Opioid and cannabinoid combinations in laboratory and clinical pain

这项实验室研究将评估大麻素是否增强阿片类药物的止痛效果 慢性疼痛患者的临床样本，为更大规模的临床试验评估 大麻类药物作为慢性阿片类药物疼痛治疗的潜在非阿片类药物辅助剂。增强的中枢神经系统 加工，或中枢敏化(CS)，发生在许多慢性疼痛条件下，是一个重要的 它本身就是治疗目标。虽然大麻类药物最初显示出作为治疗或辅助药物的希望 慢性疼痛状况和临床前数据表明对CS的影响，但对其程度知之甚少 大麻素和阿片类药物联合使用可减轻CS介导的慢性疼痛。我们建议在学科内部，单一的 暴露，双盲，安慰剂对照，人体实验室调查的程度 大麻素增强模型慢性疼痛人群(例如膝关节患者)的阿片类止痛 骨关节炎)。人体实验室研究是这种初步评估的理想方法，因为它们提供了 有机会严格控制研究药物剂量并提供高灵敏度的测量，并使 严格控制混杂变量，否则可能存在于临床治疗人群中，并可能 对结果产生不同的影响。这种方法将最大限度地减少确定 是否存在积极的信号，同时允许对研究目标进行严格和优雅的评估。主要 研究结果将包括临床疼痛和中枢敏感化、身体功能、药物效果的测量 (例如，滥用责任、不良事件、认知表现)和药代动力学分析。AIMS将 检查大麻素/阿片类药物联合用药在减轻临床疼痛和中枢神经系统中的量值和持续时间 敏感化；对身体功能、不良事件和滥用倾向指数的影响；以及 单药和联合用药的药代动力学和药效学概况。这项研究将提供 最系统和最严格的大麻类药物增强镇静效果的评估 阿片类药物在人类受试者中的应用，并将在相关的和可推广的临床疼痛人群中这样做 具有CS，这使得这些结果与在健康人群中进行的研究相比更直接相关 人口。这些发现将是至关重要的，以告知有效性和安全性概况，以促进 阿片/大麻素联合方案用于慢性疼痛患者的临床试验。

This laboratory study will evaluate whether a cannabinoid enhances the analgesic efficacy of an opioid in a clinical sample of chronic pain patients, laying the foundation for a larger clinical trial evaluating the utility of cannabinoids as potentially opioid-sparing adjuvants to chronic opioid therapy for pain. Heightened CNS processing, or central sensitization (CS), occurs across numerous chronic pain conditions and is an important treatment target in its own right. While cannabinoids show initial promise as treatments or adjuncts for some chronic pain conditions and pre-clinical data suggest effects on CS, little is known about the degree to which combining cannabinoids with opioids alleviates CS-mediated chronic pain. We propose a within-subject, single exposure, double-blind, placebo-controlled, human laboratory investigation of the extent to which a cannabinoid enhances opioid analgesia in a model chronic pain population (e.g., patients with knee osteoarthritis). Human laboratory studies are an ideal method for this initial evaluation because they provide the opportunity to tightly control study drug dosing and afford high sensitivity of measurements, and enable tight control of confounding variables that may otherwise exist in clinical treatment populations and could differentially impact outcomes. This approach will minimize the number of participants needed to determine whether a positive signal exists while permitting rigorous and elegant evaluation of the study aims. Primary study outcomes will include measures of clinical pain and central sensitization, physical function, drug effects (e.g., abuse liability, adverse events, cognitive performance), and pharmacokinetic analyses. The Aims will examine the magnitude and duration of cannabinoid/opioid combination in reducing clinical pain and central sensitization; the effects on physical functioning, adverse events and indices of abuse liability; and the pharmacokinetic and pharmacodynamics profiles for the individual and combined drugs. This study will provide the most systematic and rigorous evaluation of the potential for cannabinoids to enhance analgesic effects of opioids in human subjects to date, and will do so in a relevant and generalizable clinical pain population who has CS, which makes these results more directly relevant compared to studies conducted in healthy populations. These findings will be critical to informing the efficacy and safety profile for the advancement of opioid/cannabinoid combination regimens to clinical trials with chronic pain patients.