ReviewA review: Fentanyl and non-pharmaceutical fentanyls
Introduction
In 2014, over 10 million individuals in the United States reported the use of illicit opioids as well as prescription opioids for non-medical reasons, contributing to drug-related overdose deaths which now outnumber traffic fatalities (Substance Abuse and Mental Health Services Administration (SAMHSA), 2014. Despite the concerted efforts to address the opioid crisis in this country, in recent years there has been a dramatic increase in overdoses from synthetic opioids, specifically fentanyl and related analogs (Drug Enforcement Administration (DEA); Rudd et al., 2016, Spies et al., 2016). From 2013 to 2014, the age-adjusted death rate from heroin, semi-synthetic opioids (i.e., oxycodone, hydrocodone), and synthetic opioids other than methadone increased by 26%, 9%, and 80%, respectively (Rudd et al., 2016). Evidence is now accumulating that drug manufacturers and dealers may be adding illicitly produced non-pharmaceutical fentanyl (NPF) to increase the potency of their products (Gladden et al., 2016, Hempstead and Yildirim, 2013, Peterson et al., 2016). While some individuals are using fentanyl and NPFs unintentionally through the use of fentanyl-laced heroin, others are knowingly seeking out fentanyl containing products due to the perception they are more desirable (Fernando, 1991, Mars et al., 2015).
The true extent of the illicit fentanyl and NPF use in the general population is difficult to ascertain, because routine toxicology screens will not detect synthetic opioids that have little structural homology to morphine and other commonly tested opioids. Nevertheless, fentanyl-related ED visits in the US increased from 9823 in 2004 to 20,034 in 2011, representing an increase of 104% (SAMHSA, 2013). At the same time, reports on state drug seizures from the National Forensic Laboratory Information System, a program of the (DEA, 2015a) office of diversion control, have noted an increase of fentanyl seizures by 259% from the second half of 2013 to the first half of 2014 (Centers for Disease Control and Prevention, 2015; DEA, 2015b). Fentanyl-related overdoses in Ohio, for example, increased from 84 in 2013 to 502 in 2014 (Spies et al., 2016). In Massachusetts, among the 1319 opioid-related death where toxicology results were available in 2015, 754 (57%) tested positive for fentanyl (Massachusetts Department of Public Health, 2016). Given the public health importance of this emerging problem, the aim of this review is to summarize the use and misuse of pharmaceutical fentanyl, clinical pharmacology of fentanyl, review of NPFs, and clinical management and prevention of fentanyl related overdoses.
Section snippets
The use and misuse of pharmaceutical fentanyl
For at least several thousand years, papaver somniferum has been cultivated by humans to harvest opium for its analgesic and medicinal properties. In the early 19th century, both morphine and codeine were isolated from opium, heralding an era of using pure alkoloids isolated from medicinal plants. From these starting materials, referred to as opiates, a variety of semi-synthetic opioids were created, including diacetyl-morphine (heroin) and oxycodone. In 1937, German scientists looking for an
Clinical pharmacology of fentanyl
Fentanyl is a full agonist at the mu-opioid receptor, and approximately 50–100 times more potent than morphine. Because fentanyl and NPFs are active in the sub–100 μg range, they are some of the most potent medications known to exist. Similar to other opioid agonists, fentanyl’s effects include analgesia, anxiolysis, euphoria, drowsiness, feelings of relaxation, respiratory depression, constipation, miosis, nausea, pruritus, and cough suppression, but also orthostatic hypotension, urinary
Review of non-pharmaceutical fentanyls (NPF)
In the winter of 1979, a series of apparent opioid overdoses were reported in Orange County, California, but no traces of heroin or opioids were identified on autopsy, yet injection drug paraphernalia were found near the bodies (syringes, needles, etc) and autopsy findings were consistent with opioid overdose (Henderson, 1988). In November of that same year, patients seeking entry into a methadone program in northern California were denied entry due to urines being negative for opioids (
Clinical management and prevention of fentanyl overdose
As in overdoses induced by other opioids, fentanyl-related overdoses are characterized principally by respiratory depression, accompanied by stupor and miosis (Boyer, 2012, Sporer, 1999). However, neither the absence of miosis nor the presence of mydriasis should be used to exclude the possibility of an overdose, as a substantial proportion of overdoses occur in the context of multiple drug ingestions (Hull et al., 2007). A variety of medical complications can result from the overdose,
Conclusions
For the past several decades, fentanyl has played an important role as an anesthetic agent and analgesic for severe pain due to its unique pharmacologic properties. However, there have also been numerous reports of inadvertent overuse, intentional misuse, and outbreaks of overdoses with fentanyl and NPFs. With the availability of large quantities of NPFs that can be produced with relative ease or ordered on-line, the growing number of overdoses attributed to these compounds is of considerable
Conflict of interest
No conflict declared.
Role of funding
Nothing declared.
Contributors
Conception and design (JS), literature review and data collection (JS, EH), writing (JS, EH), editing (JS, EH), approval of final version (JS, EH).
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