Tramadol can precipitate serotonin syndrome when combined with SSRIs. In addition to weak μ-opioid receptor agonism, its other mechanism that contributes to this risk is:

• A Direct serotonin 5-HT2 receptor agonism
• B Inhibition of serotonin and norepinephrine reuptake transporters (SNRI-like action) ✓
• C MAO-A inhibition increasing synaptic serotonin
• D Stimulation of presynaptic serotonin autoreceptors promoting serotonin release

Explanation

Tramadol has a dual mechanism: weak agonism at μ-opioid receptors AND inhibition of neuronal reuptake transporters for serotonin (SERT) and norepinephrine (NET), similar to SNRIs. When combined with SSRIs or other serotonergic drugs, excessive serotonin accumulation at synapses can precipitate serotonin syndrome. This is why co-administration with MAOIs, SSRIs, or other serotonergic agents is contraindicated.

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

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Written and medically reviewed by the StethoPrep medical team.