TRAMADOL with CYP2D6-inhibiting antidepressants was associated with higher seizure rates in nursing home residents in Medicare. The association came from a population-based cohort using a complete Medicare nursing home sample from 2010 to 2021. Investigators evaluated two exposure sequences that reflect common prescribing pathways in long-term care. One group started an antidepressant while already receiving tramadol. The other group started tramadol while already receiving an antidepressant. The central comparison focused on concomitant tramadol with CYP2D6-inhibiting antidepressants versus tramadol with CYP2D6-neutral antidepressants. Incident medical encounters coded as seizures were modeled using negative binomial or Poisson regression with inverse probability of treatment weighting. Covariates included pain status and measures of depressive, physical, and cognitive function to reduce confounding.
Seizure Risk with Tramadol and Antidepressants
Among 11,162 residents who added an antidepressant to tramadol and 58,994 who added tramadol to an antidepressant, seizure incidence was 16.10 and 20.17 per 100 patient-years, respectively. Across both sequences, co-use of tramadol with CYP2D6-inhibiting antidepressants produced higher adjusted incidence rate ratios for seizures than co-use with CYP2D6-neutral agents. Point estimates were 1.09 with a 95% confidence interval of 1.02 to 1.18 in the tramadol-first sequence and 1.06 with a 95% confidence interval of 1.03 to 1.10 in the antidepressant-first sequence. A negative control exposure analysis substituting hydrocodone for tramadol did not show an association between CYP2D6-inhibiting antidepressants and seizures. This supports specificity of the observed signal to tramadol within this nursing home population.
Study Design and Key Outcomes
The cohort included long-term residents aged 65 years or older who met new-use definitions for the paired therapies. Follow-up continued for one year, discharge from the nursing home, death, or the end of the study period. The study provides Class II evidence that the combination of tramadol and CYP2D6-inhibiting antidepressants is associated with a higher risk of seizures than the combination of tramadol and CYP2D6-neutral antidepressants. Findings are generalizable to long-term nursing home residents receiving Medicare coverage and remain subject to residual confounding despite extensive adjustment.
Clinical Considerations for Older Adults
These results indicate incremental seizure risk with tramadol when paired with CYP2D6-inhibiting antidepressants in geriatric long-term care. Clinicians should review antidepressant selection, assess individual seizure risk factors, and monitor closely when initiating or modifying concomitant therapy. Where clinically appropriate, consider CYP2D6-neutral alternatives and ensure rapid evaluation of new neurologic symptoms.
Reference: Wei YJ et al. Risk of Seizure Associated With Concomitant Use of Tramadol and Antidepressants in Older Nursing Home Residents. Neurology. 2025;105(9).
