Paracetamol is used for reducing fever.[53] However, there has been a lack of research on itsantipyretic properties, particularly in adults, and thus its benefits are unclear.[14] As a result, it has been described asover-prescribed for this application.[14] In addition, low-qualityclinical data indicates that when used for thecommon cold, paracetamol may relieve astuffed orrunny nose, but not other cold symptoms such assore throat,malaise,sneezing, orcough.[54]
For people incritical care, paracetamol decreases body temperature by only 0.2–0.3°C more than control interventions and has no effect on theirmortality.[18] It did not change the outcome in febrile patients with stroke.[55] The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported.[18] Paracetamol offered no benefit in the treatment ofdengue fever and was accompanied by a higher rate of liver enzyme elevation: a sign of potential liver damage.[56] Overall, there is no support for a routine administration of antipyretic drugs, including paracetamol, to hospitalized patients with fever and infection.[21]
The efficacy of paracetamol in children with fever is unclear.[57] Paracetamol should not be used solely to reduce body temperature; however, it may be considered for children with fever who appear distressed.[58] It does not preventfebrile seizures.[58][59] It appears that 0.2°C decrease of the body temperature in children after a standard dose of paracetamol is of questionable value, particularly in emergencies.[14] Based on this, some physicians advocate using higher doses that may decrease the temperature by as much as 0.7°C.[19] Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis[60]), including children younger than 2 years old,[61] with equivalent safety.[20]Exacerbation of asthma occurs with similar frequency for both medications.[62]
Paracetamol is used for the relief of mild to moderate pain such as headache, muscle aches, minor arthritis pain, and toothache, as well as pain caused by cold, flu, sprains, anddysmenorrhea.[63] It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient.[15]
The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain.[15]
It appears to provide only small and not clinically important benefits inosteoarthritis.[15][26]American College of Rheumatology andArthritis Foundation guideline for the management of osteoarthritis notes that theeffect size inclinical trials of paracetamol has been very small, which suggests that for most individuals it is ineffective.[25] The guideline conditionally recommends paracetamol for short-term and episodic use to those who do not tolerate nonsteroidal anti-inflammatory drugs. For people taking it regularly, monitoring for liver toxicity is required.[25] Essentially the same recommendation was issued byEuropean League Against Rheumatism (EULAR) for hand osteoarthritis.[64] Similarly, the ESCEO algorithm for the treatment of knee osteoarthritis recommends limiting the use of paracetamol to short-term rescue analgesia only.[65]
Paracetamol is ineffective for acute low back pain.[15][27] No randomized clinical trials evaluated its use for chronic orradicular back pain, and the evidence in favor of paracetamol is lacking.[28][26][27]
Paracetamol is effective for acute migraine:[16] 39% of people experience pain relief at one hour compared with 20% in the control group.[66] The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as afirst-line treatment for migraine".[22] Paracetamol on its own only slightly alleviates episodictension headache in those who have them frequently.[17] However, the aspirin/paracetamol/caffeine combination is superior to both paracetamol alone and placebo and offers meaningful relief of tension headache: two hours after administering the medication, 29% of those who took the combination were pain-free as compared with 21% on paracetamol and 18% on placebo.[67] The German, Austrian, and Swiss headache societies and the German Society of Neurology recommend this combination as a "highlighted" one for self-medication of tension headache, with paracetamol/caffeine combination being a "remedy of first choice", and paracetamol a "remedy of second choice".[68]
Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain.[69] For the relief of such pain, paracetamol is inferior to ibuprofen.[23] Full therapeutic doses of nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen,naproxen, ordiclofenac are clearly more efficacious than theparacetamol/codeine combination which is frequently prescribed for dental pain.[70] The combinations of paracetamol and NSAIDs ibuprofen or diclofenac are promising, possibly offering better pain control than either paracetamol or the NSAID alone.[23][24][71][72] Additionally, theparacetamol/ibuprofen combination may be superior to paracetamol/codeine andibuprofen/codeine combinations.[24]
A meta-analysis of general post-surgical pain, which included dental and other surgery, showed the paracetamol/codeine combination to be more effective than paracetamol alone: it provided significant pain relief to as much as 53% of the participants, while the placebo helped only 7%.[73]
The studies to support or refute the use of paracetamol for cancer pain and neuropathic pain are lacking.[29][30] There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department.[77] The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain.[78]
Paracetamol has long been established as a safe medication to treat short-term fever and significant pain in pregnant patients. Regulatory agencies, including theEuropean Medicines Agency (EMA),[79] theMedicines and Healthcare products Regulatory Agency (MHRA),[80] theWorld Health Organization (WHO),[81] and the U.S. Food and Drug Administration (FDA)[82] recommend paracetamol as a first-line analgesic and antipyretic in pregnancy, with use limited to situations where necessary, at the lowest effective dose, and for the shortest duration.
Some observational studies have suggested a possible association between prenatal paracetamol use and neurodevelopmental disorders, includingADHD andautism. However, these studies are limited byconfounding factors such as maternal fever and infection, and do not demonstrate causation.[83][84][85][86]
Large, well-controlled studies, including sibling-controlled analyses, find no causal link after adjusting for maternal conditions.[83][87][85][86]
Untreated pain and fever can harm mother andfetus.[32][31]
Paracetamol is excreted inbreast milk at measurable concentrations (milk/plasma ratio approximately 1), but the amount ingested by the infant is much lower than paediatric therapeutic doses and rarely associated with clinical effects.[88][89] Use during breastfeeding is considered compatible at recommended doses, with extra caution for preterm infants or infants with liver disease.[90]
Paracetamol helps ductal closure inpatent ductus arteriosus. It is as effective for this purpose as ibuprofen orindomethacin, but results in less frequent gastrointestinal bleeding than ibuprofen.[91] Its use for extremely low birth weight and gestational age infants however requires further study.[91]
In clinical trials forosteoarthritis, the number of participants reporting adverse effects was similar for those on paracetamol and on placebo. However, the abnormal liver function tests (meaning there was some inflammation or damage to the liver) were almost four times more likely in those on paracetamol, although the clinical importance of this effect is uncertain.[95] After 13 weeks of paracetamol therapy for knee pain, a drop in hemoglobin level indicatinggastrointestinal bleeding was observed in 20% of participants, this rate being similar to the ibuprofen group.[39]
Due to the absence ofcontrolled studies, most of the information about the long-term safety of paracetamol comes fromobservational studies.[38] These indicate a consistent pattern of increasedmortality as well ascardiovascular (stroke,myocardial infarction), gastrointestinal (ulcers,bleeding) andrenal adverse effects with increased dose of paracetamol.[39][38][96] Use of paracetamol is associated with 1.9 times higher risk of peptic ulcer.[38] Those who take it regularly at a higher dose (more than 2–3g daily) are at much higher risk (3.6–3.7 times) of gastrointestinal bleeding and other bleeding events.[97] Meta-analyses suggest that paracetamol may increase the risk ofkidney impairment by 23%[98] and kidney cancer by 28%.[96] Paracetamol slightly but significantly increasesblood pressure and heart rate.[38] A review of available research has suggested that increase in systolic blood pressure and increased risk of gastrointestinal bleeding associated with chronic paracetamol use shows a degree of dose dependence.[97]
The association between paracetamol use andasthma in children has been a matter of controversy.[99] However, the most recent research suggests that there is no association,[100] and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer, ibuprofen.[62]
In recommended doses, theside effects of paracetamol are mild to non-existent.[101] In contrast to aspirin, it is not ablood thinner (and thus may be used in patients where bleeding is a concern), and it does not cause gastric irritation.[102] Compared to Ibuprofen—which can have adverse effects that include diarrhea, vomiting, and abdominal pain—paracetamol is well tolerated with fewer side effects.[103] Prolonged daily use may cause kidney or liver damage.[102][104] Paracetamol is metabolized by the liver and ishepatotoxic; side effects may be more likely inchronic alcoholics or patients with liver damage.[101][105]
Overdose of paracetamol is caused by taking more than the recommended maximum daily dose of paracetamol for healthy adults (three or four grams),[40] and can cause potentially fatalliver damage.[106][107] A single dose should not exceed 1000 mg, doses should be taken no sooner than four hours apart, and no more than four doses (4000 mg) in 24 hours.[40] While a majority of adult overdoses are linked to suicide attempts, many cases are accidental, often due to the use of more than one paracetamol-containing product over an extended period.[108]
Paracetamol ishepatotoxic and depletes the stock of theantioxidantglutathione in theliver as glutathione is consumed much faster than it can be replenished.
Paracetamol toxicity has become the foremost cause of acute liver failure in the United States by 2003,[44] and as of 2005[update], paracetamol accounted for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.[109] As of 2004, paracetamol overdose resulted in more calls topoison control centers in the U.S. than overdose of any other pharmacological substance.[110] According to the FDA, in the United States, "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year [were] related to acetaminophen-associated overdoses during the 1990s. Within these estimates, unintentional acetaminophen overdose accounted for nearly 25% of the emergency department visits, 10% of the hospitalizations, and 25% of the deaths."[111][needs update]
Overdoses are frequently related to high-doserecreational use of prescriptionopioids, as these opioids are most often combined with paracetamol.[112] The overdose risk may be heightened by frequent consumption of alcohol.[113]
Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent ornon-specific symptoms. The first symptoms of overdose usually begin several hours after ingestion, withnausea,vomiting, sweating, and pain as acute liver failure starts.[114] People who take overdoses of paracetamol do not fall asleep or lose consciousness, although most people who attempt suicide with paracetamol wrongly believe that they will be rendered unconscious by the drug.[115][116]
Treatment is aimed at removing the paracetamol from the body and replenishingglutathione.[116]Activated charcoal can be used to decrease absorption of paracetamol if the person comes to the hospital soon after the overdose. While the antidote,acetylcysteine (also calledN-acetylcysteine or NAC), acts as a precursor for glutathione, helping the body regenerate enough to prevent or at least decrease the possible damage to the liver; aliver transplant is often required if damage to the liver becomes severe.[42][117]
NAC was usually given following a treatmentnomogram (one for people with risk factors, and one for those without), but the use of the nomogram is no longer recommended as evidence to support the use of risk factors was poor and inconsistent, and many of the risk factors are imprecise and difficult to determine with sufficient certainty in clinical practice.[118][119] Toxicity of paracetamol is due to itsquinone metaboliteNAPQI and NAC also helps in neutralizing it.[116]Kidney failure is also a possible side effect.[113]
Prokinetic agents such asmetoclopramide accelerate gastric emptying, shorten time (tmax) to paracetamolpeak blood plasma concentration (Cmax), and increase Cmax. Medications slowing gastric emptying such aspropantheline andmorphine lengthen tmax and decrease Cmax.[120][121] The interaction with morphine may result in patients failing to achieve the therapeutic concentration of paracetamol; the clinical significance of interactions with metoclopramide and propantheline is unclear.[121]
There have been suspicions thatcytochrome inducers may enhance the toxic pathway of paracetamol metabolism toNAPQI (seeParacetamol#Pharmacokinetics). By and large, these suspicions have not been confirmed.[121] Out of the inducers studied, the evidence of potentially increased liver toxicity in paracetamol overdose exists forphenobarbital,primidone,isoniazid, and possiblySt John's wort.[122] On the other hand, the anti-tuberculosis drugisoniazid cuts the formation of NAPQI by 70%.[121]
Paracetamol raises plasma concentrations ofethinylestradiol by 22% by inhibiting its sulfation.[121] Paracetamol increasesINR duringwarfarin therapy and should be limited to no more than 2 g per week.[123][124][125]
Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical nonsteroidal anti-inflammatory drugs (NSAIDs) that act by inhibitingCOX-1 andCOX-2 enzymes and especially similar to selectiveCOX-2 inhibitors.[127] Paracetamol inhibitsprostaglandin synthesis by reducing the active form of COX-1 and COX-2 enzymes. This occurs only when the concentration ofarachidonic acid andperoxides is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of paracetamol. Accordingly, the anti-inflammatory action of paracetamol is slight.[126][127]
In 2018, Suemaruet al. found that, in mice, paracetamol exerts an anticonvulsant effect by activation of theTRPV1 receptors[130] and a decrease in neuronal excitability byhyperpolarization of neurons.[131] The exact mechanism of the anticonvulsant effect of paracetamol is not clear. According to Suemaruet al., acetaminophen and its active metaboliteAM404 show a dose-dependent anticonvulsant activity against pentylenetetrazol-induced seizures in mice.[130]
In 2025, Maatufet al. reported that AM404 is also produced by peripheral sensory neuronsin vitro and blocks the action of pain-sensingNav1.8 and1.7 channels at nanomolar concentrations. AM404 injected into the hind paw of rats increase the pain threshold for the treated paw, but not the untreated paw, confirming the peripheral nature of this effect. It also lowers pain responses in a few otherin vivo models when injected directly into the affected area. Other tested metabolites of paracetamol do not block pain-sensing sodium channelsin vitro.[132][133]
After being taken by mouth, paracetamol is rapidly absorbed from thesmall intestine, while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach's emptying and absorption, but the total amount absorbed stays the same.[134] In the same subjects, the peak plasma concentration of paracetamol was reached after 20 minutes when fasting versus 90 minutes when fed. High carbohydrate (but not high protein or high fat) food decreases paracetamol peak plasma concentration by four times. Even in the fasting state, the rate of absorption of paracetamol is variable and depends on the formulation, with maximum plasma concentration being reached after 20 minutes to 1.5 hours.[7]
Paracetamol'sbioavailability is dose-dependent: it increases from 63% for 500mg dose to 89% for 1000mg dose.[7] Its plasma terminal elimination half-life is 1.9–2.5 hours,[7] andvolume of distribution is roughly 50L.[135] Protein binding is negligible, except under the conditions of overdose, when it may reach 15–21%.[7] The concentration in serum after a typical dose of paracetamol usually peaks below 30μg/mL (200μmol/L).[136] After 4 hours, the concentration is usually less than 10μg/mL (66μmol/L).[136]
Important pathways of paracetamol metabolism
Paracetamol ismetabolized primarily in the liver, mainly byglucuronidation andsulfation, and the products are then eliminated in the urine (see the Scheme on the right). Only 2–5% of the drug is excreted unchanged in the urine.[7] Glucuronidation byUGT1A1 andUGT1A6 accounts for 50–70% of the drug metabolism. Additional 25–35% of paracetamol is converted to sulfate by sulfation enzymesSULT1A1,SULT1A3, andSULT1E1.[137]
A minor metabolic pathway (5–15%) of oxidation bycytochrome P450 enzymes, mainly byCYP2E1, forms a toxic metabolite known asNAPQI (N-acetyl-p-benzoquinone imine).[137] NAPQI is responsible for the liver toxicity of paracetamol. At usual doses of paracetamol, NAPQI is quickly detoxified by conjugation withglutathione. The non-toxic conjugate APAP-GSH is taken up in the bile and further degraded to mercapturic and cysteine conjugates that are excreted in the urine. In overdose, glutathione is depleted by a large amount of formed NAPQI, and NAPQI binds tomitochondria proteins of the liver cells causingoxidative stress and toxicity.[137]
Yet another minor but important direction of metabolism is deacetylation of 1–2% of paracetamol to formp-aminophenol.p-Aminophenol is then converted in the brain byfatty acid amide hydrolase intoAM404, a compound that may be partially responsible for the analgesic action of paracetamol.[135]
An alternative industrial synthesis developed atCelanese involves firstly direct acylation of phenol with acetic anhydride in the presence ofhydrogen fluoride to a ketone, then the conversion of the ketone withhydroxylamine to aketoxime, and finally the acid-catalysedBeckmann rearrangement of the cetoxime to the para-acetylaminophenol product.[138][141]
Celanese method for the preparation of paracetamol
Paracetamol crystals (crystallized from an aqueous solution) under a microscopeClose-up image of Paracetamol crystals produced by acetylation of 4-aminophenol
4-Aminophenol may be obtained by the amidehydrolysis of paracetamol. This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid,4-aminophenol reacts in ammonia solution with a phenol derivate, e.g. salicylic acid, to form anindophenol dye under oxidization by air.[142]
Julius Axelrod(pictured) andBernard Brodie demonstrated that acetanilide and phenacetin are both metabolized to paracetamol, which is a better-tolerated analgesic.
Acetanilide was the firstaniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name ofAntifebrin by Cahn & Hepp in 1886.[143] But its unacceptable toxic effects—the most alarming beingcyanosis due tomethemoglobinemia, an increase of hemoglobin in its ferric [Fe3+] state, calledmethemoglobin, which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissue—prompted the search for less toxic aniline derivatives.[144] Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852.[46][47]
Harmon Northrop Morse synthesized paracetamol atJohns Hopkins University via the reduction ofp-nitrophenol withtin in glacialacetic acid in 1877,[145][146] but it was not until 1887 that clinical pharmacologistJoseph von Mering tried paracetamol on humans.[144] In 1893, von Mering published a paper reporting on the clinical results of paracetamol withphenacetin, another aniline derivative.[147] Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to producemethemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin establishedBayer as a leading pharmaceutical company.[148]
Von Mering's claims remained essentially unchallenged for half a century until two teams of researchers from the United States analysed the metabolism of acetanilide and phenacetin.[148] In 1947,David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.[149] In 1948,Bernard Brodie,Julius Axelrod and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans, and established that it was just as efficacious an analgesic as its precursor.[150][151][152] They also suggested that methemoglobinemia is produced in humans mainly by another metabolite,phenylhydroxylamine. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.[153] This led to a "rediscovery" of paracetamol.[144]
Paracetamol was first marketed in the United States in 1950 under the name Trigesic, a combination of paracetamol, aspirin, and caffeine.[146] Reports in 1951 of three users stricken with the blood diseaseagranulocytosis led to its removal from the marketplace, and it took several years until it became clear that the disease was unconnected.[146] The following year, 1952, paracetamol returned to the U.S. market as a prescription drug.[154] In the United Kingdom, marketing of paracetamol began in 1956 bySterling-Winthrop Co. as Panadol, available only by prescription, and promoted as preferable to aspirin since it was safe for children and people with ulcers.[155][156] In 1963, paracetamol was added to theBritish Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents.[155][146]
Concerns about paracetamol's safety delayed its widespread acceptance until the 1970s, but in the 1980s paracetamol sales exceeded those of aspirin in many countries, including the United Kingdom. This was accompanied by the commercial demise of phenacetin, blamed as the cause ofanalgesic nephropathy and hematological toxicity.[144] Available in the U.S. without a prescription since 1955[154] (1960, according to another source[157]), paracetamol has become a common household drug.[citation needed] In 1988, Sterling Winthrop was acquired byEastman Kodak which sold the over the counter drug rights toSmithKline Beecham in 1994.[158]
In June 2009, an FDA advisory committee recommended that new restrictions be placed on paracetamol use in the United States to help protect people from the potential toxic effects. The maximum single adult dosage would be decreased from 1000mg to 650mg, while combinations of paracetamol and other products would be prohibited. Committee members were particularly concerned by the fact that the then-present maximum dosages of paracetamol had been shown to produce alterations in liver function.[159]
In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount to no more than 325mg per tablet or capsule and began requiring manufacturers to update the labels of all prescription combination paracetamol products to warn of the potential risk of severe liver damage.[160][161][162][163][164] Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325mg per dosage unit.[161][163]
In September 2013, "Use Only as Directed", an episode of the radio programThis American Life[166] highlighted deaths from paracetamol overdose. This report was followed by two reports byProPublica alleging that the "FDA has long been aware of studies showing the risks of acetaminophen. So has the maker of Tylenol,McNeil Consumer Healthcare, a division of Johnson & Johnson"[167] and "McNeil, the maker of Tylenol, … has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug."[168]
In September 2025, US PresidentDonald Trump andHHS SecretaryRobert F. Kennedy Jr. claimed that Tylenol may cause autism and urged pregnant women to avoid it; medical experts, major health organizations, and international studies strongly dispute any causal link, emphasizing that the drug remains safe for treating pain and fever in pregnancy.[169]
Paracetamol is available in oral, suppository, andintravenous forms.[177] Intravenous paracetamol is sold under the brand name Ofirmev in the United States.[178]
In some formulations, paracetamol is combined with theopiatecodeine, sometimes referred to asco-codamol (BAN) and Panadeine in Australia. In the U.S., this combination is available only by prescription.[179] As of 1 February 2018, medications containing codeine also became prescription-only in Australia.[180] Paracetamol is also combined with other opioids such asdihydrocodeine,[181] referred to asco-dydramol (British Approved Name (BAN)),oxycodone[182] orhydrocodone.[183] Another very commonly used analgesic combination includes paracetamol in combination withpropoxyphene napsylate.[184] A combination of paracetamol, codeine, and thedoxylamine succinate is also available.[185] Paracetamol is also available combined withbutalbital and caffeine as a treatment for tension and migraine headaches.[186]
Paracetamol is extremely toxic to cats, which lack the necessaryUGT1A6 enzyme to detoxify it. Initial symptoms include vomiting, salivation, and discoloration of the tongue and gums. Unlike an overdose in humans, liver damage is rarely the cause of death; instead,methemoglobin formation and the production ofHeinz bodies in red blood cells inhibit oxygen transport by the blood, causingasphyxiation (methaemoglobinaemia andhaemolytic anaemia).[195]Acetylcysteine is used to treat cats with toxicity arising from paracetamol.[196]
Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs.[197] Paracetamol is considered a weak analgesic and is usually combined withcodeine, although the efficacy of this formulation has not been evaluated.[196]
The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported.[198][199][200][201] Acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion.[198][197]
Paracetamol is lethal to snakes[202] and has been suggested as a chemical control program for the invasivebrown tree snake (Boiga irregularis) inGuam.[203][204] Doses of 80mg are inserted into dead mice that are scattered by helicopter[205] as lethal bait to be consumed by the snakes.
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