This is the seventh in a series of blog posts on new research in emergency toxicology. The last post was about antipsychotics for acute behavioural disturbances, and may be found here.
A lot has been published this year about nitazenes, which represent a growing problem in emergency medicine. I was in the mood for a deep dive, so prepare yourself for not one, but three (!) recent studies from Medical Toxicology, EMJ, and Drug & Alcohol Review.
First, however, an introduction to nitazenes for those who are unfamiliar…
What are nitazenes and why should I care?
Nitazenes are a class of synthetic opioids that were developed in the 1950s, but never approved for medical use. Examples include metonitazene, protonitazene, isotonitazene, and etonitazene. These drugs have significant overdose potential due to their potency, which is far higher than that of heroin:
Table reproduced from Holland et al. (2024)
WEDINOS reports show that nitazenes are sold in powdered, crystalline, and tablet forms. They also indicate that nitazenes are being used to adulterate other opioids sold on the street, such as heroin.
Nitazene-related fatalities have been reported here in Virchester and throughout the United Kingdom. The situation seems to be worse in Scotland.
How do I pronounce “nitazene” correctly?
Unclear. There does not seem to be any consensus on whether we should be saying ‘knit’-azene or ‘night’-azene. I use the latter.
Why are nitazenes only now becoming a problem?
To understand why we are seeing more nitazenes on the street, we need to take a step back and look at how the global heroin market has changed over the last few years.
Broadly speaking, opium and heroin are produced in three locations worldwide: South America, South-East Asia, and Afghanistan. In Europe, the vast majority (>90%) of our supply comes from Afghanistan in the form of a dark powder – “Afghan Brown” – of variable purity. However, in 2021, the Taliban re-took control of Afghanistan, and shortly thereafter criminalised the cultivation of opium poppies. The ban appears to have been successful, with one UN report estimating a 95% drop in production by 2023.
While the supply of Afghan heroin to Europe does not been appear to have been interrupted by Taliban policies, the market has changed drastically since 2022. The price of stockpiled heroin base / hydrochloride has risen, and this has had a knock-on effect on virtually every other level of the supply chain. Concerns have been expressed that some heroin traffickers, forced to “economise” with a more expensive drug, are adulterating or substituting their product with synthetic opioids – and that this practice will become widespread when the Afghan supply finally dries up.
Nitazenes, with their high potency and relatively low cost, are a natural choice of synthetic alternative. Currently, the major exporter of nitazenes to European traffickers is China, where chemical companies openly manufacture, distribute, and advertise these drugs online. This situation may change over the coming months, as the Chinese government has just announced its re-categorisation of all nitazene-based substances.
Alright — tell me about these studies…
The first two papers I want to cover were published in the EMJ and Medical Toxicology this year.
The former was a prospective study (2022-2024) conducted at an ED in Glasgow, where a high number of nitazene-related deaths have been reported. Twenty-one patients were included, all of whom had blood samples testing positive for protonitazene or metonitazene, as well as bromazolam (n=18), morphine (n=15), diazepam (n=13), cocaine (n=12), and xylazine (n=12). The latter was an analysis of thirty-two referrals to the Emerging Drugs Network of Australia (EDNA) between 2020 and 2024. Again, all tested positive for protonitazene or metonitazene.
In both of these cohorts, few patients (<16%) were aware that they had taken a nitazene. Most were under the impression they had taken an oral opioid, benzodiazepine, or gabapentinoid. This is consistent with WEDINOS reports, collected over the last four years, demonstrating the presence of nitazenes in “Oxy,” “Xanax,” and “Valium” purchased on the street. These results are not necessarily surprising – illicit drugs are often mis-sold! — but the risk of misdiagnosis is a cause for concern.
This brings me to the other key finding of these studies. Critical care admission was required in a higher number of cases (24-41%) despite the majority of patients in both cohorts receiving naloxone. This is a lot higher than I would expect, and it is worrying. Most of the opioid overdoses we encounter here in Virchester can be rapidly turned around with one or two boluses of naloxone — or, if an extended-release drug was taken, an infusion. The challenge is often avoiding over-treatment.
So: what is going on? One possibility is that nitazenes are “naloxone resistant” and require higher doses to achieve opioid receptor blockade. If this is the case, patients who have taken nitazenes are unlikely to improve with the “tester doses” of naloxone (~400-800 micrograms) typically given in ED. It is easy to see how this situation could escalate: lack of response to naloxone in a comatose patient may be taken as evidence against opioid toxicity, and failure to improve with time — as is seen with nitazenes — is often reason to intubate.
Helpfully, the third paper I came across was a systematic review on exactly this problem. It was published in Medical Toxicology a few months ago. A broad methodology was used: the authors searched the usual databases for papers featuring the terms ‘naloxone’ and ‘nitazene’ (or a nitazene subclass) to generate an aggregated sample of nineteen analytically-confirmed exposures. The median titrated doses of naloxone varied from 1mg for protonitazene to 3mg and 6mg for isotonitazene and metonitazene, respectively. This was consistent with an earlier review in Clinical Toxicology, which reported a median dose of 1.2mg in a sample that was larger (n=30) but non-specific with regard to nitazene used, and inclusive of fentanyl exposures.
The quality of data used in all of these papers was low (observational only) but empirical studies on nitazenes are few and far between, and we are unlikely to get an RCT any time soon…
Give me the bottom line!
These studies indicate that nitazenes have the potential to cause severe, naloxone-resistant opioid toxicity. Our patients, and those who accompany them to hospital, may not know that they have taken nitazenes. In EDs where the local narcotic supply is contaminated with nitazenes, higher doses of naloxone should be trialled before a suspected opioid overdose is attributed to another drug.
We are likely to see many more cases of nitazene poisoning over the next decade, as traditional routes of heroin supply to Europe are disrupted and traffickers make further use of synthetic alternatives.
References
Holland A, Copeland CS, Shorter GW, Connolly DJ, Wiseman A, Mooney J, Fenton K, Harris M. Nitazenes—heralding a second wave for the UK drug-related death crisis?. The Lancet Public Health. 2024 Feb 1;9(2):e71-2.
Turner R, Dunlop LC, Lowe DJ, Norman F, Craik V, Jarvie N, Hudson S, Walters M, Dear J, McHenry R. Nitazene detections and clinical characteristics: data from a prospective observational study in a Glasgow emergency department. Emergency Medicine Journal. 2025 Jun 4.
Isoardi KZ, Alfred S, Weber C, Harris K, Soderstrom J, Syrjanen R, Thompson A, Schumann J, Stockham P, Sakrajda P, Fatovich D. Clinical toxicity of nitazene detections in two Australian emergency department toxicosurveillance systems. Drug and Alcohol Review. 2025 Jan 19.
Stangeland M, Dale O, Skulberg AK. Nitazenes: review of comparative pharmacology and antagonist action. Clinical Toxicology. 2025 May 23:1-4.
Berger JC, Severe AD, Jalloh MS, Manini AF. Naloxone Dosing and Hospitalization for Nitazene Overdose: A Scoping Review. Journal of Medical Toxicology. 2025 Feb 4:1-8.
