- Gabapentinoids like pregabalin were originally developed as antiseizure drugs, but frequently are used off-label in many countries.
- In Australia, three major interventions coincided with fewer pregabalin prescriptions and overdoses, according to retrospective data.
- Interventions included raising public awareness of pregabalin's risks through the media and adding boxed warnings to prescribing information.
High-profile media coverage of the harms associated with the gabapentinoid pregabalin (Lyrica) and tighter safeguards coincided with fewer prescriptions and overdoses in Australia, a retrospective study showed.
Following a media campaign, tighter dispensing rules, and boxed warnings, pregabalin prescriptions and overdoses dropped significantly below projected trends -- falling by 25% and 47%, respectively -- reported Rose Cairns, PhD, of the University of Sydney, and co-authors in The BMJ.
This was a reversal from a steep upward trajectory that had persisted since 2013, the researchers noted. The shift corresponded to ongoing monthly reductions in prescriptions of 0.7% (95% CI 0.5-0.9) and in poison center overdose calls of 1.6% (95% 1.0-2.3).
Australia historically has had a big problem with pregabalin use and overdose, and many other countries face similar issues, Cairns noted.
"Importantly, the interventions that were associated with a decrease in harms included things like raising public awareness of the risks via the media and boxed warnings. These relatively 'soft' interventions can still have an impact," she told MedPage Today.
The findings are "really positive, but we think use of pregabalin is still far too high," Cairns continued. "There's a lot of off-label use for conditions with minimal evidence to back that up. And while high-risk use has decreased, we really need to continue to minimize co-use with opioids, which has been shown to increase the risk of death."
Gabapentinoids -- pregabalin and gabapentin -- were originally developed as antiseizure drugs. Subsequent indications have expanded to include neuropathic pain, postherpetic neuralgia, and fibromyalgia.
"Despite this relatively narrow range of approved indications, gabapentinoids are considered 'blockbuster' drugs," Cairns and colleagues wrote. "High-income countries have the highest rates of gabapentinoid consumption, while low- and middle-income countries have had the highest consumption growth in recent years. Most of this consumption is driven by off-label use for non-registered indications."
In the U.S., pregabalin is scheduled under the Controlled Substances Act. Gabapentin is not scheduled at the federal level but eight states have enacted legislation to classify gabapentin as a schedule V controlled substance.
In 2019, the FDA warned that respiratory depression or death may occur in patients taking pregabalin or gabapentin with opioid pain medicines or other drugs that depress the central nervous system. Despite this, co-prescribing of gabapentinoids and opioids persists.
In the U.K., one-third of substance use deaths involve a gabapentinoid, predominantly pregabalin, and deaths involving gabapentinoids have more than doubled from 2018 to 2022, Cairns and co-authors noted.
The study in Australia is "timely and rigorous, but these figures warrant caution," noted David Juurlink, MD, PhD, of the Sunnybrook Health Sciences Centre in Toronto, in an accompanying editorial. "The ecological design cannot establish causation, and poison center calls are an imperfect measure of poisoning incidence, influenced by reporting practices and patterns of healthcare use," he pointed out.
Pregabalin should be used more selectively, Juurlink argued. "Although it can provide meaningful relief in some patients with neuropathic pain or fibromyalgia, most do not achieve substantial pain relief," he wrote.
"For other painful conditions, the evidence is even less encouraging," Juurlink added. "Randomized trials and meta-analyses have found no convincing evidence of benefit for low back pain or sciatica, conditions for which the drug is nevertheless frequently prescribed. Pregabalin's commercial success, in other words, has far outstripped its demonstrated clinical utility."
To evaluate pregabalin use and misuse in Australia, Cairns and colleagues evaluated dispensing claims and poison center overdose data from 2016 to 2024, focusing on three key events: widespread media reporting about the harms of pregabalin in December 2018, tighter prescribing restrictions after April 2020, and the introduction of boxed warnings in February 2021.
The researchers randomly sampled 10% of Australians with drug subsidies and 50% of calls placed to the country's largest poison control center. During the study period, 227,864 people were dispensed 3,441,851 pregabalin prescriptions, and 4,871 pregabalin overdose calls were reported.
Use and overdoses peaked in 2018 before plateauing and declining. Dispensing dropped significantly at three time points: in December 2018 (corresponding to high-profile press coverage), in May 2020 (after tighter prescribing restrictions were introduced), and in December 2021 (after boxed warnings were in effect).
The findings are observational, the researchers acknowledged. The study analyzed subsidized prescriptions only and poisons center data may be subject to reporting bias, they added. The researchers also could not determine patients' access to pain treatments.
Disclosures
Researchers were supported by National Health and Medical Research Council investigator grants.
Cairns reported a relationship with Reckitt. Co-authors had no disclosures.
Juurlink has provided expert witness services in the context of ongoing civil and criminal legal actions.
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