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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.
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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.)

Last updated on: August 6, 2018
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