Gabapentinoid/opioid mixtures: abuse and toxicity

摘要/摘要 这份来自一位“新调查员”的申请是对家长公告PA-20-185“NIH Research”的回应 项目资助(不允许家长R01临床试验)“，并要求提供5年的资助以研究该贡献 加巴喷丁对阿片类药物危机的影响。阿片类药物过量和死亡人数继续增加，尽管 阿片类药物处方数量的显著减少。同时，加巴喷丁的使用 (加巴喷丁[Neurontin®])和普瑞巴林[Lyrica®])显著增加。尽管通常是规定的 为了治疗癫痫发作和抽搐，越来越多的加巴喷丁类药物被用作阿片类药物和 人们越来越担心滥用加巴喷丁类药物会导致阿片类药物引起的发病率和 死亡率。普瑞巴林被美国药品监督管理局列为附表V管制物质 (DEA)。尽管加巴喷丁目前没有被DEA安排，但它计划在五个州进行，并且有 来自各种消费者和倡导团体的压力越来越大，要求DEA安排加巴喷丁的时间表。这些 毒品对公众健康构成的风险似乎比人们所认为的要大得多，尤其是 因为在阿片类药物过量的受害者中越来越多地检测到加巴喷丁。因为他们被推定为 加巴喷丁非常安全，不太可能被滥用，但人们对与加巴喷丁联合使用时的潜在风险知之甚少 其他药物，包括：1)加巴喷丁是否加强与滥用有关的和/或毒性影响 2)阿片类药物使用史是否增加了滥用加巴喷丁的可能性；以及3)是否 加巴喷丁导致身体依赖和/或影响阿片类药物的身体依赖。我们的初步研究表明 加巴喷丁降低纳洛酮逆转海洛因通气性抑制的效力，并增加 芬太尼在药物鉴别试验中的效力。拟议的研究解决了以下方面的信息匮乏问题 加巴喷丁的潜在不良影响，特别是与阿片类药物联合使用，并探讨三个具体的 目的是检验以下假设：1)加巴喷丁降低纳洛酮逆转血管紧张素转换酶的效力 Mu阿片受体激动剂的呼吸机抑制作用；2)阿片类药物暴露史 揭示/增强加巴喷丁的积极强化作用；以及3)加巴喷丁减弱阿片类药物 戒断，并加剧阿片类药物的身体依赖。因为这是一个未被探索的研究领域，所以 不清楚加巴喷丁/阿片类药物的相互作用是否具有性别依赖性。通过系统地比较它们的效果 对于加巴喷丁和阿片类药物，单独和混合，在雌性和雄性大鼠身上，这些研究将提供更多- 需要对潜在风险进行全面评估(呼吸性抑郁、自我管理、 恢复、药物歧视和身体依赖)与加巴喷丁联合使用时 阿片类药物。阿片类药物危机在大流行期间显著恶化，以前未被认识到的形式 药物使用(例如，在服用阿片类药物的个人中增加使用加巴喷丁类药物)需要我们注意 以解决日益严重的国家公共卫生危机，这场危机正在降低美国人的预期寿命。

ABSTRACT/SUMMARY This application from a “New Investigator” is in response to Parent Announcement PA-20-185 “NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)” and requests 5 years of support to study the contribution of gabapentinoids to the opioid crisis. The number of opioid overdoses and deaths continues to increase despite a significant decrease in the number of prescriptions for opioids. At the same time, the use of gabapentinoids (gabapentin [Neurontin®]) and pregabalin [Lyrica®]) has increased significantly. Although typically prescribed to treat seizures and convulsions, increasingly gabapentinoids are used off-label as alternatives to opioids and there is mounting concern that misuse of gabapentinoids is contributing to opioid-induced morbidity and mortality. Pregabalin is classified as a Schedule V controlled substance by the Drug Enforcement Administration (DEA). Although gabapentin currently is not scheduled by the DEA, it is scheduled in five states and there is mounting pressure from various consumer and advocacy groups for the DEA to schedule gabapentin. These drugs appear to pose a significantly greater risk to public health than has thought to be the case, particularly because gabapentinoids are increasingly detected in opioid overdose victims. Because they are presumed to be very safe and not likely to be abused, little is known about the potential risk of gabapentinoids when used with other drugs, including the following: 1) whether gabapentinoids enhance the abuse related and/or toxic effects of opioids; 2) whether a history of opioid use increases the likelihood of misuse of gabapentinoids; and 3) whether gabapentinoids cause physical dependence and/or impact opioid physical dependence. Our pilot studies show that gabapentinoids reduce the potency of naloxone to reverse ventilatory depression by heroin and increase the potency of fentanyl in a drug discrimination assay. Proposed studies address the paucity of information regarding potential adverse effects of gabapentinoids, particularly in combination with opioids, and explore three specific aims that test the following hypotheses: 1) gabapentinoids reduce the potency of naloxone to reverse the ventilatory-depressant effects of mu opioid receptor agonists; 2) a history of opioid exposure unmasks/enhances the positive reinforcing effects of gabapentinoids; and 3) gabapentinoids attenuate opioid withdrawal, and exacerbate opioid physical dependence. Because this is an unexplored area of research, it is unclear whether gabapentinoid/opioid interactions are sex dependent. By systematically comparing the effects of gabapentinoids and opioids, alone and in mixtures, in female and male rats, these studies will provide a much- needed comprehensive assessment of the risk potential (ventilatory depression, self-administration, reinstatement, drug discrimination, and physical dependence) of gabapentinoids when used in combination with opioids. The opioid crisis has worsened significantly during the pandemic and previously unappreciated forms of drug use (e.g., increasing use of gabapentinoids in individuals also taking opioids) demand our attention in order to address this growing national public health crisis that is decreasing the life expectancy of Americans.