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It is nowadays considered axiomatic that innovation is a key element of human existence, but when it comes to the invention, or more accurately the re-invention of certain types of drugs, that may not actually be true. This was brought home to me upon reading that the United Nations Commission on Narcotic Drugs at its annual meeting last year decided to bring a number of new drugs under international control. These included an opioid called isotonitazene and three ‘designer’ benzodiazepines. 

The first wave started around 1999 with prescription opioids, chiefly the now-notorious oxycodone

According to a review by staff from the EU’s Drugs Agency (EMCDDA) published in March 2021 in Chemical Neuroscience, isotonitazene and related molecules such as etonitazene are 2-benzylimidazoles invented by researchers at the Swiss company CIBA in the late 1950s. The appearance on the black market of isotonitazene (‘iso’ or ‘toni’) and similar molecules such as metonitazene and protonitazene, often referred to collectively as ‘the Nitazenes’, is illustrative of how clandestine drug manufacturers carefully scan older research papers and pharmaceutical patents describing opioid drugs that at some time in the past had been evaluated for their potential as analgesics. Likely compounds are then pirated for clandestine synthesis and sold online, or on the street. A 2021 overview in Pharmacology & Therapeutics linked synthetic opioids such as fentanyl, as well as isotonitazene and etonitazene, to a third wave of opioid-related overdose deaths in the US. The first wave started around 1999 with prescription opioids, chiefly the now-notorious oxycodone. Heroin-related deaths in addicts who could no longer access oxycodone and hydromorphone easily constituted a second wave from about 2010. That synthetics-driven third wave dates to 2013 and the Americans are now having to cope with a fourth wave involving opioids and stimulants such as cocaine and methamphetamine. 

The death toll from these successive waves has been enormous, rising to over 100,000 in the past year alone. In addition, the Pharmacology & Therapeutics paper estimates that for every one of the 69,000 opioid-related overdose deaths in the USA in 2020, there were between 6.4 and 8.4 non-fatal overdoses requiring medical intervention. This represents a huge burden on individuals and the healthcare system. 

The authors suggest an estimated economic cost of $1.02 trillion in 2017, noting that this does not include the cost of the 33 per cent increase in deaths reported between 2017 and 2020. It is believed that 80 per cent of overdoses involve synthetic opioids, mainly fentanyl, but the benzylimidazoles such as isotonitazene are increasingly being implicated. 

Isotonitazene and the other benzylimidazoles are selective μ opioid receptor agonists with morphine-like pharmacological and, unfortunately, toxicological effects. In vitro assays using μ-receptors indicated that the potency of ‘iso’ is about 20 times than hydromorphone and slightly higher than that of fentanyl, which itself is known to be 50 times more potent than heroin. The higher potency was confirmed in tests of anti-nociceptive activity in mice in which ‘iso’ was 500 times more potent than morphine, and metonitazene was 1,000 times more potent. Public comments on the increased potency of ‘iso’, and indeed the various fentanyl analogues that have appeared on the black market, can have unintended consequences. On the one hand, drug workers and healthcare professionals need to be alerted to the increased risks associated with the use of such highly-potent molecules, not least the requirement to use multiple doses of naloxone to resuscitate individuals who have overdosed on them and the increased likelihood of such overdoses, given the difficulty street users are likely to have when trying to judge doses in any way accurately. On the other hand, media reports that drug ‘x’ is 500 times more potent than morphine or heroin can result in some drug users actively seeking out the more potent drug in the erroneous belief that 

their ‘turn on’ or ‘hit’ will be correspondingly 500 times more pleasurable, thus creating an additional market for the drug. 

An added complication arises from the fact that none of the benzylimidazoles were developed into licensed medicinal products and so are only available as black-market products. Clinical trials did indicate analgesic effects, but the high level of respiratory depression with even 1mg doses meant that further larger trials could not be justified. Black market ‘iso’ occurs as coloured powders, as a liquid, as a ready-to-use nasal spray, and as tablets. Worryingly, it has been found mixed with heroin, with fentanyl or with another novel opioid U-47,700 as well as with benzodiazepines in fake dosage forms. In Canada, ‘iso’ has been found in fake Dilaudid tablets instead of hydromorphone. 

Isotonitazene was first detected in Europe in 2019, coinciding with reports of three deaths in Switzerland linked to very low (nanogram/litre) concentrations that led to the authors concluding that consumption of ‘iso’ was “a real hazard for human health”. To date, this drug is implicated 

in at least 200 fatalities in Europe and North America, with deaths in the USA running at 40 a month. 

There was a public health alert in England last August, warning of an unprecedented number of overdoses and deaths in London and surrounding counties in heroin users where contamination with isotonitazene was implicated. An EU-wide ban on ‘iso’ came into force in September 2020 and this was extended worldwide through the UN Conventions in March 2021. 

The CND decision also included three ‘designer’ benzos, namely clonazolam, diclazepam and flubromazolam. These are just three out of at least 16 such molecules notified to the EU’s Drugs Agency. They are all highly potent, with the effective dose below 1mg. Invariably, they are sold as fake versions of licensed medicinal benzodiazepines, such as flubromazolam sold as diazepam tablets. In addition to the ‘normal’ risks we associate with benzodiazepines, such as dependence, driving hazards and the risk of overdoses, these fake products present other challenges. Not least, there is huge variation in content between individual tablets because of poor tabletting technique, leading to some tablets having multiples of the effective dose. Worryingly, the EMCDDA received a number of “concerning” reports that these new benzos had been used to cause incapacitation in cases of rape and sexual assault. 


Dr Des Corrigan, Best Contribution in Pharmacy Award (winner), GSK Medical Media Awards 2014, is a former Director of the School of Pharmacy at TCD 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. He currently chairs the Advisory Subcommittee on Herbal Medicines and is a member of the Advisory Committee on Human Medicines at the IMB. He is a National Expert on Committee 13B (Phytochemistry) at the European Pharmacopoeia in Strasbourg and he is an editorial board member of the Journal of Herbal Medicine and of FACT — Focus on Alternative and Complementary Therapy.