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15 Articles in Volume 18, Issue #5
Chronic Pelvic Pain: The Need for Earlier Diagnosis and Diverse Treatment
Cross-Linked Hyaluronic Acid for the Management of Neuropathic Pelvic Pain
Fentanyl: Separating Fact from Fiction
Gender Bias and the Ongoing Need to Acknowledge Women’s Pain
Letters to the Editor: 90 MME/day Ceiling; Ehlers-Danlos; Redefining Pain
Post-Menopausal MSK Pain and Quality of Life
PPM Welcomes Dr. Fudin and Dr. Gudin as New Co-Editors
Practitioner as Patient: Understanding Disparities in CRPS
States Take Action to Manage Opioid Addiction
Step-by-Step Injection Technique to Target Endometriosis-Related Neuropathic Pelvic Pain
The Many Gender Gaps in Pain Medicine
The Need for Better Responses to Vulvar Pain
Topical Analgesics for Chronic Pain Conditions
Topical Medications for Common Orofacial Pain Conditions
What’s the safest, effective way to taper a patient off of opioid therapy?

Fentanyl: Separating Fact from Fiction

Understanding the differences between pharmaceutical and illicit fentanyl and their analogues could save the opioid crisis.

This article provides a sneak preview into the upcoming July/August 2018 issue of Practical Pain Management.

The US Centers for Disease Control and Prevention continue to report increasing opioid-related deaths despite declining rates of opioid prescribing.1,2 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.3

Part of the discrepancy is 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.3

Despite this inaccurate categorization of opioid overdose deaths, which a group of CDC researchers discussed in an April 2018 editorial in the American Journal of Public Health, the increasing presence of illicit fentanyl is clear. Between 2016 and 2017, the US Drug Enforcement Administration (DEA) reported a 117% increase in the identification of fentanyl and fentanyl-related compounds,4 and research in Ohio revealed that fentanyl-related overdose deaths coincided with increased confiscation of illicitly-produced fentanyl by law enforcement.5 Illicit fentanyl has been used as a supplement fluctuating the purity of heroin, leading to increased overdose deaths.6 In 2017, the DEA reported that when fentanyl was identified in a confiscated sample, it was the single ingredient in approximately 43% of them, highlighting additional concerns over the combining or “lacing” of potent illicit fentanyl products without the knowledge of the end user. 4

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. 2 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), buprenorphine, oxycodone, hydrocodone, oxymorphone, and a variety of others. 7 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).7

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. 8,9 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.

Pharmaceutical Fentanyl

Over the past 40 years, several pharmaceutical fentanyl formulations have come to market for the management of pain including Sublimaze, 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. 8,9

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. 10,11 Its potency is a major reason for its indication for opioid-tolerant patients. This potency also greatly increases fentanyl’s opioid-related risks. Like all other opioids, pharmaceutical fentanyl products have several black box warnings, contraindications, and precautions in place to encourage responsible and appropriate prescribing. Risks such as addiction, and abuse and misuse are extremely important to consider in all patients when prescribing fentanyl, as the risk of potentially life-threatening respiratory depression should not be underestimated.

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.11,12 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.11,12 (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: alfentanil, remifentanil, and sufentanil. Their pharmacokinetic, structural, and potency differences compared to fentanyl are shown in Tables I and II.

While remifentanil and alfentanil are primarily used via intravenous injection, sufentanil may also be administered by direct infusion (epidural injection) into the central nervous system (CNS) for analgesia during labor and delivery. As such, all three medications are limited to utility in an inpatient setting. Irrespective, they may still be abused in the community if diverted or illicitly processed, although this is rarely reported. Importantly, the FDA recently provided a response letter to AcelRx regarding its New Drug Application (NDA) of DSUVIA, a dosage form of sufentanil administered with a single-dose applicator (SDA)—the dosage is meant to be provided in a medically supervised setting, particularly in military combat settings.13

Alfentanil is specifically approved as an analgesic adjunct in maintenance anesthesia, a primary anesthetic for induction of anesthesia, and as the analgesic component for monitored anesthesia care. It is metabolized in the liver by CYP3A4 and 3A5 via piperidine and amide N-dealkylation, respectively, to inactive metabolites noralfentanil and N-phenylpropionamide. 14-16 Alfentanil is about one quarter as potent as fentanyl, and has a half-life of 90 to 111 minutes, approximately half that of fentanyl. 8

Remifentanil has similar indications as alfentanil, although the medication is vastly different pharmacokinetically and structurally. As illustrated in Table I, remifentanil has a structure such that its labile ester linkage renders it susceptible to hydrolysis by non-specific blood and tissue esterases, which are in abundance throughout the body. 15,17,18 Therefore, the drug is rapidly converted into inactive remifentanil acid within minutes. This process allows for rapid titration or discontinuation of effect, which are useful for procedures and surgeries optimized by rapid induction and recovery from anesthesia. Also, of note, this compound is approximately 100 to 200 times more potent than morphine and one to two times more potent than fentanyl. 15,17, 18

Sufentanil citrate is indicated for use as an adjunctive analgesic agent or as a primary anesthetic agent in patients who are intubated and ventilated in the hospital. This medication is metabolized by CYP3A4 via O-demethylation to methylsufentanil, which has 10% of the activity of the parent drug. 8,11,12 The important distinction associated with this fentanyl derivative is that it has been shown to be between 500 to 1,000 times more potent than morphine and 5 to 10 times more potent than fentanyl.10,11,12 See also Table II.




Although carfentanil is not approved for use in humans, it is technically a pharmaceutical fentanyl derivative with Schedule II status designated by the DEA and FDA. It is currently only approved for use as a tranquilizing agent for elephants and other large mammals, as it is approximately 10,000 times more potent than morphine and 100 times more potent than fentanyl. 19 Pharmacokinetic data on carfentanil is therefore scarce. However, a study published in 2016 demonstrated production of 12 metabolites with N-dealkylation and monohydroxylation of the piperidine ring being the primary mediator of carfentanil metabolism in human liver microsomes and hepatocytes. 19

Non-Pharmaceutical Fentanyls

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. 3 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. Predictably, there is a paucity of data for most of these compounds, particularly regarding relative potency. For those which potency information is available, none have been studied in humans. Furthermore, the potency ratios that do exist were primarily calculated by comparing median effective dose (ED50) values in mice following hot-plate tail-flick testing. Although somewhat useful, such preclinical data cannot be validly or reliably extrapolated to humans. Of those studied to date, perhaps the most important to be aware of are non-pharmaceutical fentanyls, which include: acryloyl fentanyl, alpha-methyl fentanyl, beta-hydroxy-3-methyl fentanyl (ohmefentanyl), 3-methyl fentanyl, and ocfentanil, mainly due to their availability of data on potency.

Acryloyl fentanyl (also known as acryl fentanyl) was first identified in the European illicit drug abuse market by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and later by in the United States by the DEA in 2016. 20,21 However, it was first studied as a fentanyl analogue in the 1980s, 21,24 A study by Zhu and colleagues calculated antinociceptive activities of morphine, pharmaceutical fentanyl, and acryloyl fentanyl following intraperitoneal administration characterized by ED50 values from hot-plate testing. 25 They found ED50 (mg/kg) values of 13.9, 0.062, and 0.082 for morphine, fentanyl, and acryloyl fentanyl, respectively, the latter two corresponding with a relative potency ratio to morphine of 224 and 169.5. 23,25 This drug has also been studied in the rat brain to determine its binding affinity for the mu-opioid receptor, in which affinity was characterized by the half-maximal inhibitory concentration (IC50) or concentration of drug displacing 50% of naloxone from mu-opioid receptors. 23, 25 IC50 (nM) values were found to be 4.2, 1.6, and 1.4 for morphine, fentanyl, and acryloyl fentanyl respectively, meaning acryloyl fentanyl had considerably higher binding affinity to the mu-opioid receptor than did morphine or pharmaceutical fentanyl. 23, 25

Since the development of pharmaceutical fentanyl, multiple methyl-type fentanyls have been synthesized, both for purposes of therapeutic drug development and in the illicit drug market. Methyl fentanyl derivatives first appeared on the black market in the 1980s, namely as alpha-methyl fentanyl, also known as “China White.” 23 A study conducted by Higashikawa and colleagues compared ED50 values of a variety of fentanyl derivatives (including methyl fentanyls) to those of morphine and pharmaceutical fentanyl, utilizing mice writhing episodes as the criterion for effectiveness.26 The investigators identified ED50 (mg/kg) values of 0.33, 0.0061, 0.0058, and 0.00058-0.0068 for morphine, pharmaceutical fentanyl, alpha-methyl fentanyl, and 3-methyl fentanyl respectively, the latter three corresponding with a relative potency ratio to morphine of 54.1, 56.9, and 48.5-569.26 3-methyl fentanyl has also been demonstrated to have roughly twice the affinity toward mu-opioid receptors than pharmaceutical fentanyl. 24 Beta-hydroxy-3-methyl fentanyl (otherwise known as ohmefentanyl) was studied by Jin and colleagues in the early 1980s, and was determined to have a potency 28 times greater than that of pharmaceutical fentanyl and 6300 times that of morphine. 27 These studies show that relatively simple manipulations to pharmaceutical fentanyl can lead to incredible differences in potency and lethality.


Ocfentanil was first clinically investigated in the 1990s as a general anesthetic, but was never FDA approved. 28 Its prevalence and abuse have varied since it was first studied; however, recently there have been increased reports of intoxication and deaths (primarily in Europe) associated with its use. 28 Unlike most other nonpharmaceutical fentanyl products, ocfentanil was studied in humans, and was determined to have a relative potency 200 times greater than that of morphine.29 Unfortunately, pharmacokinetic data are still scarce regarding this drug.

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.30 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.

Last updated on: April 12, 2019
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