Aromatic agents account for virtually all antiepileptic-associated cases, with the burden varying sharply by age and geography.
Antiepileptic drugs have been implicated in almost a quarter of Stevens-Johnson syndrome and toxic epidermal necrolysis cases worldwide, with aromatic agents responsible for virtually all AED-associated cases.
The systematic review and meta-analysis of 50 studies involving 4403 patients, including Australians, found 22.9% of all SJS/TEN cases were associated with antiepileptic drugs (AEDs).
Among cases attributed specifically to drugs, rather than infection or unknown causes, the proportion rose to 27.3%.
“Taken together, these data reinforce the substantial global contribution of AEDs to the SJS/TEN burden and underscore the need to explore factors, such as drug type, geographic variation, and pharmacogenetic risk, that may influence this association,” the researchers wrote.
Published in JAMA Dermatology, the findings point to a striking concentration of risk among aromatic AEDs and support preferential use of nonaromatic alternatives when clinically appropriate.
SJS and TEN are the most severe forms of cutaneous adverse drug reactions, characterised by mucosal erosions, epidermal detachment, and necrosis.
Although rare, with an estimated annual incidence of one to 10 cases per million people, mortality ranges from 20% to 50%. Drug exposure is the leading cause, with allopurinol, aromatic AEDs, sulfonamide antibiotics, and oxicam NSAIDs among the recognised triggers.
AED exposure is widespread beyond epilepsy, with the drugs also prescribed for trigeminal neuralgia, neuropathic pain, migraine prophylaxis, and mood disorders. Their overall use has increased since the early 2000s, while prescribing has progressively shifted from older drugs towards newer agents.
When it comes to serious skin reactions, however, an important distinction is whether an AED is classified as aromatic or nonaromatic.
Aromatic AEDs, which include carbamazepine, oxcarbazepine, phenytoin, phenobarbital, and lamotrigine, contain at least one aromatic ring and are associated with a greater risk of severe cutaneous adverse reactions such as SJS/TEN.
Some of the classic aromatic AEDs, including carbamazepine and phenytoin, are metabolised to reactive compounds known as arene oxide intermediates, which have historically been thought to contribute to these reactions.
Nonaromatic AEDs, including valproic acid, gabapentin, and pregabalin, do not undergo bioactivation to arene oxide intermediates and have a substantially lower incidence of SJS/TEN than aromatic agents, although rare cases still occur.
For the new analysis, researchers searched MEDLINE and Embase through March 2026 and included experimental and observational studies reporting patient-level triggers of SJS/TEN.
All 50 studies ultimately included were retrospective observational studies, spanning Asia, North America, Europe, Africa, and Australia.
Single drugs were responsible for about 88% of SJS/TEN cases. Among the AED-associated cases, aromatic AEDs accounted for 96.1%, while nonaromatic agents accounted for only 1.9%.
Carbamazepine was by far the most frequently implicated AED, accounting for 39.1% of AED-associated SJS/TEN. Phenytoin accounted for 19.0%, lamotrigine 14.6%, and phenobarbital 3.0%. Oxcarbazepine accounted for just 0.1%.
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The distinction between aromatic and nonaromatic AEDs may be clinically important, the researchers noted, especially as AED prescribing has expanded for non-seizure conditions and shifted away from older drugs towards newer agents.
Age emerged as another important difference. In seven paediatric studies involving 288 patients, 34.5% of SJS/TEN cases were associated with AEDs, compared with 23.4% in 21 adult-only studies involving 2215 patients, a statistically significant difference.
There were similarly pronounced geographical differences. The pooled proportion of AED-associated SJS/TEN reached 41.9% in West Asia and 34.9% in South Asia, compared with 23.4% in Southeast Asia and North America, 22.6% in East Asia, and 19.1% in Australia. Europe recorded 13.8% and Africa 10.4%, with the differences between regions statistically significant.
Pharmacogenetics may explain some of that variation, the researchers suggested.
HLA-B*15:02 and other B75 serotype HLA alleles have been linked to an increased risk of carbamazepine-associated SJS/TEN and occur at higher frequencies in some Asian populations. This has led to recommendations for pre-emptive genetic screening before starting carbamazepine in high-risk populations.
But most studies did not report HLA testing, meaning the researchers could not directly assess how much genetic susceptibility contributed to the regional differences. They also cautioned that differences in AED availability, prescribing patterns, and access to newer drugs were potential confounders.
The proportion of AED-associated SJS/TEN also appeared to increase modestly in more recently published studies, they noted.
Sensitivity analyses strengthened the main result, the researchers said. Restricting the analysis to 30 studies considered at lower risk of bias produced an AED-associated proportion of 24.2%, while the 23 studies in which SJS/TEN diagnoses were supported by skin biopsy produced a figure of 24.5%.
However, the researchers cautioned that the certainty of the evidence was low. All included studies were observational, drug causality was often not clearly established, and substantial heterogeneity remained.
Differences in case identification, diagnostic practices, prescribing patterns, healthcare infrastructure, and reporting could all have influenced the results.
“In this systematic review and meta-analysis of observational studies, AEDs were implicated in approximately one-quarter of SJS/TEN cases reported worldwide,” the researchers concluded.
“Nearly all AED-associated cases were attributed to aromatic compounds, with carbamazepine, phenytoin, and lamotrigine being the most frequently implicated.
“These findings suggest aromatic AEDs as leading causes of SJS/TEN and support the preferential use of nonaromatic AEDs, especially in high-risk populations and when clinically appropriate.”
