Using Cannabinoids to Enhance Opioid Analgesic Effects in Humans

本研究将系统评价大麻素是否能增强阿片类药物的镇痛效果， 这将促进大麻素用于治疗急性和/或慢性疼痛的用途。慢性疼痛影响 超过一亿美国人阿片类药物是公认的最有效的药物， 痛苦和折磨，但美国现在正遭受着虐待、吸毒和意外死亡的流行病 这是由于阿片类药物销售和使用增加造成的。有合法的价值，以确定非法移民， 减少对阿片类药物的依赖，同时保持足够的疼痛缓解。临床前研究报告称， 与阿片激动剂一起施用大麻素显著且可靠地减少了所需的阿片量 但这一假设尚未在人类中得到严格评估。该提案将在2 将评估不同大麻素的作用的独立研究（研究1：屈大麻酚，研究2： nabilone）对阿片样物质诱导的镇痛作用。每项研究将招募60名健康成年人（30名男性/女性）， 大麻素对氢吗啡酮（二氢吗啡酮）镇痛作用的受试者内剂量反应评价。 受试者将完成每周一次的资格考试和6次实验考试， 要求受试者在会议前一天晚上进入临床研究单位， 学习会。受试者将接受一剂氢吗啡酮（1 mg，IM）和双盲口服研究剂量 药物或安慰剂，并将进行定量感觉测试（QST; 一个全面的疼痛测试电池），提供自我报告的药物效果评级，并完成一个 神经认知成套测验QST测试将全面系统地测量疼痛敏感性， 提供关于各种疼痛测量中可能的全方位镇痛效果的信息， 包括阈值反应（热，压力），时间总和，冷加压，条件性疼痛 调制和辣椒素敏化。主要结局将是疼痛的程度和持续时间， 研究药物剂量。其他主要目的包括滥用倾向和神经认知的代理措施 性能所有措施都将作为性别的函数进行评估，因为有大量证据表明， 在疼痛感知、内源性大麻素受体密度和阿片样物质反应方面存在差异。我们 假设大麻素将移动氢吗啡酮的镇痛曲线并增强镇痛效果。 这将是第一个使用QST评估大麻素和阿片类药物组合的人类实验室研究， 并且结果将识别是否存在该药物组合的信号， 临床疼痛人群的随机对照试验评价。本研究还将评估 会影响药物开发（滥用倾向，神经认知障碍），以及性别和 cannabinoid大麻type类型on outcomes结果.这项研究的结果将有助于促进大麻素的接受， 从仅用于难治性疼痛病症到广泛用于临床疼痛的社会用途。

This study will systematically evaluate whether cannabinoids can enhance the analgesic efficacy of opioids, which will advance the use of cannabinoids for the treatment of acute and/or chronic pain. Chronic pain affects over 100 million Americans. Opioids are unanimously recognized as the most effective drugs for the relief of pain and suffering6, but the US is now suffering from an epidemic of abuse, addiction and accidental deaths resulting from the increased sale and use of opioids. There is legitimate value in identifying adjuncts that might reduce reliance on opioids while maintaining adequate pain relief. Preclinical studies report that co- administering cannabinoids with opioid agonists significantly and reliably reduce the amount of opioids required for analgesia but this hypothesis has not been rigorously evaluated in humans. This proposal will conduct 2 independent studies that will evaluate the effects of a different cannabinoid (Study 1: dronabinol, Study 2: nabilone) on opioid-induced analgesia. Each study will enroll 60 healthy adults (30 men/women) to conduct a within-subject, dose-response evaluation of cannabinoids on the analgesic effect of hydromorphone (Dilaudid). Subjects will complete a Qualifying session and 6 experimental sessions that will occur once weekly and will require subjects to admit themselves into the clinical research unit the night before the session to complete the study session. Subjects will receive a dose of hydromorphone (1mg, IM) and a double-blind oral dose of study drug or placebo the morning of each experimental session, and will undergo quantitative sensory testing (QST; a comprehensive pain testing battery), provide self-report ratings of drug effects, and complete a neurocognitive battery. QST testing will comprehensively and systematically measure pain sensitivity, and provide information on the full range of analgesic effects possible across a wide variety of pain measures, including threshold responses (thermal, pressure), temporal summation, cold pressor, conditioned pain modulation, and capsaicin sensitization. Primary outcomes will be magnitude and duration of pain as a function of study drug dose. Additional primary aims include proxy measures of abuse liability and neurocognitive performance. All measures will be assessed as a function of sex, due to substantial evidence that men/women differ with regard to pain perception, endogenous cannabinoid receptor density, and opioid response. We hypothesize that cannabinoids will shift the analgesic curve of hydromorphone and enhance analgesia effects. This will be the 1st human laboratory study to evaluate combinations of cannabinoids and opioids using QST, and results will identify whether a signal for this medication combination exists that should be advanced into randomized controlled trial evaluations with clinical pain populations. This study will also assess aspects that would impact drug development (abuse liability, neurocognitive impairment), as well as the effects of sex and cannabinoid type on outcomes. Results from this study will help advance the acceptance of cannabinoids from use with only treatment-refractory pain conditions to widespread societal use for clinical pain.