MajorSelective serotonin reuptake inhibitors×Other opioids
Updated · Methodology
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
If a patient taking fluoxetine needs tramadol, start at the lowest dose and keep it at the low end of the therapeutic range. The fluoxetine SmPC requires this for all drugs metabolised by CYP2D6, including for 5 weeks after fluoxetine is stopped. Fluoxetine reduces formation of tramadol's active metabolite, so analgesia may be weaker while the risk of seizures and serotonin syndrome is higher (FDA tramadol label). At the start and after each dose increase, watch for signs of serotonin syndrome and stop tramadol if it is suspected. Paracetamol is a suitable analgesic. NSAIDs taken with SSRIs increase bleeding risk (fluoxetine SmPC).
Check the full regimen, not just this pair
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Sources
- FDA: Tramadol hydrochloride tablets prescribing information (Amneal) (2026)– FDA label, DailyMed setid 8ec4e4e5-a56e-4198-8428-6b770b9bf27d, sections 5.9, 5.10, 7
- FDA: Prozac (fluoxetine) prescribing information (2017)– ; DailyMed setid c88f33ed-6dfb-4c5e-bc01-d8e36dd97299
- AEMPS: Ficha técnica de Prozac 20 mg cápsulas duras (fluoxetina) (2020)– AEMPS CIMA, nregistro 57954, secciones 4.4, 4.5