Dr Des Corrigan looks at the many dangers of the new synthetic opioids known as nitazines
It is just over a year since the first of several HSE alerts were issued about the risk of overdose linked to the new synthetic opioids called nitazenes. I first wrote about these drugs in early 2022 as I wanted to alert pharmacists to their existence and associated risks, but I did not suspect then that they would become so problematic.
On November 26, 2023, The Irish Times reported that 57 overdoses had been reported among homeless service users over a period of just five days. Further alerts followed relating to 20 overdoses in Cork in December and five in a Dublin prison. Another alert was issued in June of this year following a cluster of overdoses in Dublin and the Mid-West, involving ingestion of a counterfeit benzodiazepine product that on analysis was found to contain a nitazene derivative.
Another alert came from the Irish Prison Service in late July and involved at least one fatal overdose. Following that death, it is reported that prisoners in Mountjoy handed over hundreds of suspected nitazene-containing tablets. Deaths have also been reported from Cork prison, Limerick, and Dublin.
So, what do we know now about these nitazenes? Well, for a start, they are failed pharmaceuticals developed as analgesics, but none were ever authorised as medicines because of the unfavourable side-effect profile. Nitazenes as benzylbenzimidazole derivatives are chemically quite different to poppy-derived (heroin and morphine) and synthetic (such as fentanyl) analgesics. They are, however, pharmacologically similar in that they also are opioid receptor antagonists, notably at the Mµ Opioid Receptor (MOR).
According to a 2024 paper in the Journal of Pharmacology and Experimental Therapeutics that evaluated 19 different nitazenes, nine molecules had higher potencies than fentanyl. Different testing methods give varying figures for the comparative potency levels between individual nitazenes and either morphine, fentanyl, or hydromorphone used as controls. A 2021 review by staff from the EU’s Drugs Agency published in ACS Chemical Neuroscience noted that etonitazene was one thousand times more potent than morphine in the tail-flick antinociceptive test while another widely-detected compound, isotonitazene, was 500 times more potent.
Regardless of the exact potency levels, it is clear that many nitazenes are highly active opioids. Lurid publicity highlighting the claim that they are supposedly several hundred or thousand times more potent than heroin can perversely add to the attractiveness of these drugs. Pharmacists, however, will be aware that such high potency means that only microscopic doses are needed for intoxication – and that also means a very narrow gap between effective and toxic doses.
It goes without saying that these nitazenes are highly dangerous. Formal human pharmacology studies are few and far between but what is known is that the analgesia they induce is accompanied by sedation, drowsiness, vertigo, confusion, nausea, and vomiting. Respiratory depression was reported in 20 per cent of volunteers in the original studies in the late 1950s as were abstinence syndromes – described in the ACS Chemical Neurosciences article as being comparable to those seen with morphine and heroin.
According to the Advisory Committee on the Misuse of Drugs (ACMD) in its July 2022 advice on nitazenes to the British government, these drugs are sold as powders or as a nasal spray, for administration IV, sublingually or nasally, or by vaping. The AMCD went on to note that nitazenes have been added to heroin or to counterfeit medicines in which case ignorance of the presence of an ultra-potent nitazene substantially increases the risk of a fatal overdose.
**According to the EU’s Drugs Agency, fake oxycodone tablets containing nitazenes have been detected here in Ireland as well as in Slovenia, Sweden, and Norway. Estonia has reported the presence of metonitazene mixed with the benzodiazepine bromazolam in what has been called ‘benzo-dope’. It is not yet clear whether this was the same type of fake that triggered the HSE alert in June.
Both Estonia and Latvia have detected what they call ‘tranq-dope’ which consists of either protonitazene or metonitazene mixed with xylazine, a development that is very dangerous given the ability of xylazine (Tranq) to cause horrendous gangrene-like skin ulceration away from the site of injection. Other counterfeit medicines found to contain nitazenes include fake Subutex and fake hydromorphone sold as pharmaceutical grade Dilaudid.
It appears that the product involved in the spate of overdoses here last November was a light brown coloured powder. Laboratory work by scientists in the pharmacology department in Trinity Medical School, the chemistry department of Trinity College Dublin, Forensic Science Ireland, and the HSE’s drug treatment centre laboratory resulted in the identification of an analogue called N-pyrrolidino protonitazene in the powder as reported in Drug Testing and Analysis earlier this year. This is claimed to be 25 times more potent than fentanyl. Thus, effective doses are in the sub-milligram range making it difficult for street users to judge what is a safe dose, even if they know that a nitazene is present.
Regardless of the exact potency levels, it is clear that many nitazenes are highly active opioids
An added danger with powder forms is inadequate mixing of the super-potent drug with its cutting agents as the concept ‘uniformity of content’ is foreign to Organised Crime Groups. Inadequate mixing leads to the creation of so-called ‘hot spots’ which have much higher drug concentrations than the bulk of the powder mix, and these add to the risk of respiratory depression associated with opioid overdose. The good news is that naloxone is an effective antidote to a nitazene overdose but because of its higher potency several doses of the antagonist might be needed.
When nitazenes emerged on the Irish market, a multidisciplinary group of Irish lab workers, first responders, and the addiction services sent a letter to the editor of the journal Addiction. As well as describing the high number of overdoses, the authors predicted that a synthetic opioid market was highly likely to emerge in Europe as the banning of poppy cultivation by the Taliban in Afghanistan in 2023 would inevitably lead to a severe shortage of heroin.
But despite the fact that more than 200 overdose deaths due to nitazenes have been reported in Europe and North America since 2019 not all of the molecules have been brought under control. This failure will seriously hamper efforts to interdict supplies and prevent more deaths by removing these highly toxic products from the market.
Dr Des Corrigan, Best Contribution in PharmacyAward (winner), GSKMedical Media Awards2014, is an Adjunct Associate Professor at the School of Pharmacy and Pharmaceutical Sciences at TCD where he was previously Director and won the Lifetime Achievement Award at the 2009 Pharmacist Awards. He was chair of the Government’s National Advisory Committee on Drugs from 2000 to 2011, having previously chaired the Scientific and Risk Assessment Committees at the EU’s Drugs Agency in Lisbon. He chaired the Advisory Subcommittee on Herbal Medicines and was a member of the Advisory Committee on Human Medicines at the HPRA from 2007 to 2024. He has been a National Expert on Committee 13B (Phytochemistry) at the European Pharmacopoeia in Strasbourg and served on the editorial boards of a number of scientific journals on herbal medicine.
