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Principal Investigator: Takato Hiranita
Organization: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
Fiscal Year: 2024
Award: $396,736
Funding agency: National Institute on Drug Abuse
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.
Terms: <3-isobutyl GABA><Accounting><Actiq><Address><Adverse effects><Advocacy><American><Area><Assay><Attention><Attenuated><Autopsy><Behavior><Bioassay><Biological Assay><Breathing><Buprenorphine><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 years><Cessation of life><Classification><Clinical><Clinical Trials><Cocaine><Common Rat Strains><Convulsions><Data><Death><Dependence><Development><Diacetylmorphine><Diamorphine><Drug usage><Drugs><Duragesic><Epidemiological data><Epidemiology data><FDA approved><Female><Fentanest><Fentanyl><Fentyl><General Population><General Public><Health><Heroin><History><Individual><Investigators><Life Expectancy><Literature><Medication><Morbidity><Morbidity - disease rate><NIH><Naloxone><Narcan><Narcanti><National Institutes of Health><Neurontin><Opiate Addiction><Opiate Dependence><Opiate agonist><Opiate receptor agonist><Opiates><Opioid><Opioid agonist><Opioid receptor agonist><Overdose><Parents><Patients><Pharmaceutical Preparations><Phentanyl><Physical Dependence><Pilot Projects><Policies><Predisposition><Procedures><Public Health><R-Series Research Projects><R01 Mechanism><R01 Program><Rat><Rats Mammals><Rattus><Recording of previous events><Relaxation><Reporting><Research><Research Grants><Research Personnel><Research Project Grants><Research Projects><Researchers><Respiratory Aspiration><Respiratory Depression><Respiratory Inspiration><Risk><Risk Assessment><Risk Factors><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><Schedule><Seizures><Self Administered><Self Administration><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Stimulus><Substance Use Disorder><Susceptibility><Systematics><Testing><Time><Toxic effect><Toxicities><Toxicology><United States National Institutes of Health><Ventilatory Depression><Withdrawal><attenuate><attenuates><clinical relevance><clinically relevant><cocaine self-administration><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><depressed breathing><depression of breathing><developmental><drug discrimination><drug use><drug/agent><epidemiologic data><experience><fentanyl seeking><fentanyl self-administration><gabapentin><histories><inspiration><licit opioid><male><medication-assisted therapy><medication-assisted treatment><mortality><mu opioid receptors><naloxone dosing><necropsy><non-medical opioid use><non-narcotic analgesic><non-opiate analgesic><non-opioid><non-opioid analgesic><non-opioid therapeutics><nonmedical opioid use><nonnarcotic analgesics><nonopiate analgesic><nonopioid><nonopioid analgesics><off-label application><off-label prescribing><off-label use><opiate consumption><opiate crisis><opiate deaths><opiate drug use><opiate exposure><opiate intake><opiate medication><opiate misuse><opiate mortality><opiate overdose><opiate related overdose><opiate use><opiate withdrawal><opioid addiction><opioid consumption><opioid crisis><opioid deaths><opioid dependence><opioid dependent><opioid detox><opioid detoxification><opioid drug overdose><opioid drug use><opioid epidemic><opioid exposure><opioid induced overdose><opioid intake><opioid intoxication><opioid medication><opioid medication overdose><opioid misuse><opioid mortality><opioid overdose><opioid overdose death><opioid poisoning><opioid related death><opioid related overdose><opioid toxicity><opioid use><opioid withdrawal><overdose death><overdose fatalities><pandemic><pandemic disease><parent><pilot study><postmortem><pregabalin><prescribed opiate><prescribed opioid><prescription opiate><prescription opioid><pressure><respiratory><response><self-administer cocaine><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><sex><substance use and disorder><μ opioid receptors><μ-OR><μOR>