Multimodal analgesia for major abdominal surgery typically includes paracetamol, an NSAID, and regional block. The 'ceiling effect' for paracetamol means that doses beyond the standard therapeutic range do not provide additional analgesia. The primary analgesic mechanism of paracetamol that is distinct from NSAIDs is:

• A Inhibition of peripheral COX-2 isoenzyme in inflamed tissue to the same extent as ibuprofen
• B Mu-opioid receptor partial agonism in the periaqueductal grey explaining its CNS analgesic effect
• C Activation of descending serotonergic pain-inhibitory pathways via spinal 5-HT3 receptor modulation and possible cannabinoid pathway activation ✓
• D NMDA receptor antagonism at therapeutic plasma concentrations preventing wind-up sensitisation

Explanation

Paracetamol's mechanism remains incompletely understood, but current evidence points to activation of descending inhibitory serotonergic pathways in the dorsal horn. Its active metabolite AM404 (formed in the CNS) inhibits anandamide reuptake, activating cannabinoid CB1 receptors and TRPV1 channels. Paracetamol does not significantly inhibit peripheral COX in inflamed tissues (unlike NSAIDs), and has no meaningful opioid or NMDA receptor activity at therapeutic doses. Its central COX-3 inhibition theory has not been replicated in humans. This distinct mechanism explains synergy when combined with NSAIDs.

Reference: Morgan & Mikhail's Clinical Anesthesiology, 6th ed.

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Written and medically reviewed by the StethoPrep medical team.