Tramadol's analgesic efficacy is derived from two synergistic mechanisms. What are these mechanisms and which CYP enzyme mediates conversion of tramadol to its more potent opioid metabolite?

• A Strong mu-opioid agonism plus NMDA receptor antagonism; CYP3A4 converts tramadol to its active metabolite
• B Kappa-opioid agonism plus COX-2 inhibition; CYP2C9 produces the active metabolite
• C Delta-opioid agonism plus GABA-B activation; CYP2C19 mediates activation
• D Weak mu-opioid receptor agonism plus inhibition of norepinephrine and serotonin reuptake; CYP2D6 converts tramadol to O-desmethyltramadol (M1), a more potent mu agonist ✓

Explanation

Tramadol exerts its analgesic effect through two complementary mechanisms: direct but weak mu-opioid receptor agonism (tramadol itself has low receptor affinity) and inhibition of norepinephrine and serotonin reuptake in descending pain-modulating pathways (monoaminergic mechanism). CYP2D6 O-demethylates tramadol to O-desmethyltramadol (M1), which has approximately 200 times higher mu-opioid affinity; therefore CYP2D6 poor metabolizers derive less analgesia, while ultra-rapid metabolizers may produce toxic M1 levels. This dual mechanism also underlies the risk of serotonin syndrome when combined with SSRIs or MAO inhibitors.

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

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