What is the mechanism of action of paracetamol and how does it differ from that of non‑steroidal anti‑inflammatory drugs?

Mechanism of Action of Paracetamol and NSAIDs

Paracetamol's Mechanism of Action

Paracetamol functions primarily through central nervous system inhibition of prostaglandin synthesis, with additional effects via the endocannabinoid system and descending serotonergic pathways, fundamentally distinguishing it from traditional NSAIDs that work through peripheral COX inhibition. 1

Central vs. Peripheral Activity

• Paracetamol inhibits prostaglandin production predominantly in the central nervous system rather than in peripheral tissues, which explains its analgesic and antipyretic effects without significant anti-inflammatory activity 1, 2
• The drug is metabolized in the brain and spinal cord through deacetylation to p-aminophenol, which is then conjugated with arachidonic acid by fatty acid amide hydrolase to form N-arachidonoylphenolamine (AM404), an endogenous cannabinoid 3, 4
• This metabolite indirectly activates cannabinoid CB1 receptors, which is now recognized as the primary mechanism for paracetamol's analgesic effect 4
• Paracetamol also modulates descending serotonergic pathways that inhibit nociceptive signal transmission in the spinal cord 1, 5

COX Pathway Interaction

• Unlike NSAIDs, paracetamol shows selective inhibition of COX enzymes only when low levels of arachidonic acid and peroxides are present, explaining why it fails to suppress severe inflammation in conditions like rheumatoid arthritis 2
• The drug may inhibit a COX-1 variant enzyme or work through COX-2 inhibition in the CNS, though the exact COX isoenzyme remains debated 3, 6
• Paracetamol is metabolized by cytochrome P450 enzymes to NAPQI when glutathione stores become saturated, leading to potential hepatotoxicity at doses exceeding 4g/24 hours 1

NSAID Mechanism of Action

Traditional NSAIDs reversibly inhibit both COX-1 and COX-2 enzymes, blocking prostaglandin synthesis peripherally to produce anti-inflammatory, analgesic, and antipyretic effects. 7

COX Enzyme Inhibition

• Nonselective NSAIDs reversibly inhibit both COX-1 and COX-2 activity throughout the body, producing robust anti-inflammatory effects 7
• Selective COX-2 inhibitors (coxibs) reversibly inhibit COX-2 more than COX-1 due to their higher affinity for COX-2 7, 8
• Aspirin irreversibly blocks COX enzymes, distinguishing it from other NSAIDs 7, 8
• COX-1 is constitutively expressed in normal cells, while COX-2 is induced in inflammatory cells 7

Prostaglandin Blockade

• NSAIDs produce analgesia by blocking the biosynthesis of prostaglandins, which are inflammatory mediators that initiate, cause, intensify, or maintain pain 8
• This peripheral prostaglandin blockade results in significant anti-inflammatory activity, unlike paracetamol 1

Key Clinical Differences

Efficacy Profile

• In conditions where inflammation is the primary component of pain (such as arthritis), NSAIDs provide superior pain control and functional outcomes compared to paracetamol alone 7, 8
• Paracetamol is effective for mild pain but lacks the robust anti-inflammatory properties needed for inflammatory conditions 7

Safety Profile

• Paracetamol lacks significant peripheral prostaglandin blockade, resulting in minimal gastrointestinal, cardiovascular, and renal toxicity at therapeutic doses 1
• NSAIDs carry dose-dependent risks including cardiovascular events, gastrointestinal bleeding (3-5 fold increased risk), platelet dysfunction, and renal failure 7, 8
• NSAID use results in approximately 100,000 hospitalizations annually in the United States 7
• Paracetamol's primary toxicity is hepatotoxicity at doses exceeding 4g/24 hours, which is independent of administration route 1

Common Pitfalls

• Do not classify paracetamol as an NSAID—it lacks significant anti-inflammatory activity, which is the defining characteristic of NSAIDs 8
• Do not assume paracetamol is risk-free; high doses can cause centrilobular hepatocyte necrosis due to NAPQI accumulation 1
• NSAIDs should not be used long-term without monitoring for gastrointestinal, cardiovascular, and renal complications 7
• Do not use NSAIDs in patients with renal impairment, heart failure, or history of gastrointestinal bleeding without gastroprotection 7

Combination Therapy

• Combining paracetamol with NSAIDs can be beneficial for pain control when paracetamol alone is insufficient, taking advantage of their different mechanisms of action 8
• Both agents are recommended at all steps of the WHO analgesic ladder for cancer pain management 7