ACMD

Advisory Council on the Misuse of Drugs

ACMD report – A review of the evidence on the

use and harms of 2-benzyl benzimidazole
(‘nitazene’) and piperidine benzimidazolone
(‘brorphine-like’) opioids

July 2022

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Contents

1. Introduction .................................................................................................... 3
2. Legal control .................................................................................................. 4
3. Chemistry ....................................................................................................... 5
4. Pharmacology ................................................................................................ 6
5. Toxicology ...................................................................................................... 9
6. Legitimate uses............................................................................................ 10
7. Misuse .......................................................................................................... 10
8. Health harms ................................................................................................ 13
9. Social harms ................................................................................................ 15
10. UK prevalence .............................................................................................. 15
11. Conclusions ................................................................................................. 18
12. Recommendations....................................................................................... 22

Annex A: International legal controls of 2-benzyl benzimidazole opioids ........ 26

Annex B: International legal controls of brorphine ............................................. 30
Annex C: Chemical structure of isotonitazene and related 2-benzyl
benzimidazole opioids ................................................................................ 31
Annex D: Chemical structure of 4-piperidinyl benzimidazolones ...................... 33
Annex E: List of abbreviations used in this report.............................................. 34
Annex F: ACMD membership, at time of publication .......................................... 36
Annex G: ACMD NPS Committee membership, at time of publication .............. 38
Annex H: Quality of evidence ................................................................................ 40

References .............................................................................................................. 42

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1. Introduction

1.1. New psychoactive substances (NPS) have presented a substantial public

health challenge over the last 13 years, with new synthetic opioids (NSO)
making an increasing recent contribution [United Nations Office on Drugs and
Crime (UNODC), 2021]. These NSO give users similar effects to those of
morphine and heroin, but some are much more potent. This means that
substantially lower doses are needed to achieve the effects desired by users,
but there is also a high risk of accidental overdose, and this may cause life-
threatening toxicity including loss of consciousness, cardiorespiratory arrest
and death.

1.2. The NSO most frequently encountered have been the fentanyl analogues,
which have caused a large number of drug-related deaths internationally and
which were the subject of an earlier ACMD report (Misuse of fentanyl and
fentanyl analogues, January 2020). Fentanyl and its analogues have
commonly been synthesised in China, but further legal controls affecting
these compounds were enacted there between 2016 and 2019 [Bao et al.,
2019], encouraging synthetic chemists in that country to explore the synthesis
of other NSO that remain uncontrolled.

1.3. This report considers two similar but distinct types of NSO, the 2-benzyl
benzimidazole (‘nitazene’) and the piperidine benzimidazolone (‘brorphine-
like’) opioids.

1.4. 2-Benzyl benzimidazole (‘nitazene’) opioids were originally developed in the

1950s as analgesics. Several were shown to have potent opioid (heroin-like)
effects [Blanckaert et al., 2020; EMCDDA, 2020; WHO, 2020], but none were
subsequently marketed anywhere as human or veterinary medicines [Gross
and Turrian 1957; Hunger et al., 1957; EMCDDA, 2020; WHO, 2020].

1.5. 2-Benzyl benzimidazole opioids have previously been encountered

internationally as substances of misuse. For example, etonitazene was
implicated in the deaths of 10 drug users in Moscow in 1998 and clandestine
laboratories manufacturing this compound have been occasionally identified
since then [Sorokin et al., 1999]. In 2003, etonitazene was manufactured by
an American chemist in Utah and placed in nasal spray bottles, apparently for
his own use [Desert News, 2003].

1.6. More recently, there have been many international reports of severe toxicity
involving 2-benzyl benzimidazole opioids, especially isotonitazene. As of
November 2021, 9 of these compounds had been reported to the UNODC
Early Warning Advisory, specifically isotonitazene, 5-aminoisotonitazene, N-
pyrrolidino-etonitazene, butonitazene, metonitazene, protonitazene,

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 etodesnitazene (etazene), flunitazene and metodesnitazene (metazene)
[UNODC, 2021].

1.7. 2-Benzyl benzimidazole opioids have been sold as powders or nasal sprays
and administered by the intravenous, sublingual or nasal routes or by vaping.
They may also be used to fortify heroin, or as constituents of counterfeit
medicines [WHO, 2020; EMCDDA, 2020]. Users may be unaware of their
inclusion and, like fentanyls, the high potency of some of these compounds
provides a substantial risk of severe and potentially fatal overdose.

1.8. There is also recent evidence of fatal and non-fatal toxicity associated with the
piperidine benzimidazolone opioid brorphine. This compound has been
detected in seized powders, and use via the oral route or by inhalation
(smoking, vaping) may be more common than use by injection [WHO, 2021].
Many other chemicals with this general structure have also been shown to
have opioid actions, although to date there are no reports of their misuse.

1.9. This report examines the available evidence of harms caused by 2-benzyl
benzimidazole and piperidine benzimidazolone opioids, and their prevalence
and public health impact in the UK. It provides recommendations, including
control under the Misuse of Drugs Act 1971 and scheduling via the Misuse of
Drugs Regulations 2001.

2. Legal control

2.1. Internationally, etonitazene and clonitazene are controlled under the United
Nations Single Convention on Narcotic Drugs of 1961 [UNODC, 1961; INCB,
2021). Isotonitazene was added to schedule I of the convention, as amended
by the 1972 Protocol, in June 2021. Metonitazene and brorphine were
subsequently also added to the same schedule in March 2022 [UNODC,
2022]. Further details of international controls are provided in Annex A.

2.2. In the UK, etonitazene and clonitazene are listed as Class A drugs in the
Misuse of Drugs Act 1971 and in schedule 2 of the Misuse of Drugs
Regulations 2001. All other 2-benzyl benzimidazole opioids and all piperidine
benzimidazolone opioids (including brorphine) are not currently controlled
under the Misuse of Drugs Act 1971, although, as psychoactive substances,
import, supply, possession with the intent to supply and possession in a
custodial institution are all offences under the Psychoactive Substances Act
2016.

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3. Chemistry

3.1. The general structure of 2-benzyl benzimidazole opioids is shown in Annex C.

They contain a benzimidazole ring with an ethylamine at the 1-position and a
benzyl group at the 2-position [DEA, 2021a].

3.2. 2-Benzyl benzimidazole opioids are structurally unrelated to other opioid drug
groups, including morphine, fentanyls and U-series analogues (‘utopioids’).
The benzimidazole ring structure is, however, also found in a wide range of
human and animal medicines, including anthelminthics (such as
mebendazole, albendazole), proton pump inhibitors (such as omeprazole),
antivirals (such as enviradine), antihypertensives (such as candesartan),
antihistamines (such as astemizole) and fungicides (such as carbendazim)
[Brishty et al., 2021].

3.3. The 2-Benzyl benzimidazoles are synthetic opioids and can be prepared in
only a few steps from readily available, uncontrolled precursors [Pardeshi et
al., 2021]. While there are preferred syntheses, a number of viable alternative
methods and variations are available. These synthetic approaches are
amenable to incorporation of structural changes to all parts of the nitazene
molecule, including changes to the electron-withdrawing-nitro substituent, to
the N,N-diethyl moiety at the end of the ethylamino sidechain and to the
benzyl group at C2 (including varying substituents on the aryl ring and
changing the methylene linker either by adding substituents or by swapping to
other elements) [Ujváry et al., 2021]. The modular nature of the synthesis
means that each part of the molecule can be varied independently, allowing
access to a large number of analogues.

3.4. The general structure of piperidyl benzimidazolone opioids is shown in Annex

D. They contain a benzimidazole-2-one ring system, substituted with a 4-
piperidinyl group on one of the ring nitrogens, with a benzylic group attached
to the piperidinyl nitrogen. They are chemically distinct from other opioid drug
groups, although there are some structural similarities to fentanyl. However,
the 4-piperidinyl benzimidazolone core is found in other medicines, including
the antipsychotics benperidol and pimozide, and the dopamine antagonist
domperidone, which is used to promote lactation and treat nausea and
vomiting, and gastroparesis.

3.5. The piperidyl benzimidazolone opioid brorphine has been encountered

recently in many countries in forensic casework and most evidence in this
report on this group of materials concerns this compound. There are,
however, other examples with opioid activity and other members of this group
that are of interest, for instance the selective nociceptin opioid peptide (NOP)

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 receptor antagonist J-113397 that is much used in research and was the lead
for a new generation of NOP antagonists [Jong et al., 2004].

3.6. Brorphine and its analogues can be made in only a few steps from readily
available precursors [Kennedy et al., 2018]. The synthetic method allows for
many close analogues to be made and structural changes can easily be made
to all parts of the molecule (e.g., R1 to R8 on Annex D). These modifications
can include having substituents on the phenyl ring of the benzimidazolone
group, varying the piperidine ring and varying the substituent attached to the
piperidine nitrogen. The synthesis is modular, allowing access to a large
number of analogues.

4. Pharmacology

4.1. The pharmacology and toxicology of opioid drugs have recently been
described in detail (ACMD report - Misuse of fentanyl and fentanyl analogues,
January 2020). Briefly, these drugs act by interacting with a series of
receptors within the brain and nervous system termed mu (MOR), delta
(DOR) and kappa (KOR) opioid receptors. Of these, the MOR is particularly
important as the principal mediator of the analgesia, respiratory depression,
euphoria and dependency associated with heroin, morphine, fentanyl and
other opioids [Gill et al., 2019]

4.2. Early studies demonstrated that several 2-benzyl benzimidazole compounds,

including isotonitazene and etonitazene, have potent centrally mediated
analgesic effects [Hunger et al., 1960b]. A recent review of early studies
administering these drugs to mice via the subcutaneous route indicated
potencies compared to morphine ranging from 1 (equal potency) for
flunitazene to 500 times more potent for isotonitazene and 1000 times more
potent for etonitazene [Ujváry et al., 2021]. In a mouse tail-flick analgesia
model, isotonitazene was 500 times more potent than morphine [Hunger et
al., 1960b]. If these studies reflect the pharmacology in humans, a dose of
isotonitazene would be expected to have the same analgesic effect as a
morphine dose 500 times larger.

4.3. Across several in vitro assays of MOR activation isotonitazene was observed
to be more potent (up to 10 times) than fentanyl in activating the receptor but
with similar agonist efficacy. The rank order of potency of a series of
nitazenes was reported to be etonitazene >= isotonitazene > protonitazene >=
metonitazene > butonitazene >= etodesnitazene >> 5-aminoisotonitazene =
flunitazene > metodesnitazene [Blanckaert et al., 2020; Vandeputte et al.,
2021].

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4.4. The N,N-dialkyl component of nitazenes can be modified in a number of ways.
Replacing the ethyl groups with other small alkyl groups retains significant
activity and the N-desalkylforms of nitazenes, where 1 of the 2 alkyl groups on
the amino group has been lost, are reported to be at least equipotent with
their parent compounds. Fusion of the two alkyl groups of the N,N-diethyl
component into a pyrrolidine ring gives N-pyrrolidino etonitazene
(etonitazepyne). Preliminary unpublished data suggested that N-pyrrolidino
etonitazene is among the most potent of the 2-benzyl benzimidazole opioids,
being 20 times more potent than fentanyl and with MOR activation similar to
that of etonitazene [Vandeputte and Stove unpublished, cited by Blankaert et
al., 2021] while the N-piperidinyl form (etonitazepipne) is reported to have
even greater potency.

4.5. Modifications at the 4- position of the benzyl structure have been extensively
explored. Replacement of ethoxy by other small ether groups such as
methoxy, propoxy and isopropoxy, retains very significant activity, with the
isopropoxy form of etonitazene (isotonitazene) being the most potent variant,
with around 500 times the potency of morphine. Replacement of the alkoxy
group by halogens results in materials such as clonitazene, with much
reduced potencies, similar to or slightly greater than that of morphine. Small
alkyl groups at this position produce materials with greater potency, with
propyl nitazene reported to have a potency around 50 times that of morphine.
Replacement of the oxygen atom of these ethers by a sulphur atom to
produce thioethers results in materials less potent than their ether equivalents
but still significantly greater than that of morphine.

4.6. Removal of the nitro group results in a reduction in potency, with

etodesnitazene (etazene, etonitazene without the nitro group) having a
potency around 70 times that of morphine. Replacement of the nitro group
with other electron-withdrawing groups, such as cyano or acetyl, results in
materials with reduced but still significant potencies.

4.7. Some other variations of the etonitazene structure have also been reported to
produce materials with significant MOR potency, though none of these
variants have so far been observed in drug markets internationally.

4.8. Three of the nitazenes have had some preliminary clinical evaluation in a
variety of settings; after single-dose oral administration, etonitazene was 80 to
120 times more potent than morphine as a euphoriant, while clonitazene (a
low-potency nitazene of comparable potency to morphine in in vitro
bioassays) was of slightly lower potency than morphine. Subcutaneous
metonitazene (a moderately potent nitazene in vitro) was around 10 times
more potent than morphine as an analgesic [Bromig, 1958; Ujváry et al.,
2021]. From these data it appears that the in vitro bioassay data are

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 reasonably predictive of clinical efficacy. None of these were taken forward as
medicines, with respiratory depression/failure being noted.

4.9. Other factors are also important in determining pharmacological effects and
the risk of toxicity. The ability to reach sites of action in the brain is essential
and increased for lipid soluble substances. 2-benzyl benzimidazole opioids,
including isotonitazene, are highly lipid soluble and, therefore, likely to cross
rapidly into the brain [WHO, 2020].

4.10. 4-piperidinyl benzimidazolones were disclosed by Janssen in the 1960s

[Janssen Pharmaceutica, 1965; Janssen and Van der Eycken, 1968] as
potent morphine-like analgesics. Recent studies have shown members of this
series (SR14968 and SR17018) have morphine-like analgesic effects in
rhesus monkeys, though their limited solubility prevented a thorough
investigation of their effects on respiration [Cornelissen et al., 2021]. SR-
14968 has also been shown to produce fentanyl-like discriminative stimulus
effects in male and female rats [Schwienteck et al., 2019].

4.11. Replacing the central piperidine group with larger (7-membered

azacycloheptane) or smaller (5-membered pyrolidine) rings, or moving the
attachment point of the benzimidazolone group from the 4-position to the 3-
position of the piperidine all resulted in reduced activity [Kennedy et al., 2018].
Groups other than a hydrogen or a methyl group on the benzylic carbon also
results in substantial loss of MOR activity [Kennedy et al., 2018].

4.12. In assays of agonist activity (G protein activation) at the MOR, brorphine has
been reported to be a potent, high-efficacy agonist [Kennedy et al., 2018;
Vandeputte et al., 2020; Verougstraete et al., 2020; Grafinger et al., 2021]
approximately 13 fold more potent than morphine [Kennedy et al., 2018] and
with potency estimates compared to fentanyl ranging from slightly less potent
(3 fold) [Vandeputte et al., 2020] to more potent (10 fold) [Grafinger et al.,
2021]. A number of close analogues reported by Kennedy et al. (2018) show
potency similar to or slightly greater than that of morphine.

4.13. Brorphine shows selectivity for the MOR over the KOR, being some 500 times
more potent as an agonist at the MOR [Grafinger et al., 2021]. A number of
synthetic opioids structurally related to brorphine have been reported in the
scientific literature to be MOR agonists. Some have similar potency to
brorphine [Kennedy et al., 2018; Schmid et al., 2017]

4.14. In mice, two brorphine analogues, SR-14968 and SR-17018, produced

reward-associated behaviour and induced physical dependence which may
indicate that they could be misused and produce physical dependence [Kudla
et al., 2022].

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4.15. In humans, brorphine is extensively metabolised – at least 11 metabolites
have been identified [Krotulski et al., 2020; Grafinger et al., 2021]. The
activities of the metabolites at the MOR have not been reported.

5. Toxicology

5.1. The acute toxicity of several 2-benzyl benzimidazole opioids has been studied
in mice and rabbits [Gross and Turrian, 1957; Ujváry et al., 2021; EMCDDA,
2020]. There is a wide range in toxicity for the various compounds studied,
with etonitazene associated with the lowest doses required to produce toxic
effects. Limited information on toxicity is available for isotonitazene. It should
be noted, however, that studies in rodents should be interpreted with caution
as they do not accurately reflect opioid toxicity in humans.

5.2. Specific antidotes antagonise opioid effects on the MOR and reverse the toxic
effects of heroin. Naloxone is widely used for this indication and has saved
many lives after overdose. Research involving isolated tissues and animals
has demonstrated that opioid antagonists, including naloxone or naltrexone,
inhibit the opioid receptor binding and clinical effects of etonitazene [Hughes
et al., 1975; Pert and Snyder, 1973; Barnett et al., 1975; Achat-Mendes et al.,
2009; Blanckaert et al., 2020]. Information on the efficacy of naloxone
specifically for treating intoxication from 2-benzyl benzimidazole opioids in
humans is lacking, but in a human volunteer, life-threatening respiratory
depression and coma caused by subcutaneous metonitazene (1mg) was
reversed by 5mg of the opioid antagonist nalorphine administered
intravenously [Bromig, 1958].

5.3. Some 2-benzyl benzimidazole metabolites (such as N-desethylisotonitazene,

N-desethyletonitazene) also have high efficacy and potency. There is very
little information available on their effects in humans and they may not be
tested for as part of post-mortem toxicology, but their effects may add to those
of the parent compounds. Toxicity in some animal species may differ from that
observed in humans due to differences in rates or routes of metabolism.

5.4. The varying potency of different 2-benzyl benzimidazole opioids for analgesic
and toxic effects means that very different doses would be needed to achieve
desired effects in users. There is a risk that this would not be adequately
taken into account by dealers or users switching from one compound to
another.

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6. Legitimate uses

6.1. 2-Benzyl benzimidazole and piperidinyl benzimidazolone opioids have

legitimate uses as analytical reference standards and potentially for research,
but no other legitimate uses have been identified [EMCDDA, 2020].

6.2. The Medicines and Healthcare products Regulatory Agency (MHRA) was
consulted about legitimate medical uses of the following compounds:
butonitazene, clonitazene, etazene, etonitazene, flunitazene, isotonitazene,
metodesnitazene, metonitazene, nitazene and protonitazene. The MHRA
confirmed that none of these compounds have ever been authorised in the
UK as medicines. There are no licences either currently or previously for any
of these substances and, as a consequence, none will have been marketed in
the UK as a medicine. None of these compounds have been the subject of
any request for scientific advice meetings with the MHRA by any company,
there have been no imports for legitimate purposes (named patient
prescriptions) and none are being used in a clinical trial where the sponsor
has applied to the MHRA for their clinical trial.

6.3. In relation to the schedule 2 compounds of 26,000 import or export licences

issued over the last year, only 5 involved etonitazene and 2 involved
clonitazene. The companies and quantities involved were consistent with use
as reference standards.

6.4. The MHRA have also stated that there are currently no marketing
authorisation applications for medicinal use of brorphine in their applications
system and, they were unable to find any evidence of clinical trials using
brorphine in the UK or internationally.

6.5. The benzimidazole ring structure and the 4-piperidinyl benzimidazolone core
are both found in a range of licensed non-opioid medicines (see ‘Section 3:
Chemistry’) and it is important that these are not captured by any legislation
based on generic chemical structure.

7. Misuse

7.1. Established opioids such as heroin, morphine, oxycodone and fentanyl have
well-recognised dependency potential and addiction to these drugs accounts
for a high proportion of problematic drug users in the UK and other countries.

7.2. Early evidence of the addictive potential in man of earlier 2-benzyl

benzimidazole examples was recently reviewed by the EMCDDA [2020].
Orally administered single doses of clonitazene and etonitazene were
compared with morphine in non-tolerant former morphine addicts. Clonitazene

10
 appeared to be about one-third to one-fifth as potent as morphine sulphate
and roughly equivalent to codeine, while etonitazene was more than 80 to 120
times as effective as morphine as a euphoriant. Both drugs supressed
symptoms of opioid withdrawal in opioid-dependent patients who had
previously been stabilised on morphine, while abrupt discontinuation of
etonitazene promoted abstinence syndrome [Anon, 1959; EMCDDA, 2020].
For etonitazene, the discriminative stimulus [Zhang et al., 2000], self-
administration [Achat-Mendes et al., 2009; Ginsberg and Lamb 2018], and
tolerance and dependence [Tang, 1982; Walker and Young, 2001] were
similar or greater than those of morphine or fentanyl [WHO, 2000].

7.3. Limited specific evidence is available for the dependency potential of more
recently encountered 2-benzyl benzimidazole opioids. There are, however,
unverified user reports of withdrawal symptoms after use of isotonitazene,
including fever, dizziness, flu-like feelings, blackouts, anxiety and panic
attacks [WHO, 2020].

7.4. In studies using rats, brorphine fully substituted for the effects of morphine. No
human studies are available relating to physical dependence or withdrawal
symptoms in human users of brorphine, although users have reported
development of tolerance and withdrawal on the social media site Reddit
[WHO, 2021].

7.5. Verougstraete et al. [2020] described a 24-year-old male who presented with
features of opioid withdrawal including generalised pain, tachycardia and
sweating, He had used brorphine orally with etizolam for 1 to 2 months after a
period of more than a year of abstention from opioid use. The patient reported
effects similar to oxycodone or fentanyl, with a long-lasting ‘high’, the
development of tolerance and intense cravings after waking.

7.6. There is limited information on the manufacture, trafficking, distribution and

use of 2-benzyl benzimidazole or piperidinyl benzimidazolone opioids. It is
reported that some of the isotonitazene sold in Europe was manufactured by
chemical companies based in China [EMCDDA, 2021]. Brorphine and several
2-benzyl benzimidazoles have been available for sale via the dark net [Lamy
et al., 2021]

7.7. Interest in NPS may be identified by posts made on social media sites before
these substances are detected in samples from human users. Posts on the
social media site Reddit mentioning isotonitazene were first made in January
2019 and brorphine in February 2019 [Barenholtz et al., 2021]. From
automated scanning of online resources discussing NPS (January to August
2020), threads concerning etazene, brorphine and fluonitazene were among
the most popular [Catalani et al., 2021].

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7.8. Isotonitazene was first identified in samples from a March 2019 toxicology
case in Alberta, Canada [WHO, 2020] and in illicit drug markets in Europe in
April 2019, following a drug seizure in Estonia [EMCDDA, 2020]. It was first
reported in the US in November 2019 from samples collected in August 2019.
The most recent, Centre for Forensic Science Research and Education
(CFSRE) trend report for January to March 2022 shows a peak in US
isotonitazene detections in October to September 2019, with subsequent
reductions, although positive detections continue at a lower rate.

7.9. Isotonitazene has been sold online as a powder, nasal spray or in counterfeit
pills with reported routes of administration including vaping, intravenous,
sublingual or intranasal (spray or insufflation). Reported doses ranged from
1mg to 10mg (intravenous, sublingual or via vaping) and 100 µg to 200 µg via
nasal spray [WHO, 2021]. Isotonitazene-containing drug seizures reported to
the EMCDDA have been of powders (brown, yellow, or white) or liquids, and
may include the free base and/or the hydrochloride salt.

7.10. The 2-benzyl benzimidazole opioid etodesnitazene was detected in a police

seizure made in Poland in May 2020 [Siczek et al., 2020).

7.11. The piperidinyl benzimidazolone opioid brorphine was first identified in US

drug markets in June 2019 and in Europe (Belgium) in February 2020 [DEA,
2020; UNODC, 2020; Vanderputte et al., 2021]. It has also been reported by
other countries including Canada, Sweden, Slovenia, Finland and the UK. It
was detected in at least 7 fatalities in the US between June and July 2020.
The National Forensic Laboratory Information System received 20 reports
involving brorphine in 2019 and 2020 from three different states, with heroin,
fentanyl, flualprazolam and diphenhydramine also identified in many cases.
The evidence suggested that brorphine was used as a replacement for heroin
or other opioids, with or without the knowledge of users [DEA, 2020]. By
October 2020, exposure to brorphine had been identified in more than 100 US
cases during forensic casework [Krotulski et al., 2021]. The increase in
brorphine detections followed the scheduling of isotonitazene in the US in
June 2020. Brorphine itself was scheduled in the US in March 2021, but
worldwide interest in this compound, assessed using Google Trends, had
already fallen substantially by that time [Vandeputte et al., 2021]. The CFSRE
trend report for January to March 2022 demonstrates a peak in brorphine
detections in the US in July to September 2020, with subsequent reductions.
There has, however, been a small increase in recent detections [NPS
Discovery, 2022].

7.12. The US’s DEA has reported that dealers have advertised brorphine as a
replacement for fentanyls and that the population likely to abuse brorphine
appears to be the same as those abusing heroin, prescription opioid

12
 analgesics and other synthetic opioids [DEA, 2021b].

8. Health harms

8.1. The most serious acute health risk from 2-benzyl benzimidazole and
piperidinyl benzimidazolone opioids is likely to be respiratory depression,
which in overdose could lead to apnoea, respiratory arrest and death
[EMCDDA, 2020]. This is consistent with the effects of established potent
opioids such as fentanyl. The unregulated nature of the drugs market may
lead to the sale of products containing inappropriately high doses of potent
compounds or preparations containing ‘hot spots’ of very potent material due
to inadequate blending during the cutting process. These factors increase the
risk of unpredictable and severe opioid toxicity.

8.2. Krutulsky et al. [2020] described 18 post-mortem cases in the US where

isotonitazene had been detected in blood, urine, or vitreous fluid. In many
cases other substances, including opioids and benzodiazepines, were also
detected and may have contributed to death, but 9 were negative for other
opioids. In these cases, median isotonitazene concentrations were 1.75ng/mL
(range 0.4ng/mL to 9.5ng/mL) in blood and 2.7ng/mL (range 0.6ng/nL to
4.0ng/mL) in urine. Many of the cases were suspected heroin users, with
visible needle marks consistent with intravenous drug use and signs of opioid
toxicity, including pulmonary and/or cerebral oedema, commonly present.
From August 2019 to February 2020, more than 100 cases were categorised
as presumptively positive for isotonitazene [Krotulski et al., 2020; DEA 2020].

8.3. In their 2020 report, the EMCDDA listed 2 deaths involving isotonitazene
reported from Europe, with the UK and Germany the reporting countries.
Subsequently, 3 further fatal cases were reported from Switzerland [Mueller et
al., 2021). Isotonitazene concentrations in femoral whole blood ranged from
0.74ng/ml to 2.28 ng/ml, but benzodiazepines were also detected in 2 cases
and ethanol in the third; these substances may also have contributed to the
fatal outcomes.

8.4. In the US, 8 post-mortem blood samples were found to contain N-pyrrolidino
etonitazene between January and April 2021. In 7 cases, other substances
were commonly identified, including benzodiazepines, fentanyl, and
methamphetamine. In one case where it was the only drug of interest, the N-
pyrrolidino etonitazene concentration was 8.3 ng/ml [NPS Discovery, 2021a).

8.5. A single case of severe toxicity, including cardiac and respiratory arrest, was
reported in an 18-year-old male presenting in Birmingham, UK, after reported
oral use of ‘Percocet®’ purchased via the dark web. Blood and urine

13
 specimens detected N-pyrrolidino etonitazene as well as flualprazolam,
flubromazepam and methadone [Pucci et al., 2021].

8.6. Etodesnitazene [NPS Discovery, 2021b], protonitazene [NPS Discovery,

2021c] and N-piperidinyl etonitazene [NPS Discovery, 2021d] have also been
detected during post-mortem death investigations in the US and Canada.

8.7. Other psychoactive substances were also present in many fatal cases in
which 2-benzyl benzimidazole opioids were detected in biological samples,
especially other opioids including heroin or benzodiazepines such as etizolam
or flualprazolam [WHO, 2020]. It may be difficult in some cases to establish
which substance made the most important contribution to the death. There
have, however, been several documented fatal cases where only a
benzimidazole opioid was detected, emphasising the severe toxicity that can
occur with these compounds. In an American study comparing fatal
overdoses involving isotonitazene with those involving other synthetic opioids,
isotonitazene deaths involved a larger number of other substances detected,
including the benzodiazepine flualprazolam [Shover et al., 2021].

8.8. Analytical findings from 20 fatal cases involving brorphine (13 male, 7 female,
median age 49, range 29 to 61 years) have been reported, most arising from
the US mid-west. Fentanyl was also present in all cases and flualprazolam in
80% [Krotulski et al., 2021]. The WHO reported that at the time of writing their
report, screening had suggested the presence of brorphine in more than 200
US cases, with declining trends in the frequency of positive samples between
July to September 2020 and January to March 2021 [WHO 2021].

8.9. A 45 year old man treated with sertraline for depression developed euphoria
and dizziness after ingesting 4 tablets purchased via the internet as
‘oxycodone’ He subsequently developed unconsciousness associated with
shivering and drooling, and later diffuse myalgia, ocular clonus, tremor, and
hyperrefexia with elevated creatine kinase and acute kidney injury. Brorphine
was identified in tablet and patient samples. The authors speculated that the
combination of brorphine and sertraline might provoke serotonin syndrome
[Razinger at al., 2021].

8.10. There is no information on the chronic health effects of 2-benzyl

benzimidazole or piperidinyl benzimidazolone opioids, but these are likely to
resemble those of established illicit opioids such as heroin and fentanyl,
including dependence [EMCDDA, 2020].

14
9. Social harms

9.1. There is no information on the social harms that may be caused by 2-benzyl
benzimidazole or piperidinyl benzimidazolone opioids, but these are also likely
to reflect the substantial social harms of established illicit opioids, such as
heroin and fentanyl.

10. UK prevalence

10.1. 2-Benzyl benzimidazole opioids had not been detected in samples collected in
prisons up to March 2021 (Forensic Early Warning System annual report
2020-21), but more recent data are not available. Border Force had not
identified any seizures involving 2-Benzyl benzimidazole opioids or brorphine
up to November 2021. The Welsh Emerging Drug & Identification of Novel
Substances (WEDINOS) study, funded by Public Health Wales, provides
laboratory testing of UK drug samples (such as pills, powders) submitted
anonymously. WEDINOS has recorded a single detection of butonitazene in a
powder sent from Colchester in March 2022 but no other 2-benzyl
benzimidazole or piperidinyl benzimidazolone opioids. TICTAC
Communications Ltd, which provides drug identification services to the
criminal justice and healthcare sectors, has not detected any compounds in
either group.

10.2. The National Poisons Information Service (NPIS) has received only one
enquiry from a clinician relating to 2-benzyl benzimidazole opioids or
brorphine between January 2019 and March 2022 and this involved
isotonitazene. It should be noted, however, that clinicians are unlikely to be
aware of the involvement of novel synthetic opioids in cases of severe opioid
toxicity as the necessary sample analysis is not performed as part of routine
clinical practice,

10.3. The Identification of Novel Psychoactive Substances (IONA) study is

collecting biological samples from patients attending approximately 30
participating emergency departments in England, Wales and Scotland after
illicit drug use. These are currently analysed by LGC Ltd. A 2-benzyl
benzimidazole opioid was identified in samples from 6 of 303 patients studied
between January 2021 and March 2022, all males (age range 18 to 55 years).
Isotonitazene was identified in 3 cases, all from London and all reporting
heroin use by smoking. All were treated with naloxone and one required
intubation and ventilation. N-pyrrolidino etonitazene was identified in 3 cases,
one from Scotland reporting oral ‘oxycodone’ use, one from the West
Midlands reporting use of ‘Percocet’ purchased via the dark net (as also
described in paragraph 8.5) and one from the East Midlands where no details

15
 of the exposure were provided. All were treated with naloxone and one was
treated by intubation and ventilation. In all 6 cases where a 2-benzyl
benzimidazole opioid was detected, other substances of misuse were also
identified, commonly benzodiazepines and other opioids. All subsequently
recovered. IONA has not identified any cases with exposure to brorphine or
other piperidinyl benzimidazolone opioids.

10.4. During August 2021 there was a significant increase in presentations to the
Emergency Department at St Thomas’ Hospital London with acute opioid
toxicity (36 during August 2021 compared to 13 to 17 monthly over the
previous 7 months). Of these, 20 required naloxone and 8 were admitted to
critical care. Comprehensive toxicological screening of serum samples taken
at the time of presentation was available for two of the presentations. One had
collapsed after smoking ‘heroin’ and was treated successfully with
intramuscular naloxone (2mg). Isotonitazene was identified in a serum sample
taken at the time of presentation (concentration 0.18ng/ml) with
buprenorphine metabolites and cocaine. The second was found unresponsive
and treated successfully with intramuscular naloxone 0.8mg. He reported
smoking a new powder earlier that day. He deteriorated within an hour of
presentation to hospital and was given further naloxone, including by infusion.
A serum sample taken at presentation showed isotonitazene (concentration of
0.81ng/ml) with buprenorphine, cocaine and their metabolites [De
Baerdemaeker et al., 2022].

10.5. Several sources of information on fatalities involving new synthetic opioids are
available. As each provides limited anonymised information, it is not possible
to exclude the possibility that some fatal cases feature in more than one of
these data sets.

10.6. LGC Ltd provide specialist drug analytical services for general toxicology
laboratories and coroners. Samples analysed between July and November
2021 identified at least one 2-benzyl benzimidazole opioid in samples from 15
fatal overdose cases (13 isotonitazene, 3 N-pyrrolidino-etonitazene, 1 both).
For isotonitazene, estimated blood concentrations, where available, ranged
from 0.06ng/ml to 0.57ng/ml. Estimated blood concentration was available for
1 N-pyrrolidino etonitazene-related fatality (9ng/ml). In 14 of the 15 fatal
cases, other substances of misuse (or their metabolites) were identified,
including heroin, cocaine, methadone or benzodiazepines. N-pyrrolidino
etonitazene was also identified in 1 further case from the West Midlands
where the clinical outcome was unknown. No cases with exposure to
piperidinyl benzimidazolone opioids, including brorphine, have been identified.

10.7. Fatalities involving other 2-benzimidazole opioids have also been reported
from other UK forensic analytical laboratories. Toxicology UK Ltd, which

16
 undertakes work for various coroners, reported the detection of metonitazene
(19ng/ml) in post-mortem femoral blood taken from a person who died in
November 2021. Analytical Services International Ltd (St. George’s,
University of London) reported the apparent presence of etodesnitazene
(awaiting reference standard for confirmation) in biological samples and a
powder analysed in the investigation of a single fatal case, as well as the
presence of isotonitazene in samples from 3 non-fatal cases presenting in
London in the second half of 2021. N-pyrrolidino-etonitazene was detected in
samples from 3 male fatalities in Birmingham between October 2021 and
January 2022.

10.8. At the end of July 2021, the Toxicology Unit at Imperial College started to
screen samples from all post-mortem cases with a history of, or toxicological
results indicating, potential heroin use [Nahar et al., 2021]. Over a 2-month
period (August to September 2021) 101 cases were screened of which 36
(36%) were positive for isotonitazene. Approximately 55% of the isotonitazene
positive cases had morphine present in the blood at sub-therapeutic
concentrations or below reportable limits. This indicates that in these cases
heroin exposure may not have been sufficient to cause death and that
isotonitazene is likely to have made an important contribution. Of note,
cocaine (or its metabolite benzoylecgonine) was also present in 34 (94%)
cases, raising the possibility of cocaine contamination with isotonitazene
[Patterson 2021, unpublished]. The Toxicology Unit has also identified
brorphine in a single fatal case from March 2021. Brorphine was detected in
stomach contents and blood along with other psychoactive drugs.

10.9. In October 2021, the National Crime Agency (Operation ROPERY) reported
on 31 suspected heroin overdoses in the UK where isotonitazene had been
identified analytically, 24 of which were fatal. Most occurred in areas covered
by the Metropolitan Police and Thames Valley Police, with clusters of
episodes across England’s South East Region. Those affected were usually
males aged between 35 and 45 years who were known drug users. In most
cases it appeared that heroin use by smoking was involved. Some of these
cases may be the same as those described in preceding paragraphs.
Operation ROPERY also reviewed results of forensic analysis of seized drugs
or associated paraphernalia. More than a quarter of cocaine samples and
more than half of heroin/diamorphine samples were found to contain
isotonitazene as an adulterant. Metonitazene and N-pyrrolidino etonitazene
has also been detected in illicit tablets in the UK.

10.10. The Office for National Statistics has published data on substances involved
in annual numbers of deaths related to drug poisoning in England and Wales
up to 2020. Those where a new synthetic opioid was mentioned on the death
certificate were 13 for 2018, 1 for 2019 and 1 for 2020. Details on the specific

17
 substances involved is not provided and data are not yet available for 2021.
Data on drug-related deaths by substance is provided by the National
Records of Scotland and by the Northern Ireland Statistics and Research
Agency to 2020, but these sources do not include details of new synthetic
opioids.

10.11. The National Programme on Substance Abuse Deaths (NPSAD) collates

information from coroners about deaths related to drugs in England and
Wales. To be included in the NPSAD database, there must be the presence of
one or more psychoactive substance(s) directly implicated in the death, a
history of dependence or abuse of drugs or the presence of controlled drugs
at post-mortem. NPSAD receives drug-related death reports from over 88% of
its coroners. Cases are recorded by year of death, so figures are subject to
change as more reports are confirmed. As of June 2022, NPSAD had
recorded 6 cases in which isotonitazene was detected (July 2019, June 2021,
two in July 2021, two in September 2021) and two cases from July and
September 2021 in which N-pyrrolidino etonitazene was detected. Other
psychoactive compounds were also detected in all 8 cases. Brorphine was
detected in a single fatal case from March 2021.

10.12. Anonymised case-level data on drug-related poisoning deaths received from

the National Records of Scotland have been examined under an ongoing
arrangement for the former EU-MADNESS project. No 2-benzyl
benzimidazole or piperidinyl benzimidazolone opioids were identified in
finalised registration data for the period 1 January 2013 to 31 December 2020
or in provisional data for 2021 and the first quarter of 2022 in the ‘cause of
death’, ‘poisons implicated in death’ or ‘other substances present in
toxicology’ fields.

11. Conclusions

11.1. 2-Benzyl benzimidazole and piperidinyl benzimidazolone opioids include

compounds with very high potency. Although direct evidence of the health
harms of these newly emerging groups of drugs is limited, these are likely to
reflect those of other potent opioids and the clinical data described to date is
consistent with this. Thus, the recent availability of these compounds presents
a significant potential threat to public health.

11.2. There is evidence of the recent emergence of several new synthetic opioids
from these groups into illicit drug markets internationally, including
isotonitazene, N-pyrrolidino-etonitazene, butonitazene, metonitazene,
protonitazene, etodesnitazene, flunitazene, metodesnitazene and brorphine.
Many cases of severe or fatal toxicity involving these compounds have been
described in Europe and North America.

18
11.3. 2-Benzyl benzimidazole opioids have also been detected in the UK, where
there were at least 24 fatalities involving isotonitazene and 3 involving N-
pyrrolidino etonitazene during 2021. In these cases, it cannot be established
that 2-benzyl benzimidazole opioids were the sole cause of death, as other
compounds were also commonly detected, but they are likely to have made
an important contribution in many cases.

11.4. The total number of fatalities recorded as associated with NSO is likely to be
an underestimate as not all drug-related deaths are investigated using
methods sufficiently sensitive to detect the involvement of these compounds.
For the same reason, it took several weeks for the involvement of
isotonitazene in drug-related fatalities in the UK to be recognised. Further
cases may emerge if retrospective analyses are conducted. More detailed
sample analysis is needed to establish the role of emerging NPS in individual
drug-related deaths, as well as to provide timely information on the cause of
clusters of drug deaths. Such analysis, however, is costly and adequate
funding would be required.

11.5. The involvement of NSO will not be recognised in most non-fatal cases of
drug-related toxicity because detailed sample analysis is not a component of
usual clinical care. Several non-fatal cases of exposure have, however, been
reported involving isotonitazene and N-pyrrolidino etonitazene. In some
cases, the opioid antagonist naloxone has been used with subsequent clinical
improvement, consistent with experimental evidence that it antagonises the
effects of 2-benzyl benzimidazole opioids as it does those of established
opioids.

11.6. Evidence collected in the UK suggests that isotonitazene may be an

adulterant in heroin or cocaine preparations and people using these are likely
to be unaware of their exposure to isotonitazene. It remains uncertain if
contamination is done deliberately to enhance the effects of the drug product
or if in some cases it results from accidental cross-contamination, such as
from using the same equipment for cutting different drug products.

11.7. The piperidinyl benzimidazolone opioid brorphine has been involved in

multiple fatalities in other countries but has been infrequently detected in the
UK, although numbers may be underestimates as analyses used to
investigate fatal cases may not be able to detect this compound. There is
currently no evidence of the misuse of other compounds from this group.

11.8. With the exception of etonitazene and clonitazene, 2-benzyl benzimidazole

opioids are not controlled via the Misuse of Drugs Act 1971, although they are
subject to the Psychoactive Substances Act 2016. This is also the situation for
the piperidinyl benzimidazolone opioids including brorphine. This position is
not consistent with that of other potent opioids including heroin, morphine and

19
 fentanyl, which are Class A drugs of misuse. The UK is obliged to control
isotonitazene, metonitazene and brorphine now that they are listed in
schedule I of the United Nations Single Convention on Narcotic Drugs of
1961, as amended by the 1972 Protocol, but control of other unlisted 2-benzyl
benzimidazole or piperidinyl benzimidazolone opioids that have been detected
in the UK or elsewhere should also be considered.

11.9. No legitimate medical uses of 2-benzyl benzimidazole opioids have been

identified in the UK or internationally, so placement in schedule 1 of the
Misuse of Drugs Regulations 2001 (as amended) would be consistent with the
current legal status for other opioids that do not have a legitimate medical
use, such as MT-45, U-47,700 and non-pharmaceutical fentanyl analogues.
Etonitazene and clonitazene are currently listed in schedule 2 – this appears
to be historic as they may have been considered as having possible
therapeutic value in the past. No legitimate medical use has since been
identified, however, so listing these in schedule 1 is appropriate and
consistent with the position of other similar compounds.

11.10. To date almost all UK evidence implicates isotonitazene and N-pyrrolidino

etonitazene, although metonitazene, etodesnitazene, butonitazene and
brorphine have also been detected. Other 2-benzyl benzimidazole opioids
detected internationally are very likely to appear in the UK and could cause
substantial health harms, so monitoring for the emergence of these
compounds and their health harms in the UK remains important. In view of the
potential risks they pose to public health, pre-emptive control of these
compounds should be considered. In view of the numbers of compounds
identified to date, there is also a future risk of misuse of new examples of 2-
benzyl-benzimidazole opioids. This could also occur with piperidinyl
benzimidazolone compounds, although the risk is likely to be lower as only
brorphine has been detected from this group so far.

11.11. Clinical advice on management of toxicity with isotonitazene is already

available for health professionals via TOXBASE, including recommendations
on the use of naloxone as an antidote. However, specific information on
brorphine and some other NSO considered in this report is not yet provided.
Public Health England (now the Office for Health Improvements and
Disparities) also issued a national patient safety alert regarding isotonitazene
in August 2021. Drug treatment services are also aware of 2-benzyl
benzimidazole opioids. It would be useful to make those who may use drugs
better aware of these compounds and the risks they carry, especially users of
heroin and cocaine. Information on isotonitazene, brorphine and related
compounds does not currently feature on the ‘Frank’ website
(www.talktofrank.com) and this could usefully be updated to include these

20
 compounds in the synthetic opioids section.

11.12. The ACMD has considered two options for control, either listing specific 2-
benzyl benzimidazole and piperidinyl benzimidazolone compounds known to
have appeared anywhere in the world as NPS or generic controls intended to
‘future-proof’ the legislation by covering known and predicted variants which
appear likely to present a significant risk to health.

11.13. Specifically listing currently identified variants for control is the simpler
approach but risks being overtaken in the future by the development of further
variants, as has been seen in other families of NPS. The NSO that have been
identified in the UK or abroad at the time of preparing this report are as
follows:

▪ Metonitazene
▪ Protonitazene
▪ Isotonitazene
▪ Butonitazene
▪ Flunitazene
▪ Metodesnitazene (metazene)
▪ Etodesnitazene (etazene)
▪ N-Pyrrolidino-etonitazene (etonitazepyne)
▪ N-Piperidinyl-etonitazene (etonitazepipne)
▪ Brorphine

11.14. Preparing generic controls is challenging, as these have to be designed so as

to avoid inadvertently including materials of legitimate pharmaceutical interest
which happen to include a 2-benzyl benzimidazole or piperidinyl
benzimidazolone components within their chemical structure. The generic
control developed in Germany (see Annex A) for 2-benzyl benzimidazoles
provides a valuable model for these compounds and wording for a UK generic
derived from this is presented below.

11.15. Currently the risk that 2-benzyl benzimidazole or piperidinyl benzimidazolone

compounds other than those listed in paragraph 11.13 may be misused in the
UK is unknown. In the absence of a generic control these new compounds
would not be classified under the Misuse of Drugs Act, but examples with
opioid activity would be captured by the Psychoactive Substances Act. The
advice of the ACMD is therefore that legislation based on a generic chemical
description should be developed, but introduction can await the following:

(a) the outcomes of work currently being done by the ACMD to reduce
barriers to legitimate research with controlled drugs

21
 (b) the outcome of a consultation with stakeholders, including academia and
the chemical and pharmaceutical industries to ensure that any proposed
legislation does not produce unintended barriers to research or legitimate
commercial activity

In the meantime, monitoring should continue to detect any evidence of the

misuse of new 2-benzyl benzimidazole or piperidinyl benzimidazolone opioids.

12. Recommendations

Recommendation 1. The following compounds should be added to Class A of the

Misuse of Drugs Act 1971, consistent with the classification of other potent
opioids. As these materials have no medical use it is recommended that they
should be placed in schedule 1 of the Misuse of Drugs Regulations 2001 (as
amended).

• Metonitazene
• Protonitazene
• Isotonitazene
• Butonitazene
• Flunitazene
• Metodesnitazene (metazene)
• Etodesnitazene (etazene)
• N-Pyrrolidino-etonitazene (etonitazepyne)
• N-Piperidinyl-etonitazene (etonitazepipne)
• Brorphine

Lead: Home Office

Measure of outcome: The inclusion of the listed compounds in Class A of the

Misuse of Drugs Act 1971 and schedule 1 of the Misuse of Drugs Regulations
2001.

Recommendation 2. The following compounds should be deleted from schedule

2 and added to schedule 1 of the Misuse of Drugs Regulations 2001 (as
amended).

• Etonitazene
• Clonitazene

Lead: Home Office

Measure of outcome: The inclusion of the listed compounds in schedule 1 of the
Misuse of Drugs Regulations 2001.

22
Recommendation 3. The ACMD recommends that a consultation should be
undertaken with stakeholders, including academia and the chemical and
pharmaceutical industries on the introduction of a generic control on 2-benzyl
benzimidazole variants, as new examples may be encountered and could present
a serious risk of harm. Following this consultation, materials covered by the
generic should be added to Class A of the Misuse of Drugs Act 1971, consistent
with the classification of other potent opioids. As these materials have no medical
use it is recommended that they should be placed in schedule 1 of the Misuse of
Drugs Regulations 2001 (as amended).

The proposed wording for the generic for addition to the Misuse of Drugs Act is as
follows:

Any compound (not being a compound for the time being specified in paragraph
(a) above) structurally derived from 2-[(2-benzyl)-benzimidazol-1-yl]ethanamine by
modification in any of the following ways, that is to say:

(i) By substitution at the nitrogen of the ethanamine to any extent by alkyl

substituents containing up to three carbon atoms or alkenyl substituents
containing up to three carbon atoms or by inclusion of the nitrogen atom
(and no other atoms of the side chain) in a cyclic structure.
(ii) By substitution in the phenyl ring of the benzyl system to any extent by
alkyl containing up to four carbon atoms, trifluoromethyl, alkoxy containing
up to four carbon atoms, trifluoromethoxy, acetyloxy, hydroxy, cyano,
thioalkyl containing up to four carbon atoms, alkylsulphonyl containing up
to four carbon atoms or halogen substituents.
(iii) By substitution at the 5- or 6- positions of the benzimidazole system by
nitro, acetyl, cyano, methoxy, trifluoromethyl or halogen substituents.
(iv) By substitution at the benzylic carbon by a methyl group
(v) By replacement of the benzylic carbon by a nitrogen, oxygen or sulphur
atom
These modifications are subject to a maximum molecular mass of any derived
compound of 500 atomic mass units.

Note: Should evidence emerge of any variants of brorphine appearing, a further

generic control, requiring a similar consultation, should be considered.

Lead: Home Office

Measure of outcome: The inclusion of the described compounds in Class A of the

Misuse of Drugs Act 1971 and schedule 1 of the Misuse of Drugs Regulations
2001, following appropriate consultation.

23
Recommendation 4. In light of the continuing emergence of NPS and particularly
synthetic opioid NPS, a working group should be established to consider and
provide recommendations on a UK-wide minimum standard set of post-mortem
toxicology tests for apparent drug-related deaths, to include testing for relevant
novel psychoactive substances to improve consistency of analysis and detection.
The best practice recommendations agreed would include standards for reporting.
This working group should include (but not necessarily be limited to)
representation from the following:

• Chief Coroner’s Office for England and Wales

• Coroners Service for Northern Ireland
• Crown Office and Procurator Fiscal Service Scotland
• UK and Ireland Association of Forensic Toxicologists
• London Toxicology Group
• Faculty of Forensic and Legal Medicine
• Office for Health Improvement and Disparities
• Home Office Forensic Early Warning System
• Police
• Local drug-related deaths review partnerships
• The ACMD

Lead: Home Office

Measure of outcome: A report detailing best practice for forensic sample analysis
in the investigation of apparent drug-related deaths

Recommendation 5. Adequate funding should be made available by government

to allow coroners, procurators fiscal and forensic toxicologists to follow the best
practice guidelines developed via Recommendation 4.

Lead: Home Office

Measure of outcome: Consistent and appropriate forensic analysis and reporting

for suspected drug-related deaths across the UK.

Recommendation 6. Information for health professionals (such as TOXBASE)

and the general public (such as Frank) on the health effects of NSO should be
reviewed and updated, ensuring that information is available in an appropriate
format on NSO compounds including benzimidazole and piperidinyl
benzimidazolone opioids and the risks that result from the inclusion of compounds
24
of varying and sometimes very high potency in heroin preparations and counterfeit
medicines.

Leads: National Poisons Information Service, UK Health Security Agency, Office

for Health Improvement and Disparities

Measure of outcome: Information available for health professionals and the

general public, including those with lived experience.

25
Annex A: International legal controls of 2-benzyl benzimidazole opioids

United Nations controls

Signatories to the United Nations’ (UN’s) drug conventions are obliged to enact
national controls on materials listed within the conventions in accordance with the
UN’s requirements.

Two of the 2-benzyl benzimidazole opioids – etonitazene and clonitazene – have,

since the 1960s, been listed within schedule 1 of the INCB’s List of Narcotic Drugs
under International Control (the ‘yellow list’ of drugs controlled under the 1961
Convention on Narcotic Drugs). These materials have, therefore, been listed by
name in each signatory country’s drug legislation, including the UK’s.

In spring 2021, following the widespread appearance of isotonitazene as an opioid

NPS, this material was added to the UN’s yellow list as a schedule 1 material. In
addition, the WHO’s Expert Committee on Drug Dependence has recently
recommended to the UN Commission on Narcotic Drugs that metonitazene should
also be added to schedule 1 of the Convention. This recommendation was ratified at
the 65th Session of the UN Commission on Narcotic Drugs, held in March 2022
[UNODC, 2022].

European controls

Within Europe, a ‘fast-track’ system has been established to respond to the risks
presented by NPS. This involves co-ordinated submission of NPS identifications to a
European early warning system, assessment of risks and, where considered
appropriate, pan-European control of materials not covered by the UN drug
conventions.

A directive issued in September 2020 added isotonitazene to the list of substances

controlled within Europe, in advance of the UN decision reported above. Under the
European Commission system, this directive came into force in early December
2020 and member states then had 6 months to bring isotonitazene under their
national controls.

In light of the risk presented by synthetic opioids, the European Monitoring Centre for
Drugs and Drugs Addiction (EMCDDA) has decided that any benzimidazole opioids
identified via the European early warning system should be placed under their
intensive monitoring system, requiring member states to report any event involving
materials on the intensive monitoring list to the EMCDDA. This is intended to ensure
timely provision of evidence to underpin decisions on legislation to control within
Europe.

The 8 other nitazene variants encountered within Europe and reported to the
EMCDDA to date are:

26
 • Etodesnitazene (notification 12 of 2020, issued in June 2020, material seized
in March 2020)
• Metodesnitazene (notification 17 of 2020, June 2020, internet purchase in
May 2020)
• Metonitazene (notification 30 of 2020, September 2020, internet purchase in
June 2020)
• Flunitazene (notification 44 of 2020, December 2020, internet purchase in
July 2020)
• Etonitazepyne (notification 8 of 2021, February 2021, internet purchase in
February 2021)
• Butonitazene (notification 9 of 2021, February 2021, internet purchase in
February 2021)
• Protonitazene (notification 21 of 2021, May 2021, internet purchase in
January 2021)
• Etonitazepipne (notification 1 of 2022, January 2022, recovered from scene of
unexplained death)

Germany

Germany has adopted a generic control on 2-benzyl benzimidazole synthetic

opioids.

German controls on NPS are set out in the Neue psychoktive Stoffe Gesetz (NpSG).
Revisions to the NpSG introduced in July 2021 include a generic control on 2-benzyl
benzimidazole derived materials. This addresses modifications to 3 areas of the
nitazene molecule: the attachments to the nitrogen atom of the diethylamino
component, substitutions onto the phenyl ring of benzyl component and substitutions
at the 5- and 6- positions of the benzimidazole core.

At each of the three sites, the structural variants which merit control are listed:

• At the diethylamino nitrogen: hydrogen or alkyl groups containing up to

three carbons, or ring formation so that the nitrogen atom forms part of
a piperidinyl, pyrrolidino or morpholino ring.
• On the phenyl ring of the benzyl group: hydrogen, alkyl groups
containing up to 4 carbons, alkoxy groups containing up to 4 carbons,
trifluoromethoxy, acetoxy, alkylsulphonyl containing up to 4 carbons,
trifluoromethyl, hydroxy, cyano and halogens.
• At the 5- and 6- positions of the benzimidazole core: hydrogen, nitro,
trifluoromethyl, methoxy, cyano, and halogens.

In addition to specifying the modifications leading to controlled status and limiting the
size of some of these, an overriding upper limit has been placed on the molecular
mass of resulting variants of 500 atomic mass units (u).

27
This approach has the advantage of controlling a broad range of variants which are
known or likely to have MOR potencies equalling or exceeding that of morphine,
thereby addressing the risk of a series of variants emerging in response to specific
legal controls, as has been seen with other NPS families.

Specifying the type and size of substituents, together with the overall mass limit on
resulting structures, avoids the risk of the generic control unintentionally including
pharmaceutical materials which happen to include a 2-benzyl benzimidazole
structure.

United States

The US system of drug control is based on the Controlled Substances Act (CSA),
supported by the Federal Analogue Act which addresses substances similar in
structure and effect to materials listed in the CSA. In addition, there is a procedure
for temporary emergency scheduling for a period of 2 (extendable to 3) years to
enable novel substances which present an imminent hazard rapidly to be controlled
under the requirements of the CSA.

The US has been severely affected by synthetic opioid NPS such as the fentanyls
and it appears that such materials have now become embedded within the US’s illicit
market for heroin and other opiates. Isotonitazene was the first of the nitazenes to be
identified as a threat within the US and it was rapidly controlled by means of the
temporary emergency scheduling procedure in August 2020. In June 2021
isotonitazene was added to the CSA.

Since international control was placed on isotonitazene, a series of other nitazene

variants have been encountered within the US. In December 2021, the US’s DEA
gave notice of its intention to place a further 7 nitazene variants under temporary
control by means of the emergency scheduling process. These are:

• Butonitazene
• Etodesnitazene
• Flunitazene
• Metodesnitazene
• Metonitazene
• Etonitazepyne
• Protonitazene

[Note: these are the same 7 nitazene variants which had been reported by the
EMCDDA at the time of the publication of the US publication of intent to schedule,
reflecting the international nature of the synthetic opioid problem.]

If the DEA’s emergency scheduling proposal is approved, these 7 materials will be

brought under temporary control for a period of 2 years.

28
Other countries

Some other countries have enacted controls on nitazenes in addition to, or in

advance of, the UN’s requirements. Examples include:

• Japan, which added isotonitazene to the list of materials controlled under its
Shitei Yakubutsu (designated substances) legislation in November 2020 (in
advance of the UN requirement) and metonitazene in October 2021.
• Sweden, which has recently added metonitazene to its list of controlled
materials.
• Canada, which includes within Part 13 of schedule 1 of its Controlled Drugs
and Substances Act “benzimidazoles…their derivatives….including…” with
etonitazene and clonitazene cited as examples, which is being interpreted to
include other narcotic nitazene variants.

29
Annex B: International legal controls of brorphine

Following a review and recommendation from the WHO’s Expert Committee on Drug
Dependence in October 2021, the UN Commission on Narcotic Drugs voted on 16
March 2022 to add brorphine to schedule 1 of the 1961 Convention on Narcotic
Drugs.

Prior to the decision to place brorphine under international control, some countries
had already acted to impose control under their national drug legislation.

These include the US where brorphine had begun to be identified in the illicit opioid
market in mid-2019. In light of the perceived imminent hazard to public safety, the
US’s DEA announced their intention to temporarily place brorphine in schedule 1 of
the Controlled Substances Act on 3 December 2020 and this came into effect on 1
March 2021. This temporary control will be subsumed by the US’s response to the
international control.

Other countries applying national controls in advance of the UN requirement include

Japan which had placed brorphine under control as a Designated Substance on 19
January 2022 and Sweden which had controlled brorphine as a schedule 1 material.

On 1 June 2021 Italy added it to their list of controlled materials, as a material

structurally similar to bezitramide [Ministero della Salute, 2022].

30
Annex C: Chemical structure of isotonitazene and related 2-benzyl
benzimidazole opioids

Nitrogen tail
Typically diethylaminoethyl,
but can be pyrrolidinylethyl
(such as pyrrolidino
etonitazene) or piperidinylethyl

Benzylic carbon can

be substituted or
replaced with N, O or S

C5-substituent
Typically nitro for
greatest potency, but Benzyl substituent
unsubstituted also seen Greatest variety seen here with ethoxy
(such as replaced by chloro (clonitazene), fluoro
etodesnitazene) (flunitazene), methoxy (metonitazene),
i-propoxy (isonitazene), propoxy
(protonitazene), butoxy (butonitazene)
and hydrogen (nitazene)

31
 Nitrogen tail Benzyl substituent C5-substituent
butonitazene N(CH2CH3)2 4-O(CH2)3CH3 5-NO2
clonitazene N(CH2CH3)2 4-Cl 5-NO2
etonitazene N(CH2CH3)2 4-OCH2CH3 5-NO2
flunitazene N(CH2CH3)2 4-F 5-NO2
isotonitazene N(CH2CH3)2 4-OCH(CH3)2 5-NO2
methylnitazene N(CH2CH3)2 4-CH3 5-NO2
metonitazene N(CH2CH3)2 4-OCH3 5-NO2
nitazene N(CH2CH3)2 H 5-NO2
protonitazene N(CH2CH3)2 4-O(CH2)2CH3 5-NO2
acetoxynitazene N(CH2CH3)2 4-OCOCH3 5-NO2
bronitazene N(CH2CH3)2 4-Br 5-NO2
N(CH2CH3)2 4-CH2CH3 5-NO2
N(CH2CH3)2 4-(CH2)2CH3 5-NO2
N(CH2CH3)2 4-C(CH3)3 5-NO2
methylthionitazene N(CH2CH3)2 4-SCH3 5-NO2
ethylthionitazene N(CH2CH3)2 4-SCH2CH3 5-NO2
N,N-dimethylamino N(CH3)2 4-OCH2CH3 5-NO2
etonitazene
N-desethyl NHCH2CH3 4-OCH(CH3)2 5-NO2
isotonitazene
etonitazepyne N- 4-OCH2CH3 5-NO2
pyrrolidino
etonitazepipne N-piperidino 4-OCH2CH3 5-NO2
desnitazene N(CH2CH3)2 H H
metodesnitazene N(CH2CH3)2 4-OCH3 H
etodesnitazene N(CH2CH3)2 4-OCH2CH3 H
4-propoxydesnitazene N(CH2CH3)2 4-O(CH2)2CH3 H
4- N(CH2CH3)2 4-OCH(CH3)2 H
isopropoxydesnitazen
e
N- 4-OCH2CH3 H
pyrrolidino
N-piperidino 4-OCH2CH3 H
5-cyanoetonitazene N(CH2CH3)2 4-OCH2CH3 5-CN
5-acetyletonitazene N(CH2CH3)2 4-OCH2CH3 5-COCH3
3,4- N(CH2CH3)2 3,4-di-OCH3 5-NO2
dimethoxynitazene
etoetonitazene N(CH2CH3)2 4-O(CH2)2OCH2CH3 5-NO2

32
Annex D: Chemical structure of 4-piperidinyl benzimidazolones

Brophine: R1-R4, R6, R7 all = H; R5=Me, R8=Br

33
Annex E: List of abbreviations used in this report

ACMD Advisory Council on the Misuse of Drugs

CFSRE Centre for Forensic Science Research and Education

DEA Drug Enforcement Agency (United States)

DHSC Department of Health and Social Care

DOR Delta opioid receptor

DSTL Defence Science and Technology Laboratory

EU- European-wide, Monitoring, Analysis and knowledge Dissemination

MADNESS project

EMCDDA European Monitoring Centre for Drugs and Drug Addiction

FEWS Forensic Early Warning System

INCB International Narcotics Control Board

IONA Identification of Novel Psychoactive Substances study

KOR Kappa opioid receptor

MDA Misuse of Drugs Act 1971

MDR Misuse of Drugs Regulations 2001

MOR Mu opioid receptor

MHRA Medicines and Healthcare products Regulatory Agency

34
NCA National Crime Agency

NISRA Northern Ireland Statistics and Research Agency

NPSAD National Programme on Substance Abuse Deaths

NPIS National Poisons Information Service

NPS Novel Psychoactive Substances

NRS National Records of Scotland

NSO New Synthetic Opioids

OHID Office for Health Improvement and Disparities

PSA Psychoactive Substances Act 2016

UK United Kingdom

UNODC United Nations Office of Drugs and Crime

US United States

WEDINOS Welsh Emerging Drug & Identification of Novel Substances

WHO World Health Organization

35
Annex F: ACMD membership at the time of publication

Dr Ann Sullivan Consultant physician in HIV and sexual health

Dr Anne Campbell Reader in substance use and mental health and

co-director of the Drug and Alcohol Research
Network at Queens University Belfast

Dr Carole Hunter Lead pharmacist at the alcohol and drug recovery

services at NHS Greater Glasgow and Clyde

Dr David Wood Consultant physician and clinical toxicologist at

Guy’s and St Thomas’ and Honorary reader in
clinical toxicology at King’s College London

Professor David Taylor Professor of psychopharmacology, King’s College,

London

Dr Derek Tracy Medical director of West London NHS Trust

Dr Emily Finch Clinical director of the Addictions Clinical Academic

Group and a consultant psychiatrist for South
London and Maudsley NHS Trust

Professor Graeme Professor of pharmacology at the University of

Henderson Bristol

Mr Harry Shapiro Director – DrugWise

Dr Hilary Hamnett Senior lecturer in forensic science, University of

Lincoln

Professor Judith Aldridge Professor of criminology at the University of

Manchester

Dr Kostas Agath Consultant psychiatrist (addictions), Change Grow

Live Southwark

36
Mr Lawrence Gibbons Head of drug threat – National Crime Agency
Intelligence Directorate – Commodities

Mr Mohammed Fessal Chief pharmacist, Change Grow Live

Professor Owen Bowden- Chair of Advisory Council on the Misuse of Drugs,

Jones
Consultant psychiatrist, Central North-West
London NHS Foundation Trust

Dr Paul Stokes Senior clinical lecturer in mood disorders, King’s

College, London

Mr Rob Phipps Former head of Health Development Policy

Branch, Department of Health, Social Services and
Public Safety, Northern Ireland

Dr Richard Stevenson Emergency medicine consultant, Glasgow Royal

Infirmary

Professor Roger Knaggs Associate professor in clinical pharmacy practice at

the University of Nottingham

Ms Rosalie Weetman Public health lead (alcohol, drugs and tobacco),

Derbyshire County Council

Professor Sarah Galvani Professor of social research and substance use at

Manchester Metropolitan University

Professor Simon Thomas Consultant physician and clinical pharmacologist,

Newcastle Hospitals NHS Foundation Trust and
professor of clinical pharmacology and
therapeutics, Newcastle University

Professor Tim Millar Professor of substance use at the University of

Manchester

37
Annex G: ACMD NPS Committee membership, at time of publication

Dr Ann Sullivan Consultant physician in HIV and sexual health

Dr Anne Campbell Reader in substance use and mental health and

co-director of the Drug and Alcohol Research
Network at Queens University Belfast

Dr Kostas Agath Consultant psychiatrist (addictions), Change Grow

Live Southwark

Mr Paul Bunt Director of Casterton Event Solutions Ltd, Former

Drug Strategy Manager for Avon and Somerset
Constabulary

Mr Peter Cain Drugs Scientific Advisor, Eurofins Forensic

Services

Dr Caroline Copeland Lecturer in Pharmaceutical Medicine at King’s

College London, and the Director of the National
Programme on Substance Abuse Deaths

Mr John Corkery Senior Lecturer in Pharmacy Practice at University

of Hertfordshire; mortality and epidemiological
lead for EU-MADNESS project

Mr Lawrence Gibbons Head of drug threat – National Crime Agency

Intelligence Directorate – Commodities

Dr Hilary Hamnett Senior lecturer in forensic science, University of

Lincoln

Professor Graeme Professor of Pharmacology at the University of

Henderson Bristol

Professor Stephen Professor of Medicinal Chemistry, University of

Husbands Bath

38
Professor Roger Knaggs Associate professor in clinical pharmacy practice
at the University of Nottingham

Professor Fiona Professor and chair in criminology, University of

Measham Liverpool; co-founder and co-director, the Loop

Mr Harry Shapiro Director – DrugWise

Dr Richard Stevenson Emergency Medicine Consultant, Glasgow Royal

Infirmary

Professor Simon Thomas NPS Committee Chair, Consultant physician and

clinical pharmacologist, Newcastle Hospitals NHS
Foundation Trust and Professor of Clinical
Pharmacology and Therapeutics, Newcastle
University

Mr Ric Treble Retired Laboratory of the Government Chemist

(LGC) expert

Dr Mike White Former Forensic Intelligence Adviser

Dr David Wood Consultant physician and clinical toxicologist at

Guy’s and St Thomas’ and Honorary reader in
clinical toxicology at King’s College London

39
Annex H: Quality of evidence

Range of evidence

Evidence gathered was considered in line the ACMD’s standard operating procedure
for quality of evidence [ACMD, 2020].

To evidence the identification and prevalence in the UK of the new synthetic opioids
considered in this report, the ACMD’s NPS Committee wrote to stakeholders
requesting available data on the 13 substances. Responses were received from the
following (which include submissions of ‘no data held’ and anecdotal evidence:

External agencies:

• EU-MADNESS project

• NCA

• NISRA

• NPSAD

• NRS

• Tictac

• Eurofins forensics

• LGC forensics

• WEDINOS

Government departments:

• Border Force Intelligence Analysis (Home Office)

• FEWS (Defence Science and Technology Laboratory)

• MHRA

This report also draws on evidence from peer-reviewed literature (UK and
international publications) and government reports. The ACMD also considered
international approaches when drafting its recommendations.

40
Quality of evidence (design, limitations, bias)

For the new synthetic opioids referred to in this report, evidence of their availability
and harm has been sought, allowing the ACMD to make an informed
recommendation on their classification and schedule.

Many agencies and departments returned ‘no data held’ for most of the compounds
considered in this report. It is important to note that owing to the ‘novelty’ of all of
these substances, forensic testing is limited and inconsistent across the UK and as a
result, information being fed into reporting agencies that were approached will not be
representative. This is supported by anecdotal reports. As reports have identified
some of these substances elsewhere in Europe, there is potential availability of
these substances in the UK.

41
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