Fentanyl and its derivatives: Pain-killers or man-killers?

Abstract

Fentanyl is a synthetic μ-opioid receptor agonist approved to treat severe to moderate pain with faster onset of action and about 100 times more potent than morphine. Over last two decades, abuse of fentanyl and its derivatives has an increased trend, globally. Currently, the United States (US) faces the most serious situation related to fentanyl overdose, commonly referred to as the opioid epidemic. Nowadays, fentanyl is considered as the number one cause of death for adults aged 18-45 in the US. Synthesis and derivatization of fentanyl is inexpensive to manufacture and easily achievable. Indeed, more than 1400 fentanyl derivatives have been described in the scientific literature and patents. In addition, accessibility and efficacy of fentanyl and its derivatives can play a potential role in misuse of these compounds as a chemical weapon. In this review, the properties, general pharmacology, and overdose death cases associated with fentanyl and selected derivatives are presented. Moreover, current opioid epidemic in the US, Moscow theatre hostage crisis, and potential misuse of fentanyl and its derivatives as a chemical weapon are disclosed.

Keywords: Drug overdose; Fentanyl; Fentanyl derivatives; Opioid epidemic; Pharmacology; Toxicology.

Fig. 1

Synthesis of fentanyl. Simplified reaction scheme as reported by Ref. [15].

Fig. 2

Signaling pathways of the MOP receptors. G protein signaling pathway (left side) is represented by fractionation of heterotrimer G_αβγ into G_α subunit and G_βγ heterodimer. The G_α subunit inhibits adenylyl cyclase which in turn inhibits production of cAMP and PKA. This results in inhibition of ion channels in the cellular membrane. Heterodimer G_βγ blocks calcium channels and opens potassium channels. These events result in reduction of excitability and nociception and result in analgesic effects. β-Arrestin signaling pathway (right side) is represented by GRK-mediated phosphorylation on C-terminus of the receptor, which results in recruitment of β-arrestin to the receptor. This results in desensitization and occasionally endocytosis of the receptor, commonly termed as receptor internalization. Both of these events decrease the responses to opioids, inducing tolerance and insufficient analgesia. MOP receptor on the endosome can be dephosphorylated and degraded by lysosomes or resensitized through trafficking back to the cellular membrane. Abbreviations: α, G_α subunit; β, G_β subunit; γ, G_γ subunit; ADP, adenosine diphosphate; ATP, adenosine triphosphate; cAMP, cyclic adenosine monophosphate; GRK, G protein-coupled receptor kinase; PKA, protein kinase A; TRPV1, transient receptor potential cation channel subfamily V member 1; VGSCs, voltage-gated sodium channels [[34], [35], [36]]. Created with BioRender.com.

Fig. 3

Binding mode of morphine and fentanyl to MOP receptor. Common and different notable interactions of the ligands with amino acid residues of the receptor [38].

Fig. 4

Metabolic pathways of fentanyl. Schematic view of metabolites detected in human. N-dealkylation represents the main metabolic pathway [44].

Fig. 5

Chemical structures of fentanyl and selected fentanyl derivatives.

Fig. 6

Drug overdose deaths in the US between 1999 and 2021. Overall drug overdose deaths (grey) are shown along with selected drugs such as heroin (purple), methadone (yellow), and synthetic opioids involving fentanyl and excluding methadone (red). Source: CDC. Statistics during 1999–2014 are based on the NCHS report (December 2020) [133]. Statistics during 2015–2021 are based on the NCHS updated report (September 2, 2022) [3].