A recent paper from researchers at the School of Pharmacy and Biomolecular Sciences RCSI, the State Lab, Forensic Science Ireland, and the HSE looked at trends in gabapentinoid prescribing, drug seizures, and postmortem toxicology – and again highlights the problems arising from the misuse and, in some cases, abuse of this group of drugs. The research puts a spotlight on the need for a changed regulatory approach to pregabalin.
This observational study from the RCSI, published in the British Journal of Clinical Pharmacology in 2023, found that prescribing rates per 100,000 of the population increased for pregabalin (mainly) but also for gabapentin. Women over the age of 45 were more likely to be prescribed pregabalin.
The rate of detection of both drugs in postmortem samples increased between 2013 and 2020. Of those fatalities that tested positive for heroin/methadone, 28 per cent also tested positive for pregabalin. More than a third of the pregabalin cases in 2018 were also positive for benzodiazepines and, in 2020, 29 per cent were also positive for prescription opioids.
The authors highlighted the potential for serious harm due to multidrug toxicity especially in those already on Opioid Substitution Therapy (OST) involving either methadone or Suboxone. Pregabalin is particularly attractive to those on methadone because of the euphoria that can be achieved, as well as the rapid absorption, faster onset of relaxant and sedative effects, and reduced withdrawal.
The report also refers to the growing illicit supply of pregabalin. There were 14 seizures in 2016 rising to 59 in 2020. I wonder on what basis these seizures were made since neither gabapentinoid is currently scheduled under the Misuse of Drugs Acts. A number of groups and individuals, myself included, believe that these drugs should be designated as controlled substances under the Misuse of Drugs Acts, partly because of the emerging black market but mainly because of the deaths linked to pregabalin.
A press release from the Health Research Board last autumn, relating to their submission to the Citizens Assembly on Drugs Use, included the latest available drug-related death figures. These revealed that there were 409 poisoning deaths in 2020, of which almost six in 10 involved prescribed benzodiazepines, anti-depressants, and anti-epileptics. In this latter category, deaths linked to pregabalin rose from less than five in 2012 to 84 in 2020. In all, there have been 519 overdose deaths where pregabalin has been detected postmortem between 2012 and 2020.
To that horrendous toll can be added another 245 cases from Northern Ireland. These cases were reviewed in a 2024 paper in the Journal of Forensic and Legal Medicine. The level of detail about these deaths is much greater than the detail we have for deaths in the republic. The majority (73 per cent) were males with a mean age of 35. Half had a documented history of depression, self-harm, and suicide attempts. A history of drug misuse was documented in 82 per cent. Tellingly, just 38 per cent were prescribed the pregabalin by their GP, suggesting a high level of illicit sourcing of the drug.
A similar study of gabapentinoid-related deaths in England, reported in the British Journal of Clinical Pharmacology, said that prescribed and illicitly sourced pregabalin accounted for roughly similar proportions of deaths. Opioids were co-detected in 92 per cent of cases. This is of concern as research suggests that such co-administration reverses opioid tolerance, and so increases the attractiveness of the combination, but obviously also increases the risk of death from opioid overdose.
Most deaths were due to central nervous system depression with respiratory failure and cardiac complications. An article in the autumn 2019 issue of Drugnet (the newsletter of Ireland’s Focal Point to the EU’s Drugs Agency) was entitled ‘Has an increase in the dispensing of pregabalin influenced poisoning deaths in Ireland?’. This looked at all Primary Care Reimbursement Service data between 2013 and 2016, and not just the GMS prescriptions that formed the basis of the RCSI study; thus, it included Long-Term Illness and Drug Payment Scheme figures and matched it to the numbers of deaths from the National Drug Related Deaths Index (NDRDI) for those years.
In 2013, there were 612,641 prescriptions dispensed and 18 pregabalin-positive toxicology poisoning deaths, rising to 755,159 scripts and 94 deaths in 2016. There was a strong positive correlation between the increase in prescribing and the level of deaths, leading the author to conclude that the results supported the reclassification of pregabalin in Ireland, similar to that which came into force in the UK in April 2019.
Pregabalin is particularly attractive to those on methadone because of the euphoria that can be achieved, as well as the rapid absorption, faster onset of relaxant and sedative effects, and reduced withdrawal
It was reported in The Irish Times this time last year that the Coroners Society of Ireland, referring to pregabalin as ‘Coffin Tablets’, called for the drug to be classified as a controlled drug in submissions to the Health Products Regulatory Authority, the Department of Justice, and the Department of Health. Their call was based on NDRDI data; inquests and reports of sale on the streets of what users call ‘Buds’ because of the euphoric drunken effects experienced when above-normal therapeutic doses are consumed.
According to the same article, SafetyNet, a charity that provides medical services to the homeless and the marginalised, also sought to have pregabalin controlled. A spokesperson noted the existence of the black market with a 100mg capsule selling for €1 and a 300mg one going for €3.
It is not possible to respond adequately to black market selling while these drugs remain outside the ambit of the Misuse of Drugs Act. In calling for the scheduling of both gabapentinoids I wonder how many deaths might have been prevented if inappropriate prescribing and black market supply had been inhibited here since 2019? However, I expect the fact that pregabalin-related deaths have not decreased in the UK since the drug was included within its Misuse of Drugs Act in 2019 would be mentioned as a possible reason for regulatory inaction.
In echoing the call by the Medical Council for prescribers to exercise caution when prescribing gabapentinoids, in particular to known opioid-dependent patients, I would probably be reminded that the 2022 CDC guidelines for the treatment of pain highlight the need to use non-opioid therapies instead of opioids. Included in the non-opioid category are the gabapentinoids. Another potential brake on changing the status of these drugs is the Supreme Court Bederev ruling relating to the unconstitutionality of government scheduling of substances under Section 2 of the Misuse of Drugs Act. Notwithstanding these points, the death toll linked to pregabalin on the island of Ireland surely dictates that regulatory action is long overdue.
