Tramadol's analgesic mechanism involves two distinct pharmacological components. These are:

• A Strong μ-opioid receptor agonism plus COX-1 inhibition
• B κ-opioid receptor agonism plus NMDA receptor antagonism
• C δ-opioid receptor agonism plus inhibition of substance P release
• D Weak μ-opioid receptor agonism plus inhibition of serotonin and noradrenaline reuptake (monoamine reuptake inhibition) ✓

Explanation

Tramadol has two complementary mechanisms: (1) it and its O-demethylated metabolite M1 (generated by CYP2D6) act as weak μ-opioid receptor agonists; (2) the parent compound inhibits reuptake of serotonin and noradrenaline in descending pain-modulatory pathways, adding non-opioid analgesia. Because of the serotonergic component, tramadol should not be combined with MAOIs, SSRIs, or other serotonergic agents due to serotonin syndrome risk. CYP2D6 ultra-rapid metabolisers convert tramadol to excess M1 (risk of opioid toxicity) while poor metabolisers may lack efficacy.

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

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