A 28-year-old woman on venlafaxine 225 mg/day is started on tramadol for post-operative pain. She develops agitation, diaphoresis, hyperreflexia, clonus, and hyperthermia. The pathophysiological basis of this syndrome is:
- A Combined noradrenergic toxicity from dual inhibition of NET by both drugs
- B Excess serotonergic stimulation of 5-HT1A and 5-HT2A receptors from combined SNRI serotonin reuptake inhibition and tramadol's active metabolite M1 stimulating serotonin release ✓
- C Dopaminergic hyperstimulation resembling neuroleptic malignant syndrome due to μ-opioid receptor cross-talk
- D Anticholinergic excess because venlafaxine's active metabolite O-desmethylvenlafaxine inhibits muscarinic receptors
Explanation
Serotonin syndrome results from excess serotonergic activity at central and peripheral 5-HT1A and 5-HT2A receptors. Venlafaxine is an SNRI that inhibits serotonin reuptake, raising synaptic 5-HT. Tramadol also inhibits serotonin and norepinephrine reuptake AND its active M1 metabolite (via CYP2D6) promotes serotonin release. Together, these produce the classic triad: altered mental status, autonomic instability, and neuromuscular abnormalities (clonus is the most specific sign). Treatment: immediate drug discontinuation, cyproheptadine (5-HT2A antagonist), and benzodiazepines for agitation.
Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.
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