Paracetamol, also known as acetaminophen or APAP, is a medication used to treat pain and fever. It is typically used for mild to moderate pain. The quality of the evidence regarding the use for fever relief in children is poor. It is often sold in combination with other ingredients such as in many cold medications. In combination with opioid pain medication, paracetamol is also used for more severe pain such as cancer pain and after surgery. It is typically used either by mouth or rectally but is also available intravenously. Effects last between two and four hours.
Paracetamol is generally safe at recommended doses. Serious skin rashes may rarely occur, and too high a dose can result in liver failure. It appears to be safe during pregnancy and when breastfeeding. In those with liver disease, it may still be used, but in lower doses. Paracetamol is classified as a mild analgesic. It does not have significant anti-inflammatory activity and how it works is not entirely clear.
Paracetamol was discovered in 1877. It is the most commonly used medication for pain and fever in both the United States and Europe. It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system. Paracetamol is available as a generic medication with trade names including Tylenol and Panadol among others. The wholesale price in the developing world is less than 0.01 USD per dose. In the United States it costs about 0.04 USD per dose.
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Medical uses
Fever
Paracetamol is used for reducing fever in people of all ages. The World Health Organization (WHO) recommends that paracetamol be used to treat fever in children only if their temperature is greater than 38.5 °C (101.3 °F). The efficacy of paracetamol by itself in children with fevers has been questioned and a meta-analysis showed that it is less effective than ibuprofen.
Pain
Paracetamol is used for the relief of mild to moderate pain. The use of the intravenous form for pain of sudden onset in people in the emergency department is supported by limited evidence.
Osteoarthritis
The American College of Rheumatology recommends paracetamol as one of several treatment options for people with arthritis pain of the hip, hand, or knee that does not improve with exercise and weight loss. A 2015 review, however, found it provided only a small benefit in osteoarthritis.
Paracetamol has relatively little anti-inflammatory activity, unlike other common analgesics such as the NSAIDs aspirin and ibuprofen, but ibuprofen and paracetamol have similar effects in the treatment of headache. Paracetamol can relieve pain in mild arthritis, but has no effect on the underlying inflammation, redness, and swelling of the joint. It has analgesic properties comparable to those of aspirin, while its anti-inflammatory effects are weaker. It is better tolerated than aspirin due to concerns about bleeding with aspirin.
Low back pain
Based on a systematic review, paracetamol is recommended by the American College of Physicians and the American Pain Society as a first-line treatment for low back pain. However, other systematic reviews concluded that evidence for its efficacy is lacking.
Headaches
A joint statement of the German, Austrian, and Swiss headache societies and the German Society of Neurology recommends the use of paracetamol in combination with caffeine as one of several first line therapies for treatment of tension or migraine headache. In the treatment of acute migraine, it is superior to placebo, with 39% of people experiencing pain relief at one hour compared with 20% in the control group.
Postoperative pain
Paracetamol combined with NSAIDs may be more effective for treating postoperative pain than either paracetamol alone or NSAIDs alone.
Dental use
NSAIDs such as ibuprofen, naproxen, diclofenac are more effective than paracetamol for controlling dental pain or pain arising from dental procedures; combinations of NSAIDs and paracetamol are more effective than either alone. Paracetamol is particularly useful when NSAIDs are contraindicated due to hypersensitivity or history of gastrointestinal ulceration or bleeding. It can also be used in combination with NSAIDs when these are ineffective in controlling dental pain alone. The Cochrane review of preoperative analgesics for additional pain relief in children and adolescents shows no evidence of benefit in taking paracetamol before dental treatment to help reduce pain after treatment for procedures under local anaesthetic, however the quality of evidence is low.
Other
The efficacy of paracetamol when used in combination with weak opioids (such as codeine) improved for approximately 50% of people but with increases in the number experiencing side effects. Combination drugs of paracetamol and strong opioids like morphine improve analgesic effect.
The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of common pain conditions including dental pain, postpartum pain, and headache.
Patent ductus arteriosus
Paracetamol is used to treat patent ductus arteriosus, a condition that affects newborns when a blood vessel used in developing the lungs fails to close as it normally does, but evidence for the safety and efficacy of paracetamol for this purpose is lacking. Nonsteroidal anti-inflammatory drugs (NSAID), particularly indomethacin and ibuprofen, have also been used but the evidence for them is also not strong. The condition appears to be caused in party by overactive prostaglandin E2 (PGE2), signalling primarily through its EP4 receptor but possibly also through its EP2 and EP3 receptors.
Acetaminophen Adverse Effects Video
Adverse effects
Healthy adults taking regular doses of up to 4,000 mg a day show little evidence of toxicity (although some researchers disagree). They are more likely to have abnormal liver function tests, but the significance of this is uncertain.
Liver damage
Acute overdoses of paracetamol can cause potentially fatal liver damage. In 2011 the U.S. Food and Drug Administration launched a public education program to help consumers avoid overdose, warning: "Acetaminophen can cause serious liver damage if more than directed is used." In a 2011 Safety Warning the FDA immediately required manufacturers to update labels of all prescription combination acetaminophen products to warn of the potential risk for severe liver injury and required that such combinations contain no more than 325 mg of acetaminophen. FDA has likewise requested prescribers to limit combination opioids to 325 mg of acetaminophen. Such overdoses are frequently related to high-dose recreational use of prescription opioids, as these opioids are most often combined with acetaminophen. The overdose risk may be heightened by frequent consumption of alcohol.
Paracetamol toxicity is the foremost cause of acute liver failure in the Western world and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand. According to the FDA, in the United States there were "56,000 emergency room visits, 26,000 hospitalizations, and 458 deaths per year 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."
Paracetamol is metabolised by the liver and is hepatotoxic; side effects are multiplied when combined with alcoholic drinks, and are very likely in chronic alcoholics or people with liver damage. Some studies have suggested the possibility of a moderately increased risk of upper gastrointestinal complications such as stomach bleeding when high doses are taken chronically. Kidney damage is seen in rare cases, most commonly in overdose.
Skin reactions
On August 2, 2013, the U.S. Food and Drug Administration (FDA) issued a new warning about paracetamol. It stated that the drug could cause rare and possibly fatal skin reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis. Prescription-strength products will be required to carry a warning label about skin reactions, and the FDA has urged manufacturers to do the same with over-the-counter products.
Asthma
There is an association between paracetamol use and asthma, but the evidence suggests that this likely reflects confounders rather than a causal role. A 2014 review found that among children the association disappeared when respiratory infections were taken into account.
As of 2014, the American Academy of Pediatrics and the National Institute for Health and Care Excellence (NICE) continue to recommend paracetamol for pain and discomfort in children, but some experts have recommended that paracetamol use by children with asthma or at risk for asthma should be avoided.
Other factors
In contrast to aspirin, paracetamol does not prevent blood from clotting (it is not an antiplatelet), and thus may be used in people who have concerns with blood coagulation. Additionally it does not cause gastric irritation. However, paracetamol does not help reduce inflammation, while aspirin does. Compared with ibuprofen--whose side effects may include diarrhea, vomiting and abdominal pain--paracetamol has fewer adverse gastrointestinal effects. Unlike aspirin, paracetamol is generally considered safe for children, as it is not associated with a risk of Reye's syndrome in children with viral illnesses. If taken recreationally with opioids, there is weak evidence suggesting that it may cause hearing loss.
Overdose
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. The process of dying from an overdose takes from 3-5 days to 4-6 weeks.
Paracetamol hepatotoxicity is by far the most common cause of acute liver failure in both the United States and the United Kingdom. Paracetamol overdose results in more calls to poison control centers in the US than overdose of any other pharmacological substance. Toxicity of paracetamol is believed to be due to its quinone metabolite.
Untreated overdose can lead to liver failure and death within days. Treatment is aimed at removing the paracetamol from the body and replacing glutathione. 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 called N-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, a liver transplant is often required if damage to the liver becomes severe. NAC was usually given following a treatment nomogram (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. NAC also helps in neutralizing the imidoquinone metabolite of paracetamol. Kidney failure is also a possible side effect.
Until 2004, tablets were available (brand-name in the UK Paradote) that combined paracetamol with an antidote (methionine) to protect the liver in case of an overdose. One theoretical, but rarely if ever used, option in the United States is to request a compounding pharmacy to make a similar drug mix for people who are at risk.
In June 2009, a U.S. Food and Drug Administration (FDA) advisory committee recommended that new restrictions be placed on paracetamol usage in the United States to help protect people from the potential toxic effects. The maximum dosage at any given time would be decreased from 1000 mg to 650 mg, while combinations of paracetamol and opioid analgesics 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 hepatic function.
In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit the amount of paracetamol to no more than 325 mg 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 325 mg per dosage unit. In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.
Pregnancy
Experimental studies in animals and cohort studies in humans indicate no detectable increase in congenital malformations associated with paracetamol use during pregnancy. Additionally, paracetamol does not affect the closure of the fetal ductus arteriosus as NSAIDs can.
Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood asthma. It is also associated with an increase in ADHD but it is unclear whether the relationship is causal. A 2015 review states that paracetamol remains a first-line recommended medication for pain and fever during pregnancy, despite these concerns.
Cancer
Some studies have found an association between paracetamol and a slight increase in kidney cancer, but no effect on bladder cancer risk.
Mechanism of action
The mechanism of action of paracetamol is not completely understood. Unlike NSAIDs such as aspirin, paracetamol does not appear to inhibit the function of any cyclooxygenase (COX) enzyme outside the central nervous system, and this appears to be the reason why it is not useful as an anti-inflammatory. It does appear to selectively inhibit COX activities in the brain, which may contribute to its ability to treat fever and pain. This activity does not appear to be direct inhibition by blocking an active site, but rather by reducing COX, which must be oxidized in order to function.
It also appears that paracetamol might modulate the endogenous cannabinoid system in the brain through paracetamol's metabolite, AM404. AM404 appears to inhibit the reuptake of the endogenous cannabinoid/vanilloid anandamide by neurons, making it more available to reduce pain. AM404 also appears to be able to directly activate the TRPV1 (older name: vanilloid receptor), which also inhibits pain signals in the brain.
Pharmacokinetics
After being taken by mouth it is rapidly absorbed by the GI tract (although absorption through the stomach is negligible); its volume of distribution is roughly 50 L. The concentration in serum after a typical dose of paracetamol usually peaks below 30 µg/ml (200 µmol/L). After four hours the concentration is usually less than 10 µg/mL (66 µmol/L).
Paracetamol is metabolised primarily in the liver, into toxic and non-toxic products. Three metabolic pathways are notable:
- Glucuronidation (45-55%), by UGT1A1 and UGT1A6;
- Sulfation (sulfate conjugation) (20-30%) by SULT1A1;
- N-hydroxylation and dehydration, then glutathione conjugation, (less than 15%). The hepatic cytochrome P450 enzyme system metabolises paracetamol (mainly CYP2E1), forming a minor yet significant alkylating metabolite known as NAPQI (N-acetyl-p-benzoquinone imine) (also known as N-acetylimidoquinone). NAPQI is then irreversibly conjugated with the sulfhydryl groups of glutathione.
All three pathways yield final products that are inactive, non-toxic, and eventually excreted by the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic. NAPQI is primarily responsible for the toxic effects of paracetamol; this constitutes an example of toxication. Production of NAPQI is due primarily to two isoenzymes of cytochrome P450: CYP2E1 and CYP3A4. At usual doses, NAPQI is quickly detoxified by conjugation with glutathione.
Chemistry
Chemical properties
Paracetamol consists of a benzene ring core, substituted by one hydroxyl group and the nitrogen atom of an amide group in the para (1,4) pattern. The amide group is acetamide (ethanamide). It is an extensively conjugated system, as the lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, the p orbital on the carbonyl carbon, and the lone pair on the carbonyl oxygen are all conjugated. The presence of two activating groups also make the benzene ring highly reactive toward electrophilic aromatic substitution. As the substituents are ortho, para-directing and para with respect to each other, all positions on the ring are more or less equally activated. The conjugation also greatly reduces the basicity of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on the phenoxide anion.
Paracetamol is part of the class of drugs known as "aniline analgesics"; it is the only such drug still in use today. It is not considered an NSAID because it does not exhibit significant anti-inflammatory activity (it is a weak COX inhibitor). This is despite the evidence that paracetamol and NSAIDs have some similar pharmacological activity.
Synthesis
Original (Boots) method
The original method for production involves the nitration of phenol with sodium nitrate gives a mixture of two isomers, from which the wanted 4-nitrophenol (bp 279 °C) can easily be separated by steam distillation. In this electrophilic aromatic substitution reaction, phenol's oxygen is strongly activating, thus the reaction requires only mild conditions as compared to nitration of benzene itself. The nitro group is then reduced to an amine, giving 4-aminophenol. Finally, the amine is acetylated with acetic anhydride. Industrially direct hydrogenation is used, but in the laboratory scale sodium borohydride serves.
Green(er) synthesis
An alternative industrial synthesis developed by Hoechst-Celanese involves direct acylation of phenol with acetic anhydride catalyzed by HF, conversion of the ketone to a ketoxime with hydroxylamine, followed by the acid-catalyzed Beckmann rearrangement to give the amide.
Direct synthesis
More recently (2014) a "one-pot" synthesis from hydroquinone has been described before the Royal Society of Chemistry. The process may be summarized as follows:
The authors go on to claim an 88% yield and 99% purity.
Reactions
4-Aminophenol may be obtained by the amide hydrolysis of paracetamol. 4-Aminophenol prepared this way, and related to the commercially available Metol, has been used as a developer in photography by hobbyists. 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
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 A. Cahn and P. Hepp in 1886. But its unacceptable toxic effects, the most alarming being cyanosis due to methemoglobinemia, prompted the search for less toxic aniline derivatives. Harmon Northrop Morse had already synthesised paracetamol at Johns Hopkins University via the reduction of p-nitrophenol with tin in glacial acetic acid in 1877, but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on humans. In 1893, von Mering published a paper reporting on the clinical results of paracetamol with phenacetin, another aniline derivative. 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. Overshadowed in part by aspirin, introduced into medicine by Heinrich Dreser in 1899, phenacetin was popular for many decades, particularly in widely advertised over-the-counter "headache mixtures", usually containing phenacetin, an aminopyrine derivative of aspirin, caffeine, and sometimes a barbiturate.
Paracetamol is the active metabolite of phenacetin and acetanilide, both once popular as analgesics and antipyretics in their own right. However, unlike phenacetin, acetanilide and their combinations, paracetamol is not considered carcinogenic at therapeutic doses.
Von Mering's claims remained essentially unchallenged for half a century, until two teams of researchers from the United States analyzed the metabolism of acetanilide and paracetamol. 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. In three papers published in the September 1948 issue of the Journal of Pharmacology and Experimental Therapeutics, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed using more specific methods that paracetamol was the major metabolite of acetanilide in human blood, 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 metabolised to paracetamol. This led to a "rediscovery" of paracetamol. It has been suggested that contamination of paracetamol with 4-aminophenol, the substance von Mering synthesised it from, may be the cause for his spurious findings.
Paracetamol was first marketed in the United States in 1950 under the name Triagesic, a combination of paracetamol, aspirin, and caffeine. Reports in 1951 of three users stricken with the blood disease agranulocytosis led to its removal from the marketplace, and it took several years until it became clear that the disease was unconnected. Paracetamol was marketed in 1953 by Sterling-Winthrop Co. as Panadol, available only by prescription, and promoted as preferable to aspirin since it was safe for children and people with ulcers. In 1955, paracetamol was marketed as Children's Tylenol Elixir by McNeil Laboratories. In 1956, 500 mg tablets of paracetamol went on sale in the United Kingdom under the trade name Panadol, produced by Frederick Stearns & Co, a subsidiary of Sterling Drug Inc. 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. In 1988 Sterling Winthrop was acquired by Eastman Kodak which sold the over the counter drug rights to SmithKline Beecham in 1994.
Available without a prescription since 1959, it has since become a common household drug. Patents on paracetamol have long expired, and generic versions of the drug are widely available.
Society and culture
Naming
Acetaminophen is the name generally used in the United States (USAN), Japan (JAN), Canada Venezuela, Colombia., and Iran; paracetamol is used in international venues (INN, AAN, BAN). In some contexts, such as on prescription bottles of painkillers that incorporate this medicine, it is simply abbreviated as APAP, for acetyl-para-aminophenol.
Both acetaminophen and paracetamol come from a chemical name for the compound: para-acetylaminophenol and para-acetylaminophenol.
Available forms
Paracetamol is available in a tablet, capsule, liquid suspension, suppository, intravenous, intramuscular and effervescent forms.
In some formulations, paracetamol is combined with the opioid codeine, sometimes referred to as co-codamol (BAN) and Panadeine in Australia. In the U.S., this combination is available only by prescription, while the lowest-strength preparation is over the counter in Canada, and in other countries other strengths may be available over the counter. Paracetamol is also combined with other opioids such as dihydrocodeine, referred to as co-dydramol (BAN), oxycodone or hydrocodone. Another very commonly used analgesic combination includes paracetamol in combination with propoxyphene napsylate. A combination of paracetamol, codeine, and the calmative doxylamine succinate is also available. The efficacy of paracetamol/codeine combinations has been questioned by recent research.
Paracetamol is commonly used in multi-ingredient preparations for migraine headache, typically including butalbital and paracetamol with or without caffeine, and sometimes containing codeine.
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.
When marketed in combination with diphenhydramine hydrochloride, it is frequently given the label "PM" and is meant as a sleep aid. Diphenhydramine hydrochloride is known to have hypnotic effects and is non-habit forming. Unfortunately it has been implicated in the occasional development of restless leg syndrome.
Controversy
In September 2013, an episode of This American Life entitled "Use Only as Directed" 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."
A report prepared by an internal FDA working group describes a history of FDA initiatives designed to educate consumers about the risk of paracetamol overdose and notes that one challenge to the Agency has been "identifying the appropriate message about the relative safety of acetaminophen, especially compared to other OTC pain relievers (e.g., aspirin and other NSAIDs)". The report notes that "Chronic use of NSAIDs is also associated with significant morbidity and mortality. NSAID gastrointestinal risk is substantial, with deaths and hospitalization estimated in one publication as 3200 and 32,000 per year respectively. Possible cardiovascular toxicity with chronic NSAID use has been a major discussion recently", finally noting that "The goal of the educational efforts is not to decrease appropriate acetaminophen use or encourage substitution of NSAID use, but rather to educate consumers so that they can avoid unnecessary health risks."
Veterinary use
Cats
Paracetamol is extremely toxic to cats, which lack the necessary glucuronyl transferase enzymes to break it down safely. 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 (methemoglobemia and hemolytic anemia).
Treatment with N-acetylcysteine, methylene blue or both is sometimes effective after the ingestion of small doses of paracetamol.
Dogs
Although paracetamol is believed to have no significant anti-inflammatory activity, it has been reported as effective as aspirin in the treatment of musculoskeletal pain in dogs.
A paracetamol-codeine product (trade name Pardale-V) licensed for use in dogs is available on veterinary prescription in the UK. It should be administered to dogs only on veterinary advice and with extreme caution.
The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported. N-acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion.
Snakes
Paracetamol is also lethal to snakes, and has been suggested as a chemical control program for the invasive brown tree snake (Boiga irregularis) in Guam. Doses of 80 mg are inserted into dead mice scattered by helicopter.
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