Hasegawa K, Minakata K, Suzuki M, et al. Forensic Toxicology. 2022;40:234-243.
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Since the prohibition of fentanyl production in China in 2019, and fentanyl core-structure scheduling in the USA in 2018, several classes of non-fentanyl-derived synthetic opioids have emerged in global illicit drug markets. This paper utilised literature searches to identify these classes – benzimidazole opioids (nitazenes) and brorphine, U-compounds (benzamides and 2-phenylacetamides), and MT-45 and its related compounds. The paper outlines the pharmacological properties of these drugs, and presents toxicological information.

Although most of these drugs were developed by pharmaceutical companies in the 1950s-1970s, they failed to become licit medical analgesics due to safety concerns. And though they have only appeared in illicit drug markets in recent years, their use is widespread, having been detected in Australasia, Europe, Japan, North America, and the UK. All classes have been implicated in human deaths.

Of note is the variable potencies of these compounds. The authors present the analgesic potencies of 14 nitazenes (a class containing at least 39 different drugs) which vary from ~50-1000x that of morphine. This makes the most potent nitazene, etonitazene, ~10-20x
more potent than fentanyl. The authors express their concern that these compounds will replace fentanyl analogues and become widely used in the coming years, further fuelling the North American opioid epidemic.

Commentary:
What this study really hammers home is that where there is demand, there will always be supply. But what makes these synthetic opioids so dangerous is their unpredictability, both due to their variable pharmacological profiles and because we don’t know where they will actually turn up. Nitazenes have been found as an adulterant in heroin and cocaine samples in the UK, and in Australia there have
been reports of contaminated heroin, oxycodone, and ketamine. Worryingly, overdoses with nitazenes have occurred after inhalation and rectal administration, which means the harm reduction advice that smoking is safer than injecting may no longer hold true in every instance. 

It seems to me that there are broadly three different groups of people who are likely to use these synthetic opioids: (1) people who normally use heroin who unintentionally use heroin adulterated with synthetic opioids; (2) people who normally use non-opioid drugs who unintentionally use drugs adulterated with synthetic opioids, and; (3) people who intentionally use synthetic opioids (i.e. socalled “psychonauts” who seek out novel drugs on the dark web). This distinction is important because different people will have different tolerances to opioids, and whilst some may be expecting an opioid effect, for others it may come as a nasty surprise.

So, as clinicians, what do we do with this information? At a minimum we should be able to provide accurate and contemporary information to patients, so that people who use drugs can make informed decisions and take steps to mitigate risks. We should continue to provide staple pharmacological harm reduction interventions like take-home naloxone and opioid substitution therapy. And finally, we should increase access to drug-checking, both at home and at fixed-site and mobile services, so that people can make informed, and hopefully safer, decisions in realtime.

Articles featured in this Clinical Update:

• Non‑fentanyl‑derived synthetic opioids emerging during recent years.
• A hospital-based managed alcohol program in a Canadian Setting.
• Acute injection-related infections requiring hospitalisation among people who inject drugs: Clinical features, microbiology and management.
• How do patients feel during the first 72 hours after initiating long-acting injectable buprenorphine? An embodied qualitative analysis.
• Can individuals with alcohol use disorder sustain non-abstinent recovery? non-abstinent outcomes 10 years after alcohol use disorder treatment.

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