A patient taking fluoxetine for depression is inadvertently given tramadol for pain. He develops agitation, clonus, hyperthermia, and diaphoresis within 30 minutes. The mechanism is:
- A Tramadol inhibits serotonin reuptake; combined with fluoxetine SSRI action, serotonin excess in synapses causes serotonin syndrome ✓
- B Fluoxetine inhibits CYP2D6, increasing tramadol levels and causing opioid toxicity
- C Fluoxetine blocks mu-opioid receptors, triggering precipitated withdrawal from tramadol
- D Both drugs compete for plasma albumin binding, increasing free fraction of each
Correct answer: A. Tramadol inhibits serotonin reuptake; combined with fluoxetine SSRI action, serotonin excess in synapses causes serotonin syndrome
Explanation
Tramadol has dual action: weak mu-opioid agonism AND inhibition of serotonin and norepinephrine reuptake. Combined with fluoxetine (SSRI), the result is serotonin syndrome from excessive serotonergic neurotransmission, manifesting as the triad of autonomic instability, neuromuscular abnormalities (clonus, hyperreflexia), and altered mental status. While fluoxetine also inhibits CYP2D6 (which activates tramadol), the acute presentation here is serotonin syndrome, not pure opioid toxicity.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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Written and medically reviewed by the StethoPrep medical team.