Duloxetine × Tramadol

Duloxetine is a serotonin and noradrenaline reuptake inhibitor (SNRI). Tramadol also inhibits serotonin and noradrenaline reuptake, so together they add up serotonergic effects and raise the risk of serotonin syndrome. Tramadol lowers the seizure threshold, and SNRIs increase this risk (tramadol SmPC). There is a kinetic part too: duloxetine is a moderate CYP2D6 inhibitor (duloxetine SmPC), and tramadol needs CYP2D6 to form the metabolite that gives most of its analgesia. Less active metabolite is formed and more tramadol itself stays in the blood (FDA tramadol label).

Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia. Autonomic features: sweating, tachycardia, labile blood pressure, fever. Gastrointestinal: nausea, vomiting, diarrhoea. Seizures can occur on this combination. When less active tramadol metabolite is formed, pain relief is weaker than expected.

Use the combination when it is clinically warranted (both SmPCs). In a patient with depression, the FDA tramadol label advises considering a non-opioid analgesic first. Keep tramadol at or below 400 mg a day, because seizure risk rises above it. Tramadol is contraindicated in epilepsy that is not controlled; in controlled epilepsy it is used only when the circumstances require it (tramadol SmPC). Watch for signs of serotonin syndrome at the start of co-treatment and after each dose increase. If they appear, stop tramadol and duloxetine at once and start symptomatic treatment (FDA labels of both drugs). Measure blood pressure before starting duloxetine and periodically during treatment, and do not start duloxetine in uncontrolled hypertension (duloxetine labels). If duloxetine is stopped and tramadol continues, more active metabolite is formed: consider lowering the tramadol dose and watch for sedation and slowed breathing (FDA tramadol label).