Dr Des Corrigan lifts the lid on toxic brain injury, an under-recognised consequence of non-fatal overdoses
In last month’s issue, I wrote about the spate of overdoses due to the nitazene-group of drugs. Happily, the vast majority of these did not end up as deaths thanks to the speedy use of naloxone.
While rapid response to overdoses by the emergency services, the Gardaí, families and peers is welcome, it would be short-sighted to believe that those saved from death are always able to walk away without consequences. International experience suggests that those who survive a non-fatal overdose run the risk of a number of health consequences, including what is increasingly referred to as ‘toxic brain injury’ arising from oxygen deprivation linked to the respiratory depression characteristic of opioid overdose in particular.
Most of our knowledge of this little-understood issue comes from North America (USA and Canada), which is not surprising since that is the epicentre of the opioid overdose catastrophe. Understandably, most attention has to be focused on the appalling death toll — 81,083 opioid-related fatalities in the USA in 2023, and the focus has been on ways to prevent such a waste of lives.
But in addition to this, another area of increasing concern arises from Canada reporting nearly 42,000 emergency medical services responses to suspected opioid overdoses, because of the emerging evidence of the long-term harm that those who survive overdoses may be facing. Now, it is almost impossible to calculate exactly how many people survive overdoses and how many overdoses they experience during their drug-using careers, unlike fatal episodes, which are sadly ‘known knowns’.
Various attempts have been made to estimate the ratio of fatal to non-fatal overdoses, dating back to an Australian study in 2003 in the journal Addiction that used self-reported data from heroin users in Sydney and concluded that the ratio varied from one-to-20, up to one fatal to 30 non-fatal overdoses.
A 2019 paper in the International Journal of Drug Policy estimated that in the USA, a staggering 3.2 million people who inject drugs had experienced at least one overdose in the previous year. A recent (2024) study in the journal Injury Prevention estimated that between 2010 and 2020, there were approximately 15 non-fatal overdoses for each fatal one. All of the studies suggest that the rate is underestimated, as it tends to be based on either self-reports or on those brought to emergency departments. One estimate from the US is that 22 per cent of overdose cases are released by first responders and not brought to hospital, or else they refused to go.
It is therefore very difficult to determine how many cases may occur in Ireland. Applying a 15-to-one ratio (with all the caveats surrounding it) to the 244 deaths reported in the recent National Drug Related Deaths Index Bulletin involving opioids, this suggests that there could have been 3,660 non-fatal overdoses in 2021 and a staggering 34,635 between 2012 and 2021, the brain health consequences of which need to be assessed urgently.
I make that point because of the Position Statement by the Brain Injury Association of America on non-lethal opioid overdose and acquired brain injury, and the British Columbia Consensus Statement of 2022 on brain injury, mental health and addiction. The former pointed out that the cognitive consequences of hypoxic brain injury included slowed reaction times; impulsive decision-making; impaired working memory, visual motor skills and executive functions; as well as an increased risk of relapse.
The Statement went on to call for increased awareness of the link between overdose and brain injury; the need for earlier diagnosis; specific rehabilitation programmes; and more detailed research into the incidence of the condition. The Canadian statement highlighted the specific brain areas affected by either anoxia or hypoxia and the consequences of that deprivation, likening it to repeated concussion and as a result, the difficulty some individuals would have in developing insight into their dependency and engaging in harm-reduction, especially overdose-avoiding behaviours, in the future.
A 2019 report on non-fatal opioid overdoses and associated health outcomes prepared for the US Dept of Health and Human Services stated that while knowledge of acute complications that arise after an opioid overdose is detailed and robust, the corresponding information for chronic complications is alarmingly scarce, given what is already known about hypoxic brain injuries arising from opioid-induced toxicity.
Fentanyl, it noted, increases the risk of acute brain complications, including hypoxia and induced brain hypothermia, partly because the muscle and chest rigidity it causes makes resuscitation and re-oxygenation more difficult. It also pointed out that the risk increases in those experiencing recurrent overdoses.
In that context, a 2017 paper in the International Journal of Drug Policy on factors associated with self-reported overdoses in drug injectors in England, Wales and Northern Ireland is particularly worrying, as it found that one-third of those reporting an overdose in the previous year reported between two and four episodes, and 7.5 per cent of them had five or more overdoses.
A pilot study of cognitive impairment associated with opioid overdose appeared in 2023 in Drug and Alcohol Dependence. In it, 35 individuals who had an overdose in the past year were compared with 43 persons with opioid use disorder who denied ever overdosing. The overdose group had significantly lower cognition scores, with the extent of the impairment linked to the cumulative number of past overdoses.
A 2021 paper in the International Journal of Drug Policy reviewed what it called a vicious cycle of neuropathological, cognitive and behavioural sequelae of repeated overdoses. It noted data that suggested that non-fatal overdose can lead to neurodegeneration resembling Alzheimer’s disease, resulting in cognitive decline that in turn leads to potentially reduced adherence to safer drug using behaviours.
These neuropathological changes have been seen in the brains of young people who had died from a heroin overdose, and are consistent with those reported in animal models of Alzheimer’s disease. Other studies noted increased levels of amyloid beta expression in brain white matter of opioid users compared to control brains. On a positive note, this same research group in a Neurochemistry International paper in 2021 referred to the significant overlap between toxic brain injury and Alzheimer’s disease, which suggested that research into treatments for the latter may also lead to therapies for the chronic effects of overdose.
The take-away messages from this are: To highlight the need for CPR and rapid oxygenation as well as naloxone; the need to call an ambulance, even if naloxone has been administered by a family or staff member; and the need to involve neurology at emergency department level to ensure early intervention if cognitive impairment is suspected. Otherwise, we may be faced with the “tip of the iceberg of a looming public health burden from long-term consequences of repeated overdose,” to quote one expert.
Dr Des Corrigan, Best Contribution in Pharmacy Award (winner), GSK Medical Media Awards
2014, 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.
