Gabapentinoid/opioid mixtures: abuse and toxicity

摘要/总结 来自“新研究者”的这份申请是对家长公告PA-20-185“NIH研究 项目补助金（不允许进行父R 01临床试验）”，并要求5年的支持，以研究贡献 加巴喷丁类药物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， 类阿片处方数量大幅减少。与此同时，使用加巴喷丁类化合物 （加巴喷丁[Neurontin®]和普瑞巴林[Lyrica®]）显著增加。虽然通常规定 为了治疗癫痫发作和惊厥，越来越多的加巴喷丁类药物被标签外使用作为阿片类药物的替代品， 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， mortality.普瑞巴林被美国缉毒局列为附表五管制物质 （DEA）。虽然加巴喷丁目前没有被DEA列入计划，但它在五个州被列入计划， 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。这些 药物对公众健康的风险似乎比人们想象的要大得多，特别是 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类药物。因为他们被认为是 非常安全，不太可能被滥用，很少有人知道加巴喷丁类化合物的潜在风险时，与 其他药物，包括：1）加巴喷丁类药物是否增强与滥用有关的和/或毒性作用 2）阿片类药物使用史是否增加了滥用加巴喷丁类药物的可能性; 3）是否 加巴喷丁类物质引起身体依赖和/或影响阿片样物质身体依赖。我们的初步研究表明 加巴喷丁类药物降低了纳洛酮逆转海洛因所致抑郁症的效力， 芬太尼在药物辨别试验中的效力。拟议的研究旨在解决以下方面的信息缺乏问题： 加巴喷丁类药物的潜在不良反应，特别是与阿片类药物联合使用，并探讨三种具体的 目的是测试以下假设：1）加巴喷丁类化合物降低纳洛酮逆转 μ阿片受体激动剂的通气抑制作用; 2）阿片类药物暴露史 揭示/增强加巴喷丁类化合物的正强化作用;和3）加巴喷丁类化合物减弱阿片样物质 戒断，并加剧阿片类药物的身体依赖。因为这是一个未探索的研究领域， 尚不清楚加巴喷丁类化合物/阿片类药物相互作用是否具有性别依赖性。通过系统地比较 在雌性和雄性大鼠中单独和混合使用加巴喷丁和阿片类药物，这些研究将提供更多- 需要对潜在风险进行全面评估（抑郁症，自我管理， 恢复、药物辨别和身体依赖性）的影响。 阿片类药物阿片类药物危机在大流行期间显著恶化， 药物使用（例如，在服用阿片类药物的人中使用加巴喷丁类药物的情况越来越多）要求我们注意， 为了解决这个日益严重的国家公共卫生危机，这是减少美国人的预期寿命。

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.