When Treated with the Drug plus Naloxone, Rats Avoided Respiratory Depression

MINNEAPOLIS — The respiratory depressant effects of fentanyl-xylazine and fentanyl-dexmedetomidine can be prevented by a combination of naloxone plus atipamezole, or dual opioid receptor and alpha-2 receptor antagonism, according to a study presented today at the Annual Meeting of the American Society for Pharmacology and Experimental Therapeutics (ASPET).

Overdoses with illicit drugs remain the leading cause of death among adolescents and adults aged 18-44 across the United States. Fentanyl is the primary contributor to these overdoses, and naloxone, an opioid receptor antagonist, is used to reverse the opioid-induced respiratory depression that causes death. However, drug adulteration is constantly evolving in the illicit supply. Recently, the addition of xylazine and/or medetomidine, both alpha-2 adrenergic receptor agonists that do not respond to naloxone, was detected in the opioid supply. The mechanism by which the combination of fentanyl and xylazine or dexmedetomidine exacerbates the effects on respiration is unknown.

Researchers led by Diana Martinez, PhD, assistant professor at Cooper Medical School of Rowan University in Camden, New Jersey, and postdoctoral fellow Thaysa Ghiarone, PhD, tested whether the respiratory-depressant effects of these drug combinations could be prevented in a new way. In the laboratory, rats were given doses of fentanyl after pretreatment with naloxone and atipamezole, an alpha-2 adrenergic receptor agonist used in veterinary settings to reverse sedation after animals have undergone surgery. The combination prevented the respiratory depressant effect in the animals, by both increasing their respiratory rate and reducing their expiratory time. The female rats exhibited a greater increase in respiratory rate and a greater reduction in expiratory time, indicating that they were more sensitive to this treatment.

“These results are exciting because they point to possible societal benefits and the future ability to help people by using atipamezole in a new way,” said Dr. Martinez. “We were surprised to see sex differences — females were more responsive to this treatment. In humans, we might need to think about how we tailor these agents to different individuals. What works for one may not work for all, as shown through the data in this study.”

The safety and efficacy of atipamezole in humans is largely untested. Additional research is needed to understand whether these results can be replicated in humans.

This research was supported by NIH.