The fentanyl epidemic and evolution of fentanyl analogs in the United States and the European Union

Abstract

BACKGROUND: Since 2013, an unprecedented surge in fentanyl overdose deaths has been caused by heroin laced with illicitly produced fentanyl and/or fentanyl analogs (FAs) sold as heroin. The US Drug Enforcement Agency’s National Forensic Laboratory Information System reported a 300% increase in fentanyl encounters from 4697 in 2014 to 14 440 in 2015. In 2015, the CDC reported 9580 deaths caused by synthetic opioids, primarily fentanyl, a 72% increase from 2014. The European Monitoring Centre for Drugs and Drug Addiction has also encountered several new FAs in the heroin supply. Counterfeit pharmaceuticals containing mixtures of fentanyl and FAs continue to be a poorly recognized worldwide problem despite the WHO classifying several FAs as a serious threat to public health. CONTENT: This review covers the epidemiology of fentanyl abuse and discusses the clinical practice implications of widespread fentanyl abuse. It includes a historical perspective on the illicit FAs that have appeared in the US and European Union and reviews the methods available to identify FAs and emerging technologies useful for identifying previously undescribed analogs. A compilation of structural and mass spectral data on FAs reported thus far is provided. SUMMARY: Fentanyl and FAs have evolved into a global public health threat. It is important to understand the analytical, clinical, and regulatory efforts underway to assist communities affected by the current fentanyl epidemic. The use of opium can be dated back to the third millennium BC. Morphine (after Morpheus, the god of dreams) was isolated by 1806 (1). By the 1850s, morphine was being used for general anesthesia and pain relief (1, 2). In search of a more effective alternative, scientists at Janssen Pharmaceutica developed highly potent opioids, including fentanyl, phenoperidine, sufentanil, alfentanil, remifentanil, and carfentanil. Fentanyl has been used as an intraoperative anesthetic since the 1960s and for chronic pain management in contemporary medicine. Sufentanil, alfentanil, and remifentanil are also clinically used fentanyl analogs (FAs) 7 . Fentanyl’s structural scaffold has been periodically modified by illicit drug manufacturers to produce novel and potent FAs. A recent surge in the supply of novel FAs into the global heroin supply via complex distribution networks has caused an unprecedented surge in opioid overdose deaths (3, 4). Structures and mass spectral properties of clinically relevant and illicit FAs and certain synthetic opioids are shown in Table 1 and in the Data Supplement that accompanies the online version of this article at http://www.clinchem.org/content/vol65/ issue2. In this review, we trace the evolution timeline of FAs, describe the epidemiology of fentanyl abuse in the US and European Union (EU), and discuss analytical and clinical practice implications of the current fentanyl epidemic.