Adverse Effects
Sonya Collins
The list of on- and off-label indications for anticonvulsants topiramate and zonisamide is ever growing and, with that, use of the drugs has been on the rise. Originally approved to control seizures in epilepsy, these drugs are now frequently prescribed for migraine prevention, weight loss, bipolar disorder, alcohol use disorder, PTSD, essential tremor, cluster headache prevention, and Parkinson’s disease.
As indications for these drugs have expanded, new prescriptions for topiramate and zonisamide went up by 24.8% and 27%, respectively, among commercially insured people between 2011 and 2019. Increasing use of these medications could lead to an increase in kidney stones, according to a study by Salka and colleagues published in the June 2025 issue of the American Journal of Kidney Disease. The research found that patients taking these drugs faced an up to 58% increased risk for kidney stones over the first 3 years after filling the prescription.
“Like many drugs, decision to prescribe is a risk-benefit analysis,” said John Hollingsworth, MD, a coauthor of the study. “Perhaps when considering a disease in which there are many treatment options, such as migraine prophylaxis, providers should consider alternatives to topiramate and zonisamide if the patient has a prior history of calcium kidney stones.” Hollingsworth, a urologist, is chief safety officer for UF Health.
Anti-epileptic use, kidney stones on the rise
While it doesn’t seem to be the mechanism of their therapeutic benefits, both topiramate and zonisamide inhibit carbonic anhydrase, an enzyme that plays a crucial role in maintaining the body’s acid-base balance, fluid regulation, and gas exchange.
“When carbonic anhydrase is inhibited, bicarbonate is lost in the urine, raising urine pH and causing a mild systemic acidosis, which leads to a fall in urine citrate,” Hollingsworth said. “Citrate is a critical inhibitor of calcium kidney stone formation.”
Knowing how these drugs act on the kidneys, the researchers aimed to determine whether the rise in prescriptions led to a subsequent rise in kidney stones. They analyzed the medical and pharmacy claims data on 1,122,301 patients generated between January 2011 and September 2019, which included 187,032 patients who filled a prescription for topiramate or zonisamide and age- and sex- matched controls. The claims information was culled from a database of commercially insured people and from Medicare enrollees.
After the researchers adjusted for other kidney stone risk factors, commercially insured patients who filled a prescription for topiramate or zonisamide were 58% more likely to have a kidney stone event between 3 months and 3 years of filling the prescription. In the Medicare cohort, these medications were associated with a 22% greater risk for symptomatic kidney stone events.
Notably, these anti-epileptics were most often prescribed for migraine in the commercially insured cohort and obesity in the Medicare group.
Practice recommendations
While lowering the dose of anticonvulsants to avoid kidney stones might be effective, this strategy hasn’t been well studied, Hollingsworth said. For patients who have other risk factors for kidney stones, prescribers may consider alternatives to anticonvulsants.
“Topiramate and zonisamide are used for many medical problems, including migraines, seizures, obesity, PTSD, and alcohol addiction. Alternative drugs would depend on the indication they are being used for,” Hollingsworth said. “In general, there are usually alternative drugs available if side effects from topiramate and zonisamide become a problem, but some patients may be wary of stopping the medication if they feel it has been more effective for their headaches and/or seizures than prior medications they have used.”
Pharmacists dispensing these anticonvulsants can ask patients about any history of kidney stones and other risk factors, counsel them on the risks of the medication, and offer risk-mitigating tips such as staying hydrated. ■