Fluoxetine, Paroxetine, Bupropion, and Other Antidepressants May Increase Seizure Risk for Older Nursing Home Residents Who Use Tramadol

Older nursing home residents who take tramadol together with antidepressants that inhibit the CYP2D6 enzyme may face a higher risk of seizures, according to a large population-based cohort study published in Neurology. Relative to those receiving CYP2D6-neutral antidepressants, older nursing home residents who used tramadol and were treated with CYP2D6-inhitibiting antidepressants showed higher adjusted incidence rate ratios of seizures. The study authors stated that clinicians should consider the potential for seizure risk when prescribing antidepressants to older patients who are using tramadol.

In the study, researchers from the University of Florida analyzed the Medicare data from 2010 to 2021 of more than 70,000 US nursing home residents aged 65 years and older who were prescribed both tramadol and an antidepressant. Participants were grouped based on whether they initiated antidepressant therapy while using tramadol or initiated tramadol therapy while using antidepressants. The researchers compared seizure rates among those taking tramadol with CYP2D6-inhibiting antidepressants—such as fluoxetine, paroxetine, or bupropion—vs those using CYP2D6-neutral agents.

Key findings included the following:

• For older nursing home residents who began taking antidepressants while already using tramadol (n=11,162), the seizure incidence rate was 16.10 per 100 patient-years.
• For those who began taking tramadol while already using antidepressants (n=58,994), the seizure incidence rate was 20.17 per 100 patient-years.
• Across both groups, concomitant use of a CYP2D6-inhibiting antidepressant and tramadol was associated higher incidence rate ratios of seizures (1.09 [95% CI, 1.02 to 1.18]) compared with concomitant use of a CYP2D6-neutral antidepressant and tramadol (1.06 [95% CI, 1.03 to 1.10]).
• No increased seizure risk was found when hydrocodone, another opioid, was used concomitantly with CYP2D6-inhibiting vs CYP2D6-neutral antidepressants.

Source: Wei YJ, Winterstein AG, Schmidt S, et al. Risk of seizure associated with concomitant use of tramadol and antidepressants in older nursing home residents. Neurology. 2025;105(p):e214270. doi: 10.1212/WNL.0000000000214270.