Fentanyl: Receptor pharmacology, abuse potential, and implications for treatment

Abstract

Opioid overdoses, many of which are attributed to use of illicit fentanyl, are currently one of the leading causes of death in the U.S. Although fentanyl has been used safely for decades in clinical settings, the widespread use of illicit fentanyl is a recent phenomenon. Starting in 2013, illicitly manufactured fentanyl and its analogs began to appear on the streets. These substances were added to or sold as heroin, often unbeknownst to the user. Because fentanyl is so potent, only small amounts are needed to produce pharmacological effects, but the margin between safe and toxic doses is narrow. Surprisingly little is known about the exact signaling mechanisms underlying fentanyl-related respiratory depression or the effectiveness of naloxone in reversing this effect. Similarly, little is known about the ability of treatment medications such as buprenorphine, methadone, or naltrexone to reduce illicit fentanyl use. The present article reviews the receptor, preclinical and clinical pharmacology of fentanyl, and how its pharmacology may predict the effectiveness of currently approved medications for treating illicit fentanyl use.

Keywords: Abuse; Beta-arrestin; Buprenorphine; Efficacy; Fentanyl; Heroin; Illicit; Methadone; Naltrexone; Pain; Pharmacology; Self-administration; Subjective effects; Treatment.

Fig. 1.

A. Pharmacological differences between fentanyl and prototypical opioid agonist morphine. Morphine binds to mu opioid receptors (MOR) and primarily produces signaling through activation of G-proteins, whereas fentanyl also activates beta-arrestin pathways that leads to respiratory depression. The enhanced respiratory depression of fentanyl compared to morphine may be due to their differences in intracellular signaling cascades. *Please note that equianalgesic conversion is dependent on route of administration and species. Opioid exposure prior to intracranial self-stimulation (ICSS) (B) or intravenous self-administration (IVSA) (C) produces activity predictive of increasing abuse potential. In contrast, pain prior to ICSS (B) or IVSA (C) has the opposite effect, where abuse potential is reduced. Note, the reduced abuse potential with prior pain to opioid exposure may not apply to individuals with comorbidities of post-traumatic stress disorder, depression and anxiety or the presence of catastrophizing (Evans & Cahill, 2016).