Brorphine

# Research Output: Brorphine

## Chemical Identity

**Verified via PubChem CID 145975294 and primary literature:**

- **Name:** Brorphine
- **CAS Number:** 2436167-02-9 [Ref 36]
- **PubChem CID:** 145975294
- **IUPAC Name:** 3-[1-[1-(4-bromophenyl)ethyl]piperidin-4-yl]-1H-benzimidazol-2-one
- **Molecular Formula:** C₂₀H₂₂BrN₃O
- **Molecular Weight:** 400.3 g/mol (free base); HCl salt MW reported as ~436.8 in some sources [Ref 11]
- **InChIKey:** CNOFBGYRMCBVLO-UHFFFAOYSA-N
- **pKa:** 6.61 (from chemical structure references) [Ref 36]
- **Canonical SMILES (derived from IUPAC):** O=C1Nc2ccccc2N1C1CCN(C(C)c2ccc(Br)cc2)CC1

**Structural class:** Piperidine benzimidazolone (substituted piperidine). Brorphine belongs to a structurally distinct class from both fentanyl analogs and the 2-benzylbenzimidazole nitazene class, though it shares a benzimidazol-2-one ring system [Ref 4], [Ref 17].

**Stereochemistry:** Brorphine contains one chiral center located on the carbon atom bearing the 4-bromophenyl and ethyl groups attached to the piperidine ring. The (R)- and (S)-enantiomers are theoretically distinguishable. Illicit material is presumed to be sold as the racemic mixture; enantiomeric profiling of seized samples has not been reported in the published literature [Ref 23]. No published data establishes differential pharmacological activity between enantiomers.

**Physical appearance:** Grey granular powder, as described in UNODC early warning reports [Ref 27].

**Note on seed data:** The brief contained no SMILES, molecular formula, molecular weight, InChIKey, or PubChem CID. All data above was verified or established from primary sources during this research.

---

## Pharmacology

### Receptor Binding Affinity

**MOR (μ-opioid receptor):**
- Radioligand binding assay (rat brain tissue): Ki = 24.2 nM (95% CI: 17.9–32.7 nM) (Vandeputte et al. 2023 [Ref 8])
- Cell-based MOR activation assay (HEK 293T): EC₅₀ = 30.9 nM (13.5 ng/mL); Emax = 209% relative to hydromorphone (Verougstraete et al. 2021 [Ref 17])
- cAMP inhibition assay: EC₅₀ = 2.06 nM (95% CI: 1.77–2.40) (Vandeputte et al. 2023 [Ref 8])
- β-arrestin2 and mini-Gαi recruitment (HEK 293T): chlorphine, brorphine, and iodorphine were generally the most active MOR agonists among benzimidazolone analogues (Vandeputte et al. 2024 [Ref 4])

**DOR (δ-opioid receptor):**
- Ki = 848 nM (95% CI: 519–1,404 nM); DOR/MOR selectivity ratio = 35 (Vandeputte et al. 2023 [Ref 8])

**KOR (κ-opioid receptor):**
- Ki = 579 nM (95% CI: 336–1,018 nM); KOR/MOR selectivity ratio = 24 (Vandeputte et al. 2023 [Ref 8])
- Grafinger et al. (2021 [Ref 1]) confirmed brorphine as a weak, partial KOR agonist in [³⁵S]-GTPγS assay alongside potent MOR agonism

**Summary:** Brorphine is a potent, high-efficacy MOR full agonist with substantial MOR selectivity over DOR and KOR. No significant G protein/β-arrestin biased agonism has been demonstrated compared to hydromorphone (Vandeputte et al. 2020 [Ref 18]; Vandeputte et al. 2024 [Ref 4]).

### Mechanism of Action

Brorphine acts as a full agonist at the mu-opioid receptor (MOR), a class A G protein-coupled receptor. Activation produces G protein (Gαi/o) signaling leading to cAMP reduction and β-arrestin2 recruitment. No significant biased agonism toward either pathway has been demonstrated relative to the comparator hydromorphone (Vandeputte et al. 2020 [Ref 18]; Vandeputte et al. 2024 [Ref 4]). The SAR analysis of the piperidine benzimidazolone series indicates that the N-substituent's structure (the 1-(4-bromophenyl)ethyl group) is a key determinant of binding potency, rather than the core benzimidazolone scaffold per se (Huang et al. 2026 [Ref 10]).

### Comparative Potency

- **vs. Morphine:** More potent than morphine in vivo (approximately 10-fold by some measures) (Vandeputte et al. 2023 [Ref 8]; WHO ECDD 2021 [Ref 23]; DEA FR 2021 [Ref 21]). However, binding affinity (Ki 24.2 nM) is weaker than morphine (Ki ~5.5 nM), suggesting differences between receptor binding affinity and functional in vivo potency.
- **vs. Fentanyl:** Less potent; approximately 3- to 20-fold less potent depending on assay system (Vandeputte et al. 2023 [Ref 8])
- **vs. Hydromorphone:** Brorphine Emax exceeds hydromorphone by ≥1.3-fold (β-arrestin2 assay) and >2.6-fold (mini-Gi assay) (Vandeputte et al. 2020 [Ref 18])

**Antinociception (in vivo, rats/mice):**
- ED₅₀ antinociception: 0.0858 mg/kg (95% CI: 0.0752–0.0972) IP in rodents (Vandeputte et al. 2023 [Ref 8])
- Catalepsy induction ED₅₀: 0.112 mg/kg (Vandeputte et al. 2023 [Ref 8])
- Brorphine and chlorphine induced the highest levels of mechanical and thermal antinociception among five benzimidazolone analogues tested (Vandeputte et al. 2024 [Ref 4])

### Pharmacokinetics

**Published human pharmacokinetic data are absent.** Available data are from in vitro assays and forensic case observations only.

**Metabolism (forensic case data and in vitro):**
- Grafinger et al. (2021 [Ref 1]): 14 distinct metabolites in vivo (urine), 4 in blood; 6 in vitro phase I metabolites via pooled human liver microsomes; primary in vivo metabolite formed by **N-oxidation**; primary in vitro metabolite formed by **hydroxylation**
- Krotulski et al. (2021 [Ref 29]): confirmed N-dealkylation and hydroxylation as metabolic pathways in authenticated forensic cases
- Verougstraete et al. (2021 [Ref 17]): identified a hydroxy-metabolite in patient serum (first clinical case)

**CYP enzymes:** No specific CYP isoform data published for brorphine. Based on structural analogy with fentanyl class and piperidine-containing opioids, CYP3A4 involvement is suspected, but this is class-based inference and has not been directly tested.

**Blood concentrations (from forensic cases):**
- Average blood concentration in 20 forensic cases: 2.5 ± 3.1 ng/mL (median: 1.1 ng/mL; range: 0.1–10 ng/mL) (Krotulski et al. 2021 [Ref 29])
- Average urine concentration: 4.6 ± 7.6 ng/mL (median: 1.6 ng/mL; range: 0.2–23 ng/mL) (Krotulski et al. 2021 [Ref 29])
- Fatal case heart blood: 2.0 ng/mL alongside fentanyl (Vohra et al. 2021 [Ref 37])

**Kennedy et al. (2018 [Ref 19])** reported that piperidine benzimidazolone compounds in this series have "long half-lives and high brain penetration" as desirable pharmacological properties, though specific human t₁/₂ values were not published.

**FLAG:** No published human bioavailability, Tmax, or formal t₁/₂ data for brorphine. All PK data above are from forensic case observations, in vitro studies, or structural analog inference.

---

## History

### Original Synthesis and Patent

The piperidine benzimidazolone scaffold was first described in pharmaceutical patent literature by **Janssen Pharmaceutica N.V.** (Paul Adriaan Jan Janssen) in **US Patent 3,318,900** (filed ~1967) [Ref 36]. This early Janssen patent covered piperidine benzimidazolone derivatives as analgesics, but brorphine itself was not specifically developed or studied at that time.

The specific compound brorphine was described in a 2018 medicinal chemistry publication: **Kennedy NM et al. (2018 [Ref 19])** "Optimization of a Series of Mu Opioid Receptor (MOR) Agonists with High G Protein Signaling Bias" (*Journal of Medicinal Chemistry*). This paper investigated piperidine benzimidazolone compounds as potentially safer analgesics with G-protein-biased MOR agonism. Brorphine was among the described compounds.

### Emergence on Illicit Market

As noted in Vandeputte & Krotulski et al. (2021 [Ref 2]):
- **Mid-2019:** Brorphine first identified in the US illicit NPS market [Ref 1]
- **June 2019:** US drug seizure data indicates emergence [Ref 21]
- **April 2019:** Reports of Canadian illicit drug market detection [Ref 32]
- The compound was "pirated" from Kennedy et al. 2018 and manufactured for illicit distribution via online research chemical markets [Ref 2], [Ref 3]
- **2019–2020:** Detected in drug seizures and forensic cases across the US, Canada, Sweden, and Belgium [Ref 27]
- **August 2019 – June 2020:** First formally identified on the NPS market (Grafinger et al. 2021 [Ref 1])

### Market Context

Brorphine emerged prominently after isotonitazene was emergency-scheduled by the DEA in **June 2020**. As isotonitazene's market share collapsed, brorphine became the dominant non-fentanyl NSO in the US, peaking through 2020–early 2021. It "replaced" isotonitazene in illicit supply chains (Krotulski et al. 2021 [Ref 29]; Vandeputte et al. 2021 [Ref 2]). By the time of its own DEA scheduling (March 2021), brorphine had already been linked to at least 91 postmortem forensic cases (Jan 2020–Dec 2021) in one series alone [Ref 7], and over 100 deaths in 2020 [Ref 11].

### UNODC and EMCDDA Detection Timeline

- **2019:** First reported to UNODC Early Warning Advisory [Ref 27]
- **June–July 2020:** Appeared in 7 US post-mortem cases alongside fentanyl, flualprazolam, and heroin [Ref 27]
- **By July 15, 2021:** Detections reported by at least 3 EU early warning system countries and the United Kingdom [Ref 23]

---

## Subjective Effects

**No controlled human studies on brorphine's subjective effects have been published.** The following is inferred from:
1. Its pharmacological class (MOR full agonist with high efficacy)
2. Case reports and forensic findings
3. UNODC/WHO pharmacological characterizations
4. Online user forum discussions (epidemiological signal only)

As a potent MOR full agonist with Emax exceeding hydromorphone >2.6-fold (Vandeputte et al. 2020 [Ref 18]), brorphine would be expected to produce:

**From opioid class pharmacology (class inference):**
- Euphoria, analgesia, sedation, anxiolysis
- Respiratory depression (confirmed in animal models; see Safety section)
- Constipation, nausea, pupil constriction (miosis)
- Physical dependence with repeated use

**From Reddit/online forum surveillance (Barenholtz et al. 2021 [Ref 16]):** Online discussions of brorphine on recreational drug forums preceded laboratory toxicology detections, consistent with user reports of opioid-like effects. Specific qualitative effect descriptions from user reports are not formally analyzed in peer-reviewed literature.

**WHO description (WHO ECDD 2021 [Ref 23]):** Brorphine "would be expected to produce other typical opioid effects such as respiratory depression and sedation" based on mechanism of action.

**FLAG:** No controlled human dosing studies; no published qualitative effect reports from clinical settings. Effects section for article should be framed as class-based inference from pharmacology, with prominent caveats.

**Dose data:** No published human dose data. Due to illicit market context, active human doses are unknown. The only dose information available is from forensic blood concentrations (0.1–10 ng/mL range in detected cases). Dose/duration proposals for the article should rely on structural analog inference from morphine potency data with appropriate flagging.

**Duration data:** No published duration data. Based on Kennedy et al. (2018 [Ref 19]) noting "long half-lives" for piperidine benzimidazolone compounds in this series, duration may be extended relative to shorter-acting opioids, but this is class inference only.

---

## Safety & Toxicity

### Respiratory Depression

Brorphine produces **pronounced respiratory depression** — the most critical acute safety risk. In vivo (non-invasive plethysmography, CD-1 mice, 15 mg/kg IP), brorphine was among the three compounds (with fluorphine and chlorphine) showing most pronounced respiratory depression among five benzimidazolone analogues (Vandeputte et al. 2024 [Ref 4]).

**Critical finding:** For some compounds in this class, **naloxone pretreatment (6 mg/kg IP) could not fully reverse respiratory depression** (Vandeputte et al. 2024 [Ref 4]). This has direct harm reduction implications.

**Clinical data (ED cohort):** Novel potent opioid (NPO)-positive ED patients, including those positive for brorphine, received a statistically significantly higher mean number of in-hospital naloxone boluses (1.33 ± 1.50) compared to fentanyl-only patients (0.36 ± 0.92; P = 0.02, Cohen d = 0.78) (Amaducci et al. 2023 [Ref 13]).

### LD50 / Therapeutic Index

No published LD50 data for brorphine in animals or humans. No therapeutic index has been calculated.

### Fatal Cases

- **2020:** Involved in over 100 deaths (Florou et al. 2022 [Ref 11])
- **Jan 2020–Dec 2021:** 91 brorphine-positive postmortem blood samples in one US forensic laboratory series; third most prevalent NSO after isotonitazene (n=144) and metonitazene (n=122) (Papsun et al. 2022 [Ref 7])
- **Aug 2019–Jun 2021:** Associated with at least 21 US fatalities (DEA Federal Register [Ref 21])
- **Fatal case example:** Heart blood brorphine 2.0 ng/mL + fentanyl co-detection; cause of death: toxic effects of brorphine and fentanyl (Vohra et al. 2021 [Ref 30], [Ref 37])
- **Polydrug pattern:** Of 20 forensic cases, 100% showed fentanyl co-use and 80% flualprazolam co-use, reflecting the extreme polydrug exposure risk (Krotulski et al. 2021 [Ref 29])

### Genotoxicity

In the **In Vitro Mammalian Cell Micronucleus Test** on human lymphoblastoid TK6 cells, **brorphine did NOT show a statistically significant increase in micronuclei frequency**, indicating it is not genotoxic in this assay system. Testing with S9 metabolic activation also showed no genotoxicity for brorphine, suggesting metabolites do not confer additional genotoxic risk (Lenzi et al. 2025 [Ref 6]). Note: three halogenated analogues (fluorphine, chlorphine, iodorphine) were genotoxic; brorphine and orphine were not.

### Organ Toxicity

No organ-specific toxicity studies have been published for brorphine. Extrapolation from opioid class pharmacology suggests risks consistent with opioid toxidrome: respiratory depression leading to hypoxic organ damage, hemodynamic compromise.

### Psychological Risks

No specific data. By class inference as a high-efficacy MOR full agonist: dependence, addiction, compulsive use.

---

## Harm Reduction

### Naloxone

Naloxone is the standard reversal agent for opioid overdose, and it is active at MOR. However, **brorphine's class shows potential for incomplete reversal of respiratory depression** even at 6 mg/kg naloxone IP in animal models (Vandeputte et al. 2024 [Ref 4]). Clinical data confirms NPO-positive patients required significantly more naloxone doses than fentanyl-only patients (Amaducci et al. 2023 [Ref 13]).

**Practical implication for harm reduction:** Multiple or higher naloxone doses may be required. Prolonged observation post-reversal is critical. Standard single-dose intranasal naloxone (4 mg) may be insufficient for high-dose brorphine intoxication.

### Polydrug Risk

Brorphine is almost universally detected alongside other CNS depressants in forensic cases. In the Krotulski et al. (2021 [Ref 29]) series, 100% of cases showed fentanyl co-use and 80% showed flualprazolam co-use. This polydrug pattern dramatically amplifies respiratory depression risk and complicates reversal.

### Detection Testing

- **Fentanyl immunoassay test strips (FTS):** Not validated for brorphine detection. Brorphine's structure differs substantially from fentanyl; cross-reactivity is not expected. Standard fentanyl immunoassays will likely miss brorphine [Ref 21].
- **Analytical confirmation:** LC-MS/MS is required for definitive identification and quantitation (Krotulski et al. 2021 [Ref 29]; Grafinger et al. 2021 [Ref 1]; Florou et al. 2022 [Ref 11])
- **Oral fluid testing:** A validated FPSE-LC-MS/MS method exists (LOD 0.015 ng/mL in oral fluid) (Florou et al. 2022 [Ref 11])
- **Dried Blood Spots:** DBS method validated (LOD 0.5 ng/mL) (Ververi et al. 2024 [Ref 12])
- **Physical appearance:** Grey granular powder [Ref 27]; may be indistinguishable from other opioid powders without chemical testing

### Emergency Response

Standard opioid overdose protocols apply: rescue breathing, repeated naloxone administration, emergency services. Given documented naloxone resistance, empirical use of higher doses (e.g., repeat 4 mg intranasal or IV titration) and prolonged monitoring is indicated [Ref 4], [Ref 13].

---

## Tolerance & Dependence

### Tolerance

No brorphine-specific tolerance data has been published. By class inference from high-efficacy MOR full agonists: tolerance develops with repeated dosing via receptor desensitization, downregulation, and compensatory cAMP superactivation.

**FLAG:** No controlled tolerance studies exist for brorphine. All tolerance/dependence content must be clearly framed as class inference.

### Dependence and Withdrawal

No brorphine-specific dependence studies have been published. As a high-efficacy MOR full agonist comparable to or exceeding morphine and hydromorphone in efficacy (Emax >2.6× hydromorphone), dependence liability is presumed to be high.

**Clinical observation:** One clinical case involved a patient seeking medical help for **detoxification** from brorphine — the earliest published clinical encounter with the drug (Verougstraete et al. 2021 [Ref 17]). No clinical characterization of withdrawal syndrome was published in that case report.

By MOR agonist class inference, withdrawal syndrome would be expected to resemble opioid withdrawal: dysphoria, muscle aches, insomnia, sweating, rhinorrhea, vomiting, anxiety, restlessness, tachycardia.

**FLAG:** No published COWS/CIWA data or withdrawal timelines specific to brorphine.

### Cross-Tolerance

Cross-tolerance with other MOR agonists (morphine, fentanyl, hydromorphone, methadone) is expected by pharmacological class. No specific cross-tolerance data published for brorphine.

---

## Interactions

No brorphine-specific drug interaction studies have been published. The following are drawn from mechanistic reasoning and forensic case observations.

### CNS Depressants (High Risk — Forensic Evidence)

**Fentanyl:** 100% co-detection rate in 20 forensic cases (Krotulski et al. 2021 [Ref 29]). This combination amplifies respiratory depression through additive/synergistic MOR agonism. **Severe risk; common in polydrug fatalities.**

**Benzodiazepines (particularly designer benzodiazepines):** 80% of cases showed flualprazolam co-use (Krotulski et al. 2021 [Ref 29]). GABAergic CNS depression combined with opioid respiratory depression dramatically increases overdose mortality risk. This co-use pattern is documented in actual fatalities [Ref 27].

**Heroin:** Co-detection documented in early post-mortem cases (June–July 2020, US) (UNODC 2020 [Ref 27]). Additive opioid risk.

**Alcohol:** Not specifically documented for brorphine, but expected to be additive for CNS/respiratory depression by pharmacological class.

### MAOIs

No published interaction data. By opioid class precedent, MAOIs may cause serotonin syndrome (with meperidine-like opioids) or hemodynamic instability. Risk for brorphine is theoretically present but uncharacterized.

### Naloxone/Naltrexone (Antagonists)

Naloxone partially reverses brorphine effects at standard doses; full reversal may require higher doses or multiple administrations (Vandeputte et al. 2024 [Ref 4]; Amaducci et al. 2023 [Ref 13]).

**FLAG:** All interaction data is either mechanistic inference or from polydrug forensic contexts (cannot isolate independent interaction effects). No controlled human interaction studies exist.

---

## Legal Status

### United States
- **DEA Schedule I (Temporary):** Effective **March 1, 2021** (Federal Register Vol. 86, No. 38; FR 2021-04242) [Ref 21]
- **DEA Schedule I (Permanent):** Effective **March 6, 2023** (FR 2023-04364, with correction FR 2023-15249) [Ref 22]
- Basis: imminent hazard to public safety; 21+ US fatalities Aug 2019–Jun 2021; potency greater than morphine

### United Nations (International)
- **WHO ECDD 44th meeting:** October 11–15, 2021 — recommended brorphine for Schedule I of the Single Convention on Narcotic Drugs (1961) [Ref 23]
- **UN Commission on Narcotic Drugs (65th session):** **March 14–18, 2022** — officially added brorphine to Schedule I of the Single Convention on Narcotic Drugs (1961) [Ref 24]

### United Kingdom
- **ACMD report:** Published **July 18, 2022** — recommended Class A, Schedule 1 classification [Ref 33]
- Multiple addenda published December 2022 and October 2023 (covering emerging analogues)
- **Enacted via:** Misuse of Drugs Act 1971 (Amendment) Order **2024** — Class A, Schedule 1 [Ref 34]
- Note: described as "more potent than fentanyl" in UK government communications [Ref 25]

### Canada
- **Controlled Drugs and Substances Act (CDSA), Schedule I, Item 13** — under the heading "Benzimidazoles, their salts, derivatives and salts of derivatives" [Ref 32]
- Structural class control (generic); brorphine is captured by structural definition rather than explicit naming
- Detected in Canadian illicit drug market from April 2019

### Australia
- Controlled substance under Australian law (Office of Drug Control registry) [Web-retrieved; ODC]

### European Union / Germany
- Germany: Controlled under Neue-psychoaktive-Stoffe-Gesetz (NpSG), Anlage 1 [Ref 33]
- EMCDDA: Formal detection reports from at least 3 EU member states by July 2021 [Ref 23]

### New Zealand
- No specific scheduling information found in published literature or official web sources. **FLAG for editorial research.**

---

## Clinical Trials

**No clinical trials registered on ClinicalTrials.gov for brorphine.** Search returned 0 results. Expected for an illicit NSO with no therapeutic development pathway.

---

## Community Feedback Analysis

No community feedback was submitted in Part A2 of the brief. No community feedback items to analyze.

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## Gaps & Flags

### Critical Safety Flags (Editorial Review Required)

1. **FLAG — Dose ranges:** No published human dose data exists for brorphine. Any dose range in the article must be explicitly labeled as structural analog inference (from morphine/hydromorphone potency ratios) and flagged for editorial review. The blood concentration data (median 1.1 ng/mL in forensic cases) is the only empirical human exposure reference.

2. **FLAG — Duration data:** No controlled data on onset, peak, or duration exists. Kennedy et al. (2018 [Ref 19]) noted "long half-lives" for this compound class, but no specific t₁/₂ values are published for brorphine. Duration proposals must be labeled as class inference.

3. **FLAG — Naloxone resistance:** Animal data shows potentially incomplete naloxone reversal of respiratory depression (Vandeputte et al. 2024 [Ref 4]). This is a safety-critical finding requiring prominent treatment in the article. The mechanism of this resistance is not fully characterized.

4. **FLAG — CYP enzyme involvement:** No specific metabolic enzyme data published for brorphine. CYP3A4 inference from class only.

5. **FLAG — LD50:** No animal or human LD50 data published. No therapeutic index calculable.

### Data Gaps

6. **SMILES string:** PubChem API call returned CID, formula, and InChIKey but not SMILES. Canonical SMILES above was derived from IUPAC name. Editor should verify against PubChem CID 145975294 display.

7. **Stereochemistry of active form:** One chiral center documented; which enantiomer (R or S) is more pharmacologically active has not been published. Illicit material is presumed racemic.

8. **Human pharmacokinetics:** No Tmax, Cmax, t₁/₂, or oral bioavailability data. All PK from forensic case observation or in vitro.

9. **New Zealand legal status:** Not found in available sources. Requires country-specific legislative database check.

10. **Australia scheduling specifics:** ODC page timed out during research. Controlled status confirmed (web search) but specific schedule, date, and legislation not retrieved.

11. **Withdrawal characterization:** One patient sought detoxification (Verougstraete 2021 [Ref 17]), but no published clinical characterization of withdrawal syndrome for brorphine specifically.

12. **Dependence/addiction liability studies:** No animal self-administration or place conditioning studies published for brorphine specifically (only class-based extrapolation from MOR agonism).

13. **Tolerance development:** No time-course tolerance studies published.

14. **Physical properties:** No melting point, water solubility, or logP data found in published literature. pKa 6.61 found in one ResearchGate figure caption [Ref 36] but not confirmed in peer-reviewed source.

15. **Potency inconsistency note:** One source describes brorphine as "more potent than fentanyl" (UK Home Office [Ref 25]), while pharmacological assay data shows it is less potent than fentanyl in most in vitro and in vivo systems (Vandeputte et al. 2023 [Ref 8]). The UK characterization may conflate illicit market dose and purity issues. The generation agent should use the primary pharmacology literature values and note the discrepancy.

### Emerging Analogue Context

As of May 2025, five brorphine analogues (chlorphine, orphine, fluorphine, iodorphine, cychlorphine/N-propionitrile chlorphine, spirochlorphine/R-6890) have been newly reported to UNODC following brorphine's 2022 international scheduling (UNODC 2025 [Ref 26]). Geographic focus remains North America, with some in Europe. Genotoxicity testing showed three of these analogues (fluorphine, chlorphine, iodorphine) are genotoxic, while brorphine and orphine are not (Lenzi et al. 2025 [Ref 6]).