Taking certain antidepressants in combination with the opioid pain medication tramadol was associated with an increased risk for seizures in older adults, a new study showed.

Using Medicare data from over 70,000 nursing home residents, researchers found that concomitant use of antidepressants that inhibit the CYP2D6 enzyme and tramadol was associated with up to 9% higher risk for seizure than those taking the opioid with antidepressants that didn’t inhibit the enzyme.

The risk was elevated regardless of the order in which the drugs were taken, investigators noted.

“These findings underscore the need for careful prescribing practices, especially for older adults with complex health conditions. 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,” said lead author Yu-Jung Jenny Wei, PhD, and associate professor of pharmaceutics and pharmacology at The Ohio State University in Columbus, Ohio, in a press release.

The study was published online on October 8th in Neurology.

Blocking a Key Enzyme

Antidepressants such as bupropion, duloxetine, and fluoxetine inhibit CYP2D6, an enzyme that helps the body metabolize many commonly prescribed drugs. Blocking the enzyme increases the drug’s concentration in the body, which can raise the risk for adverse events such as seizures, particularly among older adults who might have reduced liver function and renal clearance, the investigators noted.

In 2016, the FDA released a safety warning about this seizure risk linked to the combined use of opioids and antidepressants. However, many nursing home residents are unaware of the association, even though this population is already at risk for seizures and is frequently prescribed both drugs.

Using Medicare data from 2010 to 2021, researchers analyzed usage patterns and seizure incidence among 70,156 nursing home residents aged 65 years or older who were prescribed both tramadol and any antidepressant.

Participants were grouped according to which drug they took first: 11,162 tramadol users who then started an antidepressant (mean age, 86 years; 81% female) and 58,994 antidepressant users who then started tramadol (mean age, 85 years; 80% female).

The researchers identified concomitant use by the continuous number of overlapping days on which tramadol was used along with an antidepressant. Seizures were identified on the basis of International Classification of Diseases (ICD) 9 and ICD-10 codes.

They adjusted for covariates including cognitive function, depression status, physical function, and pain intensity.

Seizure Risk Elevated

Among patients with concomitant use of tramadol and an antidepressant, 16% used a CYP2D6-inhibiting antidepressant and 83.9% used tramadol plus CYP2D6-neutral antidepressants.

Tramadol users who then started CYP2D6-inhibiting antidepressants had a 9% higher seizure risk than participants on antidepressants that don’t block this enzyme (adjusted incident rate ratio [aIRR], 1.09; P < .016). This group also had a higher rate of seizures (18 seizures per 100 person-years) than those on other antidepressants (16 seizures per 100 person-years).

For those who took the CYP2D6-inhibiting antidepressant first and then tramadol, seizure risk was 6% higher than for those on other antidepressants (aIRR, 1.06; P < .001). This group had a seizure rate of 22 seizures per 100 person-years compared with 20 seizures per 100 person-years for those taking other antidepressants.

There was no association between seizure risk and the use of pain opioid hydrocodone plus CYP2D6-inhibiting antidepressants.

Among the study limitations, Medicare data only accounted for drugs dispensed but not consumed. In addition, the researchers could not evaluate the variety of effects on seizure risk associated with this combination across subgroups by CYP2D6 genotypes due to a lack of genetic information.

The authors reported having no relevant disclosures. This research was supported by grant R01AG073442 to Wei from the National Institute on Aging.