Gabapentinoid/opioid mixtures: abuse and toxicity

点击翻译按钮获取中文摘要

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.