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The word "only" is subjective and inappropriate for an encyclopedic lead section. "Only" compared to what? Sentences should state facts, not judgements. |
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| pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web |title=Acetaminophen Use During Pregnancy |website=Drugs.com |date=14 June 2019 |url=https://www.drugs.com/pregnancy/acetaminophen.html |access-date=25 February 2020 |archive-date=9 March 2020 |archive-url=https://web.archive.org/web/20200309154313/https://www.drugs.com/pregnancy/acetaminophen.html |url-status=live }}</ref>
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*[[Analgesic]];
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<!-- Definition and medical uses -->
'''Paracetamol''' ('''acetaminophen'''{{Efn|Commonly called "acetaminophen" in the US, Canada, Japan, South Korea, and Colombia{{cn|date=April 2024}}}}) is a non-opioid [[analgesic]] and [[antipyretic]] agent used to treat [[fever]] and mild to moderate [[pain]].<ref name=":2">{{cite journal | vauthors = Prescott LF | title = Paracetamol: past, present, and future | journal = American Journal of Therapeutics | volume = 7 | issue = 2 | pages = 143–147 | date = March 2000 | pmid = 11319582 | doi = 10.1097/00045391-200007020-00011 | s2cid = 7754908 }}</ref><ref name="pmid19058473" /><ref name=
At a standard dose, paracetamol
<!-- Side effects and mechanism-->
In the short term, paracetamol is safe and effective when used as directed.<ref>{{cite web |date=11 October 2012 |title=Acetaminophen |url=https://www.canada.ca/en/health-canada/services/drugs-medical-devices/acetaminophen.html |access-date=22 September 2022 |website=[[Health Canada]] |url-status=live |archive-date=3 November 2022 |archive-url=https://web.archive.org/web/20221103234259/https://www.canada.ca/en/health-canada/services/drugs-medical-devices/acetaminophen.html}}</ref> Short term adverse effects are uncommon and similar to [[ibuprofen]],<ref>{{cite journal |vauthors=Southey ER, Soares-Weiser K, Kleijnen J |title=Systematic review and meta-analysis of the clinical safety and tolerability of ibuprofen compared with paracetamol in paediatric pain and fever |journal=Current Medical Research and Opinion |volume=25 |issue=9 |pages=2207–2222 |date=September 2009 |pmid=19606950 |doi=10.1185/03007990903116255 |s2cid=31653539 |url=https://figshare.com/articles/journal_contribution/11815293 |access-date=2 December 2022 |archive-date=3 January 2023 |archive-url= https://web.archive.org/web/20230103023230/https://figshare.com/articles/journal_contribution/Systematic_review_and_meta-analysis_of_the_clinical_safety_and_tolerability_of_ibuprofen_compared_with_paracetamol_in_paediatric_pain_and_fever/11815293 |url-status=live}}</ref> but paracetamol is typically safer than [[
<!-- Society and culture -->
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====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.<ref name="pmid32027199">{{cite journal |vauthors=Pergolizzi JV, Magnusson P, LeQuang JA, Gharibo C, Varrassi G |title=The pharmacological management of dental pain |journal=Expert Opin Pharmacother |volume=21 |issue=5 |pages=591–601 |date=April 2020 |pmid=32027199 |doi=10.1080/14656566.2020.1718651 |s2cid=211046298}}</ref> For the relief of such pain, paracetamol is inferior to ibuprofen.<ref name= "pmid24338830">{{cite journal |vauthors=Bailey E, Worthington HV, van Wijk A, Yates JM, Coulthard P, Afzal Z |title=Ibuprofen and/or paracetamol (acetaminophen) for pain relief after surgical removal of lower wisdom teeth |journal=Cochrane Database Syst Rev |volume= |issue=12 |pages=CD004624 |date=December 2013 |pmid=24338830 |doi= 10.1002/14651858.CD004624.pub2}}</ref> Full therapeutic doses of [[non-steroidal anti-inflammatory drug|nonsteroidal anti-inflammatory drug]]s (NSAIDs) ibuprofen, [[naproxen]] or [[diclofenac]] are clearly more efficacious than the [[Codeine/paracetamol|paracetamol/codeine]] combination which is frequently prescribed for dental pain.<ref name="pmid32286125">{{cite journal |vauthors=Hersh EV, Moore PA, Grosser T, Polomano RC, Farrar JT, Saraghi M, Juska SA, Mitchell CH, Theken KN |title=Nonsteroidal Anti-Inflammatory Drugs and Opioids in Postsurgical Dental Pain |journal=J Dent Res |volume=99 |issue=7 |pages=777–786 |date=July 2020 |pmid=32286125 |doi=10.1177/0022034520914254 |pmc=7313348 }}</ref> The combinations of paracetamol and NSAIDs ibuprofen or [[diclofenac]] are promising, possibly offering better pain control than either paracetamol or the NSAID alone.<ref name="pmid24338830"/><ref name="pmid23904576">{{cite journal |vauthors=Moore PA, Hersh EV |title=Combining ibuprofen and acetaminophen for acute pain management after third-molar extractions: translating clinical research to dental practice |journal=J Am Dent Assoc |volume=144 |issue=8 |pages=898–908 |date=August 2013 |pmid=23904576 |doi=10.14219/jada.archive.2013.0207}}</ref><ref name="pmid23794268">{{cite journal |vauthors=Derry CJ, Derry S, Moore RA |title=Single dose oral ibuprofen plus paracetamol (acetaminophen) for acute postoperative pain |journal=Cochrane Database Syst Rev |volume= 2019|issue=6 |pages=CD010210 |date=June 2013 |pmid=23794268 |pmc=6485825 |doi=10.1002/14651858.CD010210.pub2}}</ref><ref name="pmid30245281">{{cite journal |vauthors=Daniels SE, Atkinson HC, Stanescu I, Frampton C |title=Analgesic Efficacy of an Acetaminophen/Ibuprofen Fixed-dose Combination in Moderate to Severe Postoperative Dental Pain: A Randomized, Double-blind, Parallel-group, Placebo-controlled Trial |journal=Clin Ther |volume=40 |issue=10 |pages=1765–1776.e5 |date=October 2018 |pmid=30245281 |doi=10.1016/j.clinthera.2018.08.019 |doi-access=free |title-link = doi }}</ref> Additionally, the paracetamol/ibuprofen combination may be superior to paracetamol/codeine and ibuprofen/codeine combinations.<ref name="pmid23904576"/>
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%.<ref name="pmid19160199">{{cite journal |vauthors= Toms L, Derry S, Moore RA, McQuay HJ |title=Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults |journal=Cochrane Database Syst Rev |volume= 2009|issue=1 |pages=CD001547 |date=January 2009 |pmid=19160199 |pmc=4171965 |doi=10.1002/14651858.CD001547.pub2}}</ref>
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====Other pain====
Paracetamol fails to relieve procedural pain in [[newborn babies]].<ref name="pmid32257982">{{cite journal |vauthors=Allegaert K |title=A Critical Review on the Relevance of Paracetamol for Procedural Pain Management in Neonates |journal=Front Pediatr |volume=8 |issue= |pages=89 |date=2020 |pmid=32257982 |pmc=7093493 |doi= 10.3389/fped.2020.00089 |doi-access=free |title-link = doi }}</ref><ref>{{cite journal |vauthors = Ohlsson A, Shah PS |title = Paracetamol (acetaminophen) for prevention or treatment of pain in newborns |journal = The Cochrane Database of Systematic Reviews |volume = 1 |pages = CD011219 |date = January 2020 |issue = 1 |pmid = 31985830 |pmc = 6984663 |doi = 10.1002/14651858.CD011219.pub4 }}</ref> For [[perineum|perineal]] pain [[postpartum period|postpartum]] paracetamol appears to be less effective than [[
The studies to support or refute the use of paracetamol for cancer pain and for neuropathic pain are lacking.<ref name="pmid28700092">{{cite journal |vauthors=Wiffen PJ, Derry S, Moore RA, McNicol ED, Bell RF, Carr DB, McIntyre M, Wee B |title=Oral paracetamol (acetaminophen) for cancer pain |journal=Cochrane Database Syst Rev |volume=7 |issue= 2|pages=CD012637 |date=July 2017 |pmid=28700092 |pmc=6369932 |doi=10.1002/14651858.CD012637.pub2}}</ref><ref name="pmid28027389">{{cite journal |vauthors= Wiffen PJ, Knaggs R, Derry S, Cole P, Phillips T, Moore RA |title=Paracetamol (acetaminophen) with or without codeine or dihydrocodeine for neuropathic pain in adults |journal=Cochrane Database Syst Rev |volume=12 |issue= 5|pages=CD012227 |date=December 2016 |pmid=28027389 |pmc=6463878 |doi=10.1002/14651858.CD012227.pub2}}</ref> There is limited evidence in favor of the use of the intravenous form of paracetamol for acute pain control in the emergency department.<ref>{{cite journal |vauthors = Sin B, Wai M, Tatunchak T, Motov SM |title = The Use of Intravenous Acetaminophen for Acute Pain in the Emergency Department |journal = Academic Emergency Medicine |volume = 23 |issue = 5 |pages = 543–53 |date = May 2016 |pmid = 26824905 |doi = 10.1111/acem.12921 |doi-access = free |title-link = doi }}</ref> The combination of paracetamol with caffeine is superior to paracetamol alone for the treatment of acute pain.<ref>{{cite journal |vauthors = Derry CJ, Derry S, Moore RA |title = Caffeine as an analgesic adjuvant for acute pain in adults |journal = The Cochrane Database of Systematic Reviews |volume = 3 |issue = 3 |pages = CD009281 |date = March 2012 |pmid = 22419343 |doi = 10.1002/14651858.CD009281.pub2 |s2cid = 205199173 |veditors = Derry S }}</ref>
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==Adverse effects==
Gastrointestinal adverse effects such as nausea and [[abdominal pain]] are extremely uncommon, and their frequency is nothing
In clinical trials for [[osteoarthritis]], the number of participants reporting adverse effects was similar for those on paracetamol and on [[placebo]]. However, the [[Elevated transaminases|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.<ref name="pmid30801133">{{cite journal |vauthors=Leopoldino AO, Machado GC, Ferreira PH, Pinheiro MB, Day R, McLachlan AJ, Hunter DJ, Ferreira ML |title=Paracetamol versus placebo for knee and hip osteoarthritis |journal=Cochrane Database Syst Rev |volume=2 |issue= 8|pages=CD013273 |date=February 2019 |pmid=30801133 |pmc=6388567 |doi=10.1002/14651858.CD013273}}</ref> 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.<ref name="pmid25732175">{{cite journal |vauthors=Roberts E, Delgado Nunes V, Buckner S, Latchem S, Constanti M, Miller P, Doherty M, Zhang W, Birrell F, Porcheret M, Dziedzic K, Bernstein I, Wise E, Conaghan PG |title=Paracetamol: not as safe as we thought? A systematic literature review of observational studies |journal=Ann Rheum Dis |volume=75 |issue=3 |pages=552–9 |date=March 2016 |pmid=25732175 |pmc=4789700 |doi=10.1136/annrheumdis-2014-206914}}</ref>
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In recommended doses, the [[Side effect|side effects]] of paracetamol are mild to non-existent.<ref name="PM: FBtCP">{{cite book |last=Hughes |first=John |title=Pain Management: From Basics to Clinical Practice |publisher=Elsevier Health Sciences |year=2008 |isbn=9780443103360}}</ref> In contrast to aspirin, it is not a [[Antiplatelet drug|blood thinner]] (and thus may be used in patients where bleeding is a concern), and it does not cause gastric irritation.<ref name="TCD">{{cite book |last=Sarg |first=Michael |title=The Cancer Dictionary |author2=Ann D Gross |author3=Roberta Altman |publisher=Infobase Publishing |year=2007 |isbn=978081606-4113}}</ref> Compared to [[Ibuprofen]]—which can have adverse effects that include diarrhea, vomiting, and abdominal pain—paracetamol is well tolerated with fewer side effects.<ref>{{cite journal |last=Ebrahimi |first=Sedigheh |author2=Soheil Ashkani Esfahani |author3=Hamid Reza Ghaffarian |author4=Mahsima Khoshneviszade |year=2010 |title=Comparison of efficacy and safety of acetaminophen and ibuprofen administration as single dose to reduce fever in children. |url=http://journals.tums.ac.ir/abs/17188 |url-status=dead |journal=Iranian Journal of Pediatrics |volume=20 |issue=4 |pages=500–501 |archive-url=https://archive.today/20120709124051/http://journals.tums.ac.ir/abs/17188 |archive-date=2012-07-09}}</ref> Prolonged daily use and may cause kidney or liver damage.<ref name="TCD" /><ref>{{cite news |date=November 23, 2003 |title=Painkillers 'cause kidney damage' |url=http://news.bbc.co.uk/2/hi/health/3271191.stm |access-date=March 27, 2010 |work=BBC News}}</ref>Paracetamol is metabolized by the liver and is [[hepatotoxic]]; side effects may be more likely in [[Alcoholism|chronic alcoholics]] or patients with liver damage.<ref name="PM: FBtCP" /><ref>{{cite book |last=Dukes |first=MNG |title=Meyler's Side Effects of Drugs, Vol XIV |author2=Jeffrey K Aronson |publisher=Elsevier |year=2000 |isbn=9780444500939}}</ref>
Until 2010 paracetamol was believed safe in pregnancy however, in a study published in October 2010 it has been linked to [[infertility]] in the adult life of the unborn.<ref>{{cite journal |author=Leffers, H |display-authors=etal |year=2010 |title=Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat |journal=Human Reproduction |volume=25 |issue=1 |pages=235–244 |doi=10.1093/humrep/deq382 |doi-access=free}}</ref> Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood.
===Use in pregnancy===
Paracetamol safety in pregnancy has been under increased scrutiny. There appears to be no link between paracetamol use in the first trimester and adverse pregnancy outcomes or [[birth defects]]. However, indications exist of a possible increase of asthma and developmental and reproductive disorders in the offspring of women with prolonged use of paracetamol during pregnancy.<ref name="pmid29863746"/>
Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood [[asthma]],<ref>{{cite journal| vauthors=Eyers S, Weatherall M, Jefferies S, Beasley R |title=Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis|journal=Clinical and Experimental Allergy |date= April 2011|volume=41|issue=4|pages=482–9|pmid=21338428|doi=10.1111/j.1365-2222.2010.03691.x |s2cid=205275267}}</ref><ref name="pmid28237129">{{cite journal |vauthors=Fan G, Wang B, Liu C, Li D |title=Prenatal paracetamol use and asthma in childhood: A systematic review and meta-analysis |journal=Allergol Immunopathol (Madr) |volume=45 |issue=6 |pages=528–533 |date=2017 |pmid=28237129 |doi=10.1016/j.aller.2016.10.014}}</ref> but so are the maternal infections for which paracetamol may be used, and separating these influences is difficult.<ref name="pmid29863746"/> Paracetamol, in a small scale meta-analysis was also associated with a 20{{ndash}}30% increase in [[autism spectrum disorder]], [[attention deficit hyperactivity disorder]]
The consensus recommendation appears to be to avoid prolonged use of paracetamol in pregnancy and use it only when necessary, at the lowest effective dosage and for the shortest time.<ref name="pmid29863746"/><ref name="pmid28986045">{{cite journal |vauthors=Toda K |title=Is acetaminophen safe in pregnancy? |journal=Scand J Pain |volume=17 |issue= |pages=445–446 |date=October 2017 |pmid=28986045 |doi=10.1016/j.sjpain.2017.09.007 |s2cid=205183310}}</ref><ref name="pmid31242344">{{cite journal |vauthors=Black E, Khor KE, Kennedy D, Chutatape A, Sharma S, Vancaillie T, Demirkol A |title=Medication Use and Pain Management in Pregnancy: A Critical Review |journal=Pain Pract |volume=19 |issue=8 |pages=875–899 |date=November 2019 |pmid=31242344 |doi=10.1111/papr.12814 |s2cid=195694287}}</ref>
In pregnancy,
==Overdose==
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[[Drug overdose|Overdose]] of paracetamol is caused by taking more than the recommended maximum daily dose of paracetamol for healthy adults (three or four grams),<ref name=UK2017/><ref name=Med2018/> and can cause potentially fatal [[Hepatotoxicity|liver damage]].<ref>{{cite web |title=Acetaminophen Information |website=U.S. [[Food and Drug Administration]] |date=14 November 2017 |url=https://www.fda.gov/drugs/information-drug-class/acetaminophen-information |archive-url= https://web.archive.org/web/20191028022254/https://www.fda.gov/drugs/information-drug-class/acetaminophen-information |archive-date=28 October 2019 |url-status=live |access-date=27 October 2019}}{{PD-notice}}</ref><ref>{{cite web |title=Using Acetaminophen and Nonsteroidal Anti-inflammatory Drugs Safely |website=U.S. [[Food and Drug Administration]] (FDA) |date=26 February 2018 |url=https://www.fda.gov/drugs/safe-use-over-counter-pain-relievers-and-fever-reducers/using-acetaminophen-and-nonsteroidal-anti-inflammatory-drugs-safely |archive-url=https://web.archive.org/web/20191028025936/https://www.fda.gov/drugs/safe-use-over-counter-pain-relievers-and-fever-reducers/using-acetaminophen-and-nonsteroidal-anti-inflammatory-drugs-safely |archive-date=28 October 2019 |url-status=live |access-date=27 October 2019}}{{PD-notice}}</ref> 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.<ref name=UK2017/> 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.<ref>{{cite journal | vauthors = Amar PJ, Schiff ER | title = Acetaminophen safety and hepatotoxicity--where do we go from here? | journal = Expert Opinion on Drug Safety | volume = 6 | issue = 4 | pages = 341–355 | date = July 2007 | pmid = 17688378 | doi = 10.1517/14740338.6.4.341 | s2cid = 20399748 }}</ref>
[[Paracetamol toxicity]] has become the foremost cause of [[acute liver failure]] in the [[United States]] by 2003,<ref name="Larson2005" /> and {{As of|2005|lc=y}}, paracetamol accounted for most drug overdoses in the United States, the United Kingdom, Australia, and New Zealand.<ref>{{cite journal | vauthors = Buckley N, Eddleston M | title = Paracetamol (acetaminophen) poisoning | journal = Clinical Evidence | issue = 14 | pages = 1738–1744 | date = December 2005 | pmid = 16620471 | url = https://pubmed.ncbi.nlm.nih.gov/16620471/ }}</ref> As of 2004, paracetamol overdose resulted in more calls to [[poison control center]]s in the
Overdoses are frequently related to high-dose [[Recreational drug use|recreational use]] of prescription [[opioids]], as these opioids are most often combined with paracetamol.<ref>{{cite news |url=https://www.cnn.com/2014/01/15/health/fda-acetaminophen-dosage/index.html |vauthors=Yan H |title=FDA: Acetaminophen doses over 325 mg may lead to liver damage |publisher=[[CNN]] |access-date=18 February 2014 |date=16 January 2014 |url-status=live |archive-url= https://web.archive.org/web/20140216091112/http://www.cnn.com/2014/01/15/health/fda-acetaminophen-dosage/index.html?hpt=hp_t2 |archive-date=16 February 2014}}</ref> The overdose risk may be heightened by frequent consumption of alcohol.<ref name="Lee2017">{{cite journal |vauthors=Lee WM |title=Acetaminophen (APAP) hepatotoxicity—Isn't it time for APAP to go away? |journal=Journal of Hepatology |volume=67 |issue=6 |pages=1324–1331 |date=December 2017 |pmid=28734939 |pmc=5696016 |doi=10.1016/j.jhep.2017.07.005}}</ref>
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===Pharmacodynamics===
Paracetamol appears to exert its effects through two mechanisms: the inhibition of [[cyclooxygenase]] (COX) and actions of its metabolite [[N-arachidonoylphenolamine]] (AM404).<ref name=Ghanem2016>{{cite journal |vauthors = Ghanem CI, Pérez MJ, Manautou JE, Mottino AD |title = Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity |journal = Pharmacological Research |volume = 109 |pages = 119–31 |date = July 2016 |pmid = 26921661 |pmc = 4912877 |doi = 10.1016/j.phrs.2016.02.020 }}</ref>
Supporting the first mechanism, pharmacologically and in its side effects, paracetamol is close to classical [[nonsteroidal anti-inflammatory drug]]s (NSAIDs) that act by inhibiting [[COX-1]] and [[COX-2]] enzymes and especially similar to
The second mechanism centers on the paracetamol metabolite [[AM404]]. This metabolite has been detected in the brains of animals and [[cerebrospinal fluid]] of humans taking paracetamol.<ref name=Ghanem2016/><ref name="pmid29238213">{{cite journal |vauthors=Sharma CV, Long JH, Shah S, Rahman J, Perrett D, Ayoub SS, Mehta V |title=First evidence of the conversion of paracetamol to AM404 in human cerebrospinal fluid |journal=J Pain Res |volume=10 |issue= |pages=2703–2709 |date=2017 |pmid=29238213 |pmc=5716395 |doi=10.2147/JPR.S143500 |doi-access=free }}</ref> It is formed in the brain from another paracetamol metabolite [[4-aminophenol]] by action of [[fatty acid amide hydrolase]].<ref name=Ghanem2016/> AM404 is a weak agonist of cannabinoid receptors [[Cannabinoid receptor type 1|CB1]] and [[Cannabinoid receptor type 2|CB2]], an inhibitor of [[endocannabinoid transporter]], and a potent activator of [[TRPV1]] receptor.<ref name=Ghanem2016/> This and other research indicate that the [[
In 2018, Suemaru ''et al''. found that, in mice, paracetamol exerts an anticonvulsant effect by activation of the [[TRPV1]] receptors<ref name="Suemaru2018">{{cite journal |vauthors = Suemaru K, Yoshikawa M, Aso H, Watanabe M |title = TRPV1 mediates the anticonvulsant effects of acetaminophen in mice |journal = Epilepsy Research |volume = 145 |pages = 153–159 |date = September 2018 |pmid = 30007240 |doi = 10.1016/j.eplepsyres.2018.06.016 |s2cid = 51652230 }}</ref> and a decrease in neuronal excitability by [[Hyperpolarization (biology)|hyperpolarization]] of neurons.<ref>{{cite journal |vauthors = Ray S, Salzer I, Kronschläger MT, Boehm S |title = The paracetamol metabolite N-acetylp-benzoquinone imine reduces excitability in first- and second-order neurons of the pain pathway through actions on KV7 channels |journal = Pain |volume = 160 |issue = 4 |pages = 954–964 |date = April 2019 |pmid = 30601242 |pmc = 6430418 |doi = 10.1097/j.pain.0000000000001474 }}</ref> The exact mechanism of the anticonvulsant effect of acetaminophen 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.<ref name="Suemaru2018" />
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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 phenacetin.<ref name=drugdiscov/> In 1947, [[David Lester (biochemist)|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.<ref>{{cite journal|vauthors = Lester D, Greenberg LA, Carroll RP|title = The metabolic fate of acetanilid and other aniline derivatives: II. Major metabolites of acetanilid appearing in the blood|journal = J. Pharmacol. Exp. Ther.|year = 1947|volume = 90|pages = 68–75|url = http://jpet.aspetjournals.org/cgi/reprint/90/1/68|pmid = 20241897|issue = 1|url-status=live|archive-url = https://web.archive.org/web/20081202161015/http://jpet.aspetjournals.org/cgi/reprint/90/1/68|archive-date = 2 December 2008}}</ref> In 1948, [[Bernard Brodie (biochemist)|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.<ref>{{cite journal| vauthors=Brodie BB, Axelrod J |author-link2=Julius Axelrod |title = The estimation of acetanilide and its metabolic products, aniline, ''N''-acetyl ''p''-aminophenol and ''p''-aminophenol (free and total conjugated) in biological fluids and tissues|journal = J. Pharmacol. Exp. Ther.|year = 1948|volume = 94|issue = 1|pages = 22–28|pmid = 18885610}}</ref><ref>{{cite journal | vauthors = Brodie BB, Axelrod J | author-link2 = Julius Axelrod | title = The fate of acetanilide in man | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 94 | issue = 1 | pages = 29–38 | date = September 1948 | pmid = 18885611 | url = http://profiles.nlm.nih.gov/HH/A/A/A/D/_/hhaaad.pdf | url-status = live | archive-url = https://web.archive.org/web/20080907110847/http://profiles.nlm.nih.gov/HH/A/A/A/D/_/hhaaad.pdf | archive-date = 7 September 2008 }}</ref><ref>{{cite journal| vauthors=Flinn FB, Brodie BB |title = The effect on the pain threshold of ''N''-acetyl ''p''-aminophenol, a product derived in the body from acetanilide|journal = J. Pharmacol. Exp. Ther.|year = 1948|volume = 94|issue = 1|pages = 76–77|pmid = 18885618}}</ref> 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.<ref>{{cite journal | vauthors = Brodie BB, Axelrod J | title = The fate of acetophenetidin in man and methods for the estimation of acetophenetidin and its metabolites in biological material | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 97 | issue = 1 | pages = 58–67 | date = September 1949 | pmid = 18140117 | url = https://jpet.aspetjournals.org/content/97/1/58 }}</ref> This led to a "rediscovery" of paracetamol.<ref name=Bertolini2006rev/>
Paracetamol was first marketed in the United States in 1950 under the name
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.<ref name=Bertolini2006rev/> Available in the
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 1000{{nbsp}}mg to 650{{nbsp}}mg, 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.<ref name="WebMD">{{cite web |url=http://www.webmd.com/pain-management/news/20090701/fda-may-restrict-acetaminophen |title=FDA May Restrict Acetaminophen |publisher=Webmd |date=1 July 2009 |access-date=19 March 2011 |url-status=live |archive-url=https://web.archive.org/web/20110321075108/http://www.webmd.com/pain-management/news/20090701/fda-may-restrict-acetaminophen |archive-date=21 March 2011 }}</ref>
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Paracetamol is available in oral, suppository, and [[intravenous]] forms.<ref>{{cite book |chapter = Acetaminophen |title=Physicians' Desk Reference |date= 2009 |publisher=Physicians' Desk Reference |location=Montvale, N.J. |isbn=978-1-56363-703-2 |oclc = 276871036 |edition=63rd |pages = 1915–1916 }}</ref> Intravenous paracetamol is sold under the brand name Ofirmev in the United States.<ref>{{cite web |vauthors = Nam S |title=IV, PO, and PR Acetaminophen: A Quick Comparison |url=https://www.pharmacytimes.com/contributor/stephanie-nam-pharmd-candidate-2017/2016/08/iv-po-and-pr-acetaminophen-a-quick-comparison |website=Pharmacy Times |access-date=24 October 2019 |archive-date=24 October 2019 |archive-url= https://web.archive.org/web/20191024195854/https://www.pharmacytimes.com/contributor/stephanie-nam-pharmd-candidate-2017/2016/08/iv-po-and-pr-acetaminophen-a-quick-comparison |url-status=dead }}</ref>
In some formulations, paracetamol is combined with the [[opiate]] [[codeine]], sometimes referred to as [[co-codamol]] ([[British Approved Name|BAN]]) and Panadeine in Australia. In the
Paracetamol is sometimes combined with [[phenylephrine hydrochloride]].<ref name="AtkinsonStanescu2014">{{cite journal| vauthors=Atkinson HC, Stanescu I, Anderson BJ |title=Increased Phenylephrine Plasma Levels with Administration of Acetaminophen|journal=New England Journal of Medicine|volume=370|issue=12|year=2014|pages=1171–1172|doi=10.1056/NEJMc1313942|pmid=24645960|doi-access=free|hdl=2292/34799|hdl-access=free}}</ref> Sometimes a third active ingredient, such as [[ascorbic acid]],<ref name="AtkinsonStanescu2014"/><ref>{{cite web |url=http://www.nhs.uk/medicine-guides/pages/selectorshow.aspx?medicine=Ascorbic%20acid/Phenylephrine/Paracetamol |publisher=[[National Health Service]] |work=NHS Choices |title= Ascorbic acid/Phenylephrine/Paracetamol |access-date=25 March 2014 |url-status=dead |archive-url= https://web.archive.org/web/20140326001907/http://www.nhs.uk/medicine-guides/pages/selectorshow.aspx?medicine=Ascorbic%20acid%2FPhenylephrine%2FParacetamol |archive-date=26 March 2014}}</ref> [[caffeine]],<ref>{{cite web |url=http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?medicine=Phenylephrine/Caffeine/Paracetamol%20dual%20relief |title=Phenylephrine/Caffeine/Paracetamol dual relief |publisher=[[National Health Service]] |work=NHS Choices |access-date=25 March 2014 |url-status=dead |archive-url=https://web.archive.org/web/20140326003729/http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?medicine=Phenylephrine%2FCaffeine%2FParacetamol%20dual%20relief |archive-date=26 March 2014}}</ref><ref>{{cite web |url= http://www.nhs.uk/Conditions/Painkillers-paracetamol/Pages/MedicineOverview.aspx?medicine=Beechams%20Decongestant%20Plus%20With%20Paracetamol |title=Beechams Decongestant Plus With Paracetamol |publisher=[[National Health Service]] |work=NHS Choices |access-date=25 March 2014 |url-status=dead |archive-url= https://web.archive.org/web/20140326001905/http://www.nhs.uk/Conditions/Painkillers-paracetamol/Pages/MedicineOverview.aspx?medicine=Beechams%20Decongestant%20Plus%20With%20Paracetamol |archive-date=26 March 2014}}</ref> [[Chlorphenamine|chlorpheniramine maleate]],<ref name="SenyuvaOzden2002">{{cite journal| vauthors=Senyuva H, Ozden T |title=Simultaneous High-Performance Liquid Chromatographic Determination of Paracetamol, Phenylephrine HCl, and Chlorpheniramine Maleate in Pharmaceutical Dosage Forms|journal=Journal of Chromatographic Science|volume=40|issue=2|year=2002|pages=97–100| doi= 10.1093/chromsci/40.2.97|pmid=11881712|doi-access=free |title-link = doi }}</ref> or [[guaifenesin]]<ref name="JaninMonnet2014">{{cite journal| vauthors=Janin A, Monnet J |title= Bioavailability of paracetamol, phenylephrine hydrochloride and guaifenesin in a fixed-combination syrup versus an oral reference product|journal=Journal of International Medical Research|volume=42|issue=2|year=2014|pages=347–359|doi=10.1177/0300060513503762|pmid= 24553480|doi-access=free |title-link = doi }}</ref><ref>{{cite web |title=Paracetamol – phenylephrine hydrochloride – guaifenesin |work=NPS MedicineWise |publisher=National Prescribing Service (Australia) |url=http://www.nps.org.au/medicines/respiratory-system/cough-and-cold-medicines/for-individuals/cough-and-cold-medicines-active-ingredients/paracetamol-phenylephrine-hydrochloride-guaifenesin |access-date=25 March 2014 |url-status=dead |archive-url=https://web.archive.org/web/20140326033356/http://www.nps.org.au/medicines/respiratory-system/cough-and-cold-medicines/for-individuals/cough-and-cold-medicines-active-ingredients/paracetamol-phenylephrine-hydrochloride-guaifenesin |archive-date=26 March 2014}}</ref><ref>{{cite web|url=http://www.nhs.uk/Conditions/Flu/Pages/selectorshow.aspx?medicine=Phenylephrine/Guaifenesin/Paracetamol |publisher=[[National Health Service]] |work=NHS Choices |title=Phenylephrine/Guaifenesin/Paracetamol |access-date=25 March 2014 |url-status=dead |archive-url= https://web.archive.org/web/20130912075213/http://www.nhs.uk/Conditions/Flu/Pages/selectorshow.aspx?medicine=Phenylephrine%2FGuaifenesin%2FParacetamol |archive-date=12 September 2013 }}</ref> is added to this combination.
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===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]] ([[methemoglobinemia]] and [[hemolytic anemia]]).<ref name="CanVetJ2003-Allen">{{cite journal |vauthors = Allen AL |title = The diagnosis of acetaminophen toxicosis in a cat |journal = The Canadian Veterinary Journal |volume = 44 |issue = 6 |pages = 509–10 |date = June 2003 |pmid = 12839249 |pmc = 340185 }}</ref> Treatment of the toxicosis with [[
===Dogs===
Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs.<ref name=smallani>{{cite book|title=Small Animal Clinical Pharmacology |vauthors = Maddison JE, Page SW, Church D |publisher=Elsevier Health Sciences|year=2002|isbn=978-0702025730|pages=260–1 }}</ref> A paracetamol–codeine product (brand name Pardale-V)<ref name="Pardale">{{cite web|title = Pardale-V Oral Tablets |work = NOAH Compendium of Data Sheets for Animal Medicines |publisher = The National Office of Animal Health (NOAH) |date=11 November 2010|access-date = 20 January 2011| url = http://www.noahcompendium.co.uk/Dechra_Veterinary_Products/documents/S3428.html| archive-url = https://web.archive.org/web/20081122104413/http://www.noahcompendium.co.uk/Dechra_Veterinary_Products/documents/S3428.html| url-status=dead| archive-date = 22 November 2008}}</ref> licensed for use in dogs is available for purchase under supervision of a vet, pharmacist or other qualified person.<ref name="Pardale" /> It should be administered to dogs only on veterinary advice and with extreme caution.<ref name="Pardale" />
The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported.<ref name="Richardson_2000">{{cite journal |title=Management of acetaminophen and ibuprofen toxicoses in dogs and cats |vauthors=Richardson JA |journal=Journal of Veterinary Emergency and Critical Care |volume=10 |issue=4 |pages=285–291 |year=2000 |doi=10.1111/j.1476-4431.2000.tb00013.x |url=http://www.aspcapro.org/mydocuments/c-veccs_july00.pdf |url-status=dead |archive-date=1 April 2010 |archive-url= https://web.archive.org/web/20100401014830/http://www.aspcapro.org/mydocuments/c-veccs_july00.pdf}}</ref><ref name="VetHumToxicol1998-Villar">{{cite journal |vauthors=Villar D, Buck WB, Gonzalez JM |title=Ibuprofen, aspirin and acetaminophen toxicosis and treatment in dogs and cats |journal = Veterinary and Human Toxicology |volume=40 |issue=3 |pages=156–62 |date=June 1998 |pmid=9610496}}</ref><ref>{{cite journal |vauthors=Gwaltney-Brant S, Meadows I |title=The 10 Most Common Toxicoses in Dogs |journal=Veterinary Medicine |pages=142–148 |date=March 2006 |url= http://veterinarymedicine.dvm360.com/toxicology-brief-10-most-common-toxicoses-dogs |url-status=dead |archive-url= https://web.archive.org/web/20110710160759/http://veterinarymedicine.dvm360.com/vetmed/Medicine/ArticleStandard/Article/detail/314007 |archive-date=10 July 2011 |access-date=28 October 2019}}</ref><ref>{{cite journal |vauthors=Dunayer E |title=Ibuprofen toxicosis in dogs, cats, and ferrets |journal=Veterinary Medicine |pages=580–586 |year=2004 |url=http://veterinarymedicine.dvm360.com/vetmed/Medicine/ArticleStandard/Article/detail/651048|url-status=live|archive-url=https://web.archive.org/web/20110710160815/http://veterinarymedicine.dvm360.com/vetmed/Medicine/ArticleStandard/Article/detail/651048 |archive-date=10 July 2011}}</ref>
===Snakes===
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