The US Centers for Disease Control and Prevention continue to report increasing opioid-related deaths despite declining rates of opioid prescribing.
Dramatically on the rise is the role of illicit synthetic fentanyl derivatives. These potent Schedule I drugs have dwarfed deaths from prescription-opioid overdose deaths, even among those that possess prescription opioids from a nonmedical source
Part of the discrepancy is that overdose deaths are frequently reported through ICD-10 codes, based on the International Statistical Classification of Diseases and Related Health Problems, which do not allow for delineation of overdoses by
- a legitimately prescribed opioid versus
- an illicit opioid, versus
- a combination of these and/or other non-opioid sedative hypnotics.
Between 2016 and 2017, the US Drug Enforcement Administration (DEA) reported a 117% increase in the identification of fentanyl and fentanyl-related compounds,
When examining opioid-related death statistics, it is crucial to understand that reported data addresses only a small fraction of fentanyl-related deaths due to prescribed product, with much higher rates attributed to illicit fentanyl derivatives.
This overview, therefore, aims to elucidate the lethality and implications of those derivatives by presenting the pharmacology of both prescription fentanyl and its illicit counterparts.
Opioid Chemical Classes
The opium poppy has been cultivated for its analgesic activity since as far back as 3000 BC, although it was not until morphine was first isolated from opium in 1806 that modern opioid analgesic production began.
Morphine is one of four naturally occurring opioid alkaloids that can be isolated from the poppy; others include codeine, papaverine, and thebaine.
There have also been a number of semi-synthetic opioids produced since morphine was first isolated by simple chemical manipulations of the four basic opioid alkaloids:
- heroin (diamorphine),
and a variety of others.
Notably, the naturally occurring opioids and most semi-synthetic opioids share a similar phenanthrene chemical structure, as shown in Figure 1.
Fully synthetic opioids, or opioids not produced by direct manipulation of the opium poppy, also account for several available opioid medications.
Synthetic opioids may be sub-divided into five chemical classes:
- phenanthrenes (including levorphanol and butorphanol)
- benzomorphans (including pentazocine and loperamide)
- phenylpiperidines (including fentanyl and its derivatives)
- diphenylheptanes (including methadone)
- phenylpropyl amines (including tramadol, tapentadol).
Fentanyl, a phenylpiperidine, was first synthesized in 1960 by Janssen Pharmaceuticals, but it did not formally enter the market until 1968 as fentanyl citrate salt (Sublimaze) for use as a general anesthetic.
Since its initial approval by the US Food and Drug Administration, a variety of other pharmaceutical fentanyls and fentanyl-derivatives, as well as non-pharmaceutical fentanyl derivatives, have been synthesized.
Over the past 40 years, several pharmaceutical fentanyl formulations have come to market for the management of pain including
- Duragesic (a transdermal patch approved for chronic pain), and
- numerous unique dosage forms including dissolving tablets, films, sprays, and a lollipop lozenge for breakthrough pain.
Importantly, these latter formulations have historically been used and indicated for terminally ill patients and/or chronic cancer-related pain and therefore require the strictest form of Risk Evaluation Mitigation Strategies (REMS) as implemented by FDA.
Primarily due to its phenylpiperidine chemical structure, fentanyl is an extremely potent full mu-opioid receptor agonist, with an estimated 50 to 100 times greater potency than morphine.
Understanding fentanyl’s pharmacokinetic profile is also important regarding its overall safety profile. After systemic absorption (see bioavailabilities in Table I), fentanyl is metabolized primarily by Cytochrome P450 3A4 (CYP3A4) in the liver via oxidative N-dealkylation to inactive norfentanyl.
Due to its heavy reliance on CYP3A4, it is prone to drug-drug interactions with CYP3A4 inhibitors and inducers, as well as pharmacogenomic variability—either of which could lead to significant variability in serum fentanyl levels.
Notably, the differences in terminal half-life between fentanyl products vary greatly.
The terminal half-life of fentanyl citrate injection is roughly 3.65 hours, for example, whereas that of the transmucosal formulations range from 3 to 14 hours.
The fentanyl transdermal patch creates a depot of medication in the skin, and accordingly provides continued release of medication when the patch is removed, resulting in linear delivery and a terminal half-life of 20 to 27 hours. (See also Table I.)
Pharmaceutical Fentanyl Derivatives Alfentanil, Remifentanil, and Sufentanil
In addition to fentanyl, pharmaceutical companies have explored other fentanyl derivatives for use in anesthesia and the management of acute pain over the past several years that have vastly different properties than the original molecule.
The three main fentanyl derivatives used medically in humans include:
- remifentanil, and
Their pharmacokinetic, structural, and potency differences compared to fentanyl are shown in Tables I and II.
Non-pharmaceutical fentanyl compounds have and continue to be illegally chemically altered to new products, which increases the difficulty of testing and identifying them.
Some are extremely potent, increasing the potential for unintentional overdose.
Such deaths are often labeled as “heroin” or named by the prescription opioid(s) present if one or more of these non-pharmaceutical fentanyls are found.
For example, since heroin is metabolized to morphine, if a person received an illicit “fentanyl-laced” version of heroin and also took oxycodone, the cause of death could very well be labeled as heroin, morphine, oxycodone, and fentanyl, or any combination thereof, and the medical examiner may never find or mention the illicit fentanyl.
Table III identifies and compares all non-pharmaceutical fentanyls currently listed by the DEA as Schedule I controlled substances.
…studies show that relatively simple manipulations to pharmaceutical fentanyl can lead to incredible differences in potency and lethality.
Discussion and Implications
Although illicit fentanyl and its analogues represent a public health issue, healthcare providers also need to consider that pharmaceutical fentanyl has served to provide analgesia to patients with a variety of chronic pain conditions since the 1950s.
The practice of reporting all opioid overdose deaths under a single umbrella has led to the stigmatizing of opioid prescribing and perpetuating the under-treatment of pain.
Despite the increase in opioid-related deaths attributed to illicit fentanyl and its analogues, pressure on prescribers to “deprescribe” opioids continue, leading patients, in some cases, to turn to illegal and inexpensive sources for relief.
The goal in publishing this review is to help educate the industry and players involved in overdose reports related to these very different drug types and how they are referenced when attributing death.
A modicum of balance, along with a clearer distinction between pharmaceutical and illicit fentanyl and its analogues, has become imperative.
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