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GLOBAL
S MART
UPDATE
THE GROWING EN
COMPLEXITY OF
THE OPIOID CRISIS
VOLUME 24
October 2020
GLOBAL
SMART
UPDATE
About the SMART Update Content
A. INTRODUCTION 3
Synthetic drugs constitute one of the most significant drug
problems worldwide. Along with synthetic drugs, the emergence The multi-faceted opioid crisis – 3
of the new psychoactive substances (NPS) market over the last What, why and how?
years has become a policy challenge and a major international Substances with opioid effects are one of 4
concern. A growing interplay between these new substances the fastest growing groups of NPS
and traditional illicit drug markets is being observed, and the
synthetic drugs market continues to evolve rapidly. The global tragedy of unnecessary pain 4
and suffering – insufficient access to
The Global SMART Updates (GSU)* are biannual publications internationally controlled opioids for medical use
of the UNODC Global Synthetics Monitoring: Analyses, Reporting
and Trends (SMART) Programme, implemented by the UNODC
B. INTERNATIONAL AND NATIONAL POLICY 5
Laboratory and Scientific Section. The GSU is published in
RESPONSES TO THE OPIOID CRISIS
English, Spanish and Russian. The Global SMART Programme
enhances the capacity of Member States in priority regions to
C. THE GROWING COMPLEXITY OF THE 6
generate, manage, analyse, report and use synthetic drugs
OPIOID CRISIS – EMERGENCE OF A NEW
information to design effective policy and programme interventions.
GENERATION OF SYNTHETIC OPIOIDS
The main products and services of the Global SMART Programme Trends in non-fentanyl related synthetic opioids 6
include capacity building workshops, online drug data collection,
national, regional and global assessment reports, and the Failed pharmaceutical opioids: from potential 8
UNODC Early Warning Advisory (EWA) on NPS. The EWA is a medicines to public health threats
web portal that provides access to information on NPS, including Structural similarity does not equate to 9
on latest developments, emergence of NPS, global trends, chemical pharmacological activity – the cases of
analysis, toxicology, pharmacology and legislative response. W-18 and benzylfentanyl
(available at: www.unodc.org/nps and www.unodc.org/tox).
Availability of falsified and unlicensed 10
Previous issues pharmaceutical opioids
• An expanding synthetic drugs market – Implications for
precursor control (GSU 23, March 2020) D. RESPONDING TO AN INCREASINGLY COMPLEX 10
OPIOID CRISIS
• The ATS market – 10 years after the 2009 Plan of Action
(GSU 22, October 2019) Improving access to opioids for medical use 10
The importance of early warning systems 10
• Understanding the global opioid crisis (GSU 21, March 2019)
Improving forensic capacities 11
• Methamphetamine continues to dominate synthetic drug
Expanding public-private partnerships 11
markets (GSU 20, September 2018)
Enhancing legislative responses 11
E. CONCLUSION 11
Impact of the COVID-19 pandemic on 12
the evolving opioid crisis
Effects on the trafficking and 12
manufacture of synthetic opioids
Effects on the use of synthetic opioids 12
Endnotes 13
* The information and data contained within this report are from the Annual
Report Questionnaire (ARQ) submitted by Member States to UNODC, the
UNODC Early Warning Advisory (EWA) on NPS, official Government reports,
press releases, scientific journals or incidents confirmed by UNODC Field
Offices. This report has not been formally edited. The contents of this publication
do not necessarily reflect the views or policies of UNODC or contributory
organizations and neither do they imply any endorsement. Suggested citation:
United Nations Office on Drugs and Crime, 2019. The growing complexity of
the opioid crisis. Global SMART Update, Volume 24 (Vienna, September 2020).
2
VOLUME 24
THE GROWING COMPLEXITY OF THE OPIOID CRISIS
A. INTRODUCTION
The current opioid crisis is a far-reaching driven by pharmaceutical opioids, heroin
drug and public health policy issue affecting ”...despite some progress, the and synthetic opioids2 over the last two
several geographical regions. Since its crisis continues both to expand decades.3,4 The present, and probably most
appearance, endeavours have been under- geographically and to deepen deadly, wave of opioid use began around 2013
taken both at the national and international in the United States and is associated with
level to develop integrated policy responses in complexity with the emer- fentanyl, fentanyl analogues and other
to address the crisis. Yet, despite some gence of a new generation of synthetic opioids in the illicit drug supply5.
progress, the crisis continues both to new psychoactive substances The United States Centers for Disease Control
expand geographically and to deepen in and Prevention reported that although
complexity with the emergence of a new
(NPS) with opioid effects,...”
overdose deaths involving all opioids, pre-
generation of new psychoactive substances scription opioids and heroin decreased
(NPS) with opioid effects, including sub- from 2017 to 2018, deaths involving synthetic
stances belonging to chemical structural The multi-faceted opioid crisis – opioids (most likely illicitly manufactured
classes which were not significantly present What, why and how? fentanyl and its analogues) increased by
on illicit drug markets previously. This 10 per cent during the same period and
evolution in chemical structural groups The current phase of the opioid crisis is accounted for two thirds (or 31,335) of
signals the potential development of similar principally defined by significant global opioid-related deaths in 2018.6 Similarly, in
new substances which may exacerbate the increases in the non-medical use of opioids and Canada, increased levels of opioid-related
already significant challenges faced by opioid-related overdoses in recent years.1 deaths were recorded from 2016 to 2019.7
public health and drug control systems. However, despite the central commonality of Between January and December 2019, there
Additionally, the onset of the COVID-19 opioids, the crisis is actually multi-faceted were a total of 3,823 apparent opioid-related
pandemic in late 2019 and early 2020 may in nature and its characteristics diverge deaths in the country, of which 94 per cent
further complicate and reshape existing sharply in different geographical regions. were accidental and 77 per cent involved
trends in the crisis. fentanyl or fentanyl analogues.8 The region
The opioid crisis in North America is charac- also experienced a twenty-six times
This issue of the Global SMART Update terised by a highly prevalent non-medical increase in seizures of fentanyl from about
provides an overview of the multi-faceted use of opioids and high rates of mortality 96 kilograms in 2015 to more than 2.9 tonnes
opioid crisis and highlights major international in 2018.9 The nature of the opioid crisis in this
and domestic policy responses to date. The region seems to be largely supply-driven
Update also presents key developments through a combination of factors including
related to NPS with opioid effects and ”...despite the central common- high prevailing rates of non-medical opioid
examines how these developments are influ- ality of opioids, the crisis is actually use and the adulteration or substitution of
enced by existing control measures. It also multi-faceted in nature and its illicit heroin and diverted pharmaceutical
outlines possible policy responses and characteristics diverge sharply in opioid supplies with fentanyl, fentanyl analogues
assesses how the COVID-19 pandemic may and other synthetic opioids by organized
affect the ongoing opioid crisis. different geographical regions.” crime groups in order to lower costs.10,11,12
In West and Central Africa and North Africa
Fig. 1: Global and regional characteristics of the dual opioid crisis however, the opioid crisis is characterised
by a high prevalence of the non-medical
Regional Opioid Crises use of pharmaceutical opioids, in particular
Non-medical tramadol. While national-level estimates
use of fentanyl
and its of prevalence are not available for most
analogues in countries in these sub-regions, studies and
North America
surveys in some countries indicate the
widespread non-medical use of tramadol.13
In Nigeria, a comprehensive drug survey
in 2017 estimated that 4.7 per cent of its
Rapid
emergence of Opioid Non-medical
use of tramadol
in West, Central
population (4.6 million people) aged
Crisis
NPS with opioid
effects and North between 15 and 64 had used pharma
Africa
ceutical opioids for non-medical purposes,
mainly tramadol and to a lesser extent
codeine or morphine.14 Likewise, Egypt has
Insufficient experienced an increase in the non-medical
access to
interna�onally use of tramadol among drug disorder
controlled treatment admissions since 2000.15 A
opioids for
medical use national survey in 2016 estimated that
Global Opioid Issues 3 per cent of the adult population had used
tramadol for non-medical purposes in the
Source: UNODC elaboration previous year, and nearly 68 per cent of those
3
GLOBAL
SMART
UPDATE
The global tragedy of unnecessary pain and suffering – insufficient access to internationally
controlled opioids for medical use
In the face of the need for international upper-middle- and low-middle-income has lowered the availability of opiates
control of the trafficking and non-medical countries fell short of their projected needs among all opioid analgesics over the
use of opioids, there is a global divide by 96.7 per cent and 99.3 per cent respec- years and ultimately the capacity of health
regarding access to internationally controlled tively.28 Another significant issue identified services to treat pain, especially in low-
opioid analgesics for pain management is that on average 88 per cent of the morphine and middle-income countries.29 The
and palliative care. Whilst an estimated manufactured between 1997 and 2016 imbalance in access to opioid analgesics
1.2 per cent of the global population was converted by pharmaceutical companies for medical use and the rising non-medical
used opioids for non-medical purposes in to codeine or other related substances use of synthetic opioids demonstrates
the past year, an estimated 80 per cent of instead of being used in morphine prepa- the duality of the opioid crisis and the
the global population has limited or no rations for palliative care. This is in part a result conflicting objectives, i.e. access versus
access to controlled medicines, especially for of the marketing and supply of more expensive control, faced by international and national
the treatment of pain.24,25 Despite a global opioids by pharmaceutical companies which drug control systems.
increase in the availability of controlled
pharmaceutical opioids for medical use in
the last 20 years, the growth is imbal- Fig. 2: Average consumption of selected opioids, by region, expressed in
anced and skewed towards higher-income defined daily doses for statistical purposes (S-DDD) per
(sub)regions especially in North America, million inhabitants per day, 2016-2018
Oceania and Western and Central Europe
(see Figure 2).26 Furthermore, the increase 0 5000 10000 15000 20000 25000 30000
is largely driven by the greater availability
of expensive synthetic analgesics (e.g. North America
fentanyl and oxycodone) concentrated
Oceania
in high-income countries, which is not
matched by an increase in the availability Europe
of more affordable opiate analgesics such
South America
as morphine.27 The Lancet Commission on
Palliative Care and Pain Relief found that Asia
of the average amount of 298.5 tonnes of Central America and
morphine-equivalent opioids distributed the Caribbean
in the world annually between 2010 and Africa
2013, 287.7 tonnes were distributed to
high-income countries, representing an Fentanyl Codeine Hydrocodone Hydromorphone Methadone
excess of 233 per cent of their projected
need for 86.4 tonnes, whilst only 0.1 tonnes Morphine Oxycodone Pethidine Others
was distributed to low-income countries,
Source: International Narcotics Control Board, Narcotic Drugs: Estimated World Requirements for 2020 –
which is 99.7 per cent short of their projected Statistics for 2018 (E/INCB/2019/2), pp. 264.
need for 37.2 tonnes. Similarly, the distri- Note: The statistics include the eight most consumed opioids and others (including tilidine), and excludes
bution of morphine-equivalent opioids to buprenorphine and preparations listed in Schedule III of the 1961 Convention.
undergoing treatment for drug use disor- as a result, particularly challenging for
ders were treated for tramadol use.16,17 The ”...there is a strong need to national authorities and international
Forensic Medicine Sector of Egypt’s Min- balance drug control and public bodies alike. Moreover, there is a strong
istry of Justice also reported 43 deaths health responses with adequate need to balance drug control and public
directly related to tramadol misuse in access to opioid analgesics for health responses with adequate access to
2017.18 Between 2014 and 2018, the opioid analgesics for scientific research and
sub-regions of West and Central Africa and scientific research and medical medical uses including pain management
North Africa together accounted for uses...” and palliative care.
around 89 per cent of the total quantities
of tramadol seized worldwide.19 There are Substances with opioid effects are one
also indications of an expansion of the and North Africa (8 per cent).21 The nature of the fastest growing groups of NPS
tramadol market in the Near and Middle of the opioid crisis in these sub-regions is
East and South-West Asia with countries likely to be a result of challenges in medicines The rapidly growing number of NPS with
such as Lebanon, Qatar and the United regulation and a high availability of diverted opioid effects on the illicit drug market
Arab Emirates20 reporting tramadol as one or illicitly manufactured pharmaceutical represents a further serious challenge
of their most misused substances in recent opioids on the informal market to meet faced by the international community.
years, and the region accounting for the demand.22,23 Over the last decade, the number of such
third largest proportion (6 per cent) of substances reported annually to the
tramadol seizures between 2014 and 2018 These essential differences make the current UNODC Early Warning Advisory (EWA) on
after West and Central Africa (81 per cent) opioid crisis multi-faceted in nature and, NPS increased significantly from just one
4
VOLUME 24
in 2009 to 55 in 2018 (see Figure 3). Fig. 3: Number of different synthetic NPS with opioid effects
Additionally, between 2015 and 2019, the 60 reported each year, by chemical structural class, 2009 – 2019
number of synthetic opioids as a pro-
portion of all synthetic NPS reported
quadrupled from 2 per cent to 8 per cent. 50
As a result of the rapid emergence and
40
increasing prevalence of opioid NPS,
coupled with substantial public health
risks, the number of such substances 30
placed under international control has also
increased. Despite representing only a small
fraction of the total synthetic NPS reported 20
to the UNODC EWA (8 per cent), almost
a third, or 17 out of 60, of the NPS scheduled 10
from 2015 to 2020 into either the Single
Convention on Narcotic Drugs of 1961 as
amended by the 1972 Protocol (“1961 0
Convention”) or the Convention on Psy- 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019
chotropic Substances of 1971 (“1971
Convention”) were substances with opioid Phenethylpiperidine Cyclohexylphenol Cinnamylpiperazine Cyclohexylbenzamide
effects. In comparison, only 18 synthetic Diphenethylpiperazine Thiambutene Nitrobenzimidazole Phenylpiperidine
cannabinoids and 17 stimulant NPS were
Source: UNODC Early Warning Advisory on NPS, 2020
put under international control during Note: A total of 77 different synthetic NPS with opioid effects were reported to UNODC between 2009 and 2019
the same period despite these pharma- (but not all of them were reported each year). Plant-based substances were excluded from the analysis as they
cological effect groups accounting for usually contain a large number of different substances some of which may not be known and their effects
and interactions not fully understood. Data for 2019 are preliminary.
around 30 per cent of synthetic NPS
reported to the UNODC EWA.
B. INTERNATIONAL AND NATIONAL POLICY RESPONSES TO THE OPIOID CRISIS
Despite these challenges, the inter Countries including Canada,37 China38 and
national community has taken major steps ”...the international community the United States39,40 have extended their
towards developing a set of balanced inter- has taken major steps towards national controls over fentanyl analogues
national and domestic responses to address developing a set of balanced and/or fentanyl precursors, and have
various aspects of the growing opioid increased cooperation with international
international and domestic
crisis (see Figure 4). In 2018, the 61 st and domestic partners to tackle illicit activ-
Session of the Commission on Narcotic responses to address various ities relating to these substances. Early
Drugs (CND) for the first time adopted aspects of the growing opioid signs following China’s 2019 extension of
a resolution with direct reference to crisis...” national control to include all fentanyl
enhancing and strengthening interna- analogues suggest that less of this class of
tional and regional cooperation to address substances is being smuggled from China
the threats posed by the non-medical use to North America, although attempts to
of synthetic opioids. In the same year, and the Drugs and Cosmetics Rules of manufacture these substances inside the
UNODC launched an integrated strategy 1945.30,31,32 This change appears to have region, especially in Mexico, using precursor
based on an overarching set of comple- had an impact on the supply of tramadol chemicals from East and South Asia, are
mentary principles to support Member in West Africa with reports from Ghana increasing.41 Countries such as the United
States and coordinate the international and Nigeria indicating a significant States have also stepped up their public
response to the opioid crisis. Furthermore, decrease in border seizures of the drug as health responses to promote the rational
between 2018 and 2020, the CND sche well as reduced availability and increases prescribing of opioids and to widen access
duled 12 fentanyl analogues under the in prices of tramadol on illicit markets in to prevention and treatment services.42,43
1961 Convention. those countries.33 This impact has not been
felt consistently across West Africa how-
There have also been responses to the crisis ever with countries such as Benin still
at the national level. In April 2018, India reporting large seizures of tramadol in the
scheduled tramadol in its Narcotics Drug first half of 2019, suggesting that large-
and Psychotropic Substances Act to regulate scale tramadol trafficking remains active
and increase law enforcement of the in the region.34,35 Likewise, despite the
manufacturing, import, export and sale of substance being under stricter national
tramadol, and to impose criminal penalties control since 2012, Egypt continues to
for breaches of these regulations, effectively seize large quantities of diverted, falsified
increasing controls over tramadol beyond and sub-standard tramadol (more than
existing prescription controls contained 231 million tablets in 2017), some of
in its Drugs and Cosmetics Act of 1940 which contains a wide range of impurities.36
5
GLOBAL
SMART
UPDATE
Fig. 4: Major international and national policy events in relation to the opioid crisis, 2012-2020
2012 2013 2015 2016 2017
Major CND Resolu�on 55/7 CND Resolu�on 56/14 CND Scheduling Decisions CND Scheduling Decisions CND Scheduling Decisions
Strengthening interna�onal Inclusion of AH-7921 in the Inclusion of butyrfentanyl
Interna�onal Promo�ng measures to
prevent overdose, in coopera�on in addressing 1961 Conven�on
Inclusion of acetylfentanyl
and MT-45 in the 1961 and U-47700 in the 1961
Resolu�ons par�cular opioid the non-medical use and Conven�on Conven�on
and overdose abuse, the illicit manufacture
and the illicit domes�c and
Inclusion of ANPP and NPP in
the 1988 Conven�on
Scheduling interna�onal distribu�on of
Decisions tramadol
Trends in
NPS Opioids 5 NPS with opioid effects 8 NPS with opioid effects 17 NPS with opioid effects 28 NPS with opioid effects 53 NPS with opioid effects
4 structural classes 5 structural classes 5 structural classes 5 structural classes 5 structural classes
Major Egypt increased na�onal Prolifera�on of synthe�c China placed acetylfentanyl, China placed carfentanil,
control over tramadol and its opioid use and overdose butyrfentanyl, ocfentanil, furanylfentanyl, acryfentanyl
Interna�onal deriva�ves by rescheduling deaths in North America β-hydroxythiofentanyl, and MT-45 under na�onal
Events to a stricter schedule in drug 4-fluorobutyrfentanyl and control by adding them to the
enforcement law 182 of 1960. isobutyrfentanyl under na�onal “Supplementary List of
control by adding them to the Controlled Narco�c Drugs
“Supplementary List of and Psychotropic Substances
Controlled Narco�c Drugs with Non-medical Use”.
and Psychotropic Substances
with Non-medical Use”.
Source: UNODC elaboration based on various CND resolutions and decisions, and the UNODC Early Warning Advisory on NPS.
Note: The “1961 Convention” refers to the Single Convention on Narcotic Drugs of 1961 as amended by the 1972 Protocol and the ”1988 Convention” refers to
the United Nations Convention against Illicit Traffic in Narcotic Drugs and Psychotropic Substances of 1988. ”CND” refers to The Commission on Narcotic Drugs.
C. THE GROWING COMPLEXITY OF THE OPIOID CRISIS – EMERGENCE OF A NEW
GENERATION OF SYNTHETIC OPIOIDS
In addition to developments related to Convention fall into four main structural average of two substances per year
tramadol and fentanyl and its analogues, classes: morphinans (including heroin, between 2009 and 2014, to ten substances
a new generation of non-fentanyl-related hydrocodone and oxycodone); phenethyl in 2018 alone.48 An analysis of NPS with
synthetic opioids has surfaced and gained piperidines (including fentanyl and fentanyl opioid effects according to their chemical
traction in the illicit market, adding greater analogues); phenylpiperidines (including structural class reveals trends in the structural
complexity to the opioid crisis. Opioids, or pethidine and ketobemidone); and diphenyl diversity and popularity of certain chemical
opioid receptor agonists, interact with the heptanes (including methadone and classes in the NPS opioid market. In 2009,
body’s opioid receptors, including the mu (μ) acetylmethadol). The remaining 17 per cent only one chemical class of NPS with opioid
opioid receptor which is responsible for belong to a variety of smaller structural effects was reported to the UNODC EWA.
triggering the brain reward system and classes including diphenylmorpholines, This number had grown to five by 2015
producing analgesia (pain relief) by thiambutenes and diphenylheptanones and eight by 2019, indicating a proliferation
decreasing pain transmission. This results in (see Figure 5). For the purpose of this in the diversity of chemical classes of NPS
a variety of physiological and psychological publication, non-fentanyl-related synthetic with opioid effects in the global market
effects including respiratory depression, opioids are defined as opioids belonging (see Figure 6). Interestingly, substances
constipation, euphoria, sedation, a sensation to dissimilar chemical structural classes belonging to four of the eight chemical
of warmth and dependence.44,45 The magnitude to fentanyl and fentanyl analogues (i.e. classes including cyclohexylbenzamides
of these effects depends on the specific phenethylpiperidines). (e.g. U-47700, AH-7921), diphenethylpipera
synthetic opioid used and the type of zines (e.g. MT-45), cinnamylpiperazines
receptor(s) activated or inhibited.46,47 Trends in non-fentanyl related synthetic (e.g. 2-methyl-AP-237) and cyclohexyl
Despite having similar pharmacological opioids phenols (e.g. O-desmethyltramadol) were
effects, opioids occur in a variety of chemical not included in the schedules of the 1961
structural classes ranging from morphinans The number of non-fentanyl-related Convention prior to 2015. In addition,
to phenethylpiperidines. About 83 per cent synthetic opioids reported has increased substances in three chemical classes of
of opioids in the Schedules of the 1961 steadily over the last decade from an opioids, cinnamylpiperazines, thiambutenes
6
VOLUME 24
2018 2019 2020
CND Resolu�on 61/8 CND Scheduling Decisions CND Resolu�on 62/4 CND Resolu�on 62/5 CND Resolu�on 63/3 CND Scheduling Decisions
Enhancing and strengthening Inclusion of acrylfentanyl, Advancing effec�ve and Enhancing the capacity of Promo�ng awareness-raising, Inclusion of cyclopropylfentanyl
interna�onal and regional carfentanil, ocfentanil, innova�ve approaches, Member States to adequately educa�on and training as part and valerylfentanyl in the
coopera�on and domes�c 4-Fluoroisobutyrfentanyl, through na�onal, regional es�mate and assess the need of a comprehensive approach 1961 Conven�on
efforts to address furanylfentanyl and and interna�onal ac�on, to for interna�onally controlled to ensuring access to and the
interna�onal threats posed tetrahydrofuranylfentanyl address the mul�faceted substances for medical and availability of interna�onally
by the non-medical use of in the 1961 Conven�on challenges posed by the scien�fic purposes controlled substances for
synthe�c opioids non-medical use of synthe�c medical and scien�fic
drugs, par�cularly synthe�c CND Scheduling Decisions purposes and improving
opioids Inclusion of cyclopropylfentanyl, their ra�onal use
methoxyacetylfentanyl,
ortho-flurofentanyl and
para-flurofentanyl in the
1961 Conven�on
73 NPS with opioid effects 77 NPS with opioid effects
5 structural classes 8 structural classes
India introduced more China listed NPP and 4-ANPP China introduced drug controls based on generic
restric�ve control measures as controlled precursors in legisla�on with regards to fentanyl, which effec�vely
for the manufacturing, the Schedule to the “Regula�on placed more than 1,400 known fentanyl analogues in
import, export and sale of on the Administra�on of the “Supplementary List of Controlled Narco�c Drugs
tramadol by scheduling it Precursor Chemicals“. and Psychotropic Substances with Non-medical Use“.
into its Narco�cs Drug and
Psychotropic Substance Act.
Launch of the integrated
UNODC Opioid Strategy
Fig. 5: Distribution of opioids in the 1961 Convention, 1961-2020
Phenylpiperidines Phenethylpiperidines
• Class of compounds 19% • Class of compounds
possessing the base possessing the base
24%
phenylpiperidine structure phenethylpiperidine
• Includes pethidine (as structure
pictured) and • Includes fentanyl (as
ketobemidone pictured) and its analogues
30%
10%
Morphinans 17% Diphenylheptanes
• Class of compounds • Class of compounds
possessing the structural possessing the base
skeleton of morphine Others diphenylheptane structure
• Includes heroin (as Includes several smaller classes of compounds including • Includes methadone (as
pictured), hydrocodone and diphenylmorpholines, thiambutenes and diphenylheptanones pictured) and
oxycodone acetylmethadol
Source: UNODC elaboration based on the Schedules of the Single Convention on Narcotic Drugs of 1961 as amended by the 1972 Protocol (“1961 Convention”),
as at 7 May 2020.
Note: Based on analysis of 124 opioids in the Schedules of the 1961 Convention, excluding opiates.
7
GLOBAL
SMART
UPDATE
Fig. 6: ChemicalFigstructural
6: Chemicalclasses ofclasses
structural NPS with
of NPSopioid effects
with opioid reported
effects toUNODC
reported to UNODC EWA,
EWA, 2009-2019
2009-2019
NITROBENZIMIDAZOLES
e.g. isotonitazene
CYCLOHEXYLBENZAMIDES THIAMBUTENES
e.g. U-47700, AH-7921 e.g. piperidylthiambutene
CYCLOHEXYLPHENOLS PHENYLPIPERIDINES PHENETHYLPIPERIDINES DIPHENETHYLPIPERZINES CINNAMYLPIPERAZINES
e.g. O-desmethyltramadol e.g. desmethylprodine e.g. isobutyrfentanyl e.g MT-45 e.g. 2-methyl AP-237,
para-AP-237
2009 2011 2012 2013 2019
Source: UNODC, Early Warning Advisory on NPS, 2020.
Note: Based on an analysis of 77 different synthetic NPS with opioid effects reported to UNODC. Plant-based substances were excluded from the analysis as they usually
contain many different substances some of which may not be known and whose effects and interactions are not fully understood. Data for 2019 are preliminary.
(e.g. piperidylthiambutene) and nitrobenzi Isotonitazene is an emergent highly potent
midazoles (e.g. isotonitazene) only surfaced ”...a shift in the synthetic opioid synthetic opioid which has been encountered
in the global NPS market in 2019. market towards newer and in seized drug samples and forensic casework
Phenethylpiperidines (or fentanyl analogues more varied chemical classes of since 2019. It was first developed in the
in general) remain the dominant and fast- mid-1950s as part of a series of nitroben-
opioids...”
est growing chemical class of opioids zimidazole class of opioids, which includes
among NPS with opioid effects, followed etonitazene, metonitazene and clonitazene,
by cyclohexylbenzamides (see Figure 3). to their chemical structures to circumvent in a search for better and safer opioid anal-
existing legislation. Although the potency and gesics.55,56,57 Two isotonitazene analogues,
Brorphine (1-{1-[1-(4-bromophenyl)ethyl] pharmacological effects of these non-fentanyl- etonitazene and clonitzene, are included in
piperidin-4-yl}-1,3-dihydro-2H-benzi related synthetic opioids may differ Schedule I of the 1961 Convention because
midazol-2-one) is an instance of a recently significant from fentanyl, they can still be of their ability to produce morphine-like
emerging non-fentanyl-related synthetic highly dependence producing and dangerous, effects and sustain and suppress abstinence
opioid that has been increasingly detected in as opioids in general have a narrow therapeutic phenomena from morphine dependence.58
seized drug samples and forensic casework index, wide interindividual response variability In vitro and in vivo studies have found that
since 2019, especially after the temporary and potentially life-threatening toxicity. For isotonitazene is a highly potent mu opioid
scheduling of isotonitazene by the United these reasons, a very small variability in receptor agonist which may potentially be as
States Drug Enforcement Administration dosage can lead to serious therapeutic failures potent as fentanyl and is 500 times more
in June 2020.49 Despite having structural and/or adverse drug reactions resulting in potent in mice relative to morphine.59,60
similarities to fentanyl, brorphine differs in significant incapacity or even death.51 In Although there is presently no information
key aspects with the additional presence of common with fentanyl and its analogues, about the side effects of consuming
the 4-bromo and 1,3-dihydro-2H-benzo non-fentanyl-related opioids may be sold as isotonitazene, its pharmacological character
imidzole-2-one groups (or the phenethyl- stand-alone products or used as adulterants istics indicate that the risks would be similar
piperidine-benzimidazolone sub-class), or constituents of drugs such as heroin or to other opioids, including dependence,
therefore falling outside the typical scope of falsified pain medication, and can be respiratory depression, and potentially
generic legislation for fentanyl analogues.50 bought from a variety of sources including life-threatening overdose. 61 Reports of
both the Internet and the Dark Web.52,53 isotonitazene in seized drug samples and
These trends in NPS with opioid effects toxicology cases in North America and
indicate a shift in the synthetic opioid market Failed pharmaceutical opioids: from Europe have been submitted to the UNODC
towards newer and more varied chemical potential medicines to public health EWA since 2019.62 Significantly, a study
classes of opioids to quickly replace “older threats found 18 deaths in the Midwestern United
generations” of substances once they are States where isotonitazene was identified
under control and become subject to rigorous Many “new” non-fentanyl-related opioids were in biological samples. Other opioids
scrutiny by law enforcement officials. Many originally developed by the pharmaceutical (fentanyl, morphine, tramadol, piperidyl
of these non-fentanyl-related synthetic opioids industry over the past five decades in attempts thiambutene and U-47700), as well as
are neither new nor recent inventions however, to search for alternative therapeutic drugs designer benzodiazepines (flualprazolam
but rather, their appearance in the illicit market to morphine without dependency-related and etizolam), were also identified in most of
is recent. The majority of these “new” opioids adverse effects, but were not further developed these cases.63 In February 2020, authorities in
fall into categories of either pharmaceuticals or were considered “not suitable for human Canada seized 1,900 falsified hydromor-
that were originally developed as therapeutic consumption”. They have subsequently been phone tablets that were found to contain
agents but were never commercialized “re-discovered” in the past few years with isotonitazene.64
(also known as “failed pharmaceuticals”), information about them taken from scientific
or are falsified or unregistered/unlicensed literature or patent filings in order to clan- Compounds in the phenethylpiperidine-
pharmaceuticals that are sold in countries destinely manufacture and sell them on the benzimidazolone opioid sub-class including
where they are not approved for medical use. illicit market.54 The following paragraphs brorphine were first developed by Janssen
Other “new” opioids are typically analogues describe examples of failed pharmaceutical Pharmaceuticals as central nervous system
of opioids from either of these two categories opioids that are prevalent or emergent in depressants with morphine-like analgesic
developed through successive modifications illicit markets. activity. While structural analogues of
8
VOLUME 24
Structural similarity does not equate to pharmacological activity – the cases of W-18 and
benzylfentanyl
An emergent synthetic opioid gaining Fig. 7: Comparison between chemical structures of W-18 and fentanyl
popularity, W-18 (or 4-chloro-N-{(2E)-1-
[2-(4-nitrophenyl)ethyl]piperidin-2-ylidene}
benzene-1-sulfonamide) was developed
in 1981 at the University of Alberta and
belongs to a class of compounds referred
to as the “W” series.65 Despite being
structurally related to fentanyl (see
Figure 7), W-18 differs in key chemical Phenethylpiperidine
aspects with the presence of an aryl sul- Class
fonamide group which could potentially
lead to differences in pharmacological
effects between the substances.
Although the original patent indicated
that W-18 had an analgesic potency
10,000 times greater than morphine,
recent animal and in vitro studies reveal
no activity for W-18 or any of its metab-
olites at the opioid receptors.66,67 Another
fentanyl analogue, benzylfentanyl, has
W-18 Fentanyl
been found to be “essentially inactive”
when assessed for morphine-like activity,
dependence liability and analgesic Source: UNODC elaboration.
effect.68,69 It is likely that its presence in
seized drug samples is due to it being
used as a precursor in the fentanyl man- similarities with known opioids do not nec- substances to predict or determine if
ufacturing process, resulting in a residual essarily equate to having similar there is a pharmacological activity that
amount of the unreacted substance after pharmacological activity. Therefore, addi- warrants control.
synthesis.70 These examples demonstrate tional structure-activity relationship studies
that substances sharing structural are always required for new emerging
brorphine have been previously reported in the potency of morphine in mice studies.81,82,83 opioids previously developed by the Upjohn
the literature,71 there is little information on Its popularity in the illicit market is presumably Company (e.g. U-47931E, U-50488 and
when the substance was first synthesized.72 due to its reportedly desirable short-lived U-51754).89 Two new analogues of U-47700,
Recent in vitro studies on brorphine found euphoric and mood-lifting effects, which are 3,4-difluoro-U-47700 and N-ethyl-U-47700,
that it has a potency greater than morphine experienced in waves and create an intense were also discovered in the United States
and acts as a full mu opioid receptor agonist urge among users to continue re-dosing.84 in the first quarter of 2020.90
which would likely result in opioid-like Negative effects have also been reported by
pharmacological effects.73,74 Brorphine users including anxiety, nausea, respiratory AH-7921 is another popular substance
users have reported similar effects including depression and abdominal pain, which are belonging to the cyclohexylbenzamide
euphoria and dependence, and the sub- all typical side effects of classic opioids.85 class of opioids, which shares structural
stance has been actively discussed and Between 2015 and 2019, U-47700 was similarities with U-47700. It was developed
compared to other synthetic opioids in reported to the UNODC EWA in seized by Allen & Hanburys Limited in 1974 but
online forums.75,76 The grey granular materials by 30 countries across the Americas, was never made available for medical use,
powder bears similarities to isotonitazene Asia and Europe, far exceeding any other possibly due to its highly addictive properties
and has been detected in seized drug samples non-fentanyl-related synthetic opioid in observed in animal studies.91,92 Limited
and toxicology cases in Belgium, Canada, terms of reach. The same substance was animal studies also indicate that AH-7921
Sweden and the United States since also reportedly detected in a total of 48 has a similar potency and risk of respiratory
2019.77,78,79 Most recently, between June toxicology cases submitted to the UNODC depression to morphine. Users of this sub-
and July 2020, brophine was detected in EWA by five countries in North America, stance have reported opioid side effects
seven post-mortem cases in the United Europe and Oceania between 2016 and 2019.86 including euphoria, mental relaxation,
States alongside fentanyl, flualprazolam After being placed under international pleasant mood lifts, analgesia, nausea and
and heroin.80 control in 2017, the number of reports of dependence.93 Though less prevalent than
U-47700 to the UNODC EWA declined U-47700, AH-7921 has been reported to
One of the most prevalent non-fentanyl-related globally.87,88 This most likely led to a search for the UNODC EWA by 16 countries94 and
synthetic opioids around the world in recent non-scheduled substances which mimic the has been detected in seized samples and
years is U-47700, which belongs to the effects of U-47700, resulting in recent cases of acute non-fatal intoxications and
cyclohexylbenzamide class of opioids. This appearances in the illicit market of U-47700 deaths in Europe,95 East Asia96 and North
substance, originally developed by the analogues (e.g. isopropyl-U-47700, America.97 It was placed under international
Upjohn Company in 1978, has one tenth of 3,4-methylenedioxy-U-47700, U-48800 control in 2015.98
the potency of fentanyl and about 7.5 times and U-49900) and other U-series synthetic
9
GLOBAL
SMART
UPDATE
Availability of falsified and unlicensed used to distribute heroin.104 The United to cancer patients in China for pain manage-
pharmaceutical opioids States Centers for Disease Control and ment.111,112 In 2012 it was included as an
Prevention reported a marked increase in essential analgesic drug in China’s National
In addition to failed pharmaceutical opioids, tianeptine exposure calls to the National Essential Medicine List, but it was removed
falsified and/or unregistered/unlicensed Poison Data Systems, from 11 cases without official explanation in 2018.113,114
pharmaceutical opioids have also surfaced between 2000 and 2013 to five in 2014 and Studies in mice indicate that AP-237 has
in markets where they are not approved 81 in 2017, suggesting an increase in the both lower potency and likelihood of
for medical use. One such substance is non-medical use of the substance which dependence compared to morphine, but
tianeptine, a tricyclic antidepressant and the United States Drug Enforcement there are no known clinical studies for
anxiolytic that is also a full mu opioid and Administration termed an “extreme public human dependence related to AP-237.115,116
delta opioid receptor agonist.99 Tianeptine health concern” in the context of the coun- Its structural analogue, 2-methyl AP-237,
does not have the common side effects of try’s current opioid crisis.105,106 A 2018 study developed in the 1980s in Italy,117 appeared
most antidepressants, such as sedation, also identified two fatalities in the United on the synthetic drug market in 2019.118
and is prescribed in Europe, Asia and Latin States associated with the use of tianeptine According to its patent, 2-methyl AP-237
America.100 There are multiple documented purchased on the Internet.107 More possesses analgesic activity and is less toxic
cases of recreational use and dependence recently, tianeptine was identified in eight than AP-237 in mice.119 Although there
related to tianeptine, presumably as a seized materials and toxicology cases in are no formal studies of its side effects, it
result of its atypical pharmacological profile, the United States from the fourth quarter is likely to share the typical physiological
ability to induce euphoria at high doses of 2019 to the first quarter of 2020, including and psychological effects of classic opioids.
and relatively mild side effects.101 Case studies three toxicology cases in 2020.108,109 In 2019, Canada and Sweden reported the
and reports of tianeptine dependence detection of this substance in seized materials
found opiate-like euphoria and withdrawal AP-237 (or bucinnazine) and its structural to the UNODC EWA120 and in the first quarter
symptoms including myalgia, nausea, vomiting analogues (2-methyl AP-237 and para-methyl of 2020, it was positively identified in one
and agitation.102,103 Though tianeptine is AP-237) are further examples of illicitly seized drug and two forensic toxicology cases
not approved for medical use in the United manufactured pharmaceutical opioids in the United States.121 Another structural
States of America, it has recently been appearing in seized materials in several analogue, para-methyl AP-237, was first
encountered by law enforcement in the countries.110 The parent compound, AP-237, reported in late 2019 in the United States,
country in various forms including bulk was originally developed in Japan in the late however there is no scientific literature to
powder, falsified hydrocodone and oxycodone 1960s as an opioid analgesic belonging to date on its pharmacological effects.122
tablets, and in individual stamp bags commonly the cinnamylpiperazines class and is prescribed
D. RESPONDING TO AN INCREASINGLY COMPLEX OPIOID CRISIS
The emergence of new non-fentanyl-related palliative care. Competent national authorities
synthetic opioids can be seen as an unintended ”The displacement/replacement may wish to refer to guidelines on estimating
consequence of the efficacy of existing effect is a by-product of a complex national requirements of controlled sub-
control measures in reducing product life cyclic interaction between the stances128 and adopt the use of online and
cycles and minimising the adverse public electronic systems developed by various
imposition and circumvention
health effects of existing synthetic opioids. international organisations to reassess their
The displacement/replacement effect is a of novel control measures amid current estimates and simplify the import and
by-product of a complex cyclic interaction changing market dynamics.” export process of controlled medicines.129
between the imposition and circumvention of Nationally, governments may wish to introduce
novel control measures amid changing market changes to their health systems in order to
dynamics. As governments introduce new availability,124 use and rate of accidental improve access and the availability of controlled
regulatory responses and enhanced forensic overdose deaths125,126,127 associated with the medicines for both pain management and
tools to detect, identify and interdict existing existing generation of synthetic opioids. It is palliative care whilst maintaining proper
substances, so organized crime groups respond therefore essential to continue engaging in oversight such as allowing electronic prescribing,
by identifying, manipulating, manufacturing this cyclic interaction to prevent synthetic especially in remote areas, permitting a larger
and distributing new synthetic substances to opioids from gaining the firm foothold in base of trained health-care professionals to
exploit the limitations of current forensic illicit markets that certain established drugs prescribe opioid analgesics and instituting
technologies as well as chemical analogue/ already have. The question is how policy- national health insurance and price-setting
generic loopholes in the law. This interaction makers can address the growing complexity systems for essential medicines. In addition,
is further driven by the preferences and of the opioid crisis and further shorten the international organisations and national
behaviours of users being influenced by product life cycles of emergent synthetic authorities alike may wish to promote ethical
factors such as the substitution and adulteration substances of abuse by influencing this approaches among pharmaceutical companies
of new substances in existing drug supplies.123 complex cycle. and physicians, rational prescribing practices
and overcoming stigma associated with opioid
Without existing control measures however, Improving access to opioids for medical use use as well as to extend training in pain
extremely potent opioids such as fentanyl and management and palliative care to more
its analogues would become entrenched on The dual nature of the opioid crisis calls health-care professionals.
illicit drug markets with potentially devastating for an informed approach that balances
effects. There is some limited evidence to stemming the non-medical use of interna- The importance of early warning systems
date indicating some degree of success of tionally controlled opioids with improving
existing control responses in reducing the access to them for pain management and The growing complexity of the opioid crisis
10VOLUME 24
highlights the key role of national, regional and Expanding public-private partnerships These agents are defined as“any substance that
global early warning systems in the monitoring is a cannabinoid receptor type 1 (CB1 receptor)
and early detection of new substances. Given The emergence of new synthetic opioids has agonist as demonstrated by binding studies
their accelerating replacement rates, access to created a compelling need for testing equipment, and functional assays” within five defined
timely information on the emergence, preva- toxicology screens, reference materials and structural classes.130 The same approach
lence and harm of new substances of abuse is forensic and chemical expertise to assist forensic could be extended to opioid analgesic
critical for stakeholders to develop policy laboratories and law enforcement with the agents demonstrated by scientific tests to
responses. However, the effectiveness of early identification of these substances and to verify bind to the body’s opioid receptors within
warning systems ultimately depends on their analysis. This presents opportunities for a set of prescribed structural classes.
unfettered and prompt information-sharing collaboration between public and private entities
among international, regional, country and local to share information and jointly develop forensic A broader approach would be the adoption
partners, which remains an on-going concern and chemical expertise, materials and of specific NPS-related legislation that controls
in several parts of the world. Breaking down technologies to reduce the time lag between the manufacture, supply, personal possession
barriers to information-sharing requires joint the initial appearance of a new substance and and/or use of any substance capable of
efforts from international and regional the capacity to detect it in samples. There are producing a psychoactive effect. This would
organisations and Member States alike and also opportunities for governments to support potentially address the general supply and/or
technical assistance with setting up national research by the scientific community related use of all NPS without needing to list all
systems should be provided wherever there is to the forensic identification, pharmacology substances individually in the legislation. Similar
a lack of capacity to identify new synthetic opioids. and epidemiology of new substances of abuse legislation has been enacted in Australia,131
which is essential for expanding knowledge Austria132 and the United Kingdom133 to varying
Improving forensic capacities and enhancing control responses related to degrees. Despite its success in eliminating the
these substances. open sale of NPS and to some extent reducing
The ability to identify new substances goes their availability, use and toxicity, such
hand in hand with a continuous need to update Enhancing legislative responses legislation is not without its challenges and
forensic capacities with advanced, and some- limitations.134 One significant challenge
times prohibitively costly, analytical technologies. The enhancement or extension of existing relates to the enforceability of this type of
In circumstances where access to chemical legislation to control the sale and/or use of legislation given the ambiguity of defining
reference materials, screening tools or forensic emergent psychoactive substances, especially “psychoactive effect”, as well as the limited
data is insufficient, the cross-border sharing synthetic opioids, represents a further option information available on the pharmacological
of investments in powerful, advanced analytical for response. Governments which have adopted activity of some of these substances.135
technologies could be considered, such as analogue or generic legislation, or a combination, Proving psychoactive effect may also require
nuclear magnetic resonance spectroscopy for may wish to consider expediting the process forensic capacities to conduct both in vivo and
determining the molecular structures and of legislating against new structural classes of in vitro testing, along with expert witnesses
purity of new substances. At the same time, synthetic opioids not yet covered by existing to adduce and interpret available evidence
investments and efforts to update the software laws. Alternatively, the adoption of a broader in court.136 In addition, such a broad legal
and spectral libraries of existing laboratory and neurochemical approach could be considered approach could inadvertently inhibit the
field-based forensic analytical technologies are to control any new substances with opioid- meaningful research, development, testing and
encouraged, along with the development like effects. The United States, for instance, use of new psychoactive substances with
and validation of analytical methodologies, to introduced such an approach for the control legitimate pharmaceutical uses and therefore
ensure the ability to identify and/or verify of cannabimimetic agents through the exceptions need to be built into the legislation
the presence of new synthetic opioids. Synthetic Drug Abuse Prevention Act of 2012. to prevent this.
E. CONCLUSION
The multifaceted opioid crisis continues to as well as reduced availability, use, harms and
grow in complexity with marked variations ”...emergence of these substances product life cycles, associated with some synthetic
in different parts of the world presenting underscores the importance of opioids are all testament to efforts undertaken
significant challenges to the international strengthening early warning in recent years. Beyond interdiction measures,
community. These challenges are com- the international community should consider
systems, expanding public-private
pounded by the emergence in illicit markets renewed efforts to improve access to controlled
of a greater variety of synthetic opioids in partnerships and enhancing opioids for pain management and palliative
chemical structural classes distinct from existing legal approaches to care to alleviate unnecessary suffering and
fentanyl and fentanyl analogues. Despite their respond to the growing complexity achieve a holistic and balanced approach
recent appearances, many such “new” to addressing the opioid crisis.
non-fentanyl related opioids are derived of the opioid crisis..."
from past failed, falsified or unregistered/
unlicensed pharmaceutical opioids introduced crisis thereby further shortening the life cycles
into the illicit market in a bid to circumvent of emergent synthetic substances of abuse.
existing controls. The emergence of these Despite the formidable challenges, experience
substances underscores the importance of shows that the international community is
strengthening early warning systems, capable of pulling together and making strides
expanding public-private partnerships and at both national and international levels to
enhancing existing legal approaches to curb the supply and demand for synthetic
respond to the growing complexity of the opioid opioids. Current increased awareness levels,
11GLOBAL
SMART
UPDATE
Impact of the COVID-19 pandemic on the evolving opioid crisis
The onset of the COVID-19 pandemic has preliminary trends in seizures indicate min- diseases such as HIV/AIDS and hepatitis
brought wide-ranging and profound effects imal disruption to illicit synthetic opioid C, while the sharing of drug parapher-
to the world, leading to unprecedented manufacturing and trafficking activities in nalia e.g. inhalation devices may also
closures of non-essential parts of the the wake of the pandemic. increase the spread of COVID-19 itself,
economy accompanied by border and further burdening already-strained
movement restrictions on a scale unmatched However, the impact of the COVID-19 healthcare systems.149 User behaviour
by past market crises. As was the case in pandemic on the production and trafficking may also shift through abstaining or
previous major crises, it is likely that the of opiates remains unclear, affecting in turn moving to lower potency or purity opi-
pandemic has affected many aspects of the wider market for opioids. At present, there oids, resulting in lower adjusted tolerance
the illicit drug market, in particular the is insufficient or inconclusive information and increased risk of opioid overdose as
evolving opioid crisis.137 available on the current state of Afghanistan’s supply and quality improve.150 Possible
opium harvest, which has accounted for reductions or suspensions of public
E ffe c t s on t he t r affi c ki n g an d approximately 84 per cent of global opium health resources and capacities for harm
manufacture of synthetic opioids production over the past five years.144,145 In reduction and drug treatment services
any event, if illicit opiate activities are as a result of the pandemic, especially
Despite early indications of disruption to indeed affected, it would be prudent for opioid substitution treatment, may further
illicit synthetic opioid manufacture and governments to closely monitor illicit drug exacerbate these vulnerabilities.151 The
trafficking in some regions, recent evidence markets for developments such as the American Medical Association recently cited
months into the pandemic suggests that adulteration or substitution of opiate supplies concerns over increases in opioid-related
these activities have resumed to normal with cheaper and potentially more harmful mortality in more than 35 states during
levels and possibly intensified.138 For synthetic opioids such as fentanyl and its the pandemic and urged flexibility in the
instance, a year-on-year comparison of analogues from illicit sources.146 provision of harm reduction services.152
fentanyl seizure trends at the borders of
the United States indicates that the earlier Effects on the use of synthetic opioids The rapidly evolving drug scenario amid
perceived disruption to the fentanyl the COVID-19 pandemic highlights the need
trade was extremely short-lived,139,140 The COVID-19 pandemic may further expose for policymakers and other stakeholders
with seizures resuming to previous levels opioid users to increased vulnerability to to actively monitor emerging trends and
as of February 2020, despite temporary problematic drug use and overdose if the enact suitable policies to respond to
restrictions on non-essential travel.141 economic fallout drives a switch to more changes in drug manufacturing, trafficking
Similarly, the pandemic seems to have efficient methods of administering drugs, and user behaviour. These changes may
had little impact on tramadol trafficking such as injecting, in order to compensate have a long-term impact on opioid markets
with large-scale seizures of the drug being for lower purchasing power and maximize and drug use patterns with corresponding
reported in Kuwait and India from February the psychoactive effects.147,148 However, this implications for future public health and
to July 2020.142,143 Taken together, these heightens the transmission risks of blood-borne drug control requirements.
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