Using Cannabinoids to Enhance Opioid Analgesic Effects in Humans

本研究将系统评价大麻类物质是否能增强阿片类药物的镇痛效果， 这将促进使用大麻类药物治疗急性和/或慢性疼痛。慢性疼痛影响 超过1亿美国人。阿片类药物被公认为最有效的缓解高血压的药物 痛苦和痛苦，但美国现在正遭受虐待、上瘾和意外死亡的流行 这是由于阿片类药物销售和使用增加造成的。识别附加语具有合法的价值，这些附加语可能 减少对阿片类药物的依赖，同时保持足够的止痛效果。临床前研究报告称，联合- 使用带有阿片激动剂的大麻类药物可以显著可靠地减少所需的阿片类药物的数量 用于止痛，但这一假说尚未在人类身上进行严格评估。这项提案将进行2 将评估不同大麻素效果的独立研究(研究1：屈诺比诺，研究2： 纳贝酮)对阿片类药物的镇痛作用。每项研究将招募60名健康成年人(30名男性/女性)进行一项 受试者内，大麻素对氢吗啡酮(地劳迪德)的镇痛作用的剂量-反应评价。 受试者将完成一次资格赛和6次实验，每周一次，并将 要求受试者在会议的前一天晚上进入临床研究单元完成 学习时间。受试者将接受一剂氢吗啡(1毫克，肌注)和双盲口服剂量的研究 药物或安慰剂在每次实验的早上，并将接受定量感觉测试(QST； 全面的疼痛测试电池)，提供药物效果的自我报告评级，并完成 神经认知电池。QST测试将全面和系统地测量疼痛敏感性，以及 提供各种止痛措施可能产生的各种止痛效果的信息， 包括阈值反应(温度、压力)、时间总和、冷加压、条件性疼痛 调制和辣椒素敏化。主要结果将是疼痛的程度和持续时间作为函数 研究药物剂量。其他主要目标包括滥用责任和神经认知的代理测量 性能。所有措施都将作为性别的作用进行评估，因为有大量证据表明， 在痛觉、内源性大麻素受体密度和阿片类药物反应方面存在差异。我们 假说大麻素可使氢吗啡酮的镇痛曲线移动，增强镇痛效果。 这将是第一个使用QST评估大麻和阿片类药物组合的人体实验室研究， 结果将确定是否存在用于该药物组合的信号，该信号应推进到 临床疼痛人群的随机对照试验评估。这项研究还将评估以下方面 将影响药物开发(滥用倾向、神经认知障碍)，以及性和 大麻素类药物对结果的影响。这项研究的结果将有助于提高人们对大麻素的接受度 仅用于治疗顽固性疼痛的情况下，可广泛用于临床疼痛。

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.