Paracetamol

• 1. Introduction

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  Paracetamol, called acetaminophen in the United States, was the 112th most commonly prescribed medication there in 2023, with more than 5 million prescriptions. That count misses the far larger number of people who buy it without a prescription, under names such as Tylenol and Panadol. It is the most commonly used medicine for pain and fever in both the United States and Europe. It also appears on the World Health Organization's List of Essential Medicines. Yet this familiar tablet raises uncomfortable questions. Why did chemists set it aside for decades after it was first made? How does it relieve pain at all, when its action seems to involve two separate mechanisms? And how can a drug so gentle on the stomach also be the foremost cause of acute liver failure in the Western world?

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• 2. A Forgotten Compound

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  In 1886, Cahn and Hepp introduced acetanilide to medicine under the name Antifebrin. It had been found by accident to ease both pain and fever. Its dangers appeared quickly. Acetanilide caused cyanosis, a bluish discoloration, because it raised levels of methemoglobin, a form of hemoglobin that cannot carry oxygen to the tissues. That alarm sent researchers looking for less toxic relatives in the same chemical family.

  Harmon Northrop Morse made paracetamol at Johns Hopkins University in the late 1870s, by reducing p-nitrophenol with tin in glacial acetic acid. Some accounts instead credit a French chemist, Charles Gerhardt, with a first synthesis in 1852. Nobody gave the compound to people until 1887, when the clinical pharmacologist Joseph von Mering tried it.

  In 1893, von Mering published his clinical results, comparing paracetamol with phenacetin, another aniline derivative. He claimed that paracetamol, unlike phenacetin, tended to produce methemoglobinemia, though only slightly. Paracetamol was quickly discarded in favor of phenacetin. The sales of phenacetin helped establish Bayer as a leading pharmaceutical company.

  Von Mering's claims went essentially unchallenged for half a century. Then two teams of American researchers studied how the body processes acetanilide and phenacetin. In 1947, David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood. Large doses given to albino rats did not cause methemoglobinemia.

  In 1948, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans. They showed it relieved pain just as well as the drug it came from. They suggested that another metabolite, phenylhydroxylamine, was the main cause of methemoglobinemia in people. A follow-up paper by Brodie and Axelrod in 1949 showed that phenacetin also turned into paracetamol. This led to what historians of the drug call its rediscovery. The compound von Mering had shelved was already circulating in the blood of patients taking the older remedies.

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• 3. Back to the Market

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  Trigesic reached American shoppers in 1950 as a blend of paracetamol, aspirin and caffeine. In 1951, reports of three users with the blood disease agranulocytosis pulled it from sale. It took several years to establish that the disease was unconnected. In 1952, paracetamol returned to the American market as a prescription drug.

  In 1956, Sterling-Winthrop began selling paracetamol in the United Kingdom as Panadol, again by prescription only. The marketing pitched it as preferable to aspirin, since it was safe for children and for people with ulcers. In 1963, it was added to the British Pharmacopoeia. Back in the United States, it became available without a prescription in 1955 by one account and 1960 by another.

  Concerns about safety held back widespread acceptance until the 1970s. By the 1980s, paracetamol outsold aspirin in many countries, including the United Kingdom. Phenacetin, blamed for analgesic nephropathy and blood toxicity, faded from the market. Ownership shifted too. Eastman Kodak acquired Sterling Winthrop in 1988 and sold the over-the-counter drug rights to SmithKline Beecham in 1994.

  The two rival names have separate origins. McNeil Laboratories coined acetaminophen in 1955, shortening N-acetyl-p-aminophenol. Frederick Stearns and Company coined paracetamol in 1956, shortening para-acetylaminophenol. Paracetamol is the Australian and British Approved Name and the international nonproprietary name used by the World Health Organization. Acetaminophen is the United States Adopted Name and the Japanese Accepted Name. American pharmacists also use the initialism APAP.

  Today the drug comes in oral, suppository and intravenous forms. The intravenous version is sold in the United States as Ofirmev.

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• 4. What It Treats

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  In trials of acute migraine, 39% of people on paracetamol had pain relief after one hour, compared with 20% of those in the control group. For tension headache, a trio of aspirin, paracetamol and caffeine performs better than paracetamol alone. Two hours after dosing, 29% of people on the combination were pain-free, against 21% on paracetamol and 18% on placebo. The German, Austrian and Swiss headache societies, with the German Society of Neurology, call the trio a highlighted option for self-medication.

  Pain after dental surgery serves as a reliable model for how painkillers work on other acute pain. Here paracetamol is inferior to ibuprofen. Full doses of ibuprofen, naproxen or diclofenac clearly beat the paracetamol and codeine mix that is often prescribed for dental pain. Pairing paracetamol with ibuprofen looks promising, and may control pain better than either drug alone. A meta-analysis of post-surgical pain found that paracetamol with codeine gave significant relief to as many as 53% of participants, while placebo helped only 7%.

  The evidence turns thin in several places. For osteoarthritis, the American College of Rheumatology and Arthritis Foundation guideline notes a very small effect in trials, suggesting most people get little from the drug. Paracetamol is ineffective for acute low back pain. It fails to relieve procedural pain in newborn babies, and studies of cancer pain and neuropathic pain are lacking.

  Fever is another uncertain case. In critical care, paracetamol lowered body temperature by only 0.2-0.3 °C more than control treatments and did not change mortality. In dengue fever it brought no benefit and came with a higher rate of liver enzyme elevation. In children, a drop of about 0.2 °C is of questionable value, and the drug does not prevent febrile seizures. Some physicians advocate higher doses that may lower temperature by as much as 0.7 °C. Meta-analyses found it less effective than ibuprofen, with equivalent safety, and asthma exacerbations occur with similar frequency on either drug.

  In some formulations paracetamol is combined with the opiate codeine, known as co-codamol in Britain and Panadeine in Australia. Since the 1st of February 2018, medicines containing codeine have been prescription-only in Australia.

  One use sits far from the pharmacy shelf. In newborns with patent ductus arteriosus, paracetamol helps close the duct, as effectively as ibuprofen or indomethacin and with less gastrointestinal bleeding. Its use in infants of extremely low birth weight still needs further study.

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• 5. How It Works

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  Two mechanisms are proposed to explain paracetamol's effects. The first involves the cyclooxygenase enzymes, COX-1 and COX-2, which the drug reduces to their inactive form, cutting prostaglandin production. This happens only when arachidonic acid and peroxides are scarce. Under those conditions COX-2 dominates, which explains the drug's apparent preference for COX-2. In inflamed tissue, peroxides are plentiful and cancel the effect, so its anti-inflammatory action is negligible there. In the central nervous system, where peroxide levels are low, the inhibition holds.

  The second mechanism centers on AM404, a metabolite detected in the brains of animals and in the cerebrospinal fluid of people taking the drug. The brain forms it from 4-aminophenol using the enzyme fatty acid amide hydrolase. AM404 weakly activates the cannabinoid receptors CB1 and CB2 and inhibits the endocannabinoid transporter. It also strongly activates the TRPV1 receptor. This points to a role for the endocannabinoid system in the drug's pain relief.

  In 2018, Suemaru and colleagues found that paracetamol has an anticonvulsant effect in mice, working through TRPV1 receptors. It lowered neuronal excitability by hyperpolarizing neurons. The exact mechanism remains unclear. In 2025, Maatuf and colleagues reported that peripheral sensory neurons also make AM404 in vitro. At nanomolar concentrations it blocks the pain-sensing sodium channels Nav1.8 and Nav1.7. Injected into a rat's hind paw, it raised the pain threshold in that paw only. Other paracetamol metabolites did not block the channels.

  After a swallowed dose, absorption happens in the small intestine, and the stomach contributes almost nothing. Speed therefore depends on how fast the stomach empties. In the same subjects, peak blood concentration arrived after 20 minutes when fasting and 90 minutes after eating. A high-carbohydrate meal cut the peak by roughly fourfold, an effect not seen with high-protein or high-fat meals. Bioavailability rises from 63% at 500 mg to 89% at 1000 mg, and the half-life is 1.9-2.5 hours.

  Morphine slows gastric emptying and can leave patients short of a therapeutic paracetamol concentration. Alongside warfarin, paracetamol raises the INR and should be limited to no more than 2 g per week.

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• 6. The Liver Problem

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  Glucuronidation by the enzymes UGT1A1 and UGT1A6 handles 50-70% of a dose of paracetamol. Sulfation accounts for another 25-35%. A minor route, 5-15%, runs through cytochrome P450 enzymes, mainly CYP2E1, and produces a toxic metabolite called NAPQI. At normal doses, glutathione in the liver neutralizes NAPQI quickly. In overdose, glutathione is used up faster than it can be replaced. NAPQI then binds to mitochondrial proteins in liver cells, causing oxidative stress and toxicity.

  The recommended ceiling for healthy adults is three or four grams a day. A single dose should not exceed 1000 mg, doses should be at least four hours apart, and no more than four doses, or 4000 mg, should be taken in 24 hours. Most adult overdoses are linked to suicide attempts, but many are accidental. The usual cause is taking more than one paracetamol-containing product over an extended period. Frequent alcohol use may heighten the risk. Overdoses are also often tied to high-dose recreational use of prescription opioids, since those are most often combined with paracetamol.

  By 2003, paracetamol toxicity had become the foremost cause of acute liver failure in the United States. It accounted for most drug overdoses in the United States, the United Kingdom, Australia and New Zealand. As of 2004, it prompted more calls to American poison control centers than any other pharmacological substance. The FDA estimated that in the 1990s, acetaminophen-related overdoses led to 56,000 emergency room visits, 26,000 hospitalizations and 458 deaths per year. Unintentional overdose made up nearly 25% of the visits, 10% of the hospitalizations and 25% of the deaths.

  Symptoms may be absent at first. They usually begin several hours after ingestion, with nausea, vomiting, sweating and pain as acute liver failure starts. People who overdose do not fall asleep or lose consciousness, although many who attempt suicide with it wrongly expect to. Treatment aims to remove the drug and replenish glutathione. Activated charcoal reduces absorption if the person reaches hospital soon enough. The antidote acetylcysteine, also called NAC, acts as a precursor of glutathione and helps neutralize NAPQI. If liver damage becomes severe, a transplant is often required.

  Long-term use raises separate questions. Most information comes from observational studies, since controlled studies are absent. Those studies show a consistent pattern of higher mortality, and of cardiovascular, gastrointestinal and kidney problems, as the dose rises. Regular users have 1.9 times the risk of peptic ulcer. Meta-analyses suggest a 23% higher risk of kidney impairment and a 28% higher risk of kidney cancer. After 13 weeks of therapy for knee pain, 20% of participants showed a hemoglobin drop suggesting gastrointestinal bleeding, a rate similar to the ibuprofen group. The FDA also warns of rare and possibly fatal skin reactions, including Stevens-Johnson syndrome.

  In June 2009, an FDA advisory committee recommended cutting the maximum single adult dose from 1000 mg to 650 mg. It also proposed banning combinations of paracetamol with other products. In January 2011, the FDA asked manufacturers of prescription combination products to cap paracetamol at 325 mg per tablet or capsule, giving them three years. In November 2011, Britain's Medicines and Healthcare products Regulatory Agency revised its dosing of liquid paracetamol for children.

  In September 2013, the radio program This American Life aired an episode titled Use Only as Directed, which highlighted deaths from overdose. Two ProPublica reports followed. They alleged that the FDA had long known of studies showing the risks, and that McNeil, the maker of Tylenol and a division of Johnson and Johnson, had repeatedly opposed safety warnings and dosage restrictions.

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• 7. The Pregnancy Question

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  In September 2025, US President Donald Trump and Health Secretary Robert F. Kennedy Jr. claimed that Tylenol may cause autism. They urged pregnant women to avoid it. Medical experts, major health organizations and international studies strongly dispute any causal link, and stress that the drug remains safe for treating pain and fever in pregnancy.

  The European Medicines Agency, Britain's Medicines and Healthcare products Regulatory Agency, the World Health Organization and the FDA all recommend paracetamol as a first-line pain and fever treatment in pregnancy. Their advice is to use it only when necessary, at the lowest effective dose and for the shortest time.

  The doubt has a traceable source. Some observational studies have suggested an association between prenatal use and neurodevelopmental disorders, including ADHD and autism. Those studies are limited by confounding factors, such as maternal fever and infection, and do not show causation. Large, well-controlled studies, including sibling-controlled analyses, find no causal link after adjusting for maternal conditions. A 2026 review found no clinically significant increase in autism, ADHD or intellectual disability among children of women who used paracetamol as directed. Untreated pain and fever can themselves harm mother and fetus.

  Paracetamol also passes into breast milk, with a milk-to-plasma ratio of approximately 1. The amount an infant takes in is much lower than pediatric therapeutic doses and rarely causes clinical effects. Doctors advise extra caution for preterm infants and for infants with liver disease.

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• 8. Other Species

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  Cats lack the UGT1A6 enzyme needed to detoxify paracetamol, which makes the drug extremely toxic to them. Early signs include vomiting, drooling and discoloration of the tongue and gums. Unlike in people, liver damage is rarely what kills a cat. Methemoglobin formation and Heinz bodies in red blood cells block oxygen transport, causing asphyxiation. Acetylcysteine is used to treat the poisoning.

  Dogs react differently. Paracetamol has been reported to work as well as aspirin for musculoskeletal pain in dogs. It is considered a weak analgesic and is usually combined with codeine, although that mixture has not been evaluated. The main toxic effect in dogs is liver damage, and stomach ulceration has been reported. Acetylcysteine works well if given within two hours of ingestion.

  On Guam, the invasive brown tree snake, Boiga irregularis, has made paracetamol a candidate for pest control, since it is lethal to snakes. The proposed program inserts 80 mg doses into dead mice. Helicopters would then scatter the mice as bait.

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