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Misuse of Novel Synthetic Opioids: A Deadly New Trend Misuse of Novel Synthetic Opioids: A Deadly New Trend
Matthew P. Prekupec
Peter A. Mansky
Touro University Nevada
Michael H. Baumann
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Prekupec, M. P., Mansky, P. A., & Baumann, M. H. (2017). Misuse of Novel Synthetic Opioids: A Deadly New
Trend.
Journal of Addiction Medicine, 11
(4), 256-265. https://doi.org/10.1097/ADM.0000000000000324
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Misuse of Novel Synthetic Opioids: A Deadly New Trend
Matthew P. Prekupec, MD, Peter A. Mansky, MD, and Michael H. Baumann, PhD
Novel syntheti c opioids (NSOs) include various analogs of fentanyl
and newly emerging non-fentanyl compounds. Together with illic-
itly manufactured fentanyl (IMF), these drugs have caused a recent
spike i n overdose deaths, whe reas deaths from pre scription opioids
have sta bilized. NSOs are used as stand-alone products, as adulter-
ants in heroin, or as constituents of counterfeit prescription medi-
cations. During 2015 alone, there were 9580 deaths from synthetic
opioids other than methadone. Most of these fatalities were associ-
ated wit h IMF rather than diverted p harmaceutical fentanyl. In
opioid overdose cases, where the presence of fentanyl analogs
was examined, analogs were implicated in 17% of fatalities. Recent
data from law enforcement sources show increasing confiscation of
acetylfentanyl, butyrylfentanyl, and furanylfentanyl, in addition to
non-fentanyl compounds such as U-47700. Since 2013, deaths from
NSOs in the United States were 52 for acetylfentanyl, 40 f or
butyrylfentanyl, 128 for furanylfentanyl, and 46 for U-47700. All
of these substances induce a classic opioid toxidrome, which can be
reversed with the compe titive antagoni st naloxone. However, due to
the putative high potency of N SOs and their growing prevalence, it is
recommended to forgo the 0.4 mg initial dose of naloxone and start
with 2 mg. Because NSOs offer enormous profit potential, and there
is stron g demand for their use, t hese drugs are being trafficked by
organized crime. NSOs present major challenges f or medical pro-
fessionals, law enforcement agencies, and policymakers. Resources
must be distributed equitably to enhance harm reduction though
public education, medication-assisted therapies, and improved
access to naloxone.
Key Words: acetylfentanyl, AH-7921, butyrylfentanyl, carfentanil,
furanylfentanyl, illicitly manufactured fentanyl, MT-45, new
psychoactive substances, novel synthetic opioids, U-47700,
valerylfentanyl, W-18
(J Addict Med 2017;11: 256–265)
N
ew psychoactive substances (NPS) are defined as ‘‘sub-
stances of abuse, either in pure form or a preparation,
that are not controlled by the 1961 Convention on Narcotic
Drugs or the 1971 Convention on Psychotropic Substances,
but which may pose a public health threat (UNODC, 2013;
Madras, 2017).’’ In the context of this definition, the term
‘‘new’’ does not necessarily refer to new chemical entities, but
rather those compounds that have recently become available
in the recreational (ie, nonmedical) drug market. Many NPS
are created by modifying the chemical structures of illegal
drugs or prescribed medications to generate substances which
circumvent existing drug control laws. As governments pass
legislation to render specific NPS illegal, new replacement
analogs are synthesized and marketed to stay 1 step ahead of
regulators and law enforcement. In recent years, there has
been explosive growth in the market for NPS, fueled by
entrepreneurs and organized crime groups who have exploited
both the man ufacturing capacity in Asian countries and the
emergence of globalized trade (Brandt et al., 2014).
Phenethylamines and piperazine derivatives were
present in the recreational drug market during the 1990s
and early 2000, but it was not until synthetic cannabinoids
(eg, ‘‘incense’’ or ‘‘spice’’) appeared around 2004 that misuse
of NPS became widespread (Vardakou et al., 2010; UNODC,
2013). The emergence of synthetic cannabinoids was fol-
lowed by the appearance of synthetic cathinones (eg, ‘‘bath
salts’’) in 2010 (Baumann et al., 2013). When the United
Nations (UN) Office on Drugs and Crime releas ed its report
on NPS in 2013, synthetic cannabinoids and cathinones
accounted for the vast majority of new street drugs, and
the only opioids mentioned were O-desmethyltramadol and
kratom (UNODC, 2013). Since then, illicitly manufactured
fentanyl (IMF) and a number of novel synthetic opioids
(NSO) have appeared in the recreational drug market in the
United States and elsewhere. Fentanyl is a prescribed opioid
medication which is 50 to 100 times more potent than
morphine, but IMF is synthesized in Asian laboratories and
marketed via the Internet much like other NPS. Figure 1
depicts the chemical structures of fentanyl, morphine, and
some commonly encountered NSOs. For the purposes of this
review, the term NSO includes emerging analogs of fentanyl
and various non-fentanyl compounds. At present, IMF and
From the Department of Internal Medicine, University of Nevada School of
Medicine, Las Vegas (MPP); Touro University College of Osteopathic
Medicine, Henderson, NV (PAM); and Designer Drug Research Unit,
Intramural Research Program, National Institute on Drug Abuse, National
Institutes of Health, Baltimore, MD (MHM).
Received for publication January 31, 2017; accepted April 19, 2017.
The authors report no conflicts of interest.
Send correspondence to Matthew P. Prekupec, MD, University of Nevada
School of Medicine, Las Vegas, NV. E-mail: mprekupec@medicine.
nevada.edu
Copyright
ß 2017 The Author(s). Published by Wolters Kluwer Health, Inc.
on behalf of the American Society of Addiction Medicine. This is an open
access article distributed under the terms of the Creative Commons
Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-
ND), where it is permissible to download and share the work provided it is
properly cited. The work cannot be changed in any way or used com-
mercially without permission from the journal.
ISSN: 1932-0620/17/1104-0256
DOI: 10.1097/ADM.0000000000000324
256 J Addict Med Volume 11, Number 4, July/August 2017
REVIEW
Copyright © 2017 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited.
NSO are causing an alarming spike in overdose deaths. This
increase in fatalities seems partially due to the fact that many
users are unknowingly consuming these compounds as adul-
terants in products sold as heroin, or as counterfeit pain killers
(Amlani et al., 2015; DEA, 2016b). It is estimated that a single
kilogram of NSO can be used to manufacture hundreds of
thousands of counterfeit prescription tablets, which can pro-
duce millions of dollars in revenue for traffickers (DEA,
2016b). The substances are usually imported through the
mail, but the small quantities of compounds being shipped
are difficult to detect and intercept when compared with
typical illicit drug freight. There is incredible financial incen-
tive for traffickers and counterfeiters to import and sell these
substances, so the trend is expected to continue or even
intensify.
This article will present a brief review of the epidemi-
ology of use, pharmacology and toxicology, clinical manage-
ment, forensic detection, and regulatory issues associated with
NSOs. Recent data from the National Forensic Laboratory
Information System (NFLIS) will also be presented. NFLIS
collects data pertaining to the psychoactive constituents of
drug products confiscated by local, state, and Federal law
enforcement agencies in the United States. This review is
intended to inform healthcare providers of this dangerous new
class of drugs, and serve as a starting point for basic scientists
and policymakers looking to explore this problem further.
EPIDEMIOLOGY OF USE
The widespread availability of NPS is a global phenom-
enon, but the prevalence of use remains enigmatic (UNODC,
2013). With regard to NSOs, information about the prevalence
of misuse is scarce, because the drug landscape is constantly
changing, the substances are not detected by standard toxi-
cology screens, and users are often unknowingly exposed to
the drugs. In the United States, trends in availability and use of
NPS can be inferred from information about confiscated drug
products such as the NFLIS database, and from overdose
death data provided by the Center for Disease Control (CDC).
Table 1 depicts the number of drug encounters for fentanyl
and selected NSOs as reporte d from 2011 to 2016 by NFLIS.
FIGURE 1. Chemical structures of novel synthetic opioids. Each compound is represented as molecular formula (top), skeletal
formula (left), and ball-and-stick model (right) (used with permission of Jessica Holland, 2016).
TABLE 1. Law Enforcement Seizures of Selected Synthetic
Opioids From 2011 to 2016
Drug 2011 2012 2013 2014 2015 2016
Fentanyl 671 694 1041 5494 15,154 28,781
Acetylfentanyl —— 8 63 2001 1584
Butyrylfentanyl ——— 7 204 91
Furanylfentanyl ———— 4 1505
U-47700 ———— 1 320
AH-7921 —— 2 —— —
MT-45 — 12—— —
Source: NFLIS database (personal communication).
Dataset for 2016 is incomplete.
J Addict Med Volume 11, Number 4, July/August 2017 Misuse of Novel Synthetic Opioids
ß 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine. 257
Copyright © 2017 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited.
Before 2015, fentanyl was the main synthetic opioid encoun-
tered by law enforcement, but more recently, fentanyl analogs
and non-fentanyl compounds have appeared.
In 2015, the Drug Enforcement Administration (DEA)
and CDC both issued nationwide alerts identifying fentanyl,
particularly IMF, as a threat to public safety (Peterson et al.,
2016). In a study which examined synthetic opioid overdose
deaths in 27 states from 2013 to 2014, the number of con-
fiscated drug products containing fentanyl (ie, fentanyl sub-
missions) increased by 426%, whereas the number of deaths
due to synthetic opioids increased by 79% (Gladden et al.,
2016). Importantly, the increase in synthetic opioid deaths
was strongly correlated with the rise in fentanyl submissions
(r ¼ 0.95), but not correlated with fentanyl prescriptions
which remained stable (Gladden et al., 2016). Eight states
carry particularly high synthetic opioid deat h burdens includ-
ing 3 in the Northeast (Massachusetts, Maine, and New
Hampshire), 4 in the South (Florida, Kentucky, Maryland,
and North Carolina), and 1 in the Midwest (Ohio). The
increase in synthetic opioid deaths is disproportionately
affecting the same demographic associated with heroin use,
namely non-Hispanic white men aged 25 to 44 years. Drug
products containing fentanyl increased a further 160%
between 2014 and 2015 to 13,822, and deaths from synthetic
opioids other than methadone increased 72% to 9580 over that
same time interval (Rudd et al., 2016).
Whereas pharmaceutical fentanyl is diverted for abuse
in the United States at low levels, the recent rise in synthetic
opioid overdose deaths is largely due to IMF (DEA, 2016e). It
is estimated the true numbers of synthetic opioid-related
deaths could be much higher than noted above, because many
medical examiners and state crime laboratories do not test for
fentanyl or NSOs unless given a specific reason to do so. IMF
is often mixed with heroin and then sold as a heroin product in
the illicit market. Thus, the role of fentanyl adulterants in
purported heroin-overdose deaths could be underestimated.
More recently, a trend of counterfeit prescription pills con-
taining IMF or NSO has been observed (DEA, 2016b; Green
and Gilbert, 2016; Armenian et al., 2017). A single kilogram
of IMF or NSO can be used to produce hundreds of thousands
of counterfeit prescription pills, yielding tens of millions of
dollars for traffickers. In 1 recent study where the presence of
fentanyl analogs was examined in forensic cases, fentanyl
analogs were implicated in 17% of fentanyl-related deaths
between January and June 2015 (Peterson et al., 2016).
The DEA reports that the current fentanyl crisis is being
fueled by fentanyl and fentanyl precursor chemicals coming
from Asian laboratories, principally in China (DEA, 2016b).
Seizures of fentanyl, pills containing NSOs, and clandestine
pill press operations from across North America indicate that
the availability of NSOs is becomi ng a trend, rather than just
isolated incidents. The 2015 National Survey on Drug Use
and Health estimates 12.5 million Americans misused pain
relievers in the past year (SAMHSA, 2016). This high
demand, combined with the tremendous profit potential,
provides strong incentives for traffickers to produce counter-
feit pills to meet market needs. The DEA reports the pattern of
abuse of fentanyl analogs mirrors that of heroin and prescrip-
tion opioid analgesics misuse (DEA, 2016b).
PHARMACOLOGY AND TOXICOLOGY
Morphine is the prototypical opioid receptor agonist,
and the standard to which all other opioid analgesics are
compared (Pasternak and Pan, 2013; Schumacher et al.,
2015). Opioid agents include not only the natural and semi-
synthetic alkaloid derivatives from opium, but also synthetic
surrogates and other opioid-like drugs whose actions are
blocked by the opioid receptor antagonist naloxone. It is
well-established that opioid drugs can interact with 3 major
opioid rece ptor subtypes in the brain and spinal cord (ie, m, d,
and k subtypes), and receptor selectivity influences in vivo
drug actions (Law et al., 2000). The discovery of m-d opioid
heteroreceptors (Fujita et al., 2015) and m-opioid receptor
gene splice variants (Pasternak, 2014) adds tremendous com -
plexity to the endogenous opioid system. Nevertheless, sev-
eral lines of evidence, including studies with opioid receptor
knockout mice, confirm the major pharmacologic actions of
morphine such as euphoria, analgesia, respiratory depression,
and dependence are all due to agonist actions at the m-opioid
receptor (Williams et al., 2013; Charbogne et al., 2014).
Among the major classes of m-opioid receptor agonists,
4-anilidopiperidines (ie, fentanyl analogs) have a prominent
place in clinical usage because of their high potency, low
cardiovascular toxicity, rapid onset, and short duration of
action (Vuckovic
´
et al., 2009). These properties arise from
their high lipophilicity, which allows them to distribute
rapidly across the blood-brain barrier (Williams et al.,
2013). Fentanyl is the prototypic 4-anilidop iperidine, and a
large number of fentanyl analogs have been synthesized sinc e
the 1960s (Vuckovic
´
et al., 2009). The same properties
which give fentanyl its therapeutic attributes can lead to
life-threatening adverse effects when the drug is consumed
illicitly, especially at high doses.
In this section, we review the pharmacology and toxi-
cology of specific NSOs including fentanyl analogs and non-
fentanyl m-opioid agonists that have entered the recreational
drug marketplace in recent years. A detailed discussion of
structure–activity relationships (SAR) is beyond the scope of
this review, but it should be noted that subtle alterations in
chemical structure can markedly affect drug potency, duration
of action, and receptor selectivity (Vardanyan and Hruby,
2014). It is also well-known that many opioid drugs exhibit
stereo-selectivity in their interactions at opioid-binding sites
(Law, 2011). Because none of the newly emerging NSOs has
been studied in controlled clinical settings, their pharmac o-
logical properties in humans can only be inf erred from animal
experiments, or from studies of related compounds in man and
toxicological case reports. Most opioid analgesics are well-
absorbed when given by subcutaneous, intramuscular, and
oral routes (Schumacher et al., 2015). However, due to first-
pass metabolism, the effective oral dose may need to be much
higher than the parenteral dose. There is significant interin-
dividual variability in both first-pass and subsequent metab-
olism related to variety of factors including genetics and
history of drug or medication exposure.
For opioid drugs, the demonstration of pain relief (ie,
antinociception) in laboratory animals is usually indicative of
analgesic actions in man (Cox, 2011). With respect to the
NSOs discussed here, estimating effective drug doses in
Prekupec et al. J Addict Med Volume 11, Number 4, July/August 2017
258 ß 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine.
Copyright © 2017 American Society of Addiction Medicine. Unauthorized reproduction of this article is prohibited.
humans based on animal studies presents significant chal-
lenges because: various opioid drugs have been tested using
diverse antinociception assay methods that are not always
comparable; drugs have been administered via different routes
of administration or in different species across studies; there is
significant variability in antinoc iceptive dose–effect curves
even among different strains of the same species (Elmer et al.,
1998). Thus, extrapolation of data from rodents to man is not
straightforward. In Table 2, ED
50
values for various NSOs in
mouse antinociception assa ys are compared with correspond-
ing values for morphine and fentanyl, where appropriate.
Keeping in mind the caveats noted above, these ratios could
be cautiously applied to estimate dosing in humans.
Acetylfentanyl
Acetylfentanyl (IUPAC name: N-phenyl-N-[1-(2-
phenylethyl)-4-piperidinyl]acetamide) is an analog also
known as des-methylfentanyl, since its chemical structure
is characterized by the removal of a single methyl group from
the N-propionyl of fentanyl. The synthesis of acetylfentanyl
was first described in 1964 by Janssen and Gardocki (Janssen
and Gardocki, 1964). In the mouse acetic acid writhing assay,
acetylfentanyl is approximately 1/3 the potency of fentanyl
and 16 times more potent than morphine. Importantly, the
drug has a narrow therapeutic index with LD
50
/ED
50
ratios 23
times and 3 times less than fentanyl and morphine, respect-
ively (Higashikawa and Suzuki, 2008). The first submission of
acetylfentanyl to NFLIS was recorded in Maine in April 2013
(DEA, 2015). Concurrently, in March to May 2013, a series of
fatal intoxications in the region was reported (Lozier et al.,
2015). Since its initial appearance, the DEA reports at least 52
confirmed fatalities, and numerous acetylfentanyl overdose
cases are described in the forensic literature (DEA, 2015;
McIntyre et al., 2015; Poklis et al., 2015; Cunningham et al.,
2016). Clinical presentation of acetylfentanyl intoxication and
overdose is similar to that of other opioid anal gesics, and the
drug was placed into temporary schedule I control in the
United States in May 2015.
Butyrylfentanyl
Butyrylfentanyl (IUPAC name: N-phenyl-N-[1-(2-
phenylethyl)-4-piperidinyl]butanamide), or butyrfentanyl, is
an analog with a methyl group added to the N-propionyl of
fentanyl. It was first mentioned in the scientific literature in
the late 1980s, where it was tested for opioid activity in variety
of assays (Woods et al., 1988). In the acetic acid writhing
assay, butyrylfentanyl displays 1/8 the potency of fentanyl and
is about 7 times more potent than morphine (Higashikawa and
Suzuki, 2008). The drug first appeared in the NFLIS database
in March 2014 when it was seized in Kansas (DEA, 2016f). To
date, the DEA confirmed at least 40 deaths related to butyr-
ylfentanyl, and several fatal cases with post mortem drug
concentrations have been described in the literature (McIntyre
et al., 2016; Poklis et al., 2016). Its clinical presentation is
similar to other fentanyls, and the drug was placed into
temporary schedule I control in the United States in
May 2016.
Furanylfentanyl
Furanylfentanyl (IUPAC name: N-phenyl-N-[1-(2-
phenylethyl)-4-piperidinyl]-2-furamide) is an analog charac-
terized by the presence of a furan ring on the carboxamide
moiety. The drug was initially described in 1986 patent
literature by scientists at the BOC group (Huang et al.,
1986). Based on the limited data available from mice,
furanylfentanyl displays an antinociceptive potency of
0.02 mg/kg after i.v. administration; however, this potency
value is difficult to compare with other studies summarized in
Table 2, which employed different assay methods and routes
of drug administration. The first report of furanylfentanyl in
NFLIS was in January 2016 in Ohio; however, it was reported
in toxicological data as early as 2015 (DEA, 2016g). There
have been at least 128 confirmed fatalities associated with
furanylfentanyl according to the DEA. Mohr et al. (2016)
recently described a series of fatal furanylfentanyl cases, with
post mortem tissue concentrations . The drug was placed into
temporary schedule I status in November 2016.
TABLE 2. Analgesic Potencies of Selected Synthetic Opioids in Mice
Drug Assay Method
ED
50
Dose, Route
[Citation]
Potency Relative
to Morphine
Potency Relative
to Fentanyl
Morphine Acetic acid writhing 0.33 mg/kg, p.o.
1 1/54
Tail flick 0.83 mg/kg, s.c.
y
1 1/46
y
Phenylquinone writhing 1.10 mg/kg, p.o.
z
Tail flick 1.50 mg/kg, s.c.
§
Tail pinch 5.90 mg/kg, s.c.
{
Fentanyl Acetic acid writhing 0.0061 mg/kg, p.o.
54
1
Tail flick 0.018 mg/kg, s.c.
y
46
y
1
Acetylfentanyl Acetic acid writhing 0.021 mg/kg p.o.
16
1/3
Butyrylfentanyl Acetic acid writhing 0.047 mg/kg, p.o.
7
1/8
Furanylfentanyl Hot plate 0.02 mg/kg, i.v.
jj
——
AH-7921 Phenylquinone writhing 0.85 mg/kg, p.o.
z
1.3
z
—
U-47700 Tail flick 0.20 mg/kg, s.c.
§
7.5
§
1/11
y,§
MT-45 Tail pinch 1.70 mg/kg, s.c.
{
3.5
{
—
Higashikawa and Suzuki, 2008.
yNarita et al., 2002.
zBrittain et al., 1973.
§Cheney et al., 1985.
{Fujimura et al., 1978.
jjHuang et al., 1986.
J Addict Med Volume 11, Number 4, July/August 2017 Misuse of Novel Synthetic Opioids
ß 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine. 259