Major
Fluoxetine × Tramadol
Selective serotonin reuptake inhibitors×Other opioids
Mechanism
Dual mechanism. Fluoxetine (SSRI) raises synaptic serotonin; tramadol weakly inhibits serotonin reuptake – combined serotonergic activity adds up. Fluoxetine also blocks CYP2D6 – the route activating tramadol to O-desmethyltramadol – so analgesia weakens.
Symptoms
Serotonin syndrome: agitation, confusion, tremor, myoclonus, hyperreflexia, dilated pupils. Autonomic features: sweating, tachycardia, hypertension, fever. First signs appear within hours of co-administration.
Management
Avoid the combination. For analgesia on fluoxetine, use paracetamol, an NSAID, or pure opioid agonists such as morphine/oxycodone. Alternative antidepressant: mirtazapine or agomelatine.