What is paracetamol (acetaminophen)?

What is Paracetamol (Acetaminophen)?

Paracetamol (also known as acetaminophen) is the most widely used over-the-counter and prescription analgesic and antipyretic medication worldwide, serving as first-line therapy for mild to moderate pain and fever. 1

Mechanism of Action

• Paracetamol works primarily by inhibiting prostaglandin production within the central nervous system and peripheral tissues, though its exact mechanism remains incompletely understood. 1
• Unlike NSAIDs, paracetamol provides analgesic and antipyretic effects but has no significant anti-inflammatory properties. 1

Clinical Uses and Positioning

• Paracetamol is the first step on the WHO pain ladder and is recommended as first-line pharmacological therapy by international guidelines (including EULAR and ACR) for multiple acute and chronic painful conditions. 1
• It is the preferred first-choice analgesic for adults with mild to moderate acute pain, including those with liver disease, kidney disease, cardiovascular disease, gastrointestinal disorders, asthma, and older adults. 2
• Paracetamol became the mainstay analgesic and antipyretic for children after aspirin was linked to Reye's syndrome in the 1980s. 3

Dosing Guidelines

• The FDA-approved maximum daily dose is 4000 mg (4 g) per day for adults, typically administered as 1000 mg every 6 hours. 4, 5
• The FDA has mandated that prescription combination products (with opioids) limit acetaminophen to 325 mg per dosage unit to reduce overdose risk. 1
• Some manufacturers have voluntarily reduced maximum daily doses to 3000-3250 mg, creating confusion, though the established monograph dose remains 3900-4000 mg. 6

Safety Profile

Paracetamol has a superior safety profile compared to NSAIDs when used at recommended doses:

• Significantly fewer gastrointestinal adverse events than NSAIDs (no more GI symptoms than placebo in meta-analyses). 1, 4
• No cardiovascular toxicity at therapeutic doses, unlike NSAIDs which show dose-dependent cardiovascular risks. 1
• Minimal renal toxicity at recommended doses, whereas NSAIDs demonstrate dose-dependent renal adverse events. 1
• No increased risk of serious GI bleeding, perforation, or obstruction at therapeutic doses. 1

Critical Safety Warnings (FDA)

Hepatotoxicity is the primary concern with paracetamol:

• Severe liver damage may occur if an adult takes more than 6 doses in 24 hours or exceeds 4000 mg daily. 5
• Risk increases when combined with other acetaminophen-containing products or when taken with 3 or more alcoholic drinks daily. 5
• Overdose can cause fatal liver damage; however, early treatment with N-acetylcysteine prevents hepatotoxicity. 3, 7
• At recommended therapeutic doses, hepatotoxicity is rare, even in patients with cirrhotic liver disease. 2

Emerging Safety Concerns

Recent systematic reviews have identified dose-dependent risks that challenge paracetamol's reputation as completely benign:

• Mortality: One study showed increased relative rate from 0.95 to 1.63 with higher doses. 1
• Cardiovascular events: Dose-response relationship with risk ratios increasing from 1.19 to 1.68. 1
• Gastrointestinal events: Dose-dependent increases in GI bleeds (relative rate 1.11 to 1.49). 1
• Renal dysfunction: Odds ratio for ≥30% decrease in kidney function increased from 1.40 to 2.19 with higher doses. 1

These findings suggest paracetamol may not be as safe as traditionally believed, particularly with chronic or high-dose use. 1

Contraindications and Precautions

• Do not use in patients with known acetaminophen allergy (may cause severe skin reactions including rash, blisters, skin reddening). 5, 8
• Avoid combining with other acetaminophen-containing products (prescription or over-the-counter). 5, 8
• Use with caution in patients taking warfarin. 5
• Patients with liver disease should consult a physician before use, though therapeutic doses are generally safe. 5, 2

Clinical Advantages Over NSAIDs

• Paracetamol should be used before NSAIDs because of its superior safety profile regarding GI, cardiovascular, and renal complications. 1, 4
• It can be used safely in aspirin-sensitive asthmatics and patients at risk of gastrointestinal complications where NSAIDs are contraindicated. 3, 2
• Long-term use (up to 2 years studied) shows significantly fewer adverse events than NSAIDs. 4
• No concerns about cardiovascular or cerebrovascular safety, unlike COX-2 inhibitors and traditional NSAIDs. 1

Combination Therapy

• When paracetamol alone fails to provide adequate pain or fever control, adding an NSAID (preferably ibuprofen) is recommended rather than exceeding paracetamol dosing limits. 4
• Standard approach: Start with paracetamol up to 4g daily, then add ibuprofen up to 2.4g daily if relief is inadequate. 4