Opioid misuse, including prescription opioids, heroin and fentanyl, is epidemic in the United States and is associated with high morbidity and mortality. The current National Survey on Drug Use and Health estimates that at least 2.6 million people met criteria for an opioid use disorder (including prescription opioids and heroin). Opioid-related overdose deaths continue to climb with nearly 30,000 deaths reported in 2014. Toxicological evidence from post-mortem studies reveals that polypharmacy is a very common finding in opioid-related deaths, and it is especially common to find co-occurring substances with sedative properties. Despite the widespread acknowledgment that non-opioid sedatives may enhance the risk of death from an opioid overdose, few controlled data exist on the pharmacodynamic effects of opioids in combination with these agents and their co-prescription by providers is common. These studies aim to fill this critical knowledge gap by assessing agents with sedative properties that commonly are 1) prescribed with opioids (i.e., benzodiazepines, gabapentin), 2) abused in combination with opioids, and 3) found in combination at autopsy (benzodiazepines, alcohol and gabapentin). Three inpatient human laboratory studies will be conducted that employ rigorous controlled experimental procedures to characterize the pharmacological interaction between oxycodone when taken in combination with either alprazolam (Experiment 1), alcohol (Experiment 2) or gabapentin (Experiment 3). Individuals with appropriate recreational drug use histories, who are otherwise healthy, will be enrolled. An initial dose finding phase will precede each study to ensure subject safety and scientific rigor before proceeding to a robust randomized controlled design. The three studies will employ randomized, placebo-controlled, within-subject, double-blind crossover designs and will be conducted in a controlled hospital setting where appropriate medical supervision is available. Key safety outcomes, including expired CO2 and other respiratory function indices, pharmacodynamic measures related to abuse potential, and cognitive/psychomotor performance will be thoroughly examined over a range of doses for all drugs alone. Pharmacokinetic data (Exp. 1) will also be collected to assess the potential pharmacokinetic interaction as an underlying mechanism of action, and experimental analgesia/algesia data will be collected in Exp. 3 as gabapentin is commonly co-prescribed for pain relief with opioids. The analytic approach will include traditional statistics and modified isobolographic analyses to further elucidate the nature of the pharmacodynamic interactions. The findings from these studies may directly inform prescribing practices and inform clinical guidelines for physicians and other providers, regulatory decision-making, and may provide new information for targeted interventions to reduce the harms of polysubstance prescribing and misuse.

Public Health Relevance

Opioid fatal and non-fatal overdoses have reached epidemic levels in the United States, and many are the result of combined use or misuse of opioids with other sedative-like substances. This research will provide important information on the relative safety and abuse-related risks of combining oxycodone with three different classes of sedatives: benzodiazepines, alcohol and gabapentinoids. The results of these studies may inform medical prescribing practices and regulatory drug control.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA016718-12
Application #
9788349
Study Section
Addiction Risks and Mechanisms Study Section (ARM)
Program Officer
Anderson, Ann
Project Start
2004-07-10
Project End
2023-07-31
Budget Start
2019-08-01
Budget End
2020-07-31
Support Year
12
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Kentucky
Department
Miscellaneous
Type
Schools of Medicine
DUNS #
939017877
City
Lexington
State
KY
Country
United States
Zip Code
40526
Coe, Marion A; Nuzzo, Paul A; Lofwall, Michelle R et al. (2017) Effects of Short-Term Oxycodone Maintenance on Experimental Pain Responses in Physically Dependent Opioid Abusers. J Pain 18:825-834
Walsh, Sharon L; Babalonis, Shanna (2017) The Abuse Potential of Prescription Opioids in Humans-Closing in on the First Century of Research. Curr Top Behav Neurosci 34:33-58
Babalonis, Shanna; Lofwall, Michelle R; Nuzzo, Paul A et al. (2016) Pharmacodynamic effects of oral oxymorphone: abuse liability, analgesic profile and direct physiologic effects in humans. Addict Biol 21:146-58
Walsh, Sharon L; Nuzzo, Paul A; Babalonis, Shanna et al. (2016) Intranasal buprenorphine alone and in combination with naloxone: Abuse liability and reinforcing efficacy in physically dependent opioid abusers. Drug Alcohol Depend 162:190-8
Hampson, Aidan J; Babalonis, Shanna; Lofwall, Michelle R et al. (2016) A Pharmacokinetic Study Examining Acetazolamide as a Novel Adherence Marker for Clinical Trials. J Clin Psychopharmacol 36:324-32
Babalonis, Shanna; Hampson, Aidan J; Lofwall, Michelle R et al. (2015) Quinine as a potential tracer for medication adherence: A pharmacokinetic and pharmacodynamic assessment of quinine alone and in combination with oxycodone in humans. J Clin Pharmacol 55:1332-43
Coe, Marion A; Walsh, Sharon L (2015) Distribution of naloxone for overdose prevention to chronic pain patients. Prev Med 80:41-3
Lofwall, Michelle R; Walsh, Sharon L (2014) A review of buprenorphine diversion and misuse: the current evidence base and experiences from around the world. J Addict Med 8:315-26
Fang, Wenfang B; Lofwall, Michelle R; Walsh, Sharon L et al. (2013) Determination of oxycodone, noroxycodone and oxymorphone by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry in human matrices: in vivo and in vitro applications. J Anal Toxicol 37:337-44
Babalonis, Shanna; Lofwall, Michelle R; Nuzzo, Paul A et al. (2013) Abuse liability and reinforcing efficacy of oral tramadol in humans. Drug Alcohol Depend 129:116-24

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