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/摘要 “新调查员”的申请是对父母公告PA-20-185“ NIH研究的回应 项目赠款（父母R01临床试验不允许）”，并要求提供5年的支持以研究贡献 阿片类药物危机的gabapentinoid。尽管 阿片类药物处方数量的显着减少。同时，使用gabapentinoids （gabapentin [neurontin®]）和pregabalin [lyrica®]）显着增加。 为了治疗癫痫发作和抽搐，越来越多的gabapentinoids被标签外用作阿片类药物的替代品 人们一直担心滥用加巴丁素正在导致阿片类药物引起的发病率和 死亡。 Pregabalin被归类为附表V受控的药物。 （DEA）。尽管Gabapentin目前未安排DEA，但它安排在五个州，有 DEA安排加巴喷丁的各个消费者和倡导团体的压力。这些 毒品似乎对公共卫生的风险显着比以前的情况要大得多，尤其是 因为在阿片类药物过量滥用中越来越多地检测到gabapentinoids。因为他们被认为是 非常安全且不太可能被滥用，与使用gabapentinoid的潜在风险知之甚少 其他药物，包括以下几点：1）gabapentinoid是否会增强与滥用相关和/或有毒作用 阿片类药物； 2）阿片类药物使用史是否增加了滥用甘巴丁素的可能性； 3）是否 甘迪固醇会导致身体依赖性和/或影响阿片类药物的物理依赖性。我们的试点研究表明 gabapentinoids降低了纳洛酮通过海洛因逆转通气抑郁症的效力，并增加了 芬太尼在药物歧视测定中的效力。拟议的研究解决了有关信息的匮乏 gabapentinoids的潜在不利影响，尤其是与阿片类药物的结合，并探索三个特定 旨在检验以下假设的目的：1）甘迪汀类动物降低了纳洛酮的效力 Mu阿片受体激动剂的呼吸抑制作用； 2）阿片类药物的历史 揭露/增强甘巴反施素素的积极增强作用； 3）甘巴丁素可以减弱阿片类药物 提取，加剧阿片类药物的物理依赖。因为这是一个意想不到的研究领域，所以 尚不清楚gabapentinoid/阿片类药物相互作用是否取决于性别。通过系统地比较效果 在女性和男性大鼠中，单独和混合物中的gabapentinoid和阿片类药物，这些研究将提供多大 需要全面评估风险潜力（通气抑郁症，自我管理， 恢复原状，药物歧视和物理依赖性）与结合使用 OOID。不幸的是，在大流行和以前未欣赏的形式期间，Ooid危机显着 吸毒的使用（例如，在患者中增加了gabapentinoids的使用也增加了阿片类药物）需要我们的注意力 为了解决这一日益增长的国家公共卫生危机，正在降低美国人的预期寿命。