Citation

Gonek M, Henderson G, Dewey WL. FASEB J. 2017; 31(Suppl 1): e985.3.

Copyright

(Copyright © 2017, Federation of American Societies for Experimental Biology)

DOI

unavailable

PMID

unavailable

Abstract

We are experiencing an unprecedented opioid overdose epidemic with over 120 people dying every day. Most individuals who become tolerant and dependent on opioids, including the prescription opioids oxycodone and hydrocodone, co-abuse other substances. The most widely co-abused drug is ethanol but other CNS depressants such as diazepam and other benzodiazepines are also co-abused. Several studies suggest that ethanol and benzodiazepines may play a role in as much as 80% of unintentional overdose deaths involving opioids. Postmortem examination of individuals who have died from chronic administration of opioids and ethanol had lower blood levels of opioids than individuals who overdosed on opioids alone. Similar results have not been reported in individuals co-abusing diazepam. Following the hourly subcutaneous administration of the acute ED80 dose for a total of 7 injections, we observed a significant shift of the dose response curve indicating a 5-fold tolerance to morphine, a 1.5-fold tolerance to oxycodone, and a 2-fold tolerance to hydrocodone in the mouse tail immersion assay. The intraperitoneal administration of 0.5 mg/kg diazepam, a dose that has no observable behavioral effect on its own, 50 minutes before testing fully reversed antinociceptive tolerance to morphine and oxycodone. Hydrocodone tolerance was not fully reversed at doses lower than 2 mg/kg diazepam. There was no potentiation of acute opioid effects. Conversely, opioid tolerance in the stretching assay, a measurement of visceral pain, was not reversed by diazepam. Further research into the differences of opioid tolerance mechanisms can lead to new insights for the development of drugs that decrease the risk of opioid overdosing and the development of drugs to relieve severe pain with limited tolerance.
Support or Funding Information
Supported by USPHS Grants RO1 DA036975 and T32DA007027.

Language: en