Review

Cite This: ACS Chem. Neurosci. 2018, 9, 2428−2437 pubs.acs.org/chemneuro

DARK Classics in Chemical Neuroscience: Fentanyl

S. Mallory Burns,† Christopher W. Cunningham,‡ and Susan L. Mercer*,†,§
†
Department of Pharmaceutical Sciences, Lipscomb University College of Pharmacy, Nashville, Tennessee 37204, United States
‡
Department of Pharmaceutical Sciences, Concordia University Wisconsin School of Pharmacy, Mequon, Wisconsin 53097, United
States
§
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States

ABSTRACT: Fentanyl rose to prominence as an alternative analgesic to morphine nearly 50 years ago; today,
fentanyl has re-emerged as a dangerous recreational substance. The increased potency and analgesic effect of
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fentanyl are advantageous in the treatment of pain but are also responsible for the rise in unintentional opioid
overdose deaths. In response to this crisis, fentanyl, its analogues, and even precursors are under heightened
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regulatory scrutiny. Despite this controversial history, derivatization of fentanyl has resulted in numerous
synthetic analogues that provide valuable insights into opioid receptor binding and signaling events. In this review,
the impact of fentanyl on chemical neuroscience is shown through its synthesis and properties, manufacturing,
metabolism, pharmacology, approved and off-label indications, adverse effects, and the responsibility it has in the
opioid epidemic.

KEYWORDS: Fentanyl, opioid, analgesic, pain, designer drug

■ INTRODUCTION
Fentanyl is a high potency mu-opioid receptor (MOR) agonist
used medically in the treatment of acute and chronic pain and
as an anesthetic adjuvant for its ability to produce analgesia and
euphoria.1 First synthesized in 1960 by Dr. Paul Janssen in
Belgium, fentanyl has become one of the most prominent
opioid analgesics in the United States (US) and has contributed
to the current opioid epidemic.2 In the past decade, overdose
deaths due to opioid abuse and misuse have steadily increased.
Fentanyl and its analogues are responsible for the sharpest
increase in 2016 opioid overdose deaths at an estimated 20 000
in the US.3 Fentanyl is 75−100 times more potent than
morphine with an LD50 of 3.1 mg/kg in rats, 0.03 mg/kg in
monkeys, and unknown in humans.4 Fentanyl almost
immediately became the opioid of choice for clinicians, quickly
replacing morphine as an anesthetic for surgeries during the
1970s5 due to the rapid onset, short duration of action, high
potency, and limited cardiovascular risks compared to
morphine along with its cost-effective production.6,7
Classified as a schedule II prescription drug, the misuse and
abuse of fentanyl by clinicians was first reported in the 1980s.8,9
A large portion of the misuse was associated with
anesthesiologists and surgeons who had immediate access to
fentanyl.10,11 After transdermal fentanyl patches were approved
in the 1990s, access to this powerful opioid expanded from
clinicians to patients and reports of overdose from misuse
emerged.12
Illicit Use. Nonpharmaceutical fentanyl (NPF) is increas-
ingly popular in the U.S., likely due to the feasibility of its
synthesis. NPF refers to illicitly produced fentanyl or fentanyl
analogues with no regulated therapeutic use. The first illicitly
produced fentanyl was found mixed in batches of heroin sold
on the streets as “Tango and Cash” in the 1970s. Other names
for adulterated heroin or pure fentanyl include Apache, China
Girl, China White, Friend, Dance Fever, TNT, Goodfella,
Jackpot, and Murder 8.8 The primary issue with illicit use of
fentanyl is the high potency and low lethal dose. Unsuspecting
heroin users are most susceptible to overdosing on fentanyl-
laced heroin or fentanyl sold as heroin.13,14 Illicit fentanyl has
been identified in counterfeit pills, capsules, powders, and on
blotter paper.15 Additionally, recent reports of fentanyl-laced
cocaine and marijuana samples have made state and national
headlines as law enforcement officials warn the public about
these potentially deadly mixtures. Due to its high potency,
ingestion of just a few milligrams of fentanyl can be deadly to
an opioid-naı̈ve individual or an unsuspecting “recreational”
drug user. First responders who come in contact with free base
fentanyl analogues are also at risk of life-threatening toxicities.16
Misuse of prescription fentanyl is not uncommon, as it is
widely used by patients with severe chronic pain. Transdermal
patches are abused and misused by applying multiple patches
simultaneously or by extracting fentanyl from the reservoir to
administer in an alternative method with a faster onset of action
to elicit a euphoric effect.17 Further, transdermal patches are
also chewed which alters the delivery device and releases a high
dose of fentanyl that is absorbed in the mouth.18
Analogues. Several FDA-approved fentanyl analogues were
developed in the 1960s for medical and veterinary purposes,
including sufentanil, alfentanil, remifentanil, and carfentanil.19
Due to the simplicity of synthesis, a number of illicit fentanyl
Special Issue: DARK Classics in Chemical Neuroscience
Received: April 12, 2018
Accepted: May 23, 2018
Published: June 12, 2018

© 2018 American Chemical Society 2428 DOI: 10.1021/acschemneuro.8b00174

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ACS Chemical Neuroscience
Scheme 1. Original Fentanyl Synthesis by Paul Janssen
Scheme 2. Two Alternative Synthetic Routes to Fentanyl
analogues have begun to emerge, presenting a substantial
regulatory challenge. In February 2018, the US Drug
Enforcement Administration (DEA) ordered all illicit fentanyl
analogues not currently regulated by the Controlled Substances
Act to be categorized as Schedule I drugs.20 This order is one of
the few federal regulations to combat the increasing overdose
death rate due to synthetic opioids.20
■ PROPERTIES AND CHEMICAL SYNTHESIS
Fentanyl (CAS no. 437-38-7; N-phenyl-N-[1-(2-phenylethyl)-
piperidin-4-yl]propanamide, C22H28N2O) is in the 4-anilidopi-
peridine series of opioids with no hydrogen bond donors, two
hydrogen bond acceptors, a low molecular weight (MW =
336.47), and a logP of 4.28.21,22 Therefore, fentanyl is
consistent with Lipinski’s “rule of five”23 and readily crosses
the blood brain barrier (BBB) via passive diffusion.24 In fact,
the higher lipophilicity of fentanyl compared to that of
morphine (logP 1.07) is responsible for improved central
bioavailability and greater potency.25
The first synthesis of fentanyl (6) was completed by Janssen
(Scheme 1). In the first step, 1-benzypiperidin-4-one (1) is
condensed with aniline and a catalyst such as toluene-p-sulfonic
acid26 and zinc chloride27 to give the corresponding Schiff base
(2). The double bond in the imine (2) is reduced with lithium
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Review
aluminum hydride, and the resulting 1-benzyl-4-anilinopiper-
idine (3) is acylated using propionic anhydride. Debenzylation
of 1-benzyl-4-N-propinoyl-anilinopiperidine (4) using standard
H2−Pd/C conditions produces norfentanyl (5), which is N-
alkylated by 2-phenylethyl chloride (or tosylate) to give the
final desired compound, fentanyl (6).2,26,28−36
The efficiency of fentanyl synthesis has improved over the
years, and two modified schemes (Scheme 2) have emerged. A
four-step synthetic approach begins with propionylation of the
starting material 4-anilinopyridine (7), yielding 4-N-propinoy-
lanilidopyridine (8).35,37,38 Intermediate 8 undergoes alkylation
with 2-phenylethyl bromide to give a pyridinium salt (9), which
then undergoes hydrogenation over PtO2 to yield 4-N-
anilinopiperidine, a key intermediate (10). Intermediate 10 is
propionylated to produce fentanyl (6). The most efficient
synthetic route, to date, is a two-step process which starts
directly from 1-(2-phenethyl)piperidin-4-one (11).35,39 Com-
pound 11 undergoes reductive amination to produce the
fentanyl precursor 10, followed by selective acylation to
generate fentanyl (6).35,40,41
Medicinal Chemistry/SAR. Since the structure of
morphine was solved in 1925 by Sir Robert Robinson, chemists
have altered the compound in search of a stronger analgesic.42
The discovery and development of opioid series occurred
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through “pruning” the structure of morphine and subsequently
analyzing the biological activity. Removal of 4,5-epoxymor-
phinan rings B, C, and E (Figure 1) produces the 4-
Figure 1. Chemical pruning of 4,5-epoxymorphinans led to develop-
ment of phenylpiperidine series, including meperidine. Understanding
the piperidine ring requirement for analgesic activity inspired the
fentanyl scaffold.
phenylpiperidine series of opioids which includes meperidine.
Janssen sought to expand this series of opioids through the
addition of a nitrogen, creating the 4-anilidopiperidine class of
synthetic opioids.26,35,43
Dr. Paul Janssen first synthesized fentanyl in an attempt to
make a more powerful analgesic with fewer unwanted side
effects. Meperidine was the parent compound for many of his
analogues due to the simplicity of the molecule relative to
morphine.1 A key structural difference between the meperidine
and fentanyl classes is the introduction of an additional
nitrogen in the structure between the phenyl and piperidine
rings. To improve understanding of the structure−activity
relationship (SAR) of fentanyl, numerous analogues were
Figure 2. Fentanyl and known major analogues.
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Review
synthesized by altering specific moieties in the fentanyl scaffold.
The structure of fentanyl can be categorized into four
modifiable groups: N-alkyl chain, piperidine ring, amide
group, and the aniline ring.35,44 Piperidine ring contractions
or expansions also shed light on the relationship between the
fentanyl scaffold and potency. Expanding or contracting the
piperidine ring by one carbon significantly decreases anti-
nociceptive potency relative to that of fentanyl; however, the
activity of resulting analogues remains comparable to that of
morphine.35,45,46 A series of analogues was created through
methyl or hydroxyl substitution at each modifiable group on the
fentanyl scaffold. Methyl substitutions on the piperidine ring, as
seen in 3-methyl fentanyl and 2,5-dimethyl fentanyl (Figure 2),
have been shown to be extremely potent and have minimal
variance in analgesic activity among isomers.47,48 Two amide
analogues, acrylfentanyl and furanylfentanyl, are fentanyl
analogues that have re-emerged as designer drugs. Acrylfentanyl
was originally developed to be a covalent MOR probe and
contains a highly reactive acrylamide toxicophore.49 Furanyl-
fentanyl was included in a 1985 patent disclosing high potency
fentanyl analogues as analgesics.50
More complex substitutions on the scaffold increase potency
(Table 1) and selectivity as seen in carfentanil. The addition of
a methyl ester moiety at the 4-position of the piperidine ring is
responsible for the 100-fold increase in potency of carfentanil,
the most potent opioid used commercially.51 Small changes in
the carfentanil structure produces additional analgesics.
Addition of a methyl group in the 3-position of the piperidine
ring of carfentanil produces highly potent and long acting
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Table 1. Comparison of Fentanyl Analogues in Regards to Scheme 3. Metabolic Pathways for Fentanyl
US DEA Scheduling and Potencya
US DEA potency ratio to ED50
schedule compound name fentanyl (mg/kg)
Schedule I acetyl fentanyl 0.29 0.021
α-methyl fentanyl 1.1 0.0085
3-methyl fentanyl 0.9−10.5 0.04
benzyl fentanyl ND ND
β-hydroxy ND 0.0018
fentanyl
butyryl fentanyl 0.03−0.13 0.22052
lofentanil >100 ND
Schedule II alfentanil 0.1−0.2 0.044
carfentanil 100 0.00041
remifentanil 2−20 0.0044
sufentanil 5−10 0.00071
fentanyl 1 0.004153
a
Limited pharmacological data is available for the illicit fentanyl
analogues. All reference values are pulled from recent review articles
which critically evaluated the current literature. Potency ratios to
fentanyl are from Suzuki and El-Haddad,7 and ED50 values from
Vardanyan and Hruby35 unless otherwise indicated. ND = not
determined.

lofentanil.4 Sufentanil, alfentanil, and remifentanil all share the

same methoxymethylene group at the 4-position of the
piperidine ring, but vary replacements on the phenyl ring of
the phenethyl group. Incorporating additional functional
groups into the scaffold has produced numerous analogues
suitable for therapeutic use due to increased potency (Table 1).
metabolites are inactive and are primarily renally excreted along
with 8−10% unchanged parent compound.62−64
■ PHARMACOLOGY

■ MANUFACTURING INFORMATION
Fentanyl was initially approved by the FDA as an intravenous
anesthetic in the U.S. under the trade name Sublimaze in 1972.
Following patent expiration in 1981, fentanyl sales drastically
increased.19 Today, fentanyl is available in a wide array of
dosage forms with Janssen Pharmaceutica Products, L.P.
remaining a major producer of fentanyl products. Oral dosage
forms include a transmucosal lozenge (Actiq), a buccal tablet
(Fentora), a buccal film (Onsolis), a sublingual tablet (Abstral),
and a sublingual spray (Subsys). Fentanyl is also available in
two topical formulations, a transdermal iontophoretic trans-
dermal device (Ionsys) and a transdermal patch (Duragesic).
Additionally, fentanyl has an intranasal formulation (Lazanda)
and injectible products for intravascular, intramuscular, and
epidural routes of administration.54,55 Fentanyl can be delivered
as the free base or in one of two salt forms, namely citrate and
hydrochloride. Naturally, the pharmacokinetic parameters vary
with each route of administration and specific formulation and
are beyond the scope of this review.
Fentanyl and analogues produce pharmacologic effects that are
primarily opioid receptor-mediated. The opioid receptors are G
protein-coupled receptors (GPCRs) consisting of a C-terminus,
7 transmembrane-spanning helical domains, and a protein-
binding intracellular N-terminus. Ligand binding induces a
conformational change in opioid receptors that recruit Gαi/o
proteins, β-arrestins1 and 2 (β-arr1, 2), and other intracellular
signaling proteins. Available pharmacodynamic effects of
fentanyl and analogues at opioid receptors are found in Table
2. Like morphine,65 fentanyl and analogues bind with MOR-
preferring to MOR-selective affinity.66−69 The 4-anilidopiper-
idines are generally high efficacy MOR agonists as determined
using the GTPγS opioid receptor functional assay.70 Affinity
and potency values are assay-dependent,25 though carfentanil,
lofentanil, and sufentanil are consistently the most potent in the
series. In particular, sufentanil carries a very high therapeutic
index (>20 000).71 Remifentanil is a MOR agonist whose short
duration of action is due to a labile N-alkyl ester function.72
Remifentanil is approximately equipotent with fentanyl as an

■
DRUG METABOLISM
Fentanyl is highly lipophilic and binds strongly to plasma
proteins.56 Its volume of distribution is large (3.5−8 l/kg) and
its clearance relatively high (30−72 l/h).6,56 Fentanyl under-
goes N1-dealkylation in the liver by cytochrome P450 isoform
3A4 (CYP3A4) to produce norfentanyl, the major metabolite
(Scheme 3).57−59 Less than 1% is metabolized by alkyl
hydroxylation, secondary N-dealkylation, or amide hydrolysis
to generate hydroxyfentanyl, hydroxynorfentanyl, and despro-
pionylfentanyl, respectively.58,60,61 A variety of hydroxylated
metabolites has been suggested as shown in Scheme 3.61 All
2431
inhibitor of electrically evoked contraction in the guinea pig
ileum (EC50(remifentanil) = 2.4 ± 0.6 nM, EC50(fentanyl) =
1.8 ± 0.4 nM). In these studies, KOR- and DOR-selective
antagonists had no effect on reversing the effects of
remifentanil;73 a subsequent study suggests remifentanil is
cardioprotective via a DOR/KOR mechanism, however.74
Fentanyl and analogues are reported to bind voltage-gated
sodium channels (NaV 1.2)75 and serotonin receptors (5-HT1A
and 5-HT2A),76 though their relative contributions to observed
effects at therapeutic concentrations are unclear.
Biased agonism, or functional selectivity, measures the
relative stimulation of intracellular signaling pathways as a
function of agonist.77 Of interest is the relationship between
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Table 2. Opioid Receptor Binding and Efficacy Data for Fentanyl Analogues
Ki ± SEMa
MOR DOR KOR
fentanyl 0.7 ± 0.3
b
152.7 ± 38.3b
84.8 ± 19.4b
alfentanil 38.9 ± 3.7c 21200 ± 3500c ND
carfentanil 0.024 ± 0.004e 3.28 ± 0.04e 43 ± 4e
lofentanil 0.023 ± 0.004e 0.24 ± 0.02e 0.60 ± 0.05e
remifentanil NA NA NA
sufentanil 0.77 ± 0.10c 20.2 ± 1.52c ND
a
Values in nM. bMOR-transfected Chinese hamster ovary (CHO) membranes.68 cRat whole brain homogenates.69 dmMOR-CHO.67 eGuinea pig
ileum.66 fSee ref 74. ND = not determined. NA = not available.
MOR-mediated stimulation of G proteins compared to β-arr2:
morphine antinociception is enhanced, whereas respiratory
depression and constipation are reduced, in β-arr2 knockout
animals.78 The β-arr2 isoform is also involved in the
development of tolerance.79,80 In the 4-anilidopiperidine series,
only fentanyl, sufentanil, and a series of spirocyclic
anilidopiperidine bioisosteres have been evaluated for MOR
pathway bias.81 Fentanyl and sufentanil were potent, β-arr2-
preferring MOR agonists in vitro. Whereas fentanyl produced
robust respiratory suppression in vivo, equianalgesic doses of G
protein-biased analogues showed little effect on respiration in
this study. Unlike morphine, which is modestly G protein-
biased, fentanyl causes MOR internalization that is mediated by
β-arr2.82 The significant pharmacologic differences between
fentanyl and morphine may be explained by a differential mode
of MOR binding and activation: fentanyl and other 4-
anilidopiperidines are proposed to bind MORs through an
alternate molecular mechanism than that of morphine and
other 4,5-epoxymorphinans. Site-directed mutagenesis and
homology modeling studies support an alternate binding
mode for fentanyl compared to morphine.83−89
Fentanyl is also more lipophilic than morphine; logP 4.28 vs
1.07, respectively.22 Due to its high lipophilicity, fentanyl
rapidly equilibrates between the plasma and the cerebrospinal
fluid, leading to a fast onset of both analgesia and respiratory
depression.90 Further, fentanyl is rapidly distributed to less
highly perfused tissues. In large doses, fentanyl progressively
saturates these tissues and effectively has a longer duration of
action requiring multiple doses of naloxone to reverse effects.
Receptor binding interactions and lipophilicity partially explain
the limited effectiveness of naloxone in reversing fentanyl- and
related 4-anilidopiperidine-induced overdoses. Fentanyl over-
dose reversal is an important concept and is further explored in
the Current Issues and Concerns section. Development of a
fentanyl specific reversal agent is likely to rely on understanding
the physicochemical and molecular actions of this class.
■ APPROVED AND OFF-LABEL INDICATIONS
Fentanyl was first approved by the FDA as an adjunct therapy
for general anesthesia and is still widely used in this manner.91
Additional approved uses include treatment of breakthrough
pain in cancer patients92 and for patients whose pain is chronic,
severe, and unmanageable by alternative therapies.93 Prescribers
are cautioned against prescribing fentanyl due to the risk of fatal
respiratory depression, drug−drug interactions and high
potential for abuse.92 Only three analogues are currently
intended for pharmaceutical use: alfentanil, remifentanil, and
sufentanil.94 Carfentanil, a more potent analogue of fentanyl, is
approved only for large-animal veterinary medicine.95 Fentanyl
is used off-label for intrathecal and epidural analgesia and
Review
EC50 ± SEMa (Emax, %)
MOR DOR KOR
8.1 ± 0.4 (100 ± 12)b
515.0 ± 102 (86 ± 19) b
2368 ± 534 (30 ± 4)b
387 ± 54 (111 ± 11)d ND ND
0.019 ± 0.002e 17 ± 8e 59 ± 28e
0.18e 1.0 ± 0.2e 13.3 ± 0.3e
2.6f 66f 6100f
4.0 ± 0.7 (104 ± 11)d ND ND
breakthrough pain in noncancer patients.96 Off-label use of
fentanyl has placed pharmaceutical companies under intense
scrutiny as the full scope of the opioid epidemic is coming to
light through the media.
■
ADVERSE EFFECTS AND DOSAGE
As a highly potent MOR agonist, serious and fatal adverse
reactions can occur with fentanyl use. Common adverse effects
among opioids can also be seen with fentanyl use: nausea,
vomiting, and itching.97 Muscle rigidity is a side effect that is
more severe with fentanyl. This often occurs after fentanyl is
used in anesthesia. 98 Central nervous system (CNS)
depression, hypotension, serotonin syndrome, and respiratory
depression are among the more severe adverse reactions.54
Pinpoint pupils, miosis, is a common physical symptom of
opioid use that accompanies respiratory depression and serves
as a key diagnostic indicator of opioid overdose.99 Respiratory
depression is common in all opioids; however, improved
central bioavailability of fentanyl leads to a more rapid onset of
respiratory depressant effects that increases the risk of
unintentional overdose death.100
Several classes of drugs used concurrently with fentanyl raise
additional health concerns. US BlackBox Warnings are in place
for the use of fentanyl with benzodiazepines and other CNS
depressants such as alcohol because concurrent use can amplify
sedation, respiratory depression, likelihood of coma, and
death.54,101 All cytochrome P450 3A4 inhibitors used
concomitantly with fentanyl carry the risk of increasing fentanyl
plasma concentrations, which could intensify or prolong any
adverse effects and lead to fatal respiratory depression.
Likewise, cessation of concurrently used cytochrome P450
3A4 inducers could increase fentanyl plasma concentration.54
Due to the significant drug−drug interactions that can occur,
dosage and frequency should be carefully monitored or an
alternative therapy selected.
Opioid addiction, misuse, or abuse is perhaps the most
relevant risk associated with fentanyl today. Overdoses are
possible regardless of the source of fentanyl but can be reversed
with naloxone, though many variables contribute to the
effectiveness of naloxone reversal. Typically the dose of
naloxone required to reverse respiratory depression is
comparable to common opioids; however, additional doses of
naloxone may be needed when larger amounts of fentanyl and
high-potency analogues are used.102
Fentanyl, like other opioids, should never be a first-line of
treatment for pain due to the serious associated risks, limited
benefits, and limited efficacy in chronic pain.103 Therapeutic
dosing varies with route of administration and patient needs.
The analgesic dosing equivalent to 10 mg of morphine is
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Figure 3. Timeline of select fentanyl events in US history.
reported as 0.125 mg intramuscularly for an onset within 7−15
min.55,104,105
■
HISTORY AND IMPORTANCE IN NEUROSCIENCE
Chronic pain can arise from numerous causes such as an
underlying health issue, injury, surgical procedures, inflamma-
tion, and other unknown causes. The National Health
Interview Study in 2012 estimates that over 11% of adults
experience chronic pain that hinders their daily activities.103
Thousands of years ago, the benefits of opium were discovered
after extraction from the poppy Papaver somniferum.106 Opium
has been used for centuries recreationally and for pain
treatment;107 however, morphine, the principal alkaloid found
in opium, was not isolated until the early 1800s.108,109 After the
structure of morphine was elucidated, many synthetic and
semisynthetic opioid compounds have been produced for the
treatment of pain.110 Janssen’s work on producing new series of
analgesics propelled the field of medicinal chemistry, as can be
seen in fentanyl and the analogues his laboratory produced.2
Though fentanyl initially entered the market to aide in
surgeries and as a therapeutic agent for chronic pain, its impact
has become grimmer. The potential for fentanyl misuse was
initially thought to be minimal, but in recent years the opposite
has proven to be true as the overdose death rate due to opioids
continues to increase.111 A mere four years after transdermal
fentanyl patches were approved, the FDA issued a warning
outlining the potential for abuse due to an increasing number of
overdoses.7,112 Despite the multiple warning reports from the
FDA throughout the early 2000s, overdoses from fentanyl are
increasing. An estimated 40% of opioid overdose deaths are
linked to prescription opioids.113 Consequently, prescribers
have been strongly advised to limit fentanyl to patients who
qualify under the approved indications.103 The incongruence
between patients reporting chronic pain and the number of
opioid prescriptions written is a contributing factor toward the
misuse of fentanyl and other opioids.114
■
CURRENT ISSUES AND CONCERNS
It is evident that in the last 50 years, fentanyl has become
increasingly abundant and is responsible for many of the
overdose deaths in the ongoing opioid epidemic in the U.S.115
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NPF contributes to this dark chapter in fentanyl’s history, as
clandestine laboratories are able to quickly and efficiently
synthesize fentanyl and more potent analogues.116 Prior to
2010, only a few outbreaks of illicit fentanyl or analogues
occurred after carfentanil entered in the market in the 1970s.
However, since 2010, there have been three major outbreaks
that have caused the NPF related death rate to spike (Figure
3).116 From 2013 to 2014, the number of deaths linked to
fentanyl increased by 426%, which marks the beginning of the
current opioid epidemic.116 As a result, public safety protocols
are being developed in states with fentanyl outbreaks. Overdose
education and naloxone distribution programs (OEND),
prescription drug monitoring programs,117 and prescription
drug take-back programs have been utilized to reduce overdose
incidence and misuse of opioids such as fentanyl.118
Currently, there are three opioid antagonists (Figure 4)
available on the market that have potential to reverse the effects
Figure 4. Opioid reversal agents currently on the market.
of fentanyl. Long-lasting opioid antagonists naltrexone and
nalmefene (Figure 4) are not as effective in reversing severe
adverse effects and are not as readily available as naloxone.
Naloxone is approved for administration by a variety of routes,
including intravenous, intramuscular, subcutaneous and intra-
nasal; sublingual and buccal formulations are under develop-
ment.119
Predicting the appropriate dose of naloxone in either a
clinical or prehospital (street) setting is challenging. There is
limited data on the effectiveness of reversal agents in patients
who overdose from fentanyl, NPF, and fentanyl analogues.120
Effective opioid reversal depends upon the type, quantity, and
potency of the opioid present, the receptor interactions,
lipophilicity/distribution, route of administration, and the
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patient’s ability to clear the drug.90,121−124 The receptor
association/dissociation kinetics of naloxone are fast, and
reversal effects can diminish before all opioids are systemically
cleared, thereby leading to renarcotization, recurrence of
toxicity and respiratory depression, and the need for additional
naloxone doses.125,126 Renarcotization is a particular concern in
using naloxone to reverse fentanyl-related overdoses.127 Recent
case reports describe fentanyl overdoses that required
continuous naloxone infusions to prevent renarcotization after
the patients were unresponsive to intranasal and intramuscular
naloxone administration.90,128−130 As outbreaks of powerful
synthetic opioids occur, the efficacy and appropriate dose of
naloxone has been challenged.131 Current opioid reversal
agents have limited utility with fentanyl-related analogues
which has led Dr. Nora Volkow, Director of the National
Institute for Drug Abuse, to lead a call for new methods to
reverse opioid overdoses.132
Fentanyl has rapidly gained a negative reputation for its role
in the opioid epidemic, crowning it among the “dark classics in
chemical neuroscience”. However, it is still a vital therapeutic
agent within the medical community and serves as an important
scaffold within pharmaceutical science research.
■ AUTHOR INFORMATION
Corresponding Author
*Telephone: 615-966-7178; E-mail: susan.mercer@lipscomb.
edu.
ORCID
Christopher W. Cunningham: 0000-0002-4468-2213
Susan L. Mercer: 0000-0002-6007-068X
Funding
S.M.B. and S.L.M. are supported by funding from the Lipscomb
University College of Pharmacy and Health Sciences. C.W.C. is
supported by departmental funds provided by Concordia
University Wisconsin.
Notes
The authors declare no competing financial interest.
■
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2437 DOI: 10.1021/acschemneuro.8b00174

ACS Chem. Neurosci. 2018, 9, 2428−2437