Brorphine and its Analogues in the Unregulated Drug Supply

"Originally synthesized in 2018 as a potential G protein–biased MOR [Mu-Opioid Receptor] agonist with reduced respiratory depression compared with conventional opioids,^1,7 brorphine was identified on the illicit drug market in 2019, often mixed with fentanyl or benzodiazepines such as flualprazolam and sold as counterfeit prescription tablets.^8,9 In early 2020, brorphine officially entered the European Union's drug market, with its presence reported in four countries: Belgium, Germany, Slovenia, and Sweden.^9,10

"Between June and July 2020, 20 deaths involving confirmed brorphine exposure were reported in the United States.¹¹ Due to its dangerous and alarming effects, the Drug Enforcement Administration (DEA) temporarily classified brorphine as a Schedule I substance under the Controlled Substances Act in December 2020, with the decision becoming permanent in March 2021.¹² After its international control in 2022, its prevalence declined; however, since 2024, several new halogenated (chlorphine, fluorphine, and iodorphine) and structurally related analogues such as 5,6-dichloro desmethylchlorphine (SR-17018), N-propionitrile chlorphine (cychlorphine), orphine, and R-6890 (spirochlorphine) have been reported to the United Nations Office on Drugs and Crime Early Warning Advisory.¹³ In Europe, since mid-2024, there has been a small but significant increase in detections of substances belonging to the 'orphine' family, with five countries reporting cychlorphine and two detecting spirochlorphine.¹⁴ These emerging 'brorphine-type' opioids illustrate the adaptability of clandestine laboratories in producing nonfentanyl MOR agonists that can circumvent current scheduling regulations.¹⁵"