A study of more than 70,000 nursing home residents has identified a heightened risk of seizures when the common opioid painkiller tramadol is taken concurrently with a specific class of antidepressant medications. The research, published on October 8, 2025, in the medical journal Neurology, highlights a significant drug interaction affecting a vulnerable elderly population, where complex conditions like chronic pain and depression often coexist and require treatment with multiple medications.
The investigation into a decade of Medicare data found a modest but measurable increase in seizure risk when tramadol was used with antidepressants that inhibit a key metabolic enzyme. While tramadol itself is known to carry a risk of seizures, this risk becomes more pronounced when its breakdown in the body is altered by other drugs. The findings underscore the challenges of polypharmacy in geriatric care and suggest that careful selection of antidepressant medication could mitigate this preventable adverse event.
Specific Medications Involved
The study focused on the interaction between tramadol, a synthetic opioid prescribed for moderate to severe pain, and a group of antidepressants known as CYP2D6 inhibitors. The cytochrome P450 2D6 (CYP2D6) enzyme is crucial for metabolizing tramadol in the body. When this enzyme is inhibited by another medication, the processing of tramadol can be disrupted.
Many commonly prescribed antidepressants function as moderate to strong inhibitors of this enzyme. The medications identified in this category include widely used drugs such as bupropion, fluoxetine, paroxetine, sertraline, and duloxetine. The study’s results suggest that the seizure risk is not associated with all antidepressants but is specific to those that interfere with the CYP2D6 metabolic pathway. This distinction is critical for prescribing physicians managing care for older adults.
Examining the Seizure Risk
Researchers quantified the elevated risk by analyzing two primary scenarios. For nursing home residents already taking tramadol who then started a CYP2D6-inhibiting antidepressant, the risk of having a seizure was 9% higher compared to those who started a non-inhibiting antidepressant. Conversely, for residents already taking a CYP2D6-inhibiting antidepressant who were newly prescribed tramadol, the seizure risk was 6% higher than for those taking a non-inhibiting antidepressant.
The incidence rates revealed a more dramatic picture. Among patients who started an antidepressant while on tramadol, the seizure rate was 22 per 100 person-years for those taking CYP2D6 inhibitors. For patients who added tramadol to an existing antidepressant regimen, the rate was 20 seizures per 100 person-years. These rates are substantially higher than the estimated baseline seizure incidence of 1.64 per 100 person-years among the general nursing home population.
Research Methodology
The findings are based on a robust cohort study that analyzed 10 years of data from the national Medicare program, focusing on 70,156 nursing home residents aged 65 and older who were prescribed both tramadol and an antidepressant. This large-scale, real-world evidence allowed researchers to examine the safety of these commonly co-prescribed medications in a frail, elderly population that is often underrepresented in clinical trials.
A Comparative Analysis
To ensure the observed seizure risk was specific to the interaction with tramadol, the research team conducted a parallel analysis using a different opioid. They replaced tramadol with hydrocodone, another frequently prescribed pain reliever, and examined its use with CYP2D6-inhibiting antidepressants. The results of this control experiment showed no increased risk of seizures, reinforcing the hypothesis that the effect is a unique pharmacologic interaction between tramadol and the specific antidepressants, not a general effect of opioids combined with antidepressants.
The Pharmacokinetic Mechanism
The increased risk of seizures is believed to stem from a pharmacokinetic interaction between the two types of drugs. Tramadol’s product label already includes a warning that seizures can occur and that this risk may be elevated when used with other drugs. The CYP2D6 enzyme is essential for converting tramadol into one of its major metabolites. When antidepressants like fluoxetine or bupropion inhibit this enzyme, it can lead to higher-than-expected concentrations of tramadol in the bloodstream, which may lower the seizure threshold.
This study provides strong evidence that this metabolic interference has clinically significant consequences. By disrupting the normal breakdown of tramadol, the inhibiting antidepressants effectively increase the drug’s potency and potential for adverse neurological effects. The risk was present whether the antidepressant was started before or after the tramadol, indicating the interaction occurs regardless of the prescribing sequence.
Clinical Guidance for Prescribers
The study’s authors emphasize that while the findings show a clear association, they do not definitively prove causation. However, the evidence is strong enough to warrant clinical caution. Experts suggest that physicians, patients, and caregivers should be more aware of the potential for seizures when tramadol and antidepressants are used together in older adults.
A key recommendation emerging from the research is for clinicians to consider alternative medications. When a patient requires both a pain reliever like tramadol and an antidepressant, selecting an antidepressant that does not significantly inhibit the CYP2D6 enzyme may be a safer therapeutic strategy. Such “CYP2D6-neutral” antidepressants would not interfere with tramadol metabolism, thereby avoiding the increased seizure risk. This approach allows for the continued treatment of both pain and depression while minimizing the potential for a serious adverse drug event in a vulnerable population.