- Nursing home residents are commonly prescribed painkillers and antidepressants to manage comorbid pain and depressive disorders.
- This study found that residents prescribed tramadol and a CYP2D6-inhibiting antidepressant had a higher seizure risk compared with those on the painkiller plus a CYP2D6-neutral antidepressant.
- Clinicians should prescribe CYP2D6-neutral antidepressants when co-use is necessary, the researchers suggested.
Combining the commonly used painkiller tramadol with certain antidepressants may increase seizure risk for elderly patients, a cohort study suggested.
From a sample of over 70,000 nursing home residents, those who initiated a CYP2D6-inhibiting antidepressant on existing tramadol use had a 9% higher seizure risk than than those taking tramadol with CYP2D6-neutral antidepressants (adjusted incidence rate ratio [aIRR] 1.09, 95% CI 1.02-1.18), Yu-Jung Jenny Wei, PhD, of the Ohio State University in Columbus, and colleagues reported in Neurology.
Also, seizure risk was 6% higher among those who added tramadol onto an existing CYP2D6-inhibiting antidepressant (aIRR 1.06, 95% CI 1.03-1.10, P<0.001).
Compared with an estimated incidence of 1.64 per 100 patient-years among general nursing home residents, incidence seizure-related medical encounters were 16.10 and 20.17 per 100 patient-years among existing tramadol/new antidepressant users and existing antidepressant/new tramadol users, respectively, increasing to 18.91 and 22.02 per 100 patient-years when focusing on tramadol plus only CYP2D6-inhibiting antidepressants.
"Clinicians, patients, and their caregivers should be mindful of the potential seizure risk when older adults concurrently use tramadol with antidepressants, particularly CYP2D6-inhibiting antidepressants," Wei told MedPage Today.
Moderate to strong CYP2D6-inhibiting antidepressants include bupropion, fluoxetine, paroxetine, sertraline, and duloxetine.
"When co-use of tramadol and antidepressants is clinically needed, selection of CYP2D6-neutral antidepressants, rather than CYP2D6-inhibiting antidepressants, may reduce the risk of seizures," the researchers advised. "Clinical attention is particularly needed for patients who are female, have moderate to severe cognitive impairment, and have a history of cardiovascular disease, all of which were observed in this study to have heightened risk of seizures associated with co-use of tramadol and CYP2D6-inhibiting antidepressants."
The FDA issued a safety warning in 2016 regarding the risk for adverse events with concomitant use of antidepressants and opioids such as tramadol. Despite this warning, the researchers said older adults in nursing homes are commonly prescribed both tramadol and antidepressants to manage comorbid pain and depressive disorders.
Used for decades, tramadol is a commonly prescribed opioid agonist. Its label warns that seizures can occur within the recommended dose range and that concomitant use with certain other drug can raise this risk. The researchers pointed out that seizures can occur with tramadol at various doses, both higher and lower than standard doses.
This was the first study to use a national Medicare nursing home sample to look at seizure safety among tramadol-antidepressant users, said Wei, but she said that the findings didn't come as much of a surprise.
Wei noted that preclinical studies "have shown 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." Data have also suggested a higher frequency of adverse events from co-use of tramadol and CYP2D6-inhibiting antidepressants among those 65 and older, since hepatic function and renal clearance decrease with aging.
For the present retrospective study, Wei's group analyzed data on 70,156 nursing home residents taking tramadol and antidepressants from January 2011 to December 2021. The cohort was restricted to residents with a diagnosis of chronic pain for tramadol and disease conditions where antidepressants are FDA approved or commonly used off-label during the 6-month baseline period.
The study cohort was split between 58,994 individuals taking antidepressants with new tramadol use (mean age 85.3 years, 79.8% women) and 11,162 peers taking tramadol with new antidepressant use (mean age 86.2 years, 81.3% women).
CYP2D6-inhibiting antidepressants comprised 14% to 16.1% of all antidepressant use.
Wei's group corroborated the findings by performing a negative control exposure analysis that found concomitant use of hydrocodone with CYP2D6-inhibiting compared with CYP2D6-neutral antidepressants was not tied with seizure risk.
One limitation of the study was that it did not examine if the tramadol dose played a role in seizure risk, as there was little variation in the dosages prescribed -- ranging from 150 mg to 300 mg per day. Wei also emphasized that the findings are specific to the average nursing home population.
"While we accounted for many potential confounders -- a total of 41 variables -- derived from Medicare claims and nursing home minimum data set, our results remain subject to unknown or unmeasured confounders, like patients' response to medications and their side effects," Wei noted.
Disclosures
The study was supported by a grant from the National Institute on Aging.
Wei and co-authors reported no disclosures.
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