Major
Established
Description
Fluoxetine combined with tramadol carries a high risk of serotonin syndrome and additionally reduces tramadol's analgesic efficacy via CYP2D6 inhibition.
Mechanism
Fluoxetine is a potent CYP2D6 inhibitor, blocking the conversion of tramadol to its active M1 metabolite, while both agents increase synaptic serotonin, producing dual pharmacokinetic and pharmacodynamic risk.
Clinical Significance
Risk of serotonin syndrome is well-documented; concurrent CYP2D6 inhibition also renders tramadol less effective as an analgesic.
Management
Avoid the combination; use alternative analgesics and consult prescribing guidelines for SSRI management around pain procedures.