New findings link tramadol and certain antidepressants to increased seizure risk in older adults
A recent study published in Neurology®, the medical journal of the American Academy of Neurology, investigated whether older adults living in nursing homes who are prescribed the pain drug tramadol alongside certain antidepressants might face a higher risk of seizures. The researchers found a modest, but measurable, association between the combination and seizure risk. While the study does not prove that one medication causes seizures, it points to a potential interaction worth careful consideration by clinicians and caregivers.
How the medicines interact in the body
Tramadol is an opioid analgesic used to treat moderate to severe pain. Some antidepressants are CYP2D6 inhibitors, meaning they can slow or alter the way the body metabolizes tramadol. When the CYP2D6 enzyme is inhibited, tramadol may accumulate in the body, potentially increasing the likelihood of side effects such as seizures. Common CYP2D6-inhibiting antidepressants include fluoxetine, paroxetine and bupropion.
What the study found
The Ohio State University team led by Yu-Jung Jenny Wei, PhD, analyzed a decade of Medicare data, focusing on 70,156 nursing home residents aged 65 and older who had been prescribed both tramadol and an antidepressant. Participants were split into two groups based on which medication was started first: tramadol first or antidepressant first.
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. These figures translate to roughly 16 or 20 seizures per 100 people followed for one year when both drugs were used.
The researchers then compared seizure rates for patients taking tramadol with CYP2D6-inhibiting antidepressants versus those taking tramadol with non-inhibiting antidepressants. Among those who started with tramadol, seizures were 18 per 100 person-years with CYP2D6-inhibiting antidepressants versus 16 with non-inhibitors. Among those who started with an antidepressant, seizures were 22 per 100 person-years with CYP2D6-inhibiting antidepressants versus 20 with non-inhibitors.
Adjusting for other factors
To avoid confounding from other health issues, the researchers adjusted for pain intensity, depression symptoms, physical function and cognitive ability. After these adjustments, the relative increases in seizure risk remained: about 9% higher for the tramadol-first group and 6% higher for the antidepressant-first group when the accompanying antidepressant inhibited CYP2D6 compared with non-inhibiting antidepressants.
The study also included a comparison with hydrocodone, another opioid pain reliever not typically linked to increased seizure risk when used with antidepressants. Hydrocodone showed no similar increase, suggesting the interaction observed with tramadol and CYP2D6 inhibitors may be specific to tramadol’s metabolic pathway.
Clinical implications
Wei emphasized that the findings underscore the importance of careful prescribing, particularly for older adults with complex health needs. For clinicians, this means evaluating the necessity of tramadol when an antidepressant that inhibits CYP2D6 is also prescribed. Where possible, alternatives or careful monitoring may be warranted to mitigate potential seizure risk.
It is important to note that the study cannot establish causation. The data derive from prescription records, which do not confirm patient adherence or whether medications were taken exactly as directed. Nonetheless, the observed associations highlight a real-world pattern that may inform safer prescribing decisions.
Practical takeaways for caregivers and clinicians
- Review all medications regularly for older adults living in nursing homes, with particular attention to drug combinations that affect metabolism.
- Consider non-CYP2D6-inhibiting antidepressants when tramadol is necessary, or explore alternative pain management strategies.
- Educate patients and families about potential adverse effects and the importance of reporting new seizure-like symptoms promptly.
The research was supported by the National Institute on Aging and adds to a growing body of literature on drug interactions in older populations. Ongoing studies will help clinicians refine safer prescribing patterns to balance pain relief with seizure risk.
