Case Report: Mislabeling of an online “alprazolam triazolobenzophenone” pill leads to severe intoxication with the novel synthetic opioid cychlorphine

Background Mislabeling of illicit drug products poses a serious risk to public health, especially in the rapidly evolving market for new psychoactive substances (NPS). Products sold as benzodiazepines may contain undisclosed novel synthetic opioids (NSOs), exposing opioid-naïve users to life-threatening respiratory depression. Case Report A 34-year-old man ingested a pink tablet purchased online and labeled as “alprazolam triazolobenzophenone”, a ring-opened alprazolam prodrug, also known as “alprazafone”. Approximately 45 min after ingestion, he developed snoring and gasping respiration, hypoxemia and deep coma (Glasgow Coma Scale 3). Prehospital bag-valve ventilation and subsequent intubation resulted in prompt stabilization. The patient could be extubated 6 hours later. Contrary to the labeling, neither alprazolam nor its prodrug was detected in the tablet, blood or urine. Instead, the tablet contained approximately 1 mg of N -propionitrile chlorphine (cychlorphine), a piperidine benzimidazolone opioid of the emerging “orphine” class. Routine immunoassay screening for opioids and benzodiazepines was negative; identification required targeted LC-MS/MS. Six hours after ingestion, cychlorphine concentrations were 0.46 ng/mL in blood and 5.0 ng/mL in urine-to our knowledge the first human concentrations reported for this substance. In vitro , cychlorphine activated the µ-opioid receptor with an EC 50 of 2.7 nM, i.e. 4.5-fold more potent than fentanyl (EC 50 = 12.2 nM) within the same assay, with a binding affinity of K i = 1.09 nM (fentanyl: K i = 1.91 nM). The nitazene protonitazepyne was additionally detected in urine but not in blood or serum, indicating earlier intake and terminal elimination at the time of the event. Conclusion This case documents cychlorphine as a highly potent NSO capable of causing life-threatening respiratory depression at sub-nanogram-per-millilitre blood concentrations, and illustrates the specific danger of benzodiazepine products adulterated with opioids. No pharmacokinetic data are available for cychlorphine. The concentration, measured 6 hours post-intake, therefore likely underestimates peak exposure. Clinicians should consider NSO exposure in unexplained respiratory depression after NPS use, even where a benzodiazepine was expected. Accessible drug-checking services, take-home naloxone and NSO-capable confirmatory analysis are needed.