Effects of inhaled aerosolized carfentanil on real-time physiological responses in mice: a preliminary evaluation of naloxone

Abstract

This study examined the real-time exposure-response effects of aerosolized carfentanil (CRF) on opioid-induced toxicity, respiratory dynamics and cardiac function in mice. Unrestrained, conscious male CD-1 mice (25-30 g) were exposed to 0.4 or 4.0 mg/m of aerosolized CRF for 15 min (Ct = 6 or 60 mg min/m) in a whole-body plethysmograph chamber. Minute volume (MV), core body temperature (T), mean arterial blood pressure (MAP) and heart rate (HR) were evaluated in animals exposed to CRF or sterile HO. Loss of consciousness and Straub tail were observed in before 1 min following initiation of exposure to 6 or 60 mg min/m of CRF. Clinical signs of opioid-induced toxicity were observed in a dose-dependent manner. Exposure to 6 or 60 mg min/m of CRF resulted in significant decrease in MV as compared to the controls. MAP, HR and T decreased 24 h in animals exposed to either 6 or 60 mg min/m of CRF as compared to the controls. Post-exposure administration of naloxone (NX, 0.05 mg/kg, i.m.) did not increase the MV of animals exposed to CRF to control levels within 24 h, but decreased clinical signs of opioid-induced toxicity and the duration of respiratory depression. This is the first study to evaluate real-time respiratory dynamics and cardiac function during exposure and up to 24 h post-exposure to CRF. The evaluation of toxicological signs and respiratory dynamics following exposure to CRF will be useful in the development of therapeutic strategies to counteract the ongoing threat of abuse and overuse of opioids and their synthetic variants.

Assessment of naloxone as a therapeutic for inhaled carfentanil in the ferret

“…During and following exposure to aerosolized carfentanil, we observed prolong periods of both bradypnea and apnea in our animal model, as well as reductions in duty cycle which is consistent with the respiratory depression seen in both humans and other animal models [ 3 , 22 , 44 ]. Naloxone treatment was able to significantly reduce the number of both bradypneic and apneic events following administration.…”

“…Ferrets have been utilized in medical research as models of respiratory function and used to investigate respiratory pathogens like influenza and severe acute respiratory syndrome-associated corona virus, mainly because of similarities between ferret and human upper and lower respiratory tracts, pathogenesis, and symptoms [ [33] , [34] , [35] ]. We observed that ferrets were more sensitive to the effects of carfentanil than previously studied rodent models [ 3 , 36 ] and that exposure to carfentanil produced severe apnea and prolonged incapacitation in ferrets, which suggests that ferrets have a closer approximation of opioid intoxication in humans when compared to mice. Treating with naloxone following exposure significantly reduced the total time the animals were incapacitated and reduced the apneic periods.…”

“…We observed a pronounced increase in mean arterial pressure (MAP) in ferrets during exposure to carfentanil. In other animal species, carfentanil has caused both increases [ 5 ] and decreases [ 3 ] in MAP, though in a human carfentanil exposure case report, the patient was reportedly found unconscious and hypotensive [ 48 ]. Following treatment with naloxone, we observed a second, smaller, increase in MAP.…”

“…Carfentanil, like most natural and synthetic opioids, elicits its main analgesic effect through binding to μ-opioid receptors in the central nervous system [ 2 ]. Intoxication from carfentanil, both from intravenous and inhaled administration, results in severe respiratory depression and the development of cardiac abnormalities [ [3] , [4] , [5] ], although case reports from fatal overdoses have typically shown no gross tissue damage [ 6 ]. The pharmacokinetics of carfentanil and current countermeasures make renarcotization (the return of respiratory depression and general opioid effects following treatment) a potential threat and a concern when treating potential acute exposure casualties or overdose patients [ 7 , 8 ].…”

Higher doses of naloxone are needed in the synthetic opioid era

“…Animal models and studies in humans support the use of higher doses of naloxone for reversal of opioid overdoses involving synthetic opioids. For example, small animal models suggest lack of clinical reversal may occur with fentanyl analogues at doses which previously reversed morphine toxicity [14]. Furthermore, animal models also suggest that the reversal of fentanyl toxicity by naloxone is dose dependent [15].…”