Pain and antidepressant drug combo linked to increased seizure risk in older adults

When older adults living in nursing homes are prescribed the pain medicine tramadol alongside certain antidepressants, their risk of seizures may go up, according to a study published Oct. 8 in Neurology®, the medical journal of the American Academy of Neurology.  

This study was led by Yu-Jung “Jenny” Wei, PhD, associate professor of pharmaceutics and pharmacology, with co-investigators at the University of Florida. Funding for the study was provided by an R01 grant from the National Institute on Aging (NIA).  

Dr. Wei’s research focuses on geriatric pharmacoepidemiology, specifically drug safety, effectiveness and quality of medication prescribing in older adults. Throughout her career, Dr. Wei has regularly studied opioid-antidepressant interactions and their association with risk of worsening pain, pain-related hospitalizations, pain-related emergency department visits, and opioid use disorder or opioid overdose. 

“Tramadol is one of the commonly prescribed opioid agonists for pain management in older adults, including those residing in nursing homes,” Dr. Wei said. “Preclinical studies and case reports have indicated that co-use of tramadol with CYP2D6-inhibiting antidepressants reduces tramadol metabolism and increases its blood concentrations, which may enhance the risk of tramadol-induced toxicity, including seizures. Yet, such an association had not been empirically investigated until the conduct of our study.” 

Some antidepressants that inhibit the CYP2D6 enzyme, called CYP2D6 inhibitors, can interfere with how the body metabolizes tramadol. When the CYP2D6 enzyme is blocked, tramadol is not metabolized properly and may build up in the body, potentially increasing the risk of side effects like seizures. Common CYP2D6-inhibiting antidepressants include fluoxetine, paroxetine and bupropion.  

“We found a modest but measurable increase in the risk of seizures when tramadol was taken with antidepressants that inhibit the CYP2D6 enzyme,” Dr. Wei said. “This risk was consistent whether the antidepressant or tramadol was started first.” 

Researchers analyzed 10 years of Medicare data to identify 70,156 nursing home residents age 65 and older who had been prescribed both tramadol and an antidepressant. 

They divided participants into two groups based on which drugs they took first. Of the participants, 11,162 took tramadol first and then an antidepressant with it, while 58,994 participants took an antidepressant first and then added tramadol. 

Seizure rates for people who took tramadol first were 16 seizures per 100 person-years, and for people who took antidepressants first, the rate was 20 seizures per 100 person-years. This means for every 100 people who used both tramadol and an antidepressant followed for one year, about 16 or 20 received a seizure diagnosis. 

In both groups, researchers then compared seizure rates between those who took tramadol with CYP2D6-inhibiting antidepressants and those who took tramadol with antidepressants that do not inhibit the enzyme. In those who took tramadol first and added an antidepressant, the rate was 18 seizures per 100 person-years for those taking CYP2D6-inhibiting antidepressants compared to 16 seizures per 100 person-years in people taking other antidepressants.  

In those who took antidepressants first and added tramadol, the rate was 22 seizures per 100 person-years for those taking CYP2D6-inhibiting antidepressants compared to 20 seizures per 100 person-years in people taking other antidepressants. 

To help ensure the differences were not due to other health issues, the researchers adjusted for factors such as pain levels, depression symptoms, physical function and cognitive ability.  

After adjustments, for people who took tramadol first, seizure risk was 9% higher when taking it with a CYP2D6-inhibiting antidepressant compared to with an antidepressant that did not inhibit this enzyme. For those who took an antidepressant first and added tramadol, the risk was about 6% higher for people who took a CYP2D6-inhibiting antidepressant compared to people who took an antidepressant that did not inhibit the enzyme. 

To test whether this interaction was specific to tramadol, the researchers repeated the analysis using hydrocodone, another opioid pain reliever that is unlikely to cause seizure risk when used with antidepressants. No increased seizure risk was observed with hydrocodone and CYP2D6-inhibiting antidepressants. 

A limitation of the study was that medication data came from prescription records, which did not confirm whether patients took the drugs as directed.  

“These findings underscore the need for careful prescribing practices, especially for older adults with complex health conditions,” Dr. Wei said. “Doctors should be aware of potential seizure risks when prescribing tramadol with antidepressants, particularly CYP2D6 inhibitors. Given how commonly both are prescribed to older adults, these interactions may be more important than previously thought.”