VIENNA, Austria – 30 May 2025: Brorphine is a potent synthetic opioid first reported to the UNODC Early Warning Advisory on NPS in 2019.[1] Since then, it was increasingly detected in seized drug samples and toxicology casework across at least six different countries in Europe and North America.

After brorphine was internationally controlled in 2022[2], the number of countries reporting the substance decreased from four in 2021 to one in 2023 and 2024. However, since 2024, several brorphine analogues, including 5,6-Dichloro desmethylchlorphine (SR-17018), chlorphine, N-propionitrile chlorphine (Cychlorphine), orphine and R-6890 (Spirochlorphine) have been reported for the first time to UNODC EWA (Figure 1).


 
Figure 1: Brorphine and new emerging analogues reported to UNODC EWA over time.


All analogues have been reported in North America. However, the global spread is evident with N-propionitrile chlorphine and R-6890 (Spirochlorphine) having been reported in Europe and North America.[3],[4] Brorphine analogues have been found in powder, rock-like solid and plant material forms.

The brorphine analogues are structurally related compounds derived from a common core scaffold, usually a benzimidazolone (Figure 2).[5]

 
Figure 2: Brorphine Analogues.

Note: Please see footnote 5 for more information.


Brorphine generally acts as a full mu-opioid receptor agonist, with greater potency than morphine, and comparable or slightly lower potency than fentanyl. The substance has been identified in various drug sample forms: as powder, crystal, tablet or capsule form, including as falsified opioid medicines.[6] Moreover, brorphine has been associated with serious adverse effects, including deaths.[7] In 2023 and 2024, six post-mortem and two clinical admission cases involving brorphine were reported to the UNODC EWA Tox-Portal from North America. Polysubstance use was evident in all these cases, involving two or more other NPS.[8] With no known therapeutic use, brorphine poses a significant risk to public health and safety.[9]

Vandeputte et al. have explored the pharmaco-toxicological, opioid-like effect profile of four brorphine analogues (orphine, fluorphine, chlorphine and iodorphine). In vitro characterization indicated that chlorphine, brorphine and iodorphine were generally the most active mu-opioid receptor agonists. In mouse experiments, chlorphine and brorphine induced the highest levels of antinociception; different analogues produced pronounced respiratory depressant effects, with observed differences in sensitivity to naloxone. Based on these findings, the authors concluded that brorphine analogues are opioid agonists with the potential to cause substantial harm, including respiratory depression.[10] More research is needed to further elucidate the effect profile and overdose management of brorphine analogues in humans.

Response options:

- The emergence of brorphine analogues as alternate synthetic opioids calls for awareness raising among law enforcement, health care providers and regulators

- Forensic drug testing and toxicology laboratories may need to further develop and validate analytical methods and consider routine screening processes to effectively identify new synthetic opioids such as brorphine analogues. Analytical data is shared where available in UNODC NPS monographs. Fentanyl and nitazene test strips are not expected to identify brorphine analogues.[11]

- Awareness and access to lifesaving treatments such as naloxone (an opioid antagonist which rapidly and safely reverses the effects of opioids, for further information, please see the  S-O-S initiative, developed by UNODC in collaboration with WHO). However, immediate medical care is critical as naloxone may not be fully effective or may require repeated dosing for some brorphine analogues.[12]

- Comprehensive drug dependence treatment and care programmes are important components of overdose prevention.

- Ongoing monitoring for brorphine and its analogues is crucial and early warning systems need to be established/strengthened to rapidly identify and respond to these emerging drug threats.[13]

 


***This Early Warning Advisory message was produced in collaboration with Marthe M. Vandeputte and Christophe P. Stove from the Laboratory of Toxicology, Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University.

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[1] United Nations Office on Drugs and Crime (UNODC), “August 2020 - UNODC EWA: Brorphine, a newly emerging synthetic opioid detected in post-mortem cases”, news clip, August 2020.[2] United Nations Office on Drugs and Crime (UNODC), “June 2022 – UNODC: CND decision on international control of brorphine and metonitazene enters into force - remaining decisions will enter into force in November 2022”, news clip, June 2022.

[3] United Nations, UNODC Early Warning Advisory on New Psychoactive Substances (EWA) and Tox-Portal, Database (accessed on 6 May 2025).

[4] Ebd. and Joanna de Morais, “Nitazenes – an update from the European Union Drugs Agency (EUDA) EU Early Warning System (EWS)” presented at the webinar “Nitazenes in Europe? – How should we prepare?”, 9 May 2025.

[5] The simplest structure of this group is orphine, which consists of a benzimidazolone core connected to a phenylethylpiperidine group. Chlorphine is very similar to the orphine structure, differing only by the presence of a chlorine atom on its phenyl ring. Brorphine is structurally related to chlorphine with the distinction being the replacement of chlorine with a bromine. Another substance, 5,6-Dichloro desmethylchlorphine lacks a methyl group on the side chain, resulting in a phenylmethyl piperidine. It also has two chlorines linked to the benzimidazole ring. N-propionitrile chlorphine extends the chlorphine structure by adding a propionitrile group to the benzimidazole nitrogen. R-6890 presents the most different structure. It replaces the benzimidazole ring with a spirocyclic system while retaining the 4-chlorophenylethyl group.

[6] World Health Organization, 44th WHO ECDD Summary assessments, findings and recommendations, 11-15 October 2021, Available at: 44 ECDD_UNSG_Annex1_15112021$2021-11-16-18-45-27~.docx (accessed on 13 May 2025).

[7] For further information, please see: United Kingdom, Advisory Council on the Misuse of Drugs, “ACMD advice on 2-benzyl benzimidazole and piperidine benzimidazolone opioids”, Research and analysis, 29 January 2025 and CFSRE and Vandeputte and others, “Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization”, Neuropharmacology, vol. 260 (December 2024).

[8] United Nations, UNODC Early Warning Advisory on New Psychoactive Substances (EWA) and Tox-Portal, Database (accessed on 6 May 2025).

[9] See footnote 6.

[10] For more information, please see: Vandeputteand others, “Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization”, Neuropharmacology, vol. 260 (December 2024).

[11] Studies have shown that brorphine does not cross-react with fentanyl test strips (e.g., Norman and others, “Evaluation of fentanyl immunoassay test strips for rapid in-situ detection of fentanyl and fentanyl analogs in seized samples and alternative matrices”, International Journal of Drug Policy, vol. 118, (August 2023); Hayes and others, “Assessment of two brands of fentanyl test strips with 251 synthetic opioids reveals “blind spots” in detection capabilities”, Harm Reduction Journal, vol. 20 (December 2023)) and nitazene test strips (De Vrieze and others, “Nitazene test strips: a laboratory evaluation”, Harm Reduction Journal, vol. 21 (August 2024)).

[12] For further information, please see: Vandeputte and others, “Elucidating the harm potential of brorphine analogues as new synthetic opioids: Synthesis, in vitro, and in vivo characterization”, Neuropharmacology, vol. 260 (December 2024).

[13] For further information, please see: UNODC, The role of drug analysis laboratories in Early Warning Systems (June 2020).