The anomalous pharmacology of fentanyl

Fentanyl is a key therapeutic used in anaesthesia and pain management. It is also increasingly used illicitly and is responsible for a large and growing number of opioid overdose deaths, especially in North America. A number of factors have been suggested to contribute to fentanyl's lethality, including rapid onset of action, in vivo potency, ligand bias, induction of muscle rigidity and reduced sensitivity to reversal by naloxone. Some of these factors can be considered to represent "anomalous" pharmacological properties of fentanyl when compared to prototypical opioid agonists such as morphine. In this review, we examine the nature of fentanyl's "anomalous" properties, to determine whether there really is a pharmacological basis to support the existence of such properties, and also discuss whether such properties are likely to contribute to overdose deaths involving fentanyls.