Brorphine—Investigation and quantitation of a new potent synthetic opioid in forensic toxicology casework using liquid chromatography‐mass spectrometry

Abstract

New synthetic opioids continue to appear as novel psychoactive substances (NPS) on illicit drug markets. Isotonitazene emerged in mid‐2019, becoming the most prevalent NPS opioid in the United States within a few months. Notification by the Drug Enforcement Administration of its intent to schedule isotonitazene in mid‐2020 led to its decline in popularity and replacement with a new NPS opioid: brorphine. Brorphine is a potent synthetic opioid, but little information was previously available regarding its toxicity or involvement in impairment and death. Our laboratory developed an assay for the identification and quantitative confirmation of brorphine using standard addition. Quantitative analysis was performed using liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). In vitro and in vivo metabolism studies were performed using pooled human liver microsomes and authentic biological specimens, respectively, with analysis by liquid chromatography quadrupole time‐of‐flight mass spectrometry (LC‐QTOF‐MS). Brorphine was confirmed in 20 authentic forensic cases, commonly found in combination with fentanyl (100%) and flualprazolam (80%). The average concentration of brorphine in blood was 2.5 ± 3.1 ng/mL (median: 1.1 ng/mL, range: 0.1–10 ng/mL). The average concentration of brorphine in urine was 4.6 ± 7.6 ng/mL (median: 1.6 ng/mL, range: 0.2–23 ng/mL). The majority of cases originated from Midwestern states. Metabolism was verified to included N‐dealkylation and hydroxylation. Detailed case histories and autopsy findings are presented herein. The prevalence of brorphine continues to increase in the United States. Forensic scientists should remain aware of the ongoing emergence of new opioids, especially those outside a standard scope of toxicology testing.

A Forward-Thinking Approach to Addressing the New Synthetic Opioid 2-Benzylbenzimidazole Nitazene Analogs by Liquid Chromatography–Tandem Quadrupole Mass Spectrometry (LC–QQQ-MS)

“…In the USA, isotonitazene was first reported in August 2019 but the drug was on the illicit drug market at least as early as April 2019 ( 9 ). By October 2020, isotonitazene was identified in more than 200 individual postmortem (PM) death investigation cases in the USA ( 11 ). NMS Labs (Horsham PA, USA) was receiving approximately 30–40 isotonitazene positive cases per month at the peak of its popularity (accounting for approximately 0.5% of all routine forensic toxicology casework screened via mass spectrometry per month) ( 11 , 12 ).…”

“…By October 2020, isotonitazene was identified in more than 200 individual postmortem (PM) death investigation cases in the USA ( 11 ). NMS Labs (Horsham PA, USA) was receiving approximately 30–40 isotonitazene positive cases per month at the peak of its popularity (accounting for approximately 0.5% of all routine forensic toxicology casework screened via mass spectrometry per month) ( 11 , 12 ). Isotonitazene was commonly found with novel psychoactive substance (NPS) benzodiazepines, such as flualprazolam and etizolam, a phenomenon that has become common for NSOs, including more recent nitazene analogs ( 11 ).…”

“…NMS Labs (Horsham PA, USA) was receiving approximately 30–40 isotonitazene positive cases per month at the peak of its popularity (accounting for approximately 0.5% of all routine forensic toxicology casework screened via mass spectrometry per month) ( 11 , 12 ). Isotonitazene was commonly found with novel psychoactive substance (NPS) benzodiazepines, such as flualprazolam and etizolam, a phenomenon that has become common for NSOs, including more recent nitazene analogs ( 11 ). In the USA, isotonitazene was reported in many states across the East and Midwest, including Illinois, Indiana, Ohio and Wisconsin ( 13 , 14 ).…”

Non-fentanyl-derived synthetic opioids emerging during recent years

“…Methylthionitazene 50 na na na na 15. Brorphine na 30.9 [ 67 ] Mentioned on drug fora that brorphine was circulated in 2019, USA [ 67 ] At least 100 [ 68 ] deaths in USA (0.1–10 ng/mL [ 68 ]) LC–MS/MS [ 68 ] LC–HRMS [ 67 ] For abbreviations, see the footnote of Table 1 a The EC 50 values were obtained from a single study [ 51 ]; the values can be compared with each other …”

“…However, the in vivo analgesic potency had not been investigated at this time. Brorphine is one of the most recent synthetic opioids, resulting in more than 100 deaths in a few months in USA [ 68 ]. Because of many deaths associated with brorphine, it has been designated as Schedule 1 in the USA, and also controlled in the UK [ 69 ] (Table 5 ).…”