Tramadol's analgesic mechanism differs from pure opioids because it additionally:

• A Inhibits neuronal reuptake of serotonin and noradrenaline in descending pain-modulating pathways ✓
• B Inhibits prostaglandin synthesis via COX-1 and COX-2 enzymes
• C Blocks NMDA glutamate receptors, preventing central sensitisation
• D Activates GABA-A chloride channels, producing spinal cord inhibition

Explanation

Tramadol has two mechanisms: weak mu-opioid receptor agonism (via its O-desmethyl-tramadol metabolite, activated by CYP2D6) and inhibition of serotonin and noradrenaline reuptake, enhancing descending inhibitory pathways. This dual mechanism provides analgesia with a lower dependence potential than pure opioids. Ultra-rapid CYP2D6 metabolisers produce excessive active metabolite and risk respiratory depression even at standard doses.

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

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