An Opioid/Cannabinoid Analgesic that Boosts Pain Relief and Blocks Opiate Reward

项目摘要 近年来，处方阿片类药物的滥用和与滥用有关的死亡人数急剧增加。 多年来，使减少滥用可能性的止痛药的开发成为主要公众 健康优先。当阿片类药物和大麻素(CB)受体激动剂联合使用时，显示出止痛作用 在许多疼痛模型中，效果似乎至少是相加的。大麻二酚(CBD)，尽管 精神活性远低于9-四氢大麻酚(THc)，其主要活性成分是 大麻，仍然保留着止痛作用。努力开发具有更好溶解性的CBD类似物 和生物利用度导致发现了CBD-戊酸酯-丁二酸半酯(CBD-VHS)，它提供了 在疼痛模型中的出色表现本身也减少了奖励效应 吗啡在条件性位置偏爱测试中。本项目涉及的下一步工作是 仔细描述CBD-VHS与常用阿片类药物联合使用的效果 治疗性羟考酮，以了解它们的止痛相互作用和滥用的可能性 这些组合。这将通过药物自我给药试验和止痛模型来完成。 为了找出强度较小的混合比例是否仍能产生良好的止痛效果。 这些目标将通过首先通过静脉途径给予羟考酮(Oxy)来实现， 建立单独对Oxy的剂量反应，然后给不同剂量的CBD-VHS，看看如何 这会影响对Oxy的反应。一旦选择了合适的剂量比，那么组合 将评估其缓解疼痛的能力。验证的等位相图和剂量添加 将使用分析来确定组合是相加的还是交互的(即，高于或 以下添加剂)的止痛效果。 这一阶段努力的结果将是选出最有希望的固定比率 羟考酮和CBD-VHS配方用于在第二阶段STTR，AS的临床前进一步开发 一种疼痛管理疗法，将滥用责任降至最低。第二阶段的发展 该计划将包括描述非人类灵长类动物之间的相互作用，药代动力学 以及口服制剂的药理评估和安全性评估。

Project Summary Abuse of prescription opioids and fatalities related to their misuse have increased sharply in recent years, making the development of pain medications with reduced abuse potential a major public health priority. When combined, opioids and cannabinoid (CB) receptor agonists show analgesic effects appear to be at least additive in a number of pain models. Cannabidiol (CBD), although much less psychoactive than 9-tetrahydrocannabinol (THC), the primary active principle in Cannabis, still retains analgesic effects. Efforts to develop analogs of CBD with improved solubility and bioavailability resulted in discovery of CBD-valinate-hemisuccinate (CBD-VHS), which gives excellent performance in its own right in pain models, but also reduces the rewarding effects of morphine in a conditioned place preference test. The next steps, addressed in this project, are to carefully delineate the effects of CBD-VHS in combination with the commonly-used opioid therapeutic oxycodone, in order to understand their analgesic interactions and the abuse liability of the combinations. This will be done by using drug self-administration tests and analgesia models to find out whether mixture ratios that are less reinforcing still produce good pain relief. These goals will be achieved by first giving oxycodone (OXY) by the intravenous route, establishing dose-responses to OXY alone, then giving CBD-VHS in various doses and see how this affects responses to OXY. Once appropriate dose ratios are selected, then the combination will be evaluated for its ability to relieve pain. Validated isobolographic and dose-addition analyses will be used to determine if the combinations are additive or interactive (i.e., supra- or infra-additive) in analgesic effect. The outcome of this Phase I effort will be the selection of the most promising fixed ratio of oxycodone and CBD-VHS formulation for further preclinical development in the phase II STTR, as a pain management therapeutic with minimized abuse liability. The Phase II development program will include characterization of the interaction in nonhuman primates, pharmacokinetic and pharmacological assessments from oral formulations, and safety evaluations.