Paracetamol

Anilides. Analgesics and antipyretics

ATC code: N02BE01 (Paracetamol)

Brand names

Tylenol, Panadol, Ofirmev

Mechanism of action

The analgesic mechanism is not fully established. Proposed pathways include central COX-2 inhibition and, per current data, interaction with the endocannabinoid system via the active metabolite AM404. Unlike NSAIDs, it does not appreciably inhibit peripheral COX and has no anti-inflammatory effect. The antipyretic effect is mediated through the hypothalamic thermoregulatory center.

Indications

Fever

First line

Paracetamol is first-line for symptomatic fever reduction in adults and children. Pediatric dose: 15 mg/kg every 4–6 hours, up to 60 mg/kg/day. Lowering fever does not speed recovery from infection and is only used when fever is poorly tolerated. In children with a history of febrile seizures, paracetamol does not prevent recurrences.

Sources

Migraine

First line

In mild to moderate migraine attacks, paracetamol 1000 mg is an acceptable first-line option in patients who cannot tolerate NSAIDs or triptans. Efficacy in severe attacks is lower than triptans and NSAIDs. Taking it early in the attack (within 30 minutes of pain onset) improves efficacy.

Sources

NICE: Hypertension in adults: diagnosis and management (NG136) (2022)

Mild to moderate pain in adults

First line

Mild to moderate pain is a core indication. Adults: 500–1000 mg every 4–6 hours, up to 4 g/day in healthy adults, up to 3 g/day in the elderly, chronic alcohol users, or malnourished patients. Paracetamol is less effective than NSAIDs for inflammatory pain (osteoarthritis, dysmenorrhea) but is preferred in patients with NSAID contraindications: peptic ulcer, anticoagulants, renal failure, heart failure, aspirin-exacerbated respiratory disease.

Sources

Osteoarthritis

Second line

In current NICE OA 2022 and ACR 2019 recommendations, paracetamol has moved to a second-line position in osteoarthritis in favor of topical NSAIDs and short-course systemic NSAIDs. It is recommended as an alternative in patients with NSAID contraindications. Long-term paracetamol for osteoarthritis has not shown substantial benefit over placebo in recent systematic reviews.

Sources

NICE: Depression in adults: treatment and management (NG222) (2022)

Practical notes

Timing and administration

Take with or without food. For pain, take as needed with a minimum 4-hour interval between doses. Effervescent and soluble formulations provide a faster onset of action (20–30 minutes versus 45–60 minutes for standard tablets) and may be preferred for acute pain.

Special situations

Maximum daily dose is 4 g in healthy adults and 3 g in the elderly, chronic alcohol users, low-body-weight patients (under 50 kg), or malnourished patients. In patients under 50 kg, calculate the dose at 60 mg/kg/day. Do not combine with other paracetamol-containing products (many combination cold medications): risk of unintentional overdose.

Common myths

Myth: 'paracetamol is the safest analgesic, take as much as you want'. Fact: paracetamol is a leading cause of acute liver failure worldwide. Safety critically depends on adhering to the maximum daily dose. Myth: 'paracetamol relieves inflammation'. Fact: paracetamol lacks anti-inflammatory activity. Inflammatory conditions are best treated with NSAIDs when not contraindicated. Myth: 'children can have it as needed'. Fact: in children the dose is strictly 15 mg/kg per dose no more often than every 4–6 hours and no more than 4–5 times daily. Overdose in children is hepatotoxic.

Safety

Boxed warning

Hepatotoxicity in overdose. Daily doses above 4 g in adults (above 3 g in at-risk patients) can cause severe acute liver injury up to hepatic failure. The antidote is N-acetylcysteine.

Contraindications

Severe hepatic impairment
Acute hepatitis
Hypersensitivity

Serious adverse effects

Hepatotoxicity in overdose — acute liver failure (a leading cause of ALF worldwide)
Anaphylaxis (very rare)
Stevens-Johnson syndrome, toxic epidermal necrolysis (very rare)

Common adverse effects

At recommended doses, adverse effects are rare and minimal

Uncommon adverse effects

Allergic skin reactions
Transaminase elevation

PregnancyFDA B

FDA category B. Paracetamol is the first-line option for pain and fever during any trimester. Long-term or high-dose third-trimester use has been discussed in literature regarding possible associations with atypical neurological outcomes in children, but no clear causal evidence exists.

Breastfeeding

Compatible with breastfeeding. Minimal concentrations in milk; one of the preferred analgesics in lactation.