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Paracetamol

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Paracetamol
Names
PronunciationParacetamol:/ˌpærəˈsiːtəmɒl/
Acetaminophen:/əˌsiːtəˈmɪnəfɪn/ (About this soundlisten)
Trade namesTylenol,Panadol,others[1]
Other namesN-acetyl-para-aminophenol (APAP), acetaminophen (USANUS)
  • N-(4-hydroxyphenyl)acetamide
Clinical data
Drug classAnalgesics, antipyretics
Main usesFever, mild pain[2]
Side effectsGenerally safe at recommended doses[3]
Pregnancy
category
Routes of
use		By mouth,through the cheek,rectal,intravenous (IV)
Onset of actionPain relief onset byroute:
By mouth – 37 minutes[5]
Buccal – 15 minutes[5]
Intravenous – 8 minutes[5]
Defined daily dose3 g (by mouth, injection, rectal)[6]
External links
AHFS/Drugs.comMonograph
MedlinePlusa681004
Legal
License data
Legal status
Pharmacokinetics
Bioavailability63–89%[7]: 73 
Protein binding10–25%[8]
MetabolismPredominantly in the liver[9]
MetabolitesAPAPgluc, APAPsulfate, APAPGSH, APAPcys,NAPQI[10]
Eliminationhalf-life2–2.5 hours[11]
ExcretionUrine (85–90%)[9]
Chemical and physical data
FormulaC8H9NO2
Molar mass151.163 g·mol−1
3D model (JSmol)
Density1.263 g/cm3
Melting point169 °C (336 °F)[12][13]
Boiling point420 °C (788 °F)
Solubility in water
  • 7.21 g/kg (0 °C)[14]
  • 8.21 g/kg (5 °C)[14]
  • 9.44 g/kg (10 °C)[14]
  • 10.97 g/kg (15 °C)[14]
  • 12.78 g/kg (20 °C)[14]
  • ~14 mg/ml (20 °C)
  • CC(=O)Nc1ccc(O)cc1
  • InChI=1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10) checkY
  • Key:RZVAJINKPMORJF-UHFFFAOYSA-N checkY


Paracetamol, also known asacetaminophen, is a medication used to treatpain andfever.[15][16] It is typically used for mild to moderate pain relief.[15] Evidence is mixed for its use to relieve fever in children.[17][18] It is often sold in combination with other medications, such as in manycold medications.[15] Paracetamol is also used for severe pain, such ascancer pain and pain after surgery, in combination withopioid pain medication.[19] It is typically used either by mouth orrectally, but is also available byinjection into a vein.[15][20] Effects last between two and four hours.[20]

Paracetamol is generally safe at recommended doses.[3][21] The recommended maximum daily dose for an adult is three to four grams.[22][23][21] Higher doses may lead to toxicity, includingliver failure.[15] Serious skin rashes may rarely occur.[15] It appears to be safe duringpregnancy and whenbreastfeeding.[15] In those with liver disease, it may still be used, but in lower doses.[24] It is classified as a mildanalgesic.[20] It does not have significantanti-inflammatory activity.[25] How it works is not entirely clear.[25][26][27]

Paracetamol was first made in 1877.[28] It is the most commonly used medication for pain and fever in both the United States and Europe.[29] It is on theWorld Health Organization's List of Essential Medicines.[30] Paracetamol is available as ageneric medication, with brand names includingTylenol andPanadol amongothers.[31] The wholesale price in thedeveloping world is less thanUS$0.01 per dose.[32] In the United States, it costs aboutUS$0.04 per dose.[33] In 2017, it was the 25th-most commonly prescribed medication in the United States, with more than 24 million prescriptions.[34][35]

Medical uses

Fever

Paracetamol is used for reducingfever in people of all ages.[15] TheWorld Health Organization recommends that paracetamol be used to treat fever in children only if their temperature is higher than 38.5 °C (101.3 °F).[36] The efficacy of paracetamol by itself in children with fevers has been questioned[37] and a meta-analysis showed that it is less effective thanibuprofen.[38] Paracetamol does not have significantanti-inflammatory effects.[25][26][27]

Pain

Paracetamol is used for the relief of mild to moderate pain.[15] The use of the intravenous form for short-term pain in people in the emergency department is supported by limited evidence.[39] In adults, it appears to be useful formigraines,tension headaches, perineal pain after childbirth, andkidney stone pain.[40]

Osteoarthritis

TheAmerican 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.[41] A 2015 review, however, found it provided only a small benefit inosteoarthritis.[21]

Paracetamol has relatively little anti-inflammatory activity,[25][26][27] unlike other common analgesics such as thenonsteroidal anti-inflammatory drugs (NSAIDs)aspirin, andibuprofen, 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.[42]

Lower back

Based on a systematic review, paracetamol was recommended by theAmerican College of Physicians and theAmerican Pain Society as a first-line treatment for lower back pain.[43][44][45] TheAmerican College of Physicians, as of 2017[update], noted evidence that it was no different than placebo in the treatment of nonradicular low back pain.[46] Other systematic reviews have also concluded that evidence for its efficacy is lacking.[21][47][48]

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 withcaffeine as one of several first-line therapies for treatment of tension andmigraine headaches.[49] 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.[50]

Postoperative

Paracetamol combined with NSAIDs may be more effective for treating postoperative pain than either paracetamol or NSAIDs alone.[51]

Teeth

NSAIDs such asibuprofen,naproxen, anddiclofenac 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.[52] Paracetamol is particularly useful whenNSAIDs are contraindicated due to hypersensitivity or history of gastrointestinal ulceration or bleeding.[53] It can also be used in combination with NSAIDs when these are ineffective in controlling dental pain alone.[54] TheCochrane 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, but the quality of evidence is low.[55]

Combination medications

The efficacy of paracetamol when used in combination with weak opioids (such ascodeine) improved for about 50% of people, but with increases in the number experiencing side effects.[56][57] Combination drugs of paracetamol and strong opioids such as morphine improve analgesic effect.[58]

The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of common pain conditions, including dental pain,post partum pain, and headache.[59]

Patent ductus arteriosus

Paracetamol is used to treatpatent 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.[60][61] NSAIDs, particularlyindomethacin and ibuprofen, have also been used, but the evidence for them is also not strong.[60] The condition appears to be caused in part by overactiveprostaglandin E2 (PGE2), signalling primarily through itsEP4 receptor, but possibly also through itsEP2 receptor andEP3 receptors.[60]

Dosage

Thedefined daily dose is 3 g (by mouth) or 3 g (parenteral) or 3 g (rectal)[6] In those who weight more than 50 kg, 1,000 mg can be taken three times per day.[62] For those 30 to 50 kg 500 mg can be used three times per day.[62] Otherwise in children over one month old 15 mg/kg three or four times per day may be used.[62] It may also be given by injection at doses of 1 gram every 6 hours in adults when the medication by mouth is not possible.[2] In those 10 to 50 kg 15 mg/kg may be used, while in those less than 10 kg the dose is 7.5 to 10 mg/kg.[2]

Side effects

Healthy adults taking regular doses up to 4,000 mg a day show little evidence of toxicity.[21] They are more likely to have abnormal liver function tests, but the importance of this is uncertain.[21] There are concerns that continuous use for a few weeks increases systolic blood pressure by about 3 to 4 mmHg; though effects of long term use are unclear.[63]

Liver damage

Acuteoverdoses of paracetamol can cause potentially fatalliver damage. In 2011, the U.S.Food and Drug Administration (FDA) launched a public-education program to help consumers avoid overdose, warning: "Acetaminophen can cause serious liver damage if more than directed is used."[64][65][66] 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.[67][68] Overdoses are frequently related to high-doserecreational use of prescriptionopioids, as these opioids are most often combined with acetaminophen.[69] The overdose risk may be heightened by frequent consumption of alcohol.[16]

Paracetamol toxicity is the foremost cause ofacute liver failure in theWestern world, and accounts for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.[70][71][72][73] 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."[74]

Paracetamol is metabolized by the liver and ishepatotoxic; side effects are multiplied when combined with alcoholic drinks, and are very likely inchronic alcoholics or people with liver damage.[75][76] Some studies have suggested the possibility of a moderately increased risk of upper gastrointestinal complications such asstomach bleeding when high doses are taken chronically.[77]Kidney damage is seen in rare cases, most commonly in overdose.[78]

Skin reactions

In 2013, the U.S. Food and Drug Administration (FDA) issued a warning that the drug could cause rare and possibly fatal skin reactions such asStevens–Johnson syndrome (SJS) andtoxic epidermal necrolysis (TEN). Prescription-strength products would be required to carry a warning label about skin reactions, and the FDA urged manufacturers to do the same with over-the-counter products.[79]

Asthma

An association exists between paracetamol use andasthma, but whether this association is causal is still debated as of 2017[update].[80] Certain evidence suggests that this association likely reflectsconfounders[81] rather than being truly causal.[82] A 2014 review found that among children, the association disappeared when respiratory infections were taken into account.[83]

As of 2014[update], theAmerican Academy of Pediatrics and theNational Institute for Health and Care Excellence continue to recommend paracetamol for pain and discomfort in children,[84][85][86][87][88][89] but some experts have recommended that paracetamol use by children with asthma or at risk for asthma should be avoided.[90][91]

Other factors

In contrast to aspirin, paracetamol does not prevent blood from clotting (it is not anantiplatelet), thus it may be used in people who have concerns with bloodcoagulation. Additionally it does not cause gastric irritation.[92] However, paracetamol does not help reduce inflammation, while aspirin does.[93] Compared withibuprofen—whose side effects may include diarrhea, vomiting and abdominal pain—paracetamol has fewer adverse gastrointestinal effects.[94] Unlike aspirin, paracetamol is generally considered safe for children, as it is not associated with a risk ofReye's syndrome in children with viral illnesses.[95] If taken recreationally with opioids, weak evidence suggests that it may cause hearing loss.[96] Paracetamol use may also inhibit the feeling ofempathy for another's pain.[97]

Overdose

Main article:Paracetamol toxicity

In general, the recommended maximum daily dose of paracetamol for healthy adults is three or four grams.[22][23] Higher doses may lead to toxicity.[medical citation needed]

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, andpain asacute liver failure starts.[98] 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.[99] The process of dying from an overdose takes from 3–5 days to 4–6 weeks.[medical citation needed]

Paracetamol hepatotoxicity is by far the most common cause of acute liver failure in both the United States and the United Kingdom.[73][100] Paracetamol overdose results in more calls topoison control centers in the US than overdose of any other pharmacological substance.[101] Toxicity of paracetamol is believed to be due to itsquinone metaboliteNAPQI.[102]

Untreated overdose can lead toliver failure and death within days.[medical citation needed] Treatment is aimed at removing the paracetamol from the body and replenishingglutathione.[102]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; aliver transplant is often required if damage to the liver becomes severe.[70][103] 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.[104][105] NAC also helps in neutralizing the imidoquinone metabolite of paracetamol.[102]Kidney failure is also a possible side effect.[16]

Until 2004, tablets were available in the UK (brand-name Paradote) that combined paracetamol with an antidote (methionine) to protect the liver in case of an overdose.[medical citation needed] One theoretical, but rarely if ever used, option in the United States is to request acompounding pharmacy to make a similar drug mix for people who are at risk.[medical citation needed]

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 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 liver function.[106]

In 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount 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.[107][68][108][109] Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325 mg per dosage unit.[68][109]In November 2011, theMedicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.[110]

Pregnancy

Experimental studies in animals and cohort studies in humans indicate no detectable increase in congenital malformations associated with paracetamol use duringpregnancy.[111] Additionally, paracetamol does not affect the closure of the fetalductus arteriosus as NSAIDs can.[112]

Paracetamol use by the mother during pregnancy is associated with an increased risk of childhoodasthma.[113] It is also associated with an increase inADHD but it is unclear whether the relationship is causal.[114] A 2015 review states that paracetamol remains a first-line recommended medication for pain and fever during pregnancy, despite these concerns.[115]

Cancer

Some studies have found an association between paracetamol and a slight increase inkidney cancer,[116] but no effect onbladder cancer risk.[117]

Pharmacology

Pharmacodynamics

Despite its common use, the mechanism of action of paracetamol is not completely understood. Unlike NSAIDs such as aspirin, paracetamol does not appear to inhibit the function of anycyclooxygenase (COX) enzyme outside thecentral nervous system, and this appears to be the reason why it is not useful as ananti-inflammatory.[26] It does appear to selectively inhibit COX activities in the brain, which may contribute to its ability to treat fever and pain.[26] This activity does not appear to be direct inhibition by blocking an active site, but rather byreducing COX, which must be oxidized in order to function.[26]

Paracetamol apparently might modulate theendogenous cannabinoid system in the brain through its metabolite,AM404, which appears to inhibit the reuptake of the endogenous cannabinoid/vanilloidanandamide by neurons, making it more available to reduce pain. AM404 also appears to be able to directly activate theTRPV1 (older name: vanilloid receptor), which also inhibits pain signals in the brain.[26]

Pharmacokinetics

Main pathways of paracetamol metabolism(click to enlarge): Pathways shown in blue and purple lead to nontoxic metabolites; the pathway in red leads to toxicNAPQI.

After being taken by mouth, paracetamol is rapidly absorbed by the gastrointestinal (GI) tract (although absorption through the stomach is negligible);[118] itsvolume of distribution is roughly 50 L.[119] The concentration in serum after a typical dose of paracetamol usually peaks below 30 µg/ml (200 µmol/L).[120] After 4 hours, the concentration is usually less than 10 µg/ml (66 µmol/L).[120]

Paracetamol ismetabolized primarily in the liver, into toxic and nontoxic products. Threemetabolic pathways are notable:[102]

All three pathways yield final products that are inactive, nontoxic, and eventually excreted by the kidneys. In the third pathway, however, the intermediate product NAPQI is toxic. NAPQI is primarily responsible for thetoxic effects of paracetamol; this constitutes an example oftoxication.[122] Production of NAPQI is due primarily to twoisoenzymes of cytochrome P450:CYP2E1[117] andCYP3A4.[122] At usual doses, NAPQI is quickly detoxified by conjugation with glutathione.[102][121]

Chemistry

Chemical properties

Paracetamol crystals (crystallized from an aqueous solution) under a microscope.
Paracetamol moleculepolar surface area
Paracetamol electrostatic potential map

Paracetamol consists of abenzene ring core,substituted by onehydroxyl group and thenitrogen atom of anamide group in thepara (1,4)pattern.[123] The amide group isacetamide (ethanamide). It is an extensivelyconjugated system, asone lone pair on the hydroxyl oxygen, the benzene pi cloud, the nitrogen lone pair, thep orbital on thecarbonyl carbon, and one lone pair on the carbonyl oxygen are all conjugated. The presence of two activating groups also make the benzene ring highly reactive towardelectrophilic aromatic substitution. As the substituents areortho, para-directing andpara with respect to each other, all positions on the ring are more or less equally activated. The conjugation also greatly reduces thebasicity of the oxygens and the nitrogen, while making the hydroxyl acidic through delocalisation of charge developed on thephenoxideanion.[medical citation needed]

Paracetamol is part of the class of drugs known as "aniline analgesics"; it is the only such drug still in use today.[124] It is not considered an NSAID because it does not exhibit significant anti-inflammatory activity (it is a weak COX inhibitor).[27][125] This is despite the evidence that paracetamol and NSAIDs have some similar pharmacological activity.[126]

Synthesis

Original (Boots) method

The original method for production involves thenitration ofphenol withsodium nitrate gives a mixture of two isomers, from which the wanted4-nitrophenol (bp 279 °C) can easily be separated bysteam distillation. In thiselectrophilic aromatic substitution reaction, phenol's oxygen is strongly activating, thus the reaction requires only mild conditions as compared to nitration of benzene itself. Thenitro group is then reduced to anamine, giving4-aminophenol. Finally, the amine is acetylated withacetic anhydride.[127] Industrially direct hydrogenation is used, but in the laboratory scale sodium borohydride serves.[128][129]

Green synthesis

An alternative industrial synthesis developed byHoechst–Celanese involves direct acylation of phenol with acetic anhydride catalyzed by HF, conversion of the ketone to aketoxime withhydroxylamine, followed by the acid-catalyzedBeckmann rearrangement to give the amide.[129][130]

Direct synthesis

More recently (2014) a "one-pot" synthesis fromhydroquinone has been described before the Royal Society of Chemistry.[131][132] The process may be summarized as follows:

Hydroquinone,ammonium acetate, andacetic acid were mixed in an argon atmosphere and heated slowly to 230 °C. The mixture was stirred at this temperature for 15 hours. After cooling the acetic acid was evaporated and the precipitate was filtered, washed with water and dried to give paracetamol as a white solid.

The authors go on to claim an 88% yield and 99% purity.

Reactions

4-Aminophenol may be obtained by the amidehydrolysis of paracetamol.4-Aminophenol prepared this way, and related to the commercially availableMetol, has been used as a developer in photography by hobbyists.[133] 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.[134]

History

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 asantipyretic properties, and was quickly introduced into medical practice under the name ofAntifebrin by Cahn & Hepp in 1886.[135] But its unacceptable toxic effects – the most alarming beingcyanosis due tomethemoglobinemia – prompted the search for less toxic aniline derivatives.[124] Harmon Northrop Morse had already synthesized paracetamol atJohns Hopkins University via the reduction ofp-nitrophenol withtin in glacialacetic acid in 1877,[136][137] but it was not until 1887 that clinical pharmacologistJoseph von Mering tried paracetamol on humans.[124] In 1893, von Mering published a paper reporting on the clinical results of paracetamol withphenacetin, another aniline derivative.[138] 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 establishedBayer as a leading pharmaceutical company.[139] Overshadowed in part byaspirin, introduced into medicine byHeinrich Dreser in 1899, phenacetin was popular for many decades, particularly in widely advertised over-the-counter "headache mixtures", usually containing phenacetin, anaminopyrine derivative or aspirin, caffeine, and sometimes abarbiturate.[124]

Paracetamol is the active metabolite ofphenacetin andacetanilide, both once popular as analgesics and antipyretics in their own right.[119][140] However, unlike phenacetin, acetanilide and their combinations, paracetamol is not consideredcarcinogenic at therapeutic doses.[141]

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.[139] 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.[142] In three papers published in the September 1948 issue of theJournal 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.[143][144][145] 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.[146] This led to a "rediscovery" of paracetamol.[124] It has been suggested that contamination of paracetamol with4-aminophenol, the substance von Mering synthesised it from, may be the cause for his spurious findings.[139]

Paracetamol was first marketed in the United States in 1950 under the name Triagesic, a combination of paracetamol,aspirin, andcaffeine.[137] 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.[137] Paracetamol was marketed in 1953 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.[137][139][147] In 1955, paracetamol was marketed as Children'sTylenol Elixir byMcNeil Laboratories.[148] In 1956, 500 mg tablets of paracetamol went on sale in the United Kingdom under the brand name Panadol, produced by Frederick Stearns & Co, a subsidiary ofSterling Drug Inc. 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.[137] 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.[124] In 1988,Sterling Winthrop was acquired byEastman Kodak which sold the over the counter drug rights toSmithKline Beecham in 1994.[149]

Availablewithout a prescription since 1959,[150] it has since become a common household drug.[151]Patents on paracetamol have long expired, and generic versions of the drug are widely available.[1][152]

Society and culture

Naming

Acetaminophen is the name generally used in the United States (United States Adopted Name), Japan (Japanese Accepted Name), Canada,[153] Venezuela, Colombia, and Iran; paracetamol is used in international venues (International Nonproprietary Name,Australian Approved Name,British Approved Name).[153][154][155] In some contexts, such as on prescription bottles of painkillers that incorporate this medicine, it is simply abbreviated as APAP, foracetyl-para-aminophenol.

Both acetaminophen and paracetamol come from a chemical name for the compound:para-acetylaminophenol andpara-acetylaminophenol.

Cost

The wholesale price in thedeveloping world is less thanUS$0.01 per dose.[32] In the United States, it costs aboutUS$0.04 per dose.[33]

In Europe, prices differ from country to country; low-cost prices for 10 doses could reach €0.54 in Portugal, €0.91 in France and €1.97 in Germany.[156]

  • Acetaminophen costs (US)

    Acetaminophen costs (US)

  • Acetaminophen prescriptions (US)

    Acetaminophen prescriptions (US)

Available forms

See also:Paracetamol brand names

Paracetamol is available intablet,capsule, liquid suspension,suppository,intravenous,intramuscular andeffervescent forms.[157][158] Intravenous acetaminophen is sold under the brand name Ofirmev in the United States.[159] It costs about 50 USD per 1,000 mg dose as of 2021.[160]

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,[161] while the lowest-strength preparation is over the counter in Canada, and in other countries other strengths may be available over the counter.[citation needed] Paracetamol is also combined with other opioids such asdihydrocodeine,[162] referred to asco-dydramol (British Approved Name (BAN)),oxycodone[163] orhydrocodone.[164] Another very commonly used analgesic combination includes paracetamol in combination withpropoxyphene napsylate.[165] A combination of paracetamol, codeine, and the calmativedoxylamine succinate is also available.[166] The efficacy of paracetamol/codeine combinations has been questioned by research from 2010.[58]

Paracetamol is commonly used in multi-ingredient preparations formigraine headache, typically includingbutalbital and paracetamol with or withoutcaffeine, and sometimes containing codeine.[medical citation needed]

Paracetamol is sometimes combined withphenylephrine hydrochloride.[167] Sometimes a third active ingredient, such asascorbic acid,[167][168]caffeine,[169][170]chlorpheniramine maleate,[171] orguaifenesin[172][173][174] is added to this combination.

When marketed in combination withdiphenhydramine 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 ofrestless leg syndrome.[175]

  • Tylenol 500 mg capsules

    Tylenol 500 mg capsules

  • Panadol 500 mg tablets

    Panadol 500 mg tablets

  • For comparison: The pure drug is a colourless crystalline powder.

    For comparison: The pure drug is a colourless crystalline powder.

Controversy

In September 2013, an episode ofThis American Life titled "Use Only as Directed"[176] 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"[177] and "McNeil, the maker of Tylenol, ... has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug."[178]

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."[179]

Veterinary use

Cats

Paracetamol is extremely toxic to cats, which lack the necessaryUGT1A6 enzyme 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 ofHeinz bodies in red blood cells inhibit oxygen transport by the blood, causingasphyxiation (methemoglobemia andhemolytic anemia).[180]

Treatment withN-acetylcysteine,[181]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 to be as effective as aspirin in the treatment of musculoskeletal pain in dogs.[182]

A paracetamol-codeine product (brand name Pardale-V)[183] licensed for use in dogs is available for purchase under supervision of a vet, pharmacist or other qualified person.[183] It should be administered to dogs only on veterinary advice and with extreme caution.[183]

The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported.[181][184][185][186] N-acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion.[181][182]

Snakes

Paracetamol is lethal to snakes, and has been suggested as a chemical control program for the invasivebrown tree snake (Boiga irregularis) inGuam.[187][188] Doses of 80 mg are inserted into dead mice that are scattered by helicopter.[189]

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