Doctors have been warned against prescribing two widely used drugs together amid fears the combination could increase the risk of seizures.
Researchers found patients given the opioid painkiller tramadol alongside certain widely used antidepressants were almost 10 per cent more likely to suffer a seizure.
The study, by scientists at Ohio State University, analysed health records from more than 70,000 nursing home residents.
It showed a 'modest but measurable increase' in seizure risk when tramadol was taken with antidepressants that inhibit the CYP2D6 liver enzyme, which helps the body process drugs.
These so-called CYP2D6 inhibitors — which include fluoxetine, paroxetine, bupropion, sertraline and fluvoxamine — can block the breakdown of tramadol, causing it to build up in the body.
The effect was consistent regardless of which medicine was started first.
Dr Yu-Jung Jenny Wei, a geriatric pharmacoepidemiologist and study co-author, said: 'Our 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.' She added: 'Given how commonly both are prescribed to older adults, these interactions may be more important than previously thought.'
Researchers analysed ten years of health records to identify 70,156 nursing home residents aged 65 and over who had been prescribed both tramadol and an antidepressant.
Participants were divided into two groups based on which drug they were given first.
Of these, 11,162 took tramadol before adding an antidepressant, while 58,994 started on an antidepressant and later added tramadol.
For every 100 people who took tramadol first, 16 experienced seizures. Among those who began with an antidepressant, the figure rose to 20.
After adjusting for other factors, the researchers found seizure risk was nine per cent higher for people who took tramadol first when it was combined with a CYP2D6-inhibiting antidepressant, compared with one that did not affect the enzyme.
For those who started on an antidepressant and later added tramadol, the risk was around 6 per cent higher when the antidepressant was a CYP2D6 inhibitor.
Writing in the journal Neurology, the scientists cautioned that their findings do not prove the drug combination causes seizures and said further research is needed.
They suggested, however, that the increased risk could be due to CYP2D6 inhibitors interfering with the way the body metabolises tramadol.
When the CYP2D6 enzyme is blocked, tramadol may not be metabolised properly and can build up in the body, increasing the risk of side effects such as seizures.
It comes as separate research this week also suggested tramadol is 'not that effective' for treating chronic pain.
Danish scientists analysed health records for more than 6,500 patients and found the drug was linked to a higher risk of serious side effects, including heart disease.
Publishing their findings in BMJ Evidence-Based Medicine, the team at Rigshospitalet in Copenhagen argued that tramadol's potential harms 'likely outweigh' its modest benefits.
Tramadol is one of the most commonly prescribed opioid painkillers in the UK, with hundreds of thousands of NHS prescriptions issued each month. In the US, it ranks among the most widely used opioids, with more than 16 million prescriptions issued annually.
The warning comes as use of antidepressants continues to rise. Around 8.7 million people in England, or roughly 15 per cent of the population, were prescribed antidepressants last year, while in the US about 13 per cent of adults take them regularly.
Doctors have long warned that patients waiting months for NHS operations are often left on tramadol and other opioids for dangerously long periods, increasing the risk of addiction.
