案将整合耶鲁大学和康涅狄格州退伍军人管理局的最先进设施，并建立 与当地阿片类药物治疗项目合作。申请人组建了一支知名的专家团队 阿片类药物、大麻素和疼痛研究领域的导师。该提案建立在以下初步工作的基础上： 大麻素对患有 OUD 和慢性疼痛的人类疼痛敏感性的调节。正式的教学法， 研讨会和国家科学会议将支持申请人的培训。具体培训目标包括 培养以下方面的特殊技能：(i) 成瘾的行为药理学 (ii) 疼痛的多模式评估，(iii) 临床试验和高级生物统计学，(iv) 资助写作，以及 (v) 负责任的研究进行。最后，这个 申请利用了申请人作为委员会认证的成瘾精神病学家的强大临床基础。这 K23 奖项的重要支持将使申请人的科学发展成为独立的 及时结合跨学科方法来开发新疗法的研究计划 OUD 和慢性疼痛。

项目成果

Fatty Acid Amide Hydrolase, Neurodevelopment, and Alcohol: Illuminating the Intricacies of the Endocannabinoid System in Addiction Susceptibility.

脂肪酸酰胺水解酶、神经发育和酒精：阐明内源性大麻素系统在成瘾易感性中的复杂性。

• DOI: 10.1016/j.biopsych.2023.06.027
• 发表时间: 2023
• 期刊: Biological psychiatry
• 影响因子: 10.6
• 作者: DeAquino,JoaoP

Buprenorphine Treatment of Fentanyl-Related Opioid Use Disorder.

丁丙诺啡治疗芬太尼相关的阿片类药物使用障碍。

• DOI: 10.4088/pcc.21cr03163
• 发表时间: 2022
• 期刊: The primary care companion for CNS disorders
• 作者: Jegede,Oluwole;Parida,Suprit;DeAquino,JoaoP
• 通讯作者: DeAquino,JoaoP

Development of pulsed intravenous nicotine infusions as a model for inhaled nicotine in humans.

开发脉冲静脉尼古丁输注作为人类吸入尼古丁的模型。

• DOI: 10.1007/s00213-022-06162-0
• 发表时间: 2022
• 期刊: Psychopharmacology
• 影响因子: 3.4
• 作者: DeAquino,JoaoP;DeVito,EliseE;Xie,Catherine;Meyerovich,Julia;Parida,Suprit;Gueorguieva,Ralitza;Sofuoglu,Mehmet
• 通讯作者: Sofuoglu,Mehmet

Alleviation of opioid withdrawal by cannabis and delta-9-tetrahydrocannabinol: A systematic review of observational and experimental human studies.

• DOI: 10.1016/j.drugalcdep.2022.109702
• 发表时间: 2022-12-01
• 期刊: DRUG AND ALCOHOL DEPENDENCE
• 影响因子: 4.2
• 作者: De Aquino, Joao P.;Bahji, Anees;Gomez, Oscar;Sofuoglu, Mehmet
• 通讯作者: Sofuoglu, Mehmet

Opioid-induced analgesia among persons with opioid use disorder receiving methadone or buprenorphine: A systematic review of experimental pain studies.

• DOI: 10.1016/j.drugalcdep.2021.109097
• 发表时间: 2021-11-01
• 期刊: Drug and alcohol dependence
• 影响因子: 4.2
• 作者: De Aquino JP;Parida S;Avila-Quintero VJ;Flores J;Compton P;Hickey T;Gómez O;Sofuoglu M
• 通讯作者: Sofuoglu M