Paracetamol

Fever Paracetamol is used for reducing fever. However, there has been a lack of research on its antipyretic properties, particularly in adults, and thus its benefits are unclear. In addition, low-quality clinical data indicates that when used for the common cold, paracetamol may relieve a stuffed or runny nose, but not other cold symptoms such as sore throat, malaise, sneezing, or cough. For people in critical care, paracetamol decreases body temperature by only 0.20.3°C more than control interventions and does not affect their mortality. It did not change the outcome in febrile patients with stroke. The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported. Overall, there is no support for a routine administration of antipyretic drugs, including paracetamol, to hospitalized patients with fever and infection. The efficacy of paracetamol in children with fever is unclear. Paracetamol should not be used solely to reduce body temperature; however, it may be considered for children with fever who appear distressed. It does not prevent febrile seizures. 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. Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis), including children younger than 2 years old, with equivalent safety. Exacerbation of asthma occurs with similar frequency for both medications. Pain 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, and dysmenorrhea. It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient. Musculoskeletal pain The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain. American College of Rheumatology and Arthritis Foundation guideline for the management of osteoarthritis notes that the effect size in clinical trials of paracetamol has been very small, which suggests that for most individuals it is ineffective. 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. Similarly, the ESCEO algorithm for the treatment of knee osteoarthritis recommends limiting the use of paracetamol to short-term rescue analgesia only. Paracetamol is ineffective for acute low back pain. No randomized clinical trials evaluated its use for chronic or radicular back pain, and the evidence in favor of paracetamol is lacking. 39% of people experience pain relief at one hour compared with 20% in the control group. The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a first-line treatment for migraine". Paracetamol on its own only slightly alleviates episodic tension headache in those who have them frequently. 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. 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". Dental and other post-surgical pain Pain after a dental surgery provides a reliable model for the action of analgesics on other kinds of acute pain. For the relief of such pain, paracetamol is inferior to ibuprofen. Full therapeutic doses of nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, naproxen, or diclofenac are clearly more efficacious than the paracetamol/codeine combination which is frequently prescribed for dental pain. The combinations of paracetamol and NSAIDs ibuprofen or diclofenac are promising, possibly offering better pain control than either paracetamol or the NSAID alone. Additionally, the paracetamol/ibuprofen combination may be superior to paracetamol/codeine and ibuprofen/codeine combinations. Other pain Paracetamol fails to relieve procedural pain in newborn babies. For perineal pain postpartum paracetamol appears to be less effective than nonsteroidal anti-inflammatory drugs (NSAIDs). The studies to support or refute the use of paracetamol for cancer pain and neuropathic pain are lacking. There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department. The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain. Patent ductus arteriosus Paracetamol helps ductal closure in patent ductus arteriosus. It is as effective for this purpose as ibuprofen or indomethacin, but results in less frequent gastrointestinal bleeding than ibuprofen. Its use for extremely low birth weight and gestational age infants, however, requires further study. == Use in pregnancy and breastfeeding ==

Pregnancy Paracetamol has long been established as a safe medication to treat short-term fever and significant pain in pregnant patients. Regulatory agencies, including the European Medicines Agency (EMA), the Medicines and Healthcare products Regulatory Agency (MHRA), the World Health Organization (WHO), and the U.S. Food and Drug Administration (FDA) 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, including ADHD and autism. However, these studies are limited by confounding factors such as maternal fever and infection, and do not demonstrate causation. Large, well-controlled studies, including sibling-controlled analyses, find no causal link after adjusting for maternal conditions. Use during breastfeeding is considered compatible at recommended doses, with extra caution for preterm infants or infants with liver disease. ==Adverse effects==

Gastrointestinal adverse effects such as nausea and abdominal pain are extremely uncommon, and their frequency is substantially lower than with ibuprofen use. According to the U.S. Food and Drug Administration (FDA), the drug may cause rare and possibly fatal skin reactions such as Stevens–Johnson syndrome and toxic epidermal necrolysis, Rechallenge tests and an analysis of American but not French pharmacovigilance databases indicated a risk of these reactions. In clinical trials for osteoarthritis, 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. After 13 weeks of paracetamol therapy for knee pain, a drop in hemoglobin level indicating gastrointestinal bleeding was observed in 20% of participants, this rate being similar to the ibuprofen group. Due to the absence of controlled studies, most of the information about the long-term safety of paracetamol comes from observational studies. These indicate a consistent pattern of increased mortality as well as cardiovascular (stroke, myocardial infarction), gastrointestinal (ulcers, bleeding) and renal adverse effects with increased dose of paracetamol. Use of paracetamol is associated with 1.9 times higher risk of peptic ulcer. and kidney cancer by 28%. The association between paracetamol use and asthma in children has been a matter of controversy. However, the most recent research suggests that there is no association, and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer, ibuprofen. In contrast to aspirin, it is not a blood thinner (and thus may be used in patients where bleeding is a concern), and it does not cause gastric irritation. Compared to Ibuprofen—which can have adverse effects that include diarrhea, vomiting, and abdominal pain—paracetamol is well tolerated with fewer side effects. Prolonged daily use may cause kidney or liver damage. Paracetamol is metabolized by the liver and is hepatotoxic; side effects may be more likely in chronic alcoholics or patients with liver damage. ==Overdose==

Overdose of paracetamol is caused by taking more than the recommended maximum daily dose of paracetamol for healthy adults (three or four grams), 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. Paracetamol is hepatotoxic and depletes the stock of the antioxidant glutathione in the liver as glutathione is consumed much faster than it can be replenished. Paracetamol toxicity had become the foremost cause of acute liver failure in the United States by 2003, As of 2004, paracetamol overdose resulted in more calls to poison control centers in the U.S. than overdose of any other pharmacological substance. 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." Overdoses are frequently related to high-dose recreational use of prescription opioids, as these opioids are most often combined with paracetamol. The overdose risk may be heightened by frequent consumption of alcohol. Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or non-specific symptoms. The first symptoms of overdose usually begin several hours after ingestion, with nausea, vomiting, sweating, and pain as acute liver failure starts. 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. Treatment is aimed at removing the paracetamol from the body and replenishing glutathione. NAC is usually given following a treatment nomogram for patients with an acute overdose at a known time of ingestion. Patients with unknown time of ingestion, unreliable history, or repeat supratherapeutic ingestion are treated based on risk assessment. Toxicity of paracetamol is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it. Kidney failure is also a possible side effect. ==Interactions==

Prokinetic agents such as metoclopramide accelerate gastric emptying, shorten time (tmax) to paracetamol peak blood plasma concentration (Cmax), and increase Cmax. Medications slowing gastric emptying such as propantheline and morphine lengthen tmax and decrease Cmax. 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. On the other hand, the anti-tuberculosis drug isoniazid cuts the formation of NAPQI by 70%. ==Pharmacology==

Pharmacodynamics Paracetamol appears to exert its effects through two mechanisms: the inhibition of cyclooxygenase (COX) and actions of its metabolite N-arachidonoylphenolamine (AM404). Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical nonsteroidal anti-inflammatory drugs (NSAIDs) that act by inhibiting COX-1 and COX-2 enzymes and especially similar to selective COX-2 inhibitors, Paracetamol inhibits prostaglandin synthesis by reducing the active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of arachidonic acid and peroxides is low; under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under typical inflammation conditions, the concentration of peroxides is high, which counteracts the reducing anti-inflammatory effect of paracetamol, rendering it negligible; in situations where peroxide levels are low, such as for COX-2 in the CNS, this inhibition and its resulting anti-inflammatory effect remain high. It is formed in the brain from another paracetamol metabolite 4-aminophenol by action of fatty acid amide hydrolase. In 2018, Suemaru et al. found that, in mice, paracetamol exerts an anticonvulsant effect by activation of the TRPV1 receptors and a decrease in neuronal excitability by hyperpolarization of neurons. The exact mechanism of the anticonvulsant effect of paracetamol is not clear. According to Suemaru et al., acetaminophen and its active metabolite AM404 show a dose-dependent anticonvulsant activity against pentylenetetrazol-induced seizures in mice. Pharmacokinetics After being taken by mouth, paracetamol is rapidly absorbed from the small 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. In the same subjects, the time to reach peak plasma concentration of paracetamol was 20 minutes in a fasting state, compared to 90 minutes in a fed state. Furthermore, a high-carbohydrate meal reduced the peak plasma concentration by approximately fourfold, an effect not observed with high-protein or high-fat meals. Paracetamol's bioavailability is dose-dependent: it increases from 63% for 500mg dose to 89% for 1000mg dose. Protein binding is negligible, except under the conditions of overdose, when it may reach 1521%. Paracetamol is metabolized primarily in the liver, mainly by glucuronidation and sulfation, and the products are then eliminated in the urine (see the Scheme on the right). Only 25% of the drug is excreted unchanged in the urine. A minor metabolic pathway (5–15%) of oxidation by cytochrome P450 enzymes, mainly by CYP2E1, forms a toxic metabolite known as NAPQI (N-acetyl-p-benzoquinone imine). NAPQI is responsible for the liver toxicity of paracetamol. At usual doses of paracetamol, NAPQI is quickly detoxified by conjugation with glutathione. 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 to mitochondria proteins of the liver cells, causing oxidative stress and toxicity. Yet another minor but important direction of metabolism is deacetylation of 12% of paracetamol to form p-aminophenol. p-Aminophenol is then converted in the brain by fatty acid amide hydrolase into AM404, a compound that may be partially responsible for the analgesic action of paracetamol. ==Chemistry==

Synthesis Classical methods The classical methods for the production of paracetamol involve the acetylation of 4-aminophenol with acetic anhydride as the last step. They differ in how 4-aminophenol is prepared. In one method, nitration of phenol with nitric acid affords 4-nitrophenol, which is reduced to 4-aminophenol by hydrogenation over Raney nickel. In another method, nitrobenzene is reduced electrolytically giving 4-aminophenol directly. Additionally, 4-nitrophenol can be selectively reduced by Tin(II) Chloride in absolute ethanol or ethyl acetate to produce a 91% yield of 4-aminophenol. Celanese synthesis An alternative industrial synthesis developed at Celanese involves firstly direct acylation of phenol with acetic anhydride in the presence of hydrogen fluoride to give a methyl ketone, then the conversion of the ketone with hydroxylamine to a ketoxime, and finally the acid-catalysed Beckmann rearrangement of the oxime to the amide in the para-acetylaminophenol product. Reactions 4-Aminophenol may be obtained by the amide hydrolysis 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 an indophenol dye under oxidization by air. ==History==

(pictured) and Bernard Brodie demonstrated that acetanilide and phenacetin are both metabolized to paracetamol, which is a better-tolerated analgesic. Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of Antifebrin by Cahn & Hepp in 1886. But its unacceptable toxic effectsthe most alarming being cyanosis due to methemoglobinemia, an increase of hemoglobin in its ferric [Fe3+] state, called methemoglobin, which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissueprompted the search for less toxic aniline derivatives. Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852. Von Mering claimed that, unlike phenacetin, paracetamol had a slight tendency to produce methemoglobinemia. Paracetamol was then quickly discarded in favor of phenacetin. The sales of phenacetin established Bayer as a leading pharmaceutical company. 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. 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. 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. This led to a "rediscovery" of paracetamol. In 1963, paracetamol was added to the British Pharmacopoeia, and has gained popularity since then as an analgesic agent with few side-effects and little interaction with other pharmaceutical agents. 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 of analgesic nephropathy and hematological toxicity. (1960, according to another source), paracetamol has become a common household drug. In 1988, Sterling Winthrop was acquired by Eastman Kodak which sold the over the counter drug rights to SmithKline Beecham in 1994. 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. 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. Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325mg per dosage unit. In September 2013, "Use Only as Directed", an episode of the radio program This American Life highlighted deaths from paracetamol overdose. This report was followed by two reports by ProPublica 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" and "McNeil, the maker of Tylenol, ... has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug." In September 2025, US President Donald Trump and HHS Secretary Robert 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. ==Society and culture==

Naming Paracetamol is the Australian Approved Name and the British Approved Name Both paracetamol and acetaminophen are contractions of chemical names for the compound. The word paracetamol is a shortened form of para-acetylaminophenol, and was coined by Frederick Stearns & Co in 1956, while the word acetaminophen is a shortened form of N-acetyl-p-aminophenol (APAP), which was coined and first marketed by McNeil Laboratories in 1955. The initialism APAP is used by dispensing pharmacists in the United States. Available forms Paracetamol is available in oral, suppository, and intravenous forms. Intravenous paracetamol is sold under the brand name Ofirmev in the United States. In some formulations, paracetamol is combined with the opiate codeine, sometimes referred to as co-codamol (BAN) and Panadeine in Australia. In the U.S., this combination is available only by prescription. As of 1 February 2018, medications containing codeine also became prescription-only in Australia. Paracetamol is also combined with other opioids such as dihydrocodeine, referred to as co-dydramol (British Approved Name (BAN)), oxycodone or hydrocodone. Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate. A combination of paracetamol, codeine, and the doxylamine succinate is also available. Paracetamol is also available combined with butalbital and caffeine as a treatment for tension and migraine headaches. Paracetamol is sometimes combined with phenylephrine hydrochloride. Sometimes a third active ingredient, such as ascorbic acid, caffeine, chlorpheniramine maleate, or guaifenesin is added to this combination. ==Veterinary use==

aerial bait cartridges consisting of dead mice with 80mg paracetamol tablets Cats Paracetamol is extremely toxic to cats, which lack the necessary UGT1A6 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 of Heinz bodies in red blood cells inhibit oxygen transport by the blood, causing asphyxiation (methaemoglobinaemia and haemolytic anaemia). Acetylcysteine is used to treat cats with toxicity arising from paracetamol. Dogs Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs. Paracetamol is considered a weak analgesic and is usually combined with codeine, although the efficacy of this formulation has not been evaluated. Acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion. and has been suggested as a chemical control program for the invasive brown tree snake (Boiga irregularis) in Guam. Doses of 80mg are inserted into dead mice that are scattered by helicopter as lethal bait to be consumed by the snakes. ==Notes==