A new large-scale study of older adults in nursing homes has identified a heightened risk of seizures when the widely used opioid pain medication tramadol is taken concurrently with a specific class of common antidepressants. The research, which analyzed a decade of Medicare data, found a modest but significant increase in seizure incidence among patients using both tramadol and antidepressants that block a key metabolic enzyme, highlighting a potentially critical drug interaction for a vulnerable population.
The findings, published on October 8, 2025, in Neurology, the medical journal of the American Academy of Neurology, address a crucial safety question given the frequent overlap of chronic pain and depression in adults over 65. Researchers focused on how certain antidepressants interfere with the body’s ability to process tramadol, leading to an accumulation of the drug that may lower the seizure threshold. While the study confirms an association rather than direct causation, its results underscore the need for cautious prescribing and diligent medication management in older patients with complex health needs.
Examining the Drug Interaction
The investigation centered on two commonly prescribed categories of medication. Tramadol is an opioid medication prescribed for moderate to severe pain. The other drugs in question are antidepressants that function as inhibitors of an enzyme known as cytochrome P450 2D6, or CYP2D6. This enzyme is essential for metabolizing many common medications, including tramadol. When its function is blocked, tramadol is not broken down and cleared from the body at a normal rate.
This impaired metabolism can cause levels of the painkiller to build up, increasing the risk of adverse effects. Seizures are a known, albeit rare, side effect of high doses of tramadol, and this risk appears to be amplified by the interaction. Common CYP2D6-inhibiting antidepressants identified in the study include popular selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and paroxetine, as well as the antidepressant bupropion. The study’s findings suggest that the specific combination of these antidepressants with tramadol warrants closer scrutiny by clinicians.
A Large-Scale Patient Data Analysis
To investigate the potential risk, researchers from The Ohio State University conducted a detailed analysis of health records for 70,156 nursing home residents aged 65 and older who were prescribed both tramadol and an antidepressant. The data was sourced from 10 years of Medicare records, providing a robust and extensive dataset for evaluating real-world outcomes. The residents were separated into groups based on which medication they started first—the antidepressant or the painkiller.
Study Design and Methodology
The research team identified two main cohorts within the dataset. One group of 11,162 residents began treatment with tramadol before adding an antidepressant. A much larger group of 58,994 residents was already taking an antidepressant before being prescribed tramadol for pain management. Within each of these groups, the scientists compared the rate of new seizure diagnoses among those taking CYP2D6-inhibiting antidepressants versus those taking other types of antidepressants that do not interfere with the enzyme.
Measuring the Seizure Risk
The results revealed a consistent pattern. Among the residents who started an antidepressant first, the seizure rate was 22 per 100 person-years for those taking a CYP2D6 inhibitor alongside tramadol. This compared to a rate of 20 seizures per 100 person-years for those taking other antidepressants. A similar increase was observed in the group that started tramadol first, where the seizure rate was 16 per 100 person-years. Person-years is a statistical measure that reflects the total time patients are followed in a study; for example, 100 people followed for one year constitutes 100 person-years.
Implications for Clinical Practice
The study authors emphasize that these findings should prompt clinicians to be more vigilant when prescribing these medications together. “We found a modest but measurable increase in the risk of seizures when tramadol was taken with antidepressants that inhibit the CYP2D6 enzyme,” stated study author Yu-Jung Jenny Wei, PhD. “This risk was consistent whether the antidepressant or tramadol was started first.” Wei noted that given the common use of both drug types in older adults, this interaction may be more significant than previously thought.
The research provides actionable information for prescribers. When treating an older adult for pain who is already on a CYP2D6-inhibiting antidepressant, a physician might consider an alternative pain medication. To strengthen their findings, the researchers performed a crucial cross-check by examining another commonly prescribed opioid, hydrocodone. They found no similar increase in seizure risk when hydrocodone was combined with the same antidepressants, indicating that the effect is specific to tramadol’s metabolic pathway and not a general effect of opioids.
Context and Study Limitations
It is important to note that the study establishes a strong correlation but does not definitively prove that the drug combination causes the seizures. This type of observational research, which analyzes past health records, cannot rule out all other contributing factors. However, the specificity of the interaction with tramadol and the known biological mechanism provide compelling evidence for a causal link.
The findings also exist within the broader context of medication safety. Antidepressants as a class have long been associated with a small but recognized risk of lowering the seizure threshold, even when used alone. This underlying risk may be exacerbated by the metabolic interference from the drug combination. The study’s focus on a nursing home population is also significant, as these patients are often managing multiple chronic conditions and taking numerous medications, a scenario known as polypharmacy, which inherently increases the risk of adverse drug interactions.
Moving Toward Safer Prescribing
The conclusions from this study serve as a reminder of the complexities of prescribing medications to older adults. Chronic pain and depression are widespread and debilitating conditions that require effective treatment, but the potential for drug interactions necessitates a careful, individualized approach. “These findings underscore the need for careful prescribing practices, especially for older adults with complex health conditions,” Wei concluded. For physicians and pharmacists, this means conducting thorough medication reviews and remaining aware of potential risks when combining tramadol with certain antidepressants. For patients and their families, it highlights the importance of open communication with healthcare providers about all medications being taken, both prescription and over-the-counter, to ensure the safest possible treatment plan.
