Risk of Seizure Associated With Concomitant Use of Tramadol and Antidepressants in Older Nursing Home Residents

Concomitant use of tramadol and antidepressants with potent inhibition of the cytochrome P450 2D6 (CYP2D6) enzyme is postulated to increase risk of seizures in older adults; yet, such an association has not been empirically tested in populations. We aimed to examine the association of concomitant tramadol and CYP2D6-inhibiting vs CYP2D6-neutral antidepressant use and the risk of seizures among older nursing home (NH) residents.

This population-based cohort study was conducted using a 100% Medicare NH sample from January 2010 to December 2021. We included long-term residents aged 65 years or older who initiated antidepressants on existing tramadol use (tramadol-antidepressant users) or initiated tramadol on existing antidepressant use (antidepressant-tramadol users). Patients were followed up until the end of 1 year, NH discharge, death, or study end. The key exposure was concomitant use of tramadol with CYP2D6-inhibiting vs CYP2D6-neutral antidepressants. The key outcome was incident rates of medical encounters with a diagnosis of seizure and analyzed using negative binomial or Poisson regression models adjusted for baseline covariates (e.g., pain status and depressive, physical, and cognitive function) through the inverse probability of treatment weighting.

We identified 11,162 concomitant tramadol-antidepressant users (mean [SD] age, 86.2 [8.5] years; 9,077 [81.3%] female) and 58,994 concomitant antidepressant-tramadol users (mean [SD] age, 85.3 [8.4] years; 47,053 [79.8%] female). The incidence rate of seizures was 16.10 and 20.17 per 100 patient-years, respectively, for the tramadol-antidepressant and antidepressant-tramadol group. In both subgroups, co-use of tramadol with CYP2D6-inhibiting (vs with CYP2D6-neutral) antidepressants was associated with higher adjusted incidence rate ratios of seizures (1.09 [95% CI 1.02-1.18] and 1.06 [95% CI 1.03-1.10]). Findings were corroborated by a negative control exposure analysis in which co-use of hydrocodone with CYPD2D6-inhibiting (vs CYP2D6-neutral) antidepressants was not associated with risk of seizures.

Concomitant use of tramadol with CYP2D6-inhibiting vs CYP2D6-neutral antidepressants was associated with increased risk of seizures. Findings are only generalizable to long-term NH populations and are subject to residual confounding. Clinicians should be mindful of seizure risk in older patients who use tramadol concomitantly with antidepressants, particularly CYP2D6-inhibiting antidepressants.

This study provides Class II evidence that the combination of tramadol and CYP2D6-inhibiting antidepressants is associated with a higher risk of seizures compared with the combination of tramadol and CYP2D6-neutral antidepressants.