Paracetamol (Acetaminophen)

TL;DR. The most widely used drug on Earth and the one with the smallest safety margin in the household cupboard. At normal doses it is remarkably clean: no stomach damage, no bleeding risk, safe in pregnancy, safe in asthma. Above roughly twice the maximum daily dose it destroys the liver, and it does so silently: you can feel completely well for a day or two while the damage happens. The antidote works brilliantly if given within 8 hours and poorly after 24. If you remember one thing from this book, make it this chapter.

1. What it is and what it treats

Paracetamol (international name) = acetaminophen (US name). The same molecule, and this duplication has itself caused overdoses.

Uses: mild to moderate pain (headache, toothache, musculoskeletal pain, period pain, post-operative pain as part of a combination) and fever reduction.

What it is not: it is not an anti-inflammatory. Unlike ibuprofen, it does little for inflammation and swelling, which is why it underperforms NSAIDs in inflammatory conditions such as gout, rheumatoid arthritis, and acute injury.

On osteoarthritis and back pain, the evidence has weakened considerably. A large 2016 Lancet network meta-analysis found paracetamol clinically ineffective for osteoarthritis pain, and the 2014 PACE trial found it no better than placebo for acute low back pain. Several guidelines, including NICE's 2020 osteoarthritis guidance, moved away from recommending it as a first-line treatment for those conditions. It remains genuinely useful for headache, fever, and acute short-term pain.

2. How it works

Honestly: not fully understood, after more than a century of use. This is a genuinely surprising fact about one of the world's most-taken drugs.

The leading account is that it inhibits cyclooxygenase enzymes centrally, in the brain and spinal cord, rather than peripherally in tissues. That would explain why it reduces pain and fever (both centrally mediated) without producing the anti-inflammatory effect, stomach damage, or antiplatelet action that peripheral COX inhibition causes (Chapter 66). Additional proposed mechanisms involve a metabolite (AM404) acting on the endocannabinoid and TRPV1 systems, and effects on serotonergic descending pain pathways.

Fever reduction works through the hypothalamus, resetting the temperature set point that prostaglandin E2 had raised.

3. How it is made

Industrial synthesis from phenol, typically nitration to nitrophenol, reduction to aminophenol, and acetylation to paracetamol. It is chemically simple, extremely cheap (a few pence for a pack of 16), and produced in enormous volume, mostly in India and China. Its low cost is exactly why it is everywhere and why overdose is so accessible.

Formulations: tablets and caplets (500 mg standard, 665 mg modified release in some markets), soluble and effervescent tablets (which carry substantial sodium, 400 to 500 mg per tablet, worth knowing on a sodium-restricted diet), oral suspension for children (120 mg/5 mL and 250 mg/5 mL), suppositories, and intravenous.

4. Dose, timing, and how to take it

The doses here are illustrative, taken from standard adult over-the-counter labelling. Follow your own product's leaflet and your clinician's instructions.

Adults (over 50 kg):

• 500 mg to 1 g every 4 to 6 hours
• Maximum 4 g (8 × 500 mg tablets) in 24 hours
• Never more than 4 doses of 1 g in 24 hours
• Leave at least 4 hours between doses

Lower maximum (typically 3 g/day or less) applies if you:

• Weigh under 50 kg
• Drink alcohol regularly and heavily
• Are malnourished, have eaten poorly for several days, or have anorexia
• Have chronic liver disease
• Are frail or elderly
• Take enzyme-inducing drugs (carbamazepine, phenytoin, rifampicin, St John's wort)

Children: dosed by weight, typically 15 mg/kg per dose, up to 4 doses in 24 hours. Use the supplied syringe or spoon, never a kitchen spoon. Weight-based dosing is why age-band labels on the bottle are a rough guide and a weight-based calculation is better.

With or without food: either. Food slightly slows absorption and does not reduce the total effect.

Onset: 30 to 60 minutes orally; peak effect around 1 to 2 hours; half-life about 2 to 3 hours.

Regular versus as-needed: for ongoing pain, taking it regularly at fixed intervals works better than waiting for pain to return, provided the total stays within the daily maximum.

5. What it actually does well

Established: reduces fever reliably; relieves mild to moderate acute pain; works well in combination with an NSAID, where the two have different mechanisms and the combination outperforms either alone; safe in pregnancy at normal doses; safe in asthma, in peptic ulcer disease, in kidney disease, and with anticoagulants, where NSAIDs are all problematic.

That safety profile at normal doses is why it is first-line for so many people. It is genuinely the safest common painkiller for a large number of patients, right up until it is not.

Weak or negative: osteoarthritis, chronic low back pain, and chronic pain generally.

On fever in children specifically: current guidance is to treat fever for the child's comfort, not to normalise the number. Fever is a functional immune response, and treating it does not prevent febrile convulsions. Alternating paracetamol and ibuprofen is common practice, has modest evidence for slightly better temperature control, and increases the risk of dosing errors, so most guidelines suggest using one agent properly first.

6. Side effects at normal doses

Remarkably few, which is the other half of paracetamol's story:

• Very rare: rash, blood disorders (thrombocytopenia, agranulocytosis).
• Very rare and serious: severe skin reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis), for which the FDA issued a warning in 2013.
• Not associated with stomach ulceration, bleeding, kidney injury at normal doses, or asthma exacerbation.

Observational associations at regular high-normal use with slightly raised blood pressure and cardiovascular events exist, and a small 2022 randomised trial found 4 g/day for two weeks raised blood pressure in hypertensive patients by around 5 mmHg. This is worth knowing for people taking it daily long term, and it does not change short-term use.

In pregnancy it is the recommended analgesic. Some observational studies have reported associations between prolonged prenatal exposure and ADHD or autism in offspring; a large 2024 Swedish sibling-control study, which compares siblings and so removes shared genetic and family confounding, found no association once that confounding was accounted for. The current consensus, including from major obstetric bodies, is to use the lowest effective dose for the shortest time, which is the standard advice for any drug in pregnancy.

7. Overdose: the part that matters most

In short: Paracetamol overdose is the leading cause of acute liver failure in the UK and US, it produces almost no symptoms for the first 24 hours, and the antidote works only if given early.

The mechanism

At normal doses, about 90 percent of paracetamol is conjugated with glucuronide or sulphate and excreted harmlessly. About 5 to 10 percent is oxidised by CYP2E1 to a reactive metabolite, NAPQI (N-acetyl-p-benzoquinone imine), which is highly toxic. Your liver neutralises it immediately using glutathione.

In overdose, the conjugation pathways saturate. More paracetamol goes down the CYP2E1 route, NAPQI production rises, and glutathione is consumed. Once glutathione stores fall below roughly 30 percent, NAPQI binds directly to liver cell proteins and kills them, producing centrilobular hepatic necrosis.

This explains every risk factor:

• Chronic alcohol use induces CYP2E1 (more NAPQI) and depletes glutathione. Both directions at once. This is the most important interaction in this chapter.
• Malnutrition, fasting, anorexia, and chronic illness deplete glutathione.
• Enzyme-inducing drugs (carbamazepine, phenytoin, rifampicin, St John's wort) increase NAPQI production.
• Low body weight means a higher dose per kilogram.

The dangerous doses

• Toxicity can begin at around 150 mg/kg, roughly 10 g (20 tablets) in a 70 kg adult, and lower in the at-risk groups above. Some sources use 75 mg/kg as the threshold for concern in high-risk patients.
• The gap between 4 g/day (maximum) and 10 g (potentially lethal) is a factor of only about 2.5.
• Staggered overdose, taking modest excesses repeatedly over days, is as dangerous as a single large one and is harder to assess, because the standard treatment nomogram does not apply.

The timeline, and why it kills

The feeling-fine period is what makes paracetamol overdose so lethal. People who take an overdose, feel physically fine that evening, and change their mind about seeking help present two days later with irreversible damage.

The antidote

N-acetylcysteine (NAC) replenishes glutathione and is extremely effective. Its efficacy is almost entirely determined by timing:

• Within 8 hours: nearly 100 percent effective. Liver damage is essentially prevented.
• 8 to 24 hours: effectiveness declines but still worthwhile.
• After 24 hours: much less effective, though still given.

If you or anyone else has taken more paracetamol than the maximum dose, seek medical help immediately, regardless of how well you feel. Call emergency services or your local poisons service. Take the packet with you. Do not wait to see whether symptoms develop, because by the time they do, the window for the antidote has largely closed. This applies to accidental overdose from combination cold remedies exactly as much as to deliberate overdose.

Pack size limits work. UK legislation in 1998 restricted pack sizes sold over the counter to 16 tablets in general retail and 32 in pharmacies. A 2013 BMJ study estimated the change was associated with a substantial reduction in paracetamol overdose deaths and liver transplants over the following decade. It is one of the better-documented examples of means restriction reducing suicide deaths.

8. Interactions

9. Brand names and combination products

Plain paracetamol: Panadol, Calpol (children's), Tylenol (US), Doliprane (France), supermarket own brands.

Combination products containing paracetamol (this list is illustrative and far from complete):

Check every box.

10. Myths and confusions

Don't be confused: paracetamol and ibuprofen are not interchangeable. Paracetamol treats pain and fever without treating inflammation and is gentle on the stomach, kidneys, and platelets. Ibuprofen treats inflammation as well, and carries stomach, kidney, cardiovascular, and bleeding risks. For a sprained ankle or gout, ibuprofen is the better choice; for a headache in someone with a stomach ulcer, paracetamol is.

• "Paracetamol is completely safe." At normal doses it is exceptionally clean. Its overdose margin is the narrowest of any household drug.
• "You would feel ill if you had taken too much." You would not, for a day or more. This is the single most dangerous misconception about it.
• "Alcohol plus a normal dose is fine." Occasional moderate drinking with a normal dose is not a problem. Chronic heavy drinking plus regular full-dose paracetamol is a genuine risk.
• "You can take paracetamol and ibuprofen together." Yes, they work by different mechanisms and combining or alternating them is standard practice, provided each stays within its own limit.
• "Fever must be brought down." Treat for comfort; the number itself is not the target, and antipyretics do not prevent febrile convulsions.
• "Paracetamol treats inflammation." It does not, meaningfully.

11. The bottom line

• Paracetamol relieves pain and fever with almost no side effects at normal doses, and is the safest common painkiller for people with ulcers, asthma, kidney disease, or on anticoagulants, and in pregnancy.
• The maximum is 4 g a day for a healthy adult, and less if you are small, unwell, malnourished, or drink heavily. The gap between that and a liver-destroying dose is only about 2.5-fold.
• Overdose produces no symptoms for the first day, and the antidote works near-perfectly within 8 hours and poorly after 24. Seek help immediately, before symptoms.
• The commonest route to accidental overdose is combination cold and flu products. Read the active ingredient on every box.
• Its evidence for osteoarthritis and chronic back pain is weak; it remains genuinely useful for fever, headache, and acute pain.

Sources and notes

Doses, cautions, and interactions follow the British National Formulary and the electronic Medicines Compendium summaries of product characteristics; US figures follow FDA labelling. Mechanism uncertainty and the central COX and AM404 hypotheses follow Graham and Scott's reviews and Anderson's pharmacology. Osteoarthritis ineffectiveness is da Costa et al., The Lancet, 2016; acute low back pain is the PACE trial, Williams et al., The Lancet, 2014. NICE's 2020 osteoarthritis guideline (NG226 in its later form) reflects this. NAPQI formation, glutathione depletion, and the risk factors that modify it follow Prescott's foundational work and the standard toxicology. The staggered overdose problem and the Rumack-Matthew nomogram's limits follow UK and US poisons guidance. N-acetylcysteine efficacy by time to treatment follows Prescott et al. and subsequent series. UK pack size legislation of 1998 and its association with reduced deaths and transplants is Hawton et al., BMJ, 2013. Blood pressure effects at 4 g/day are Maclagan et al., Circulation, 2022. The prenatal exposure sibling-control analysis finding no association is Ahlqvist et al., JAMA, 2024. Severe skin reaction warnings follow the FDA's 2013 safety communication.

Open questions. Paracetamol's mechanism remains genuinely unresolved after more than a century of use. Whether regular long-term full-dose use carries a meaningful cardiovascular cost is an emerging and unsettled question.

👉 Next: ibuprofen and the NSAIDs.