Nitazenes are a group of synthetic opioid drugs first developed in the 1950s for potential use as analgesics but never commercialised. Several nitazenes, including isotonitazene and etonitazene, have been identified in unregulated drug markets around the world since the 1990s. In Australia, nitazenes have been found in counterfeit pharmaceuticals, as contaminants of other illicit drugs, and more recently in vape liquid.
While not chemically related to natural opioids like morphine or to other synthetic opioids like fentanyl, nitazenes share the ability of these molecules to activate opioid receptors in the brain, producing pain relief and euphoria. As with all strong opioids, the most important adverse effect of nitazenes is respiratory depression, which can lead to death.
There have been very few controlled studies of nitazenes in humans and none directly comparing them to fentanyl, but laboratory studies show isotonitazine binds to opioid receptors more potently than fentanyl and activates those receptors at least as well as, and perhaps even more than, fentanyl.
Likewise, we know relatively little about how humans absorb and metabolise (break down) nitazenes but there is evidence that some metabolites produced when nitazenes are broken down by the liver are also biologically active. The combination of these properties could contribute to nitazenes having higher potency than fentanyl.
Everyone should be familiar with signs of opioid overdose: pinpoint pupils, slow or shallow breathing, drowsiness, unconsciousness and blue/grey skin.
Any drug that activates the opioid receptor has the potential to produce tolerance – the need to take increasingly higher doses to achieve the same effect – and dependence.
Dependence develops as the brain adapts to repeated consumption of the drug, trying to continue to work “as normal” in the presence of something that profoundly changes the function of some brain cells; repeated rewards can also lead to a change in decision-making in favour of seeking out and consuming the rewarding substance.
Watch for the signs
It should be noted most people who use strong opioids for pain relief or otherwise do not become dependent on them, but nitazenes activate opioid receptors very effectively, so they’re likely to be as prone as other strong opioids to producing dependence in vulnerable people.
An important risk with unregulated high-potency opioids is that it is very difficult for people using them to know what dose they are taking or even to be sure what they are consuming. Given the relatively small amounts of strong opioids needed to produce adverse or fatal effects, nitazene products are likely to be dangerous.
Of particular concern is the addition of nitazenes to products that are supposed to contain lower-potency opioids like oxycodone or no opioid at all, like cocaine, stimulants or fake benzodiazepines. If you are not expecting an opioid, you are likely not prepared for an opioid overdose.
Some drug testing services check drugs for nitazenes, among many other things. If the subjective effects of a drug are different from what the user is expecting, alarm bells should sound, and everyone should be familiar with signs of opioid overdose: pinpoint pupils, slow or shallow breathing, drowsiness, unconsciousness and blue/grey skin.
The opioid antagonist naloxone can reverse nitazene overdose quite rapidly, but its effect may wear off before the nitazene is completely cleared by the body, so repeated naloxone doses may be needed.
Naloxone is available free to anyone in New South Wales; it can be obtained from some community pharmacies, needle and syringe exchange programs and some NGOs, and can also be prescribed by a physician. If you know or are around people who use opioids including prescription opioids, think about carrying naloxone or having some in your home.
We don’t know what proportion of unregulated vapes may contain nitazenes (or other strong opioids), but several fatalities have been reported in Australia. Inhalation generally produces more rapid effects than oral consumption, and the rapid onset of euphoria with opioids can be particularly rewarding, but so far we know little about whether “vaping” nitazenes changes their chemical properties or leads to more variable effects.
Professor Mark Connor is a pharmacologist in the Macquarie Medical School.
