Major
Established
Description
Venlafaxine and tramadol together pose a high risk of serotonin syndrome due to complementary serotonergic mechanisms.
Mechanism
Venlafaxine inhibits both SERT and NET reuptake transporters; tramadol independently inhibits serotonin reuptake and has weak mu-opioid agonism, producing supra-additive serotonin elevation.
Clinical Significance
Case reports of life-threatening serotonin syndrome exist; the FDA has issued warnings for all SNRI + tramadol combinations.
Management
Contraindicated in most clinical contexts; if pain management is essential, use a pure opioid analgesic and monitor closely.