18 July 2022 [Note also addendums to recommendations in 2023 and 2024]

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.

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, encouraging synthetic chemists in that country to explore the synthesis of other NSO that remain uncontrolled.

This report considers two similar but distinct types of NSO, the 2-benzylbenzimidazole (‘nitazene’) and the piperidine benzimidazolone (‘brorphine-like’) opioids. 2-Benzyl benzimidazole (‘nitazene’) opioids were originally developed in the 1950s as analgesics. Several were shown to have potent opioid (heroin-like) effects, but none were subsequently marketed anywhere as human or veterinary medicines. 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. In 2003, etonitazene was manufactured by an American chemist in Utah and placed in nasal spray bottles, apparently for his own use. 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, etodesnitazene (etazene), flunitazene and metodesnitazene (metazene).

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. 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. 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. 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.

This 2022 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.

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See also, press release from the UK Home Office, 27 November 2023 - Fifteen new synthetic opioids to be made illegal - The fifteen new synthetic opioids to be added to Class A of the Misuse of Drugs Act 1971, subject to parliamentary approval, are:

metonitazene
protonitazene
isotonitazene
butonitazene
flunitazene
metodesnitazene (metazene)
etodesnitazene (etazene)
N-pyrrolidino-etonitazene (etonitazepyne)
N-piperidinyl-etonitazene (etonitazepipne)
N-pyrrolidino protonitazene
ethyleneoxynitazene
N-desethyl protonitazene
N-desethylisotonitazene
N-desethyl-etonitazene
brorphine

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15 December 2023 - Research and analysis Addendum to ACMD's report on the use and harms of 2-benzyl benzimidazole ('nitazenes') and piperidine benzimidazolone ('brorphine-like') opioids, 

Third addendum to ACMD report on the use and harms of 2-benzyl benzimidazole (‘nitazene’) and piperidine benzimidazolone (‘brorphine-like’) opioids

On 6 October 2023, the ACMD published a second addendum to its advice on 2-benzyl benzimidazole (nitazene) and piperidine benzimidazolone (‘brorphine-like’) opioids. This advice recommended control of a further four 2-benzyl benzimidazole compounds which had been detected in the UK: N-Pyrrolidino protonitazene, ethyleneoxynitazene, N-desethyl protonitazene and N-desethyl etonitazene. The ACMD also noted ethyleneoxynitazene would not be controlled by the generic definition proposed in the report.

On 18 October 2023, the Government accepted the revised ACMD recommendation to control these four compounds, including ethyleneoxynitazene. However, the ACMD have concluded it would be possible for other nitazene variants to be developed that were structurally related to ethyleneoxynitazene and could therefore fall outside the proposed generic definition.

Therefore, the ACMD recommends the proposed generic definition be updated to address other structurally related compounds similar to ethyleneoxynitazene that might appear in the future.

The ACMD has also reviewed international approaches to nitazene generic controls as they became available. The ACMD is not aware of examples of compounds which would evade the proposed generic definition and would be captured by these international controls. However, on a precautionary basis, the ACMD has considered further updates to the proposed generic definition to align with these international approaches.

Recommendation 3 has therefore been updated with a revised generic definition, intended to cover compounds structurally similar to ethyleneoxynitazene.

Updated 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 and other nitazenes. 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) and the Misuse of Drugs (Designation) (England, Wales, and Scotland) Order 2015, Northern Ireland 2001.

The proposed wording for the generic for addition to the Misuse of Drugs Act is as follows (amended text indicated): 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:

1. 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.
2. ii) By substitution in the phenyl ring of the benzyl system to any extent by alkyl or haloalkyl containing up to six carbon atoms, alkoxy or haloalkoxy containing up to five carbon atoms, acetyloxy, hydroxy, cyano, halogen, thioalkyl containing up to five carbon atoms or alkylsulphonyl containing up to five carbon atoms.
3. iii) By substitution at the 5- or 6- positions of the benzimidazole system by nitro, acetyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy or halogen substituents.
4. iv) By substitution at the benzylic carbon by a methyl group
5. v) By replacement of the benzylic carbon by a nitrogen, oxygen or sulphur atom.
6. vi) By substitution in the phenyl ring of the benzyl system by an ethoxy group linked back to the phenyl ring to form a dihydrobenzofuran structure.

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 revised generic definition in the Misuse of Drugs Act 1971, following appropriate consultation.

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21 March 2024

UK Government response to the third addendum to the ACMD's report on 2-benzyl benzimidazole and piperidine benzimidazolone opioids

Dear Owen and Simon,

The government response to the ACMD’s third addendum to its report on the use and harms of 2-benzyl benzimidazole (‘nitazenes’) and piperidine benzimidazolone (‘brorphine-like’) opioids.

I am grateful to the Advisory Council on the Misuse of Drugs (ACMD), especially the Novel Psychoactive Substances Committee, for providing the third addendum to its advice on the use and harms of 2-benzyl benzimidazole (‘nitazenes’) and piperidine benzimidazolone (‘brorphine-like’) opioids.

In February 2023, I accepted recommendation 3 of the original report to consult relevant interested stakeholders on the introduction of a generic definition for nitazenes, following which legislation would be brought forward to control them under the Misuse of Drugs Act 1971, the Misuse of Drugs Regulations 2001 and the Misuse of Drugs (Designation) (England, Wales and Scotland) Order 2015.

This addendum included an update to recommendation 3, which is set out below:

Updated 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 and other nitazenes. 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) and the Misuse of Drugs (Designation) (England, Wales, and Scotland) Order 2015, Northern Ireland 2001.

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 [amended text indicated by square brackets]:

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 [or haloalykl] containing up to [six] carbon atoms, alkoxy [or haloalkoxy] containing up to [five] carbon atoms, acetyloxy, hydroxy, cyano, halogen, thioalkyl containing up to [five] carbon atoms or alkylsulphonyl containing up to [five] carbon atoms.

iii) By substitution at the 5- or 6- positions of the benzimidazole system by nitro, acetyl, cyano, methoxy, trifluoromethyl, [trifluoromethoxy] 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.

vi) [By substitution in the phenyl ring of the benzyl system by an ethoxy group linked back to the phenyl ring to form a dihydrobenzofuran structure].

These modifications are subject to a maximum molecular mass of any derived compound of 500 atomic mass units.

I formally accept this update to recommendation 3 and thank the ACMD for their continued vigilance in identifying new dangerous or otherwise harmful substances and providing advice accordingly. We are consulting key stakeholders as recommended.

As always, I remain extremely grateful for the expertise and timely reports provided by the ACMD to ensure that we continue to enact the appropriate control for dangerous or otherwise harmful substances.

Yours sincerely,

Rt Hon Chris Philp MP, Minister of State for Crime, Policing and Fire

___________________________________________

April 2024

Updated 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 and other nitazenes. 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) and the Misuse of Drugs (Designation) (England, Wales, and Scotland) Order 2015, Northern Ireland 2001. The proposed wording for the generic for addition to the Misuse of Drugs Act is as follows (amended text in bold):
Any compound (not being a compound for the time being specified in sub-paragraph (a) above), with a maximum molecular mass of 500 atomic mass units, 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 or haloalkyl containing up to six carbon atoms, alkoxy or haloalkoxy containing up to five carbon atoms, acetyloxy, hydroxy, cyano, halogen, thioalkyl containing up to five carbon atoms or alkylsulphonyl containing up to five carbon atoms.
iii) By substitution at the 5- or 6- positions of the benzimidazole system by nitro, acetyl, cyano, methoxy, trifluoromethyl, trifluoromethoxy 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.
vi) By substitution in the phenyl ring of the benzyl system by an ethoxy group linked back to the phenyl ring to form a dihydrobenzofuran structure.
vii) By replacement of the phenyl ring of the benzyl system by methylenedioxyphenyl.

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 revised generic definition in the Misuse of Drugs Act 1971, following appropriate consultation.