Non-fatal intoxications involving the novel benzodiazepine clonazolam: case series from the Emerging Drugs Network of Australia – Victoria project

Abstract

Introduction

Clonazolam is an unregistered novel benzodiazepine which emerged in global illicit drug markets in 2014. We describe the clinical features of four cases of non-fatal clonazolam mono-intoxications from patients presenting to emergency departments in Australia.

Cases

Four patients aged between 16 and 19 years presented to hospital with a sedative toxidrome (Glasgow Coma Scale range 8–13) and elevated heart rate (median heart rate 100 beats per minute, range 92–105) following reported benzodiazepine exposure. Three patients reported the use of a large quantity (7–20 tablets) of Xanax^®, a brand of alprazolam not commercially available in Australia. Two patients required nasopharyngeal airway insertion following the development of airway obstruction. The median time to return of a normal conscious state (Glasgow Coma Scale 15) was 23 h (range 5–30 h). Clonazolam (range 0.2–2.1 µg/L) and its main metabolite 8-aminoclonazolam (range 5.9–19.1 µg/L) were the only substances detected by liquid chromatography-tandem mass spectrometry in blood samples of all patients.

Conclusion

Clonazolam intoxication resulted in sedation with mild sinus tachycardia. Three patients who reported multiple tablet exposures experienced prolonged sedation, and two of these patients developed airway obstruction. In this series, clonazolam was unknowingly ingested through possible illicit substitution within an unregulated counterfeit benzodiazepine product.

Keywords:

• NPS
• new psychoactive substance
• novel benzodiazepine
• clonazolam
• early warning system
• toxicosurveillance

Introduction

Clonazolam (6-(2-Chlorophenyl)-1-methyl-8-nitro-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine) is a triazolo-substituted 1,4-benzodiazepine derived from clonazepam [1]. Clonazolam was first characterised in 1971 [1] but has never been registered for pharmaceutical use. In 2014 clonazolam re-emerged in illicit drug markets, with notification to the European Union Early Warning System in 2015 following the detection in a Swedish drug seizure [2]. Clonazolam continues to be detected within global illicit drug seizures, with a parallel increase in clonazolam-related enquires to poisons information centres [3,4]. Currently, there is only one non-fatal clonazolam mono-intoxication with analytical confirmation described in the literature [5]. More recently, a fatality attributed to clonazolam has also been described but does not detail the clinical toxidrome proximate to death [6].

The Emerging Drugs Network of Australia – Victoria project, is a multi-institutional study providing intelligence on emergency department presentations involving illicit drug intoxications in the state of Victoria, Australia [7]. This project has Human Research Ethics Committee approval for the collection and storage of de-identified clinical and analytical data in a secure online registry (HREC/66506/Austin-2020). A waiver of consent for data collection was granted by the Human Research Ethics Committee and hence approval for publication of de-identified data.

Antemortem blood samples obtained at the time of hospital presentation were analysed at the Victorian Institute of Forensic Medicine using liquid chromatography-tandem mass spectrometry techniques targeting a total of 575 pharmaceutical, illicit and novel drugs [7]. Detection and quantitation of clonazolam and its metabolite 8-aminoclonazolam was achieved using extracted matrix-matched calibrators fortified with certified reference material (Clonazolam: Cerilliant, US, supplied by Novachem, Australia; 8-aminoclonazolam: Chiron, Norway, supplied by PM Separations, Australia). Analytes were confirmed on the basis of matching retention time and transition ion ratios to the reference material.

We describe the clinical features of four analytically confirmed clonazolam mono-intoxications from the Emerging Drugs Network of Australia – Victoria cohort.

Case cluster

One male and three females (age range 16-19 years) presented to hospital following the reported ingestion of benzodiazepines (Table 1). The male was reported to use alprazolam of an unknown strength and quantity. All three females reported deliberate self-poisoning, ingesting between 7-20 “Xanax^®” tablets. Although alprazolam is an approved pharmaceutical in Australia, the brand Xanax^® is not commercially available. Notably, novel benzodiazepines have previously been detected within counterfeit “Xanax^®” products in Australia [8].

Table 1. Description of four cases of clonazolam mono-intoxication presenting to an emergency department as part of the Emerging Drugs Network of Australia – Victoria project.

	Patient A	Patient B	Patient C	Patient D
Clinical presentation and outcome
Reported exposure (source of information)	Alprazolam, cannabis, and magic mushrooms (family)	Seven 2mg “Xanax^®” tablets (patient)	Fifteen “Xanax^®” tablets (patient)	Twenty “Xanax^®” tablets (patient)
Intent	Unknown	Deliberate self-poisoning	Deliberate self-poisoning	Deliberate self-poisoning
Estimated timing between ingestion and hospital presentation	Unknown	∼10 hours	∼1 hour	∼1.5 hours
Initial clinical observations^†
Respiratory rate (breaths/min)	16	14	14	16
Heart rate (beats/min)	92	100	105	100
Systolic blood pressure (mmHg)	110	101	105	140
Diastolic blood pressure (mmHg)	70	72	65	80
Body temperature (degrees celsius)	36.4	35.8	37.5	–
Blood glucose concentration (mmol/L)	6.0	3.6	5.4	–
Initial Glasgow Coma Scale score	11	13	14	12
Oxygen saturation	100% on Room air	100% on Room air	97% on Room air	98% on Room air
Lowest Glasgow Coma Scale	11	13	8	11
Complications	Nil	Nil	Intermittent airway obstruction	Intermittent airway obstruction
Management	Supportive care only	Supportive care only	Nasopharyngeal airway insertion	Nasopharyngeal airway insertion
Hospital length of stay (hours)	27.4	4.9	29.7	19.3
Discharge disposition	Discharged against medical advice	Home	Home	Home
Toxicological analysis
Clonazolam (µg/L)	0.2	2.1	1.0	1.1
8-Aminoclonazolam (µg/L)	5.9	19.1	6.4	10.8
Ethanol measurement^‡	Not detected	Not measured	Not detected	Not measured

^†All observations were recorded by paramedics on scene or reported at the time of call to emergencies services (prior to arrival at hospital).

^‡Ethanol measurement was conducted at the discretion of the treating physician within the emergency department.

Three of the four patients presented to hospital with sinus tachycardia (median 107 beats/min, range: 92–116 beats/min), median 100 beats/min, range 92–105 beats/min systolic blood pressures of 101–140 mmHg, normoglycaemia (3.6–6.0 mmol/L), and normothermia (35.8–37.5 °C). All patients were sedated, with trough Glasgow Coma Scale (GCS) of 8-13. Two patients (GCS 8 and 11) required temporary insertion of a nasopharyngeal airway to relieve airway obstruction. All patients recovered with supportive care after a period of observation (median 23 h, range 5-30 h). The patients reporting deliberate self-poisoning with 15 and 20 tablets required prolonged observation until the return of a normal conscious state (19 h and 30 h, respectively).

Clonazolam and its metabolite 8-aminoclonazolam were analytically detected in each case (Table 1). The concentrations of clonazolam and 8-aminoclonazolam ranged between 0.2–2.1 µg/L and 5.9–19.1 µg/L, respectively. Comprehensive toxicological analysis for all other targeted drugs was negative. No patients reported consumption of ethanol. Serum ethanol was analysed in-hospital for two patients and was not detected in either case.

Findings from this series of patients led to local dissemination of a clinician alert, raising awareness of counterfeit benzodiazepines, the possibility of prolonged sedation associated with exposure, and the unpredictability of novel benzodiazepine detections.

Discussion

It has been suggested that clonazolam has a high potency, with the dosages documented in consumer reports ranging from 0.2 to 1.0 mg [9]. This appears to correspond with in-silico quantitative structure-activity relationship studies demonstrating clonazolam confers one of the highest predicted $\gamma$-aminobutyric acid type A binding affinities in comparison to other novel and pharmaceutical benzodiazepines, including alprazolam [10].

The pharmacokinetic profile of clonazolam is largely uncharacterised. It is estimated that clonazolam has an elimination half-life of 3.6 h [11] and duration of action 6–10 h, with after-effects described up to 24h post ingestion [4,9,11]. Clonazolam is metabolised extensively, undergoing reduction (8-aminoclonazolam), acetylation (8-acetamiclonazolam), hydroxylation (hydroxyclonazolam) and glucuronidation [12]. Both the parent molecule and metabolites are renally excreted [12].

All four cases presented with a sedative-hypnotic toxidrome, consistent with previous reports of clonazolam intoxication [4,9]. Prolonged sedation in those patients with deliberate self-poisoning involved ingestion of 15 and 20 tablets and was similar to the reported case of a young female who remained somnolent for 24 h post ingestion of clonazolam powder (10 mg) [5]. Notably, three of the patients were tachycardic at the time of presentation, a clinical finding not typically associated with benzodiazepine intoxication. Tachycardia may be associated with benzodiazepine withdrawal but is unlikely in the described cases, given the proximity of the exposure and hospital presentation. The aetiology of the tachycardia in the current cases remains unclear. Possible mechanisms could include reflex tachycardia following benzodiazepine-induced vasodilation [13] and/or alterations in vagal tone post-benzodiazepine use [14].

The blood clonazolam concentration range identified in our cases (0.2–2.1 µg/L) was substantially lower than concentrations previously reported. The female who ingested 10 mg of clonazolam had a serum clonazolam concentration of 77 µg/L 4 h post ingestion [5]. Similarly, a patient who had used both etizolam and clonazolam (one tablet containing clonazolam 1.1 mg) had a maximum serum clonazolam concentration of 10.2 µg/L [11]. However, the concentration of the active metabolite, 8-aminoclonazolam, in all four cases was substantially higher, suggesting peak clonazolam concentration had passed at the time of sampling. Ultimately, it is difficult to draw conclusions without knowledge of the concentration of clonazolam per tablet, and the exact time between tablet ingestion and blood sampling. In addition, although comprehensive drug screening was utilised, there may have been undetected substances which could further explain the presenting toxidromes.

Of particular concern, all patients reported that they ingested an alprazolam-containing product and were unaware of the clonazolam substitution. Continued monitoring efforts are warranted to mitigate harm associated with the proliferation of unregulated, counterfeit benzodiazepine products.

Conclusion

Clonazolam intoxication resulted in sedation with mild sinus tachycardia. Three patients that reported multiple tablet exposures experienced prolonged sedation, and two of these patients developed airway obstruction. Unsuspecting consumers exposed to unregulated benzodiazepine products are at risk of unexpected adverse effects, which may require acute medical intervention.

Acknowledgements

The authors additionally thank all EDNAV project site investigators for their assistance in case collection and Dr Linda Glowacki and Miss Samantha Joubert from the Victorian Institute of Forensic Medicine for their analytical assistance.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

The authors acknowledge funding from the Victorian Department of Health and the National Health and Medical Research Council (APP2001107).