New Findings Spotlight Drug Interaction risk for older adults
A study published on October 8, 2025, in Neurology®, the journal of the American Academy of Neurology, highlights a modest but measurable increase in seizure risk when the pain medicine tramadol is prescribed alongside certain antidepressants in older adults living in nursing homes. While the research shows an association, it does not prove causation. The findings emphasize the importance of careful medication management for seniors with complex health needs.
How tramadol interacts with antidepressants
Tramadol is an opioid used to treat moderate to severe pain in adults. Some antidepressants inhibit the CYP2D6 enzyme, a key pathway the body uses to metabolize tramadol. When CYP2D6 is blocked, tramadol may accumulate in the body, potentially increasing the risk of side effects such as seizures. Common CYP2D6-inhibiting antidepressants include fluoxetine, paroxetine and bupropion.
What the study found
Researchers led by Yu-Jung Jenny Wei, PhD, of Ohio State University, analyzed a decade of Medicare data, focusing on 70,156 nursing home residents aged 65 and older who were prescribed both tramadol and an antidepressant. Participants were split into two groups: those who started tramadol first and then added an antidepressant, and those who started with an antidepressant and then added tramadol.
Seizure rates were 16 per 100 person-years for the tramadol-first group and 20 per 100 person-years for the antidepressant-first group. This means that, on average, among 100 residents followed for a year, 16 to 20 received a seizure diagnosis in the two-drug exposure periods.
Dissecting the interaction: CYP2D6 inhibition matters
To isolate the drug interaction, researchers compared seizure rates when tramadol was taken with CYP2D6-inhibiting antidepressants versus non-inhibiting antidepressants. Among those who started tramadol first, seizure risk was 18 per 100 person-years with a CYP2D6-inhibiting antidepressant versus 16 with other antidepressants. Among those who started with an antidepressant and added tramadol, the rate was 22 per 100 person-years with a CYP2D6-inhibiting antidepressant versus 20 with non-inhibitors.
After adjusting for pain levels, depressive symptoms, physical function and cognitive ability, the increased risk persisted—but was modest. Specifically, the study found about a 9% higher risk for the tramadol-first group and a roughly 6% higher risk for the antidepressant-first group when a CYP2D6-inhibiting antidepressant was used compared with non-inhibiting options.
Is the finding specific to tramadol?
To determine whether this interaction was unique to tramadol, the researchers conducted a parallel analysis using hydrocodone, an opioid pain reliever not typically associated with seizure risk when paired with antidepressants. Hydrocodone did not show an increased seizure risk with CYP2D6-inhibiting antidepressants, suggesting a tramadol-specific interaction pattern.
Clinical implications for prescribers
The authors stress that these results have real-world relevance for clinicians managing pain and mood symptoms in older adults, especially in nursing homes where polypharmacy is common. Dr. Wei noted that the interaction could be more consequential than previously thought given the high prevalence of both tramadol and antidepressant prescriptions in this population.
Healthcare providers should consider alternative pain management strategies when possible, or closely monitor patients when combining tramadol with CYP2D6-inhibiting antidepressants. Shared decision-making with patients and caregivers about the risks and benefits is essential, particularly for residents with a history of seizures or other neurologic concerns.
Limitations and future directions
A notable limitation of the study is its reliance on prescription records to infer drug use. This approach cannot confirm whether patients adhered to prescribed regimens. The authors call for prospective studies or randomized trials to establish causality and to explore whether switching to non-inhibiting antidepressants or alternative analgesics can mitigate seizure risk without compromising pain and mood relief.
What this means for older adults and caregivers
For seniors in nursing homes, the interplay between pain control and mental health treatment is a daily reality. The new Neurology study adds a layer of caution to the combined use of tramadol and certain antidepressants. Care plans should prioritize regular medication reviews, pain assessment, and neurological monitoring, especially after initiating or changing therapy.
A note on ongoing research
The study was supported by the National Institute on Aging. As the elderly population grows and polypharmacy remains common, researchers and clinicians will continue to evaluate how best to balance effective pain relief with safety in older adults.
