Accidental protonitazene intoxication: clinical management and detection of a novel opioid

Summary

We describe the management by a pre-hospital medical team of a typical opioid toxidrome in a young man after consumption of an unknown substance with complete reversion after injection of unusually high doses of naloxone.

The initial toxicological screening was negative. The secondary identification of protonitazene was performed several months after the first intoxication, both in the substance consumed and in the patient’s blood samples. Protonitazene is a morphine derivative representing an emerging drug whose consumption is underestimated, escaping conventional toxicological screening and detected for the first time in France.

The implementation of rapid detection procedures by the Lyon toxicology laboratory and the testing of these procedures during a second intoxication of the same patient allowed for the diagnosis to be reached again in record time.

Background

Drug overdoses are a major public health issue. The emergence of new synthetic drugs is making their management more complex, combining difficulties in clinical diagnosis, in identifying the substance and in treatment. Protonitazene, an emerging synthetic drug, combines these three difficulties, even though an effective antidote exists.

Case presentation

Following a call to the emergency medical services (EMS) during a night shift, a French prehospital medical team intervened in a drug-induced coma.

On the arrival of the EMS team and firefighters, the patient (a man in his 20s) was bradypnoeic, greyish skinned with oxygen saturation at 40%, rising to 100% with 15 L of oxygen support.

His heart rate was 81 beats per minute and blood pressure was 117/65 mm Hg.

Pulmonary auscultation also revealed diffuse ronchi.

The patient was totally unresponsive, with a score of 3 on the Glasgow Coma Scale (GCS).

His eyes were partially revolted and off-centred. However, the pupils were in very tight miosis and unresponsive.

The rest of the clinical examination did not present any abnormalities.

The aetiological investigation and interview of the patient’s companion at the scene were carried out by the EMS physician. His partner reported that the patient regularly used cannabis and dextromethorphan. The patient was also taking clomipramine for a depressive syndrome but had no other medical history. A white powder in a plastic bag, ordered over the internet from a retailer and labelled dimethyltryptamine (DMT), was found at the scene.

The patient’s partner reported to the medical team on-site that the patient had taken cannabis and clomipramine. He had also mixed white powder with tobacco for the first time and smoked the combination, several hours before the call was made to the emergency services.

A portable blood analysis system (i-STAT 1, that delivers lab-quality diagnostic results in minutes) revealed a venous pH of 6.97 of hypercapnic origin (pCO2 measured at 11.9 kPa) and venous lactates of 2.9 mM, suggestive of a significant drop in ventilatory minute volume related to the clinical bradypnoea.

The toxidrome, biological results and pharmacokinetics suggested an opiate-induced coma, instead of one induced by DMT consumption. Indeed, DMT is a powerful hallucinogen with a short half-life, known to produce mydriasis, psychomotor agitation, tachycardia and hypertension, but none of these signs were present in this case.

Orotracheal intubation was delayed until a naloxone reversal test could be performed.

A total of 4 ampoules of 0.4 mg naloxone each were administered directly intravenously, 1–2 min apart from each other.

After the first and second ampoule administration, no clinical changes were observed. After the third ampoule administration, the eyeballs refocused and the pupils became intermediate and reactive. However, the patient was still in a persistent GCS 3 unresponsive coma. Once the fourth ampoule was administered, the patient suddenly awoke and was in a very agitated state, requiring five people to restrain him. The patient spontaneously returned to a calm state after a few minutes.

On suspicion of opiate intoxication reversible after naloxone, the patient was referred to intensive care.

In intensive care, the patient was initially disoriented, but returned to his normal state within a few hours without any malfunction. Against medical advice, the patient was discharged the following day and returned home.

Investigations

Plasma and urine samples were sent to the hospital toxicological laboratory (toxlab hereafter) for analysis. The screening was performed by liquid chromatography coupled with high-resolution mass spectrometry (LCMS-HR), and detected more than 250 drugs and substances. The screening identified traces of cannabis and clomipramine at 0.08 mg/mL (corresponding to a therapeutic concentration) in the plasma and dextromethorphan’s traces in urine. No DMT or opioid compounds were detected.

The patient was contacted the day he returned home (< 24 hours after the intoxication) and agreed to collect the powder residues from the table he had used to prepare the drug’s mix (cannabis, tobacco and the unknown powder). He handed them over to the National Identification System for Toxics and Substances (known by the French acronym SINTES), the French monitoring system providing drug analysis data on illegal substances circulating in the country (samples given by users via a harm-reduction centre or seizures by law enforcement authorities).¹

After qualitative analysis of the powder using three different methods—gas chromatography-mass spectrometry (GCMS), LCMS-HR and nuclear magnetic resonance —the SINTES drug analysis laboratory identified the protonitazene molecule. Protonitazene is derived from nitazenes (a family to which isotonitazene also belongs). Based on this result, and on data from the literature,² a retrospective analysis was performed on plasma and urine samples in the toxlab, and the compound was identified. Following this analysis, the chromatography and MS data were added to the spectral database of the toxlab.

A few months after the first intoxication mentioned above, the patient used protonitazene again. The EMS team needed to come back because of a second overdose, but this time the clinical symptoms were different. The resulting toxidrome was impure, with intermediate pupils and peripheral hypertonicity. As a result of this second protonitazene intoxication, the patient was intubated by the prehospital team, without receiving naloxone, and transferred to intensive care. Toxicological LCMS-HR qualitative screening of the toxlab confirmed the presence of protonitazene in the plasma sample in just a few hours. This speedy detection was possible thanks to the previous experience of the first case. In addition, the plasma’s screening revealed cannabis metabolites and clomipramine at toxic levels (0.77 mg/L, three times higher than the toxicity threshold). A urine screening also detected traces of dextromethorphan. Clomipramine, a tricyclic antidepressant, was present in therapeutic concentration in our patient’s first polyintoxication and may explain the impure toxidrome in the second intoxication.

Differential diagnosis

At the start of the treatment, an intoxication due to a more conventional opiate was suspected. In France, and more generally in Europe, the main opiates encountered are morphine and heroin, more rarely sufentanyl, oxycodone, methadone and fentanyl.³

Given the high dose of naloxone required to induce awakening and the small amount reportedly inhaled by the patient’s companion (a few puffs), any of these substances were unlikely.

Co-intoxication was also a possibility but was also unlikely due to the complete reversal of symptoms after naloxone was administered.

These differential diagnoses were quickly ruled out after obtaining the standard toxicological screening, which came back negative for all the drugs mentioned above.

Outcome and follow-up

After these two protonitazene intoxications, which required two stays in critical care, the patient returned home without any after-effects. 6 months after his second overdose, the patient was contacted again. He had not used protonitazene again and agreed to the distribution of this case report. He, however, wished to remain anonymous.

Discussion

The nitazene chemical family, to which protonitazene belongs, binds to µ-opioid receptors with greater affinity than fentanyl.

These compounds, synthesised in the late ‘50s as potential analgesics, have an opioid-like pharmacotoxicological profile, with some having an affinity for µ-receptors and a potency far superior to morphine or fentanyl.

They were never developed or marketed as drugs for clinical prescription. However, they have recently emerged on the market as substances of abuse, associated with serious clinical consequences, that is, severe opioid toxidrome or even death.

Their pharmacotoxicological potency, coupled with their clandestine presence in various products (powders or counterfeit drugs), is all the more alarming in terms of public health.^{4 5}

Protonitazene, whose chemical structure is shown in figure 1, was detected for the first time in the recreational drug market in 2021 in both the USA and Germany. Since then, other European countries have formally identified it on their territory, especially in 2023.

Figure 1. Protonitazene chemical structure.

On the clinical side, we have so far identified only four communications reporting acute intoxication and its consequences. The toxidrome—when described—is expected to be opioid-like, and the route of administration assumed or reported is intravenous,⁶ nasal^{7 8} or respiratory.⁹ The effects were reversed by naloxone in all but one case, and the route of administration was not always specified.

Detections of nitazenes have been increasing since 2020, and these synthetic opioids are likely to bear at least partial responsibility for the current opioid crisis in the USA. The relative strength of nitazenes relative to both fentanyl and morphine are shown in table 1.

Table 1. Relative strength of nitazenes to both fentanyl and morphine¹⁶.

Synthetic opioids—nitazene class	Strength relative to fentanyl	Strength relative to morphine
Protonitazene	1.07–1.29× greater	130× greater
Isotonitazene	Roughly equal	2.5× greater

This case report is of interest to the scientific community in several ways.

To our knowledge, this represents the first formal identification of protonitazene in France, and only the eighth in Europe.¹⁰ We would therefore like to draw attention to the arrival of nitazenes in this part of the world, which highlights the need to adapt standard toxicological screenings to account for these substances and ensure their detection.

Moreover, the structure of nitazenes is markedly different from other opiates derived naturally from opium. As a result, they cannot be detected by rapid opiate screening techniques such as immunochromatography (strips) or enzyme-linked immunosorbent assays. Their identification requires more complex methods, such as GCMS or LCMS.^{4 11} Following the addition of protonitazene to the spectral database of the toxlab, protonitazene was detected in the patient’s blood and urine on two occasions.

To our knowledge, this is the first time protonitazene has been identified not only in the product used by the patient but also in both his blood and urine. Other cases have only identified it in the powder used by victims, mostly after their tragic death due to intoxication.^{12 13} This identification strengthens the link between protonitazene and these overdoses.

We are now able to detect and identify protonitazene intoxication within a few hours. Unfortunately, this ability currently applies only to protonitazene, but other nitazenes could also be detected once encountered. This case demonstrates the possibility of detecting nitazenes when the laboratory employs screening methods such as LCMS-HR. It also underscores the importance of the anamnesis and of obtaining information about the substances consumed by patients. In this regard, toxicological laboratories can enhance their screening capabilities to offer more efficient detection. Therefore, we strongly recommend that other toxicological laboratories in Europe incorporate nitazene detection into their routine or semiroutine procedures.

In addition, the medical team administered a very large dose of naloxone, prompted by a toxidrome characteristic of opiates. As a reminder, intravenous naloxone is 5–10 times more effective than intranasal naloxone,¹⁴ with 4 ampoules of intravenous naloxone (0.4 mg) corresponding to around four inhalations on an intranasal device dosed at 2 mg or 4 mg.

In our experience, 0.4 mg of intravenous naloxone has been sufficient to reverse most cases of coma induced by opiates. This was confirmed by a retrospective review in which we found a median dose of 1.6 mg of intramuscular naloxone and 0.6 mg intravenous (three times less efficient¹⁴) for heroin-induced coma.¹⁵ Thus, the clinical history reinforces the need for a higher dose of naloxone in protonitazene intoxication compared with other µ-opioid receptor ligands

Another important lesson learnt is the significance of trusting the opioid toxidrome and persisting in its treatment, always considering the safety, low cost and rapid administration of naloxone. Any coma with tight miosis should be treated with high doses of naloxone (four doses in this case) before considering any differential diagnosis other than opiate or opiate derivative intoxication. Although benzodiazepine intoxication can present similar symptoms, tight miosis is less indicative of this. After ruling out polyintoxication with proconvulsant drugs, a second trial with flumazenil may also be considered.

We also strongly recommend suspecting a new synthetic opioid in the event of a negative toxicological immunoscreening associated with an opioid toxidrome, necessitating further investigation to obtain a definitive result. In the coming months and years, these drugs could represent a major public health and safety concern.

Finally, the patient presented here consumed protonitazene in an inhaled form, smoked with tobacco. To the best of our knowledge, this is the first reported case of this mode of consumption, and it was initially hypothesised that the substance might be inactivated by the smoking process. This assumption was based on the chemical nature of protonitazene, as outlined in the WHO critical review report of 2022,⁴ which noted that it could either be in hydrochloride form (considered unstable when heated) or as a freebase, potentially suitable for smoking. Unfortunately, we could not determine the exact chemical form involved in this clinical case.

Learning points.

• Nitazenes are emerging synthetic drugs responsible for a major life-threatening opioid toxidrome.

• Nitazenes escape conventional toxicological screening but can be easily identified by complementary techniques.

• Nitazenes respond to high doses of naloxone, the antidote for opiate intoxication.

• Nitazenes can be smoked, which considerably increases their consumption risk.