Gabapentinoid/opioid mixtures: abuse and toxicity

加巴喷丁/阿片类混合物：滥用和毒性

• 批准号: 10639396
• 负责人: Takato Hiranita
• 金额: $ 46.02万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10639396
• 关键词: Accounting; Address; Adverse effects; Advocacy; American; Area; Attention; Attenuated; Autopsy; Behavior; Biological Assay; Breathing; Buprenorphine; COVID-19 pandemic; Cessation of life; Classification; Clinical; Clinical Trials; Cocaine; Convulsions; Data; Dependence; Development; Dose; Drug usage; FDA approved; Female; Fentanyl; General Population; Health; Heroin; Individual; Life Expectancy; Literature; Morbidity - disease rate; Naloxone; Opiate Addiction; Opioid; Opioid agonist; Overdose; Parents; Patients; Pharmaceutical Preparations; Physical Dependence; Pilot Projects; Policies; Predisposition; Procedures; Public Health; Rattus; Recording of previous events; Relaxation; Reporting; Research; Research Personnel; Research Project Grants; Risk; Risk Assessment; Risk Factors; Schedule; Seizures; Self Administration; Stimulus; Substance Use Disorder; Testing; Time; Toxic effect; Toxicology; United States National Institutes of Health; Ventilatory Depression; Withdrawal; clinically relevant; cocaine self-administration; drug discrimination; epidemiologic data; experience; fentanyl seeking; fentanyl self-administration; gabapentin; male; medication-assisted treatment; mortality; mu opioid receptors; non-opioid analgesic; off-label use; opioid epidemic; opioid exposure; opioid misuse; opioid mortality; opioid overdose; opioid use; opioid withdrawal; overdose death; pandemic disease; pregabalin; prescription opioid; pressure; respiratory; response; sex

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.

摘要/总结 “新研究者”的这份申请是对家长公告 PA-20-185“NIH 研究”的回应 项目拨款（不允许母公司 R01 临床试验）”并要求 5 年的支持来研究贡献 加巴喷丁类药物对阿片类药物危机的影响。尽管阿片类药物过量和死亡人数继续增加 阿片类药物处方数量显着减少。同时，使用加巴喷丁类药物 （加巴喷丁 [Neurontin®]）和普瑞巴林 [Lyrica®]）显着增加。虽然通常规定 为了治疗癫痫和惊厥，越来越多的加巴喷丁类药物被超说明书使用作为阿片类药物的替代品， 人们越来越担心加巴喷丁类药物的滥用会导致阿片类药物引起的发病， 死亡。普瑞巴林被缉毒局列为附表 V 管制物质 （数据包络分析）。尽管加巴喷丁目前尚未被 DEA 列入管制范围，但已在 5 个州列入管制范围，并且有 来自各个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 毒品对公众健康造成的风险似乎比人们想象的要大得多，特别是 因为阿片类药物过量受害者中越来越多地发现加巴喷丁类药物。因为他们被认为是 非常安全且不太可能被滥用，但人们对加巴喷丁类药物与药物一起使用时的潜在风险知之甚少。 其他药物，包括以下药物：1) 加巴喷丁类药物是否会增强滥用相关和/或毒性作用 阿片类药物； 2) 阿片类药物使用史是否会增加滥用加巴喷丁类药物的可能性； 3) 是否 加巴喷丁类药物会导致身体依赖性和/或影响阿片类药物的身体依赖性。我们的试点研究表明 加巴喷丁类药物会降低纳洛酮逆转海洛因通气抑制的效力，并增加 芬太尼在药物辨别测定中的效力。拟议的研究解决了有关信息匮乏的问题 加巴喷丁类药物的潜在副作用，特别是与阿片类药物联合使用时，并探讨了三种具体的副作用 目的是检验以下假设：1）加巴喷丁类药物降低纳洛酮逆转疾病的效力 mu 阿片受体激动剂的通气抑制作用； 2）阿片类药物接触史 揭示/增强加巴喷丁类药物的积极强化作用； 3) 加巴喷丁类药物可减弱阿片类药物的作用 戒断，并加剧阿片类药物的身体依赖性。因为这是一个尚未探索的研究领域， 尚不清楚加巴喷丁/阿片类药物的相互作用是否具有性别依赖性。通过系统地比较效果 加巴喷丁类药物和阿片类药物（单独或混合）在雌性和雄性大鼠中的研究将提供更多信息 需要对潜在风险进行全面评估（通气抑制、自我管理、 与加巴喷丁类药物联合使用时的恢复、药物歧视和身体依赖性） 阿片类药物。阿片类药物危机在大流行期间显着恶化，其形式此前未被重视 药物使用的情况（例如，同时服用阿片类药物的个人越来越多地使用加巴喷丁）需要我们的关注 为了解决日益严重的全国公共卫生危机，该危机正在缩短美国人的预期寿命。