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

Abstract

In 2020, fentanyl and its analogs contributed 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.

Correspondence of fentanyl brain pharmacokinetics and behavior measured via engineering opioids biosensors and computational ethology

“…However, to our knowledge, there are no reports of hyperactivity and repetitive locomotor behavior in humans. There is a monotonic relationship between increased fentanyl dose and increased respiratory depression 62 and peak hyperactivity at 1.0 mg/kg fentanyl 63 , the dose used in this work. However, prior works had not reconciled the apparent paradox of Straub tail/respiratory depression alongside hyperactivity.…”

An Update on Psychoactive Substances: Pharmacology and Toxicology Issues

“…The six published articles highlight different aspects of the pharmacology and toxicology of several psychotropics; most of them are represented by opiates/opioids, e.g., tramadol [ 4 , 5 ], tapentadol [ 4 ], and fentanyl [ 6 ], but other categories here mentioned are selective serotonin reuptake inhibitor (SSRI) antidepressants [ 7 ], new psychoactive substances (NPSs) known as cathinones [ 8 ], and the hallucinogen drug psilocybin [ 9 ].…”

“…Consistent with the need to investigate not only psychiatric but also medical issues related to the use of opioids, in a review from Chamoun et al [ 6 ], the medical risks of opioids, including new synthetic opioids, were described. According to the authors, central nervous system depression resulting from opioid overdose and/or misuse of fentanyl analogues is clinically characterized by the onset of consciousness impairment, pinpoint miosis, and bradypnea.…”