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，使开发具有减少滥用潜力的止痛药成为一个主要的公共 健康优先。当联合使用时，阿片类药物和大麻素（CB）受体激动剂表现出镇痛作用。 在许多疼痛模型中，效果似乎至少是累加的。Cannabidiol（CBD） 精神活性远低于109-四氢大麻酚（THC），THC是大麻中的主要活性成分。 大麻，仍然保留镇痛作用。开发具有改善的溶解度的CBD类似物的努力 和生物利用度导致了CBD-缬氨酸-半琥珀酸盐（CBD-VHS）的发现， 在疼痛模型中表现出色，但也降低了 吗啡在条件性位置偏爱测试中的作用本项目所涉及的下一步是 仔细描述CBD-VHS与常用阿片类药物联合使用的效果 治疗羟考酮，以了解其镇痛相互作用和滥用倾向， 密码这将通过使用药物自我给药试验和镇痛模型来完成 以发现是否混合比例，少加强仍然产生良好的缓解疼痛。 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，然后给予不同剂量的CBD-VHS， 这会影响对OXY的反应。一旦选择了合适的剂量比， 将评估其缓解疼痛的能力。经验证的等效线和剂量添加 将使用分析来确定组合是相加的还是交互的（即，上或 下添加剂）的镇痛作用。 第一阶段工作的结果将是选择最有前途的固定比率， 羟考酮和CBD-VHS制剂用于II期STTR的进一步临床前开发， 具有最小化滥用倾向的疼痛管理治疗剂。第二期发展 计划将包括非人灵长类动物中相互作用的表征，药代动力学 和口服制剂的药理学评估以及安全性评价。

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.