Mechanisms of Neurorespiratory Toxicity Induced by Fentanyl Analogs-Lessons from Animal Studies

In 2020, fentanyl and its analogs contributed to similar to 65% of drug-attributed fatalities in the USA, with a threatening increasing trend during the last ten years. These synthetic opioids used as potent analgesics in human and veterinary medicine have been diverted to recreational aims, illegally produced and sold. Like all opioids, central nervous system depression resulting from overdose or misuse of fentanyl analogs is characterized clinically by the onset of consciousness impairment, pinpoint miosis and bradypnea. However, contrasting with what observed with most opioids, thoracic rigidity may occur rapidly with fentanyl analogs, contributing to increasing the risk of death in the absence of immediate life support. Various mechanisms have been proposed to explain this particularity associated with fentanyl analogs, including the activation of noradrenergic and glutamatergic coerulospinal neurons and dopaminergic basal ganglia neurons. Due to the high affinities to the mu-opioid receptor, the need for more elevated naloxone doses than usually required in morphine overdose to reverse the neurorespiratory depression induced by fentanyl analogs has been questioned. This review on the neurorespiratory toxicity of fentanyl and analogs highlights the need for specific research focused on these agents to better understand the involved mechanisms of toxicity and develop dedicated strategies to limit the resulting fatalities.

Automated summary

In 2020, fentanyl and its analogs accounted for around 65% of drug-related deaths in the USA, showing a concerning upward trend in the past decade. These synthetic opioids, originally intended for medical use, have been illegally diverted to recreational purposes. Unlike most opioids, fentanyl analogs can rapidly cause thoracic rigidity, increasing the risk of death. Further research is needed to better understand the mechanisms of neurorespiratory toxicity associated with fentanyl and its analogs, and to develop strategies to reduce fatalities.