New Findings on Drug Interactions in Senior Care
A study published on October 8, 2025, in Neurology®, the medical journal of the American Academy of Neurology, reports a modest but meaningful link between taking tramadol for pain and certain antidepressants that inhibit the CYP2D6 enzyme in older adults living in nursing homes. The researchers found an increased risk of seizures when tramadol is used together with these antidepressants, though the data do not prove causation.
What Is Tramadol and Why the Interaction Matters
Tramadol is a widely prescribed opioid for managing moderate to severe pain in adults. Some antidepressants, especially those that inhibit the CYP2D6 enzyme such as fluoxetine, paroxetine, and bupropion, can alter how the body metabolizes tramadol. When CYP2D6 is blocked, tramadol may accumulate in the body, potentially heightening the risk of adverse effects, including seizures.
The Study Design and Key Findings
Researchers analyzed ten years of Medicare data to identify 70,156 nursing home residents aged 65 and older who had been prescribed both tramadol and an antidepressant. Participants were divided into two groups: those who started tramadol first and then added an antidepressant, and those who started with an antidepressant and later added tramadol.
In the tramadol-first group, seizure rates were 16 per 100 person-years; in the antidepressant-first group, rates were 20 per 100 person-years. This means that, on average, among 100 people followed for a year, 16–20 seizure diagnoses occurred depending on the drug sequence.
When the analysis compared CYP2D6-inhibiting antidepressants with non-inhibiting ones, the seizure risk varied by group. For those who started tramadol first, the seizure rate was 18 per 100 person-years with CYP2D6-inhibiting antidepressants vs. 16 with non-inhibiting antidepressants. For those who started with an antidepressant and added tramadol, the rate was 22 vs. 20 per 100 person-years, respectively.
To ensure the results were not simply due to other health issues, the researchers adjusted for pain levels, depression symptoms, physical function, and cognitive ability. After adjustment, the risk remained modest but higher: about 9% greater seizure risk for the tramadol-first group when paired with a CYP2D6-inhibiting antidepressant, and about 6% higher for the antidepressant-first group that later added tramadol.
As a control, the team looked at hydrocodone, another opioid pain reliever not typically associated with CYP2D6 interactions. No increased seizure risk emerged with hydrocodone when used with CYP2D6-inhibiting antidepressants, suggesting the tramadol–CYP2D6 interaction may be specific.
What This Means for Prescribing in Geriatrics
“These findings underscore the need for careful prescribing practices, especially for older adults with complex health conditions,” said Yu-Jung Jenny Wei, PhD, of The Ohio State University. She noted that the risk was present regardless of which drug was started first and emphasized awareness among clinicians about potential seizure risks when tramadol is co-prescribed with CYP2D6 inhibitors.
The study’s authors stressed that prescription data come from records and do not confirm whether patients adhered to their medications. Despite this limitation, the associations observed point to a tangible interaction that clinicians should consider when treating pain and mood disorders in seniors who reside in nursing facilities.
The research was supported by the National Institute on Aging, highlighting the growing importance of understanding polypharmacy in aging populations as the number of older adults receiving both analgesics and antidepressants continues to rise.
Practical Recommendations for Clinicians and Caregivers
- Review medication lists to identify CYP2D6 inhibitors when tramadol is on the regimen.
- Consider alternative pain management strategies or antidepressants without CYP2D6 inhibition when possible.
- Monitor for signs of seizures, especially after initiating or changing tramadol and antidepressant therapy.
- Engage patients, families, and care teams in shared decision-making about risks and benefits.
As the population ages, maximizing safety in pharmacotherapy for older adults will require ongoing assessment of drug–drug interactions and individualized care plans.
