View source for Paracetamol

{{Short description|Common medication for pain and fever}}
{{Use dmy dates|date=January 2024}}
{{redirect-distinguish|Captin|Captain}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{drugbox
| Watchedfields = changed
| verifiedrevid = 456349142
| image = Paracetamol-skeletal.svg
| image_class = skin-invert-image
| width = 210
| alt = 
| caption = 
| width2 = 
| alt2 = 
| imageL = Paracetamol-from-xtal-3D-balls.png
| imageR = Paracetamol-from-xtal-3D-vdW.png
| USAN = acetaminophen

<!-- Clinical data -->| pronounce = Paracetamol: {{IPAc-en|ˌ|p|ær|ə|ˈ|s|iː|t|ə|m|ɒ|l|audio=LL-Q1860 (eng)-Naomi Persephone Amethyst (NaomiAmethyst)-paracetamol.wav}}<br />Acetaminophen: {{IPAc-en|audio=En-acetaminophen.oga|ə|ˌ|s|iː|t|ə|ˈ|m|ɪ|n|ə|f|ɪ|n}}
| tradename = [[Tylenol (brand)|Tylenol]], [[Panadol (brand)|Panadol]], [[Paracetamol brand names|others]]<ref name=drugs.com-internatl>{{drugs.com|international| acetaminophen}}</ref>
| Drugs.com = {{drugs.com|monograph|acetaminophen}}
| MedlinePlus = a681004
| DailyMedID = Acetaminophen
| pregnancy_AU = A
| 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>
| pregnancy_category = 
| routes_of_administration = [[Oral administration|By mouth]], [[intravenous administration|intravenous]], [[rectal administration|rectal]]
| class = {{plainlist|
*[[Analgesic]];
*[[antipyretic]]}}
| ATC_prefix = N02
| ATC_suffix = BE01
| ATC_supplemental = {{ATC|N02|BE51}} {{ATC|N02|BE71}}

<!-- Legal status -->| legal_AU = S4
| legal_AU_comment = OTC, and unscheduled
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment = 
| legal_CA = OTC
| legal_CA_comment = /&nbsp;Rx-only<ref>{{cite web |url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00565 |title=Regulatory Decision Summary – Acetaminophen Injection |website=[[Health Canada]] |date=23 October 2014 |access-date=7 June 2022 |archive-date=7 June 2022 |archive-url=https://web.archive.org/web/20220607080419/https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00565 |url-status=live }}</ref>
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment = 
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment = 
| legal_UK = GSL
| legal_UK_comment = 
| legal_US = OTC
| legal_US_comment = /&nbsp;Rx-only
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment = 
| legal_status = [[China|CN]]: [[Over-the-counter drug|OTC]]

<!-- Pharmacokinetic data -->| bioavailability = 63–89%<ref>{{cite book |isbn=978-0-9873236-7-5 |title=Acute Pain Management: Scientific Evidence |veditors=Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J |vauthors=((Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine)) |year=2015 |edition=4th |publisher=Australian and New Zealand College of Anaesthetists (ANZCA), Faculty of Pain Medicine (FPM) |location=Melbourne |url=http://fpm.anzca.edu.au/documents/apmse4_2015_final |format=PDF |access-date=28 October 2019 |archive-url=https://web.archive.org/web/20190731120330/http://fpm.anzca.edu.au/documents/apmse4_2015_final |archive-date=31 July 2019 |url-status=dead }}</ref>{{rp|73}}
| protein_bound = negligible to 10–25% in overdose<ref name="pmid7039926"/>
| metabolism = Predominantly in the [[liver]]<ref name = TGA>{{cite web|title=Codapane Forte Paracetamol and codeine phosphate product information|work=TGA eBusiness Services|publisher=Alphapharm Pty Limited|date=29 April 2013|access-date=10 May 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05623-3|format=PDF|archive-date=6 February 2016|archive-url=https://web.archive.org/web/20160206163239/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-05623-3|url-status=live}}</ref>
| metabolites = APAP [[Glucuronide|gluc]], APAP [[sulfate]], APAP [[Glutathione|GSH]], APAP [[cys]], AM404, [[NAPQI]]<ref>{{cite web |title= Acetaminophen Pathway (therapeutic doses), Pharmacokinetics |url= https://www.pharmgkb.org/pathway/PA165986279 |access-date= 13 January 2016 |url-status= dead |archive-url= https://web.archive.org/web/20160304220600/https://www.pharmgkb.org/pathway/PA165986279 |archive-date= 4 March 2016 }}</ref>
| onset = [[Oral administration|Oral]]: 37{{nbsp}}minutes<ref name="Buccal route">{{cite journal |vauthors = Pickering G, Macian N, Libert F, Cardot JM, Coissard S, Perovitch P, Maury M, Dubray C |title = Buccal acetaminophen provides fast analgesia: two randomized clinical trials in healthy volunteers |journal = Drug Design, Development and Therapy| volume = 8 |pages = 1621–1627 |date = September 2014 |pmid = 25302017 |pmc = 4189711 |doi = 10.2147/DDDT.S63476 |quote =  In postoperative conditions for acute pain of mild to moderate intensity, the quickest reported time to onset of analgesia with APAP is 8 minutes9 for the iv route and 37 minutes6 for the oral route. |doi-access = free }}</ref><br />[[Intravenous]]: 8{{nbsp}}minutes<ref name="Buccal route" />
| elimination_half-life = 1.9–2.5 hours<ref name="pmid7039926"/>
| duration_of_action = 
| excretion = [[Kidney]]<ref name="pmid7039926"/>

<!-- Identifiers -->| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 103-90-2
| CAS_supplemental = 
| PubChem = 1983
| PubChemSubstance = 46506142
| IUPHAR_ligand = 5239
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB00316
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 1906
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 362O9ITL9D
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00217
| KEGG2 = C06804
| ChEBI_Ref = {{ebicite|correct|EBI}}
| ChEBI = 46195
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 112
| NIAID_ChemDB = 
| PDB_ligand = TYL
| synonyms = ''N''-acetyl-''para''-aminophenol (APAP)

<!-- Chemical and physical data -->| IUPAC_name = ''N''-(4-hydroxyphenyl)acetamide
| C = 8
| H = 9
| N = 1
| O = 2
| SMILES = CC(=O)Nc1ccc(O)cc1
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10)
| StdInChI_comment = 
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = RZVAJINKPMORJF-UHFFFAOYSA-N
| density = 1.293
| density_notes = 
| melting_point = 169
| melting_high = 
| melting_notes = <ref>{{cite journal |doi = 10.1021/ci0500132 |title = General Melting Point Prediction Based on a Diverse Compound Data Set and Artificial Neural Networks |year = 2005 |vauthors=Karthikeyan M, Glen RC, Bender A |journal = Journal of Chemical Information and Modeling |volume = 45 |issue = 3 |pages = 581–590 |pmid = 15921448|s2cid = 13017241 }}</ref><ref>{{cite web |url = http://lxsrv7.oru.edu/~alang/meltingpoints/meltingpointof.php?csid=1906 |title = melting point data for paracetamol |publisher = Lxsrv7.oru.edu |access-date = 19 March 2011 |url-status = dead |archive-url = https://archive.today/20120630213835/http://lxsrv7.oru.edu/~alang/meltingpoints/meltingpointof.php?csid=1906 |archive-date = 30 June 2012 }}</ref>
| boiling_point = 
| boiling_notes = 
| solubility = {{ubl| 7.21{{nbsp}}g/kg (0{{nbsp}}°C)<ref name="paracetamol-solubility">{{cite journal| doi = 10.1021/je990124v| title = Solubility of paracetamol in pure solvents| vauthors=Granberg RA, Rasmuson AC| journal = [[Journal of Chemical & Engineering Data]]| volume = 44 |issue = 6 |pages = 1391–95| year = 1999}}</ref>| 8.21{{nbsp}}g/kg (5{{nbsp}}°C)<ref name="paracetamol-solubility" />| 9.44{{nbsp}}g/kg (10{{nbsp}}°C)<ref name="paracetamol-solubility" />| 10.97{{nbsp}}g/kg (15{{nbsp}}°C)<ref name="paracetamol-solubility" />| 12.78{{nbsp}}g/kg (20{{nbsp}}°C)<ref name="paracetamol-solubility" />| ~14{{nbsp}}mg/ml (20{{nbsp}}°C)}}
| sol_units = 
| specific_rotation = 
}}
<!-- Definition and medical uses -->

'''Paracetamol''',{{Efn|Used by the World Health Organization (WHO)}} or '''acetaminophen''',{{Efn|Commonly called "acetaminophen" in the United States, Canada, Japan, South Korea, Colombia and Venezuela}} 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="pmid31892511" /> It is a widely available [[over-the-counter drug]] sold under various brand names, including '''Tylenol''' and '''Panadol'''.

Paracetamol relieves pain in both acute mild [[migraine]] and episodic [[tension headache]].<ref name="pmid25600718"/><ref name="pmid27306653"/> At a standard dose, paracetamol slightly reduces fever,<ref name="pmid19058473"/><ref name="pmid27992852"/><ref name= "pmid26518691"/> though it is inferior to [[ibuprofen]] in that respect<ref name="pmid20150507"/> and the benefits of its use for fever are unclear, particularly in the context of fever of viral origins.<ref name="pmid19058473"/><ref name="pmid12076499">{{cite journal |vauthors=Meremikwu M, Oyo-Ita A |title=Paracetamol for treating fever in children |journal=Cochrane Database Syst Rev |volume= 2002|issue=2 |pages= CD003676 |date=2002 |pmid=12076499 |pmc=6532671 |doi=10.1002/14651858.CD003676}}</ref><ref name="pmid31116598"/>  The [[aspirin/paracetamol/caffeine]] combination also helps with both conditions when the pain is mild and is recommended as a [[Therapy#Lines of therapy|first-line treatment]] for them.<ref name="pmid29671521" /><ref name="pmid21181425" /> Paracetamol is effective for post-[[surgical]] pain, but is inferior to ibuprofen for this purpose.<ref name="pmid24338830" /> The [[paracetamol/ibuprofen]] combination increases the drugs' potency and is superior to either drug alone.<ref name="pmid24338830"/><ref name="pmid23904576"/> The pain relief paracetamol provides in [[osteoarthritis]] is small and clinically insignificant.<ref name="pmid31892511"/><ref name=BMJ2015/><ref name="pmid31908149"/> Evidence supporting its use in low back pain, [[cancer pain]], and [[neuropathic pain]] is insufficient.<ref name="pmid31892511"/><ref name=BMJ2015/><ref name="pmid28192789"/><ref name=Saragiotto2016/><ref name="pmid28700092"/><ref name="pmid28027389"/>

<!-- 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 [[Nonsteroidal anti-inflammatory drug|nonsteroidal anti-inflammatory drugs]] (NSAIDs) for long-term use.<ref>{{cite web |title=Acetaminophen vs Ibuprofen: Which is better? |url=https://www.drugs.com/medical-answers/difference-between-ibuprofen-acetaminophen-3016163/ |access-date=22 September 2022 |website=Drugs.com |archive-date=19 February 2023 |archive-url=https://web.archive.org/web/20230219010941/https://www.drugs.com/medical-answers/difference-between-ibuprofen-acetaminophen-3016163/ |url-status=live }}</ref> Paracetamol is also often used in patients who cannot tolerate NSAIDs like ibuprofen.<ref name="pmid31156845">{{cite journal |vauthors=Moore RA, Moore N |title=Paracetamol and pain: the kiloton problem |journal=European Journal of Hospital Pharmacy |volume=23 |issue=4 |pages=187–188 |date=July 2016 |pmid=31156845 |pmc=6451482 |doi=10.1136/ejhpharm-2016-000952 |doi-access=free |title-link=doi}}</ref><ref name="pmid31073920"/> Chronic consumption of paracetamol may result in a drop in [[hemoglobin]] level, indicating possible [[gastrointestinal bleeding]],<ref name="pmid25732175"/> and [[Elevated transaminases|abnormal liver function tests]]. The recommended maximum daily dose for an adult is three to four grams.<ref name="BMJ2015" /><ref name="UK2017">{{cite web |url=https://www.nhs.uk/medicines/paracetamol-for-adults/ |title=Paracetamol for adults: painkiller to treat aches, pains and fever |website=[[National Health Service]] |access-date=22 August 2017 |url-status=live |archive-url= https://web.archive.org/web/20170822174155/https://beta.nhs.uk/medicines/paracetamol-for-adults |archive-date=22 August 2017}}</ref> Higher doses may lead to toxicity, including [[liver failure]].<ref name="AHFS2016">{{cite web| title=Acetaminophen| url=https://www.drugs.com/monograph/acetaminophen.html| publisher=The American Society of Health-System Pharmacists| access-date=16 September 2016| archive-url= https://web.archive.org/web/20160605063136/http://www.drugs.com/monograph/acetaminophen.html|archive-date=5 June 2016| url-status=live}}</ref> [[Paracetamol poisoning]] 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.<ref name="Daly2008">{{cite journal |vauthors=Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA |date=March 2008 |title=Guidelines for the management of paracetamol poisoning in Australia and New Zealand—explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres |journal=[[The Medical Journal of Australia]] |volume=188 |issue=5 |pages=296–301 |doi=10.5694/j.1326-5377.2008.tb01625.x |pmid=18312195 |s2cid=9505802}}</ref><ref name="Hawkins2007">{{cite journal |vauthors=Hawkins LC, Edwards JN, Dargan PI |year=2007 |title=Impact of restricting paracetamol pack sizes on paracetamol poisoning in the United Kingdom: a review of the literature |journal=Drug Saf |volume=30 |issue=6 |pages=465–79 |doi=10.2165/00002018-200730060-00002 |pmid=17536874 |s2cid=36435353}}</ref><ref name="Larson2005">{{cite journal |vauthors=Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, Reisch JS, Schiødt FV, Ostapowicz G, Shakil AO, Lee WM, ((Acute Liver Failure Study Group)) |year=2005 |title=Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study |journal=Hepatology |volume=42 |issue=6 |pages=1364–72 |doi=10.1002/hep.20948 |pmid=16317692 |s2cid=24758491 |doi-access= |title-link=doi}}</ref>

<!-- Society and culture -->
Paracetamol was first made in 1878 by [[Harmon Northrop Morse]] or possibly in 1852 by [[Charles Frédéric Gerhardt]].<ref>{{cite book |vauthors = Mangus BC, Miller MG |title=Pharmacology application in athletic training |date=2005 |publisher=F.A. Davis |location=Philadelphia, Pennsylvania |isbn=9780803620278 |page=39 |url=https://books.google.com/books?id=tV72AAAAQBAJ&pg=PA39 |access-date=7 September 2017 |archive-date=8 September 2017 |archive-url=https://web.archive.org/web/20170908185108/https://books.google.com/books?id=tV72AAAAQBAJ&pg=PA39 |url-status=live }}</ref><ref name="ourarchive.otago.ac.nz">{{cite thesis |vauthors = Eyers SJ |date = April 2012 |title = The effect of regular paracetamol on bronchial responsiveness and asthma control in mild to moderate asthma |degree = Ph.D. |publisher = University of Otago). |url = https://ourarchive.otago.ac.nz/handle/10523/2454 |access-date = 24 August 2021 |archive-date = 24 August 2021 |archive-url = https://web.archive.org/web/20210824161722/https://ourarchive.otago.ac.nz/handle/10523/2454 |url-status = live }}</ref><ref name = "Roy_2011">{{cite book |vauthors = Roy J |chapter = Paracetamol – the best selling antipyretic analgesic in the world |chapter-url = https://books.google.com/books?id=0IdmAgAAQBAJ&pg=PA270 |page = 270 |title = An introduction to pharmaceutical sciences: production, chemistry, techniques and technology |date = 2011 |publisher = Biohealthcare |location = Oxford |isbn = 978-1-908818-04-1 |access-date = 24 August 2021 |archive-date = 24 August 2021 |archive-url = https://web.archive.org/web/20210824194752/https://books.google.com/books?id=0IdmAgAAQBAJ&pg=PA270 |url-status = live }}</ref> It is the most commonly used medication for pain and fever in both the United States and Europe.<ref>{{cite book |vauthors = Aghababian RV |title=Essentials of emergency medicine |url=https://books.google.com/books?id=HnbKaRQAXOIC&pg=PA814 |date=22 October 2010 |publisher=Jones & Bartlett Publishers |isbn=978-1-4496-1846-9 |page=814 |url-status=live |archive-url= https://web.archive.org/web/20160817202827/https://books.google.com/books?id=HnbKaRQAXOIC&pg=PA814 |archive-date=17 August 2016 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO23rd">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023) | year = 2023 | hdl = 10665/371090 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MHP/HPS/EML/2023.02 | hdl-access=free }}</ref> Paracetamol is available as a [[generic medication]], with brand names including [[Tylenol (brand)|Tylenol]] and [[Panadol (brand)|Panadol]] among [[Paracetamol brand names|others]].<ref>{{cite book| vauthors = Hamilton RJ |title=Tarascon pocket pharmacopeia: 2013 classic shirt-pocket edition|date=2013|publisher=Jones & Bartlett Learning| location= Burlington, Massachusetts|isbn=9781449665869|page=12|edition=27th|url=https://books.google.com/books?id=lwueJ4IAl4oC&pg=PA12|url-status=live|archive-url= https://web.archive.org/web/20170908185107/https://books.google.com/books?id=lwueJ4IAl4oC&pg=PA12|archive-date=8 September 2017 }}</ref> In 2022, it was the 114th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2022 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=30 August 2024 | archive-date=30 August 2024 | archive-url=https://web.archive.org/web/20240830202410/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Acetaminophen Drug Usage Statistics, United States, 2013 - 2022 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Acetaminophen | access-date = 30 August 2024 }}</ref>
{{TOC limit}}

==Medical uses==

===Fever===
Paracetamol is used for reducing fever.<ref name=":2" /> However, there has been a lack of research on its [[antipyretic]] properties, particularly in adults, and thus its benefits are unclear.<ref name="pmid19058473" /> As a result, it has been described as [[Overmedication|over-prescribed]] for this application.<ref name="pmid19058473">{{cite journal |vauthors=Warwick C |title=Paracetamol and fever management |journal=J R Soc Promot Health |volume=128 |issue=6 |pages=320–323 |date=November 2008 |pmid=19058473 |s2cid=25702228 |doi=10.1177/1466424008092794}}</ref> In addition, low-quality [[Randomized clinical trial|clinical data]] indicates that when used for the [[common cold]], paracetamol may relieve a [[nasal congestion|stuffed]] or [[rhinorrhea|runny]] nose, but not other cold symptoms such as [[sore throat]], [[malaise]], [[sneezing]], or [[cough]].<ref name="pmid23818046">{{cite journal |vauthors=Li S, Yue J, Dong BR, Yang M, Lin X, Wu T |title=Acetaminophen (paracetamol) for the common cold in adults |journal=Cochrane Database Syst Rev |volume=2013 |issue=7 |pages=CD008800 |date=July 2013 |pmid=23818046 |pmc=7389565 |doi=10.1002/14651858.CD008800.pub2}}</ref>

For people in [[Critical care medicine|critical care]], paracetamol decreases body temperature by only 0.2{{ndash}}0.3{{nbsp}}°C more than control interventions and has no effect on their [[Mortality rate|mortality]].<ref name="pmid27992852">{{cite journal |vauthors=Chiumello D, Gotti M, Vergani G |title=Paracetamol in fever in critically ill patients-an update |journal=J Crit Care |volume=38 |issue= |pages=245–252 |date=April 2017 |pmid=27992852 |doi=10.1016/j.jcrc.2016.10.021 |s2cid=5815020}}</ref> It did not change the outcome in febrile patients with stroke.<ref name="pmid28289240">{{cite journal |vauthors=de Ridder IR, den Hertog HM, van Gemert HM, Schreuder AH, Ruitenberg A, Maasland EL, Saxena R, van Tuijl JH, Jansen BP, Van den Berg-Vos RM, Vermeij F, Koudstaal PJ, Kappelle LJ, Algra A, van der Worp HB, Dippel DW |title=PAIS 2 (Paracetamol [Acetaminophen] in Stroke 2): Results of a Randomized, Double-Blind Placebo-Controlled Clinical Trial |journal=Stroke |volume=48 |issue=4 |pages=977–982 |date=April 2017 |pmid=28289240 |doi= 10.1161/STROKEAHA.116.015957 |doi-access=free |title-link = doi }}</ref> The results are contradictory for paracetamol use in sepsis: higher mortality, lower mortality, and no change in mortality were all reported.<ref name="pmid27992852"/> Paracetamol offered no benefit in the treatment of [[dengue fever]] and was accompanied by a higher rate of liver enzyme elevation: a sign of potential liver damage.<ref name="pmid31000122">{{cite journal |vauthors=Deen J, von Seidlein L |title=Paracetamol for dengue fever: no benefit and potential harm? |journal=Lancet Glob Health |volume=7 |issue=5 |pages=e552–e553 |date=May 2019 |pmid=31000122 |doi=10.1016/S2214-109X(19)30157-3 |doi-access=free |title-link = doi }}</ref> Overall, there is no support for a routine administration of antipyretic drugs, including paracetamol, to hospitalized patients with fever and infection.<ref name="pmid31116598">{{cite journal |vauthors=Ludwig J, McWhinnie H |title=Antipyretic drugs in patients with fever and infection: literature review |journal=Br J Nurs |volume=28 |issue=10 |pages=610–618 |date=May 2019 |pmid=31116598 |doi=10.12968/bjon.2019.28.10.610 |s2cid=162182092}}</ref>

The efficacy of paracetamol in children with fever is unclear.<ref>{{cite journal |vauthors=Meremikwu M, Oyo-Ita A |title=Paracetamol for treating fever in children |journal=Cochrane Database Syst Rev |issue=2 |page=CD003676 |year=2002 |volume=2002 |pmid=12076499 |doi=10.1002/14651858.CD003676|pmc=6532671 }}</ref> Paracetamol should not be used solely to reduce body temperature; however, it may be considered for children with fever who appear distressed.<ref name=NICE>{{cite web |url= https://www.nice.org.uk/guidance/ng143/chapter/Recommendations#antipyretic-interventions |title= Recommendations. Fever in under 5s: assessment and initial management |website= nice.org.uk |date= 7 November 2019 |publisher=  |format=  |access-date=  |archive-date= 10 February 2021 |archive-url= https://web.archive.org/web/20210210232531/https://www.nice.org.uk/guidance/ng143/chapter/Recommendations#antipyretic-interventions |url-status= live }}</ref> It does not prevent [[febrile seizures]].<ref name=NICE/><ref name= "pmid33125519">{{cite journal |vauthors=Hashimoto R, Suto M, Tsuji M, Sasaki H, Takehara K, Ishiguro A, Kubota M |title=Use of antipyretics for preventing febrile seizure recurrence in children: a systematic review and meta-analysis |journal=Eur J Pediatr |volume=180 |issue=4 |pages=987–997 |date=April 2021 |pmid=33125519 |doi= 10.1007/s00431-020-03845-8 |doi-access= |title-link = doi |s2cid=225994044 }}</ref> It appears that 0.2{{nbsp}}°C decrease of the body temperature in children after a standard dose of paracetamol is of questionable value, particularly in emergencies.<ref name="pmid19058473"/> Based on this, some physicians advocate using higher doses that may decrease the temperature by as much as 0.7{{nbsp}}°C.<ref name="pmid26518691">{{cite journal |vauthors=de Martino M, Chiarugi A |title=Recent Advances in Pediatric Use of Oral Paracetamol in Fever and Pain Management |journal=Pain Ther |volume=4 |issue=2 |pages=149–68 |date=December 2015 |pmid=26518691 |pmc=4676765 |doi=10.1007/s40122-015-0040-z}}</ref> Meta-analyses showed that paracetamol is less effective than ibuprofen in children (marginally less effective, according to another analysis<ref name="pmid28437025">{{cite journal |vauthors=Narayan K, Cooper S, Morphet J, Innes K |title=Effectiveness of paracetamol versus ibuprofen administration in febrile children: A systematic literature review |journal=J Paediatr Child Health |volume=53 |issue=8 |pages=800–807 |date=August 2017 |pmid=28437025 |doi=10.1111/jpc.13507 |s2cid=395470}}</ref>), including children younger than 2 years old,<ref name="pmid33125495">{{cite journal |vauthors=Tan E, Braithwaite I, McKinlay CJ, Dalziel SR |title=Comparison of Acetaminophen (Paracetamol) With Ibuprofen for Treatment of Fever or Pain in Children Younger Than 2 Years: A Systematic Review and Meta-analysis |journal=JAMA Netw Open |volume=3 |issue=10 |pages=e2022398 |date=October 2020 |pmid= 33125495 |pmc=7599455 |doi=10.1001/jamanetworkopen.2020.22398}}</ref> with equivalent safety.<ref name="pmid20150507">{{cite journal |vauthors=Pierce CA, Voss B |title= Efficacy and safety of ibuprofen and acetaminophen in children and adults: a meta-analysis and qualitative review |journal=Ann Pharmacother |volume=44 |issue=3 |pages= 489–506 |date=March 2010 |pmid=20150507 |doi=10.1345/aph.1M332 |s2cid= 44669940}}</ref> [[Exacerbation]] of asthma occurs with similar frequency for both medications.<ref name= "pmid32293369">{{cite journal |vauthors=Sherbash M, Furuya-Kanamori L, Nader JD, Thalib L |title=Risk of wheezing and asthma exacerbation in children treated with paracetamol versus ibuprofen: a systematic review and meta-analysis of randomised controlled trials |journal=BMC Pulm Med |volume=20 |issue=1 |pages=72 |date=March 2020 |pmid= 32293369 |pmc=7087361 |doi=10.1186/s12890-020-1102-5 |doi-access=free }}</ref> Giving paracetamol and ibuprofen together at the same time to children under 5 is not recommended; however, doses may be alternated if required.<ref name= NICE/>

===Pain===
Paracetamol is used for the relief of mild to moderate pain such as headache, muscle aches, minor arthritis pain, and toothache, as well as pain caused by cold, flu, sprains, and [[dysmenorrhea]].<ref name="pmid17227290">{{cite journal |vauthors=Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S |title=Paracetamol: new vistas of an old drug |journal=CNS Drug Rev |volume=12 |issue=3–4 |pages=250–75 |date=2006 |pmid=17227290 |pmc=6506194 |doi=10.1111/j.1527-3458.2006.00250.x}}</ref> It is recommended, in particular, for acute mild to moderate pain, since the evidence for the treatment of chronic pain is insufficient.<ref name="pmid31892511">{{cite journal |vauthors= Saragiotto BT, Abdel Shaheed C, Maher CG |title=Paracetamol for pain in adults |journal=BMJ |volume=367 |issue= |pages=l6693 |date=December 2019 |pmid=31892511 |doi= 10.1136/bmj.l6693 |s2cid=209524643}}</ref>

====Musculoskeletal pain====
The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain.<ref name="pmid31892511"/>

It appears to provide only small and not clinically important benefits in [[osteoarthritis]].<ref name="pmid31892511"/><ref name=BMJ2015>{{cite journal|vauthors=Machado GC, Maher CG, Ferreira PH, Pinheiro MB, Lin CW, Day RO, McLachlan AJ, Ferreira ML |title=Efficacy and safety of paracetamol for spinal pain and osteoarthritis: systematic review and meta-analysis of randomised placebo-controlled trials.|journal=BMJ |date=March 2015| volume= 350| pages= h1225| pmid= 25828856 |doi= 10.1136/bmj.h1225|pmc=4381278 }}</ref> [[American College of Rheumatology]] and [[Arthritis Foundation]] guideline for the management of osteoarthritis notes that the [[effect size]] in [[clinical trial]]s of paracetamol has been very small, which suggests that for most individuals it is ineffective.<ref name="pmid31908149">{{cite journal |vauthors= Kolasinski SL, Neogi T, Hochberg MC, Oatis C, Guyatt G, Block J, Callahan L, Copenhaver C, Dodge C, Felson D, Gellar K, Harvey WF, Hawker G, Herzig E, Kwoh CK, Nelson AE, Samuels J, Scanzello C, White D, Wise B, Altman RD, DiRenzo D, Fontanarosa J, Giradi G, Ishimori M, Misra D, Shah AA, Shmagel AK, Thoma LM, Turgunbaev M, Turner AS, Reston J |title=2019 American College of Rheumatology/Arthritis Foundation Guideline for the Management of Osteoarthritis of the Hand, Hip, and Knee |journal=Arthritis Care & Research |volume=72 |issue=2 |pages=149–162 |date=February 2020 |pmid=31908149 |doi=10.1002/acr.24131 |pmc=11488261 |hdl=2027.42/153772 |s2cid=210043648 |hdl-access=free }}</ref> The guideline conditionally recommends paracetamol for short-term and episodic use to those who do not tolerate nonsteroidal anti-inflammatory drugs. For people taking it regularly, monitoring for liver toxicity is required.<ref name="pmid31908149"/> Essentially the same recommendation was issued by [[European League Against Rheumatism|EULAR]] for hand osteoarthritis.<ref name="pmid30154087">{{cite journal |vauthors=Kloppenburg M, Kroon FP, Blanco FJ, Doherty M, Dziedzic KS, Greibrokk E, Haugen IK, Herrero-Beaumont G, Jonsson H, Kjeken I, Maheu E, Ramonda R, Ritt MJ, Smeets W, Smolen JS, Stamm TA, Szekanecz Z, Wittoek R, Carmona L |title=2018 update of the EULAR recommendations for the management of hand osteoarthritis |journal=Ann Rheum Dis |volume=78 |issue=1 |pages=16–24 |date=January 2019 |pmid=30154087 |doi= 10.1136/annrheumdis-2018-213826 |doi-access=free |title-link = doi |hdl=2437/257176 |hdl-access=free }}</ref> Similarly, the ESCEO algorithm for the treatment of knee osteoarthritis recommends limiting the use of paracetamol to short-term rescue analgesia only.<ref name="pmid31126594">{{cite journal |vauthors=Bruyère O, Honvo G, Veronese N, Arden NK, Branco J, Curtis EM, Al-Daghri NM, Herrero-Beaumont G, Martel-Pelletier J, Pelletier JP, Rannou F, Rizzoli R, Roth R, Uebelhart D, Cooper C, Reginster JY |title=An updated algorithm recommendation for the management of knee osteoarthritis from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) |journal=Semin Arthritis Rheum |volume=49 |issue=3 |pages=337–350 |date=December 2019 |pmid=31126594 |doi=10.1016/j.semarthrit.2019.04.008 |doi-access=free |title-link = doi |hdl=10447/460208 |hdl-access=free }}</ref>

Paracetamol is ineffective for acute low back pain.<ref name="pmid31892511"/><ref name="pmid28192789">{{cite journal |vauthors=Qaseem A, Wilt TJ, McLean RM, Forciea MA |title=Noninvasive Treatments for Acute, Subacute, and Chronic Low Back Pain: A Clinical Practice Guideline From the American College of Physicians |journal=Ann Intern Med |volume=166 |issue=7 |pages=514–530 |date=April 2017 |pmid=28192789 |doi=10.7326/M16-2367 |s2cid=207538763|doi-access=free }}</ref> No randomized clinical trials evaluated its use for chronic or [[radicular pain|radicular]] back pain, and the evidence in favor of paracetamol is lacking.<ref name=Saragiotto2016>{{cite journal |vauthors=Saragiotto BT, Machado GC, Ferreira ML, Pinheiro MB, Abdel Shaheed C, Maher CG |title=Paracetamol for low back pain |journal=Cochrane Database Syst Rev |date=June 2016| volume=6| issue=6| page=CD012230 |doi=10.1002/14651858.CD012230 |pmid=27271789 |pmc=6353046}}</ref><ref name=BMJ2015/><ref name="pmid28192789"/>

====Headaches====

Paracetamol is effective for acute migraine:<ref name="pmid25600718">{{cite journal |vauthors=Marmura MJ, Silberstein SD, Schwedt TJ |title=The acute treatment of migraine in adults: the american headache society evidence assessment of migraine pharmacotherapies |journal=Headache |volume=55 |issue=1 |pages=3–20 |date=January 2015 |pmid= 25600718 |doi=10.1111/head.12499 |s2cid=25576700}}</ref> 39% of people experience pain relief at one hour compared with 20% in the control group.<ref>{{cite journal |vauthors= Derry S, Moore RA |title=Paracetamol (acetaminophen) with or without an antiemetic for acute migraine headaches in adults |journal=Cochrane Database Syst Rev |volume=4 |issue= 4|pages= CD008040 |year=2013 |pmid=23633349 |doi=10.1002/14651858.CD008040.pub3 |pmc=4161111}}</ref> The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a [[Therapy#Lines of therapy|first-line treatment]] for migraine".<ref name="pmid29671521">{{Cite journal |vauthors=Mayans L, Walling A |date=February 2018 |title=Acute Migraine Headache: Treatment Strategies |url=https://www.aafp.org/pubs/afp/issues/2018/0215/p243.html |journal=Am Fam Physician |volume=97 |issue=4 |pages=243–251 |pmid=29671521}}</ref> Paracetamol on its own only slightly alleviates episodic [[tension headache]] in those who have them frequently.<ref name="pmid27306653">{{cite journal |vauthors=Stephens G, Derry S, Moore RA |title=Paracetamol (acetaminophen) for acute treatment of episodic tension-type headache in adults |journal=Cochrane Database Syst Rev |volume= 2019|issue=6 |pages=CD011889 |date=June 2016 |pmid=27306653 |pmc=6457822 |doi=10.1002/14651858.CD011889.pub2}}</ref> However, the aspirin/paracetamol/caffeine combination is superior to both paracetamol alone and placebo and offers meaningful relief of tension headache: two hours after administering the medication, 29% of those who took the combination were pain-free as compared with 21% on paracetamol and 18% on placebo.<ref name="pmid25406671">{{cite journal |vauthors=Diener HC, Gold M, Hagen M |title=Use of a fixed combination of acetylsalicylic acid, acetaminophen and caffeine compared with acetaminophen alone in episodic tension-type headache: meta-analysis of four randomized, double-blind, placebo-controlled, crossover studies |journal=J Headache Pain |volume=15 |issue= 1|pages=76 |date=November 2014 |pmid=25406671 |pmc=4256978 |doi=10.1186/1129-2377-15-76 |doi-access=free }}</ref> The German, Austrian, and Swiss headache societies and the German Society of Neurology recommend this combination as a "highlighted" one for self-medication of tension headache, with paracetamol/caffeine combination being a "remedy of first choice", and paracetamol a "remedy of second choice".<ref name="pmid21181425">{{cite journal |vauthors=Haag G, Diener HC, May A, Meyer C, Morck H, Straube A, Wessely P, Evers S |title=Self-medication of migraine and tension-type headache: summary of the evidence-based recommendations of the Deutsche Migräne und Kopfschmerzgesellschaft (DMKG), the Deutsche Gesellschaft für Neurologie (DGN), the Österreichische Kopfschmerzgesellschaft (ÖKSG) and the Schweizerische Kopfwehgesellschaft (SKG) |journal=J Headache Pain |volume=12 |issue=2 |pages=201–217 |date=April 2011 |pmid=21181425 |pmc=3075399 |doi=10.1007/s10194-010-0266-4}}</ref>

====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|pmc=11561150 }}</ref> Full therapeutic doses of nonsteroidal anti-inflammatory drugs (NSAIDs) ibuprofen, [[naproxen]] or [[diclofenac]] are clearly more efficacious than the paracetamol/codeine combination which is frequently prescribed for dental pain.<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>

====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 [[Nonsteroidal anti-inflammatory drug|nonsteroidal anti-inflammatory drugs]] (NSAIDs).<ref name="pmid33427305">{{cite journal |vauthors=Wuytack F, Smith V, Cleary BJ |title=Oral non-steroidal anti-inflammatory drugs (single dose) for perineal pain in the early postpartum period |journal=Cochrane Database Syst Rev |volume=1 |issue= 1|pages=CD011352 |date=January 2021 |pmid=33427305 |doi= 10.1002/14651858.CD011352.pub3 |pmc=8092572}}</ref>

The studies to support or refute the use of paracetamol for cancer pain and 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>

=== Patent ductus arteriosus ===
Paracetamol helps ductal closure in [[patent ductus arteriosus]]. It is as effective for this purpose as ibuprofen or [[indomethacin]], but results in less frequent gastrointestinal bleeding than ibuprofen.<ref name=":0">{{cite journal |vauthors=Jasani B, Mitra S, Shah PS |title=Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants |journal=The Cochrane Database of Systematic Reviews |volume=2022 |pages=CD010061 |date=December 2022 |issue=12 |pmid=36519620 |doi=10.1002/14651858.CD010061.pub5|pmc=6984659 }}</ref> Its use for extremely low birth weight and gestational age infants however requires further study.<ref name=":0"/>

==Adverse effects==
Gastrointestinal adverse effects such as nausea and [[abdominal pain]] are extremely uncommon, and their frequency is nothing 
like that of ibuprofen.<ref name="pmid31073920"/> Increase in risk-taking behavior is possible.<ref>{{cite journal |vauthors=Keaveney A, Peters E, Way B |title=Effects of acetaminophen on risk taking |journal=Social Cognitive and Affective Neuroscience |volume=15 |issue=7 |pages=725–732 |date=September 2020 |pmid=32888031 |pmc=7511878 |doi=10.1093/scan/nsaa108}}</ref> According to the U.S. [[Food and Drug Administration]] (FDA), the drug may cause rare and possibly fatal skin reactions such as [[Stevens–Johnson syndrome]] and [[toxic epidermal necrolysis]],<ref name=":1">{{cite web |title=FDA Drug Safety Communication: FDA warns of rare but serious skin reactions with the pain reliever/fever reducer acetaminophen |website=U.S. [[Food and Drug Administration]] (FDA) |date=1 August 2013 |url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-rare-serious-skin-reactions-pain-relieverfever-reducer |archive-url= https://web.archive.org/web/20191028034057/https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-rare-serious-skin-reactions-pain-relieverfever-reducer |archive-date=28 October 2019 |url-status=live |access-date=27 October 2019}} {{PD-notice}}</ref> [[Rechallenge]] tests and an analysis of American but not French [[pharmacovigilance]] databases indicated a risk of these reactions.<ref name=":1" /><ref name="pmid28963996">{{cite journal |vauthors=Lebrun-Vignes B, Guy C, Jean-Pastor MJ, Gras-Champel V, Zenut M |title=Is acetaminophen associated with a risk of Stevens-Johnson syndrome and toxic epidermal necrolysis? Analysis of the French Pharmacovigilance Database |journal=Br J Clin Pharmacol |volume=84 |issue=2 |pages=331–338 |date=February 2018 |pmid=28963996 |pmc=5777438 |doi=10.1111/bcp.13445}}</ref>

In clinical trials for [[osteoarthritis]], the number of participants reporting adverse effects was similar for those on paracetamol and on placebo. However, the abnormal liver function tests (meaning there was some inflammation or damage to the liver) were almost four times more likely in those on paracetamol, although the clinical importance of this effect is uncertain.<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>

Due to the absence of [[Randomized controlled trial|controlled studies]], most of the information about the long-term safety of paracetamol comes from [[Observational study|observational studies]].<ref name="pmid31073920">{{cite journal |vauthors=Conaghan PG, Arden N, Avouac B, Migliore A, Rizzoli R |title=Safety of Paracetamol in Osteoarthritis: What Does the Literature Say? |journal=Drugs Aging |volume=36 |issue=Suppl 1 |pages=7–14 |date=April 2019 |pmid=31073920 |pmc=6509082 |doi=10.1007/s40266-019-00658-9}}</ref> These indicate a consistent pattern of increased [[mortality rate|mortality]] as well as [[Cardiovascular disease|cardiovascular]] ([[stroke]], [[myocardial infarction]]), gastrointestinal ([[Peptic ulcer disease|ulcers]], [[Gastrointestinal bleeding|bleeding]]) and [[Kidney|renal]] adverse effects with increased dose of paracetamol.<ref name="pmid25732175"/><ref name="pmid31073920"/><ref name="pmid23400756">{{cite journal |vauthors=Choueiri TK, Je Y, Cho E |title=Analgesic use and the risk of kidney cancer: a meta-analysis of epidemiologic studies |journal=Int J Cancer |volume=134 |issue=2 |pages=384–96 |date=January 2014 |pmid=23400756 |pmc=3815746 |doi=10.1002/ijc.28093}}</ref> Use of paracetamol is associated with 1.9 times higher risk of peptic ulcer.<ref name="pmid31073920"/> Those who take it regularly at a higher dose (more than 2{{ndash}}3{{nbsp}}g daily) are at much higher risk (3.6{{ndash}}3.7 times) of gastrointestinal bleeding and other bleeding events.<ref name= "pmid29863746"/> Meta-analyses suggest that paracetamol may increase the risk of [[kidney failure|kidney impairment]] by 23%<ref name="pmid32172553">{{cite journal |vauthors=Kanchanasurakit S, Arsu A, Siriplabpla W, Duangjai A, Saokaew S |title=Acetaminophen use and risk of renal impairment: A systematic review and meta-analysis |journal=Kidney Res Clin Pract |volume=39 |issue=1 |pages=81–92 |date=March 2020 |pmid=32172553 |pmc=7105620 |doi=10.23876/j.krcp.19.106}}</ref> and kidney cancer by 28%.<ref name="pmid23400756"/> Paracetamol slightly but significantly increases [[blood pressure]] and heart rate.<ref name="pmid31073920"/> A 2022 double-blind, placebo-controlled, crossover study has provided evidence that daily, high-dose use (4 g per day) of paracetamol increases systolic BP.<ref name="pmid35130054">{{cite journal |vauthors=MacIntyre IM, Turtle EJ, Farrah TE, Graham C, Dear JW, Webb DJ |date=February 2022 |title=Regular Acetaminophen Use and Blood Pressure in People With Hypertension: The PATH-BP Trial |journal=Circulation |volume=145 |issue=6 |pages=416–423 |doi=10.1161/CIRCULATIONAHA.121.056015 |pmc=7612370 |pmid=35130054}}</ref>{{Primary source inline|date=April 2024}}  A review of available research has suggested that increase in systolic blood pressure and increased risk of gastrointestinal bleeding associated with chronic paracetamol use shows a degree of dose dependence.<ref name="pmid29863746">{{cite journal |vauthors=McCrae JC, Morrison EE, MacIntyre IM, Dear JW, Webb DJ |title=Long-term adverse effects of paracetamol – a review |journal=Br J Clin Pharmacol |volume=84 |issue=10 |pages=2218–2230 |date=October 2018 |pmid= 29863746 |pmc=6138494 |doi=10.1111/bcp.13656}}</ref>

The association between paracetamol use and [[asthma]] in children has been a matter of controversy.<ref name="Lourido2017">{{cite journal|vauthors=Lourido-Cebreiro T, Salgado FJ, Valdes L, Gonzalez-Barcala FJ |title=The association between paracetamol and asthma is still under debate|journal=The Journal of Asthma|date=January 2017 |volume= 54|issue=1|pages=32–8|doi=10.1080/02770903.2016.1194431|pmid=27575940|s2cid=107851|type=Review}}</ref> However, the most recent research suggests that there is no association,<ref>{{cite journal|vauthors=Cheelo M, Lodge CJ, Dharmage SC, Simpson JA, Matheson M, Heinrich J, Lowe AJ|title=Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis|journal=Archives of Disease in Childhood|date=January 2015|pmid=25429049|doi=10.1136/archdischild-2012-303043|volume=100|issue=1|pages=81–9|s2cid=13520462|url=http://nbn-resolving.de/urn:nbn:de:bvb:19-epub-37262-5|access-date=28 October 2022|archive-date=27 March 2023|archive-url=https://web.archive.org/web/20230327065603/https://epub.ub.uni-muenchen.de/37262/|url-status=live}}</ref> and that the frequency of asthma exacerbations in children after paracetamol is the same as after another frequently used pain killer, ibuprofen.<ref name="pmid32293369"/>

In recommended doses, the [[Side effect|side effects]] of paracetamol are mild to non-existent.<ref name="PM: FBtCP">{{cite book | vauthors = Hughes J |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 | vauthors = Sarg M, Gross AD, Altman R |title=The Cancer Dictionary |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 | vauthors = Ebrahimi S, Esfahani SA, Ghaffarian HR, Khoshneviszade M |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 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 | vauthors = Dukes MN, Aronson JK |title=Meyler's Side Effects of Drugs, Vol XIV  |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 | vauthors = Kristensen DM, Hass U, Lesné L, Lottrup G, Jacobsen PR, Desdoits-Lethimonier C, Boberg J, Petersen JH, Toppari J, Jensen TK, Brunak S, Skakkebaek NE, Nellemann C, Main KM, Jégou B, Leffers H | title = Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat | journal = Human Reproduction | volume = 26 | issue = 1 | pages = 235–244 | date = January 2011 | pmid = 21059752 | 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. One recent research study showed evidence that paracetamol can ease psychological pain, but more studies are needed to draw a stronger conclusion.<ref>{{cite web |date=16 July 2014 |title=Could Tylenol Ease Emotional Pain? |url=http://www.evergreen-magazine.com/2014/07/tylenol-ease-emotional-pain/ |url-status=dead |archive-url=https://web.archive.org/web/20140819090402/http://www.evergreen-magazine.com/2014/07/tylenol-ease-emotional-pain/ |archive-date=19 August 2014 |access-date=17 August 2014 |publisher=Evergreen Magazine}}</ref> Unlike aspirin, it is safe for children, as paracetamol is not associated with a risk of [[Reye syndrome]] in children with viral illnesses.<ref>{{cite journal |vauthors=Lesko SM, Mitchell AA |year=1999 |title=The safety of acetaminophen and ibuprofen among children younger than two years old |journal=Pediatrics |volume=104 |issue=4 |pages=e39 |doi=10.1542/peds.104.4.e39 |pmid=10506264 |s2cid=3107281 |doi-access=free}}</ref> Chronic users of paracetamol may have a higher risk of developing [[Hematological malignancy|blood cancer]].<ref>{{cite journal |author1=Roland B. Walter |author2=Filippo Milano |author3=Theodore M. Brasky |author4=Emily White |year=2011 |title=Long-Term Use of Acetaminophen, Aspirin, and Other Nonsteroidal Anti-Inflammatory Drugs and Risk of Hematologic Malignancies: Results From the Prospective Vitamins and Lifestyle (VITAL) Study |journal=Journal of Clinical Oncology |volume=29 |issue=17 |pages=2424–31 |doi=10.1200/JCO.2011.34.6346 |pmc=3107756 |pmid=21555699}}</ref>

===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 in the risk 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]], and [[conduct disorder]], with the association being lower in a meta-analysis where a larger demographic was used, but it is unclear whether this is a causal relationship and whether there was potential bias in the findings.<ref name="pmid29863746"/><ref name="pmid29688261">{{cite journal |vauthors=Masarwa R, Levine H, Gorelik E, Reif S, Perlman A, Matok I |title= Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies |journal=Am J Epidemiol |volume=187 |issue=8 |pages=1817–1827 |date=August 2018 |pmid=29688261 |doi=10.1093/aje/kwy086 |doi-access= free |title-link = doi }}</ref><ref name="pmid31664451">{{cite journal |vauthors=Ji Y, Azuine RE, Zhang Y, Hou W, Hong X, Wang G, Riley A, Pearson C, Zuckerman B, Wang X |title= Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood |journal=JAMA Psychiatry |volume=77 |issue=2 |pages=180–189 |date=February 2020 |pmid=31664451 |pmc=6822099 |doi=10.1001/jamapsychiatry.2019.3259}}</ref> There is also an argument that the large number, consistency, and robust designs of the studies provide strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders.<ref name="pmid29341895">{{cite journal |vauthors=Bauer AZ, Kriebel D, Herbert MR, Bornehag CG, Swan SH |title=Prenatal paracetamol exposure and child neurodevelopment: A review |journal=Horm Behav |volume=101 |issue= |pages=125–147 |date=May 2018 |pmid=29341895 |doi=10.1016/j.yhbeh.2018.01.003 |s2cid=4822468}}</ref><ref name="pmid30654621">{{cite journal |vauthors=Gou X, Wang Y, Tang Y, Qu Y, Tang J, Shi J, Xiao D, Mu D |title=Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: A meta-analysis |journal=Aust N Z J Psychiatry |volume=53 |issue=3 |pages=195–206 |date=March 2019 |pmid= 30654621 |doi=10.1177/0004867418823276 |s2cid=58575048}}</ref> In animal experiments, paracetamol disrupts fetal [[testosterone]] production, and several epidemiological studies linked [[cryptorchidism]] with mother's paracetamol use for more than two weeks in the second trimester. On the other hand, several studies did not find any association.<ref name="pmid29863746"/>

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, paracetamol and [[metoclopramide]] are deemed safe as are NSAIDs until the [[third trimester]].<ref name="Gilmore2011">{{cite journal | vauthors = Gilmore B, Michael M | title = Treatment of acute migraine headache | journal = American Family Physician | volume = 83 | issue = 3 | pages = 271–280 | date = February 2011 | pmid = 21302868 }}</ref>

==Overdose==
{{Main|Paracetamol poisoning}}
[[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/> 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=dead |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=dead |access-date=27 October 2019}}{{PD-notice}}</ref> A single dose should not exceed 1000&nbsp;mg, doses should be taken no sooner than four hours apart, and no more than four doses (4000&nbsp;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 U.S. than overdose of any other pharmacological substance.<ref name="Lee2004">{{cite journal |vauthors=Lee WM |title=Acetaminophen and the U.S. Acute Liver Failure Study Group: lowering the risks of hepatic failure |journal=Hepatology |volume=40 |issue=1 |pages=6–9 |year=2004 |pmid=15239078 |doi=10.1002/hep.20293|s2cid=15485538 |doi-access=free |title-link = doi }}</ref> 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."<ref>{{cite web| publisher=US Food and Drug Administration| date=14 January 2011| website=regulations.gov| url=http://www.regulations.gov/#!documentDetail;D=FDA-2011-N-0021-0001 |title=Prescription Drug Products Containing Acetaminophen: Actions to Reduce Liver Injury from Unintentional Overdose| archive-url=https://web.archive.org/web/20120925153342/http://www.regulations.gov/ |archive-date=25 September 2012 |access-date=23 February 2014}}{{PD-notice}}</ref>{{needs update|date=February 2024}}

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>

Untreated paracetamol overdose results in a lengthy, painful illness. Signs and symptoms of paracetamol toxicity may initially be absent or [[non-specific symptom]]s. The first symptoms of overdose usually begin several hours after ingestion, with [[nausea]], [[vomiting]], sweating, and pain as acute liver failure starts.<ref name="Rumack1975">{{cite journal |vauthors=Rumack B, Matthew H |title=Acetaminophen poisoning and toxicity |journal=Pediatrics |volume=55 |issue=6 |pages=871–876 |year=1975 |doi=10.1542/peds.55.6.871 |pmid=1134886| s2cid=45739342}}</ref> 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.<ref>{{cite web|title=Paracetamol|date=25 March 2013|url=http://cebmh.warne.ox.ac.uk/csr/resparacet.html |publisher=University of Oxford Centre for Suicide Research |access-date=20 April 2013|url-status=dead|archive-url= https://web.archive.org/web/20130320041145/http://cebmh.warne.ox.ac.uk/csr/resparacet.html|archive-date=20 March 2013}}</ref><ref name="met1">{{cite web |vauthors=Mehta S |title=Metabolism of Paracetamol (Acetaminophen), Acetanilide and Phenacetin |website=PharmaXChange.info |date=25 August 2012 |url= https://pharmaxchange.info/2012/08/metabolism-of-paracetamol-acetaminophen-acetanilide-and-phenacetin/ |access-date=27 October 2019 |url-status=dead |archive-url= https://web.archive.org/web/20191028061441/https://pharmaxchange.info/2012/08/metabolism-of-paracetamol-acetaminophen-acetanilide-and-phenacetin/ |archive-date=28 October 2019}}</ref>

Treatment is aimed at removing the paracetamol from the body and replenishing [[glutathione]].<ref name="met1"/> [[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.<ref name="Daly2008"/><ref>{{cite web |url=http://acetadote.com/Acetadote21-539-12_PI_Clean_June2013.pdf |title=Highlights of Prescribing Information |publisher=Acetadote |access-date=10 February 2014 |url-status=dead |archive-url= https://web.archive.org/web/20140222012224/http://acetadote.com/Acetadote21-539-12_PI_Clean_June2013.pdf |archive-date=22 February 2014 }}</ref>

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.<ref>{{cite web|title=Paracetamol overdose: new guidance on treatment with intravenous acetylcysteine |website=Drug Safety Update |date=September 2012 |volume=6 |issue=2 |pages=A1 |url=http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON185624 |archive-url=https://web.archive.org/web/20121027163355/http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON185624 |url-status=dead |archive-date=27 October 2012}}</ref><ref>{{cite web |title=Treating paracetamol overdose with intravenous acetylcysteine: new guidance |website=GOV.UK |date=11 December 2014 |url=https://www.gov.uk/drug-safety-update/treating-paracetamol-overdose-with-intravenous-acetylcysteine-new-guidance |access-date=24 January 2021 |archive-date=28 October 2019 |url-status=live |archive-url=https://web.archive.org/web/20191028073251/https://www.gov.uk/drug-safety-update/treating-paracetamol-overdose-with-intravenous-acetylcysteine-new-guidance}}</ref> Toxicity of paracetamol is due to its [[1,4-Benzoquinone|quinone metabolite]] [[NAPQI]] and NAC also helps in neutralizing it.<ref name="met1" /> [[Kidney failure]] is also a possible side effect.<ref name="Lee2017" />

==Interactions==

[[Prokinetic agent]]s such as [[metoclopramide]] accelerate gastric emptying, shorten time (t<sub>max</sub>) to paracetamol [[Cmax (pharmacology)|peak blood plasma concentration]] (C<sub>max</sub>), and increase C<sub>max</sub>. Medications slowing gastric emptying such as [[propantheline]] and [[morphine]] lengthen t<sub>max</sub> and decrease C<sub>max</sub>.<ref name="pmid4694406">{{cite journal |vauthors=Nimmo J, Heading RC, Tothill P, Prescott LF |title=Pharmacological modification of gastric emptying: effects of propantheline and metoclopromide on paracetamol absorption |journal=Br Med J |volume=1 |issue=5853 |pages=587–9 |date=March 1973 |pmid=4694406 |pmc= 1589913 |doi= 10.1136/bmj.1.5853.587}}</ref><ref name="pmid15662293">{{cite journal |vauthors=Toes MJ, Jones AL, Prescott L |title=Drug interactions with paracetamol |journal=Am J Ther |volume=12 |issue=1 |pages=56–66 |date=2005 |pmid=15662293 |doi=10.1097/00045391-200501000-00009 |s2cid=39595470}}</ref> The interaction with morphine may result in patients failing to achieve the therapeutic concentration of paracetamol; the clinical significance of interactions with metoclopramide and propantheline is unclear.<ref name="pmid15662293"/>

There have been suspicions that [[List of cytochrome P450 modulators|cytochrome inducers]] may enhance the toxic pathway of paracetamol metabolism to [[NAPQI]] (see [[Paracetamol#Pharmacokinetics]]). By and large, these suspicions have not been confirmed.<ref name="pmid15662293"/> Out of the inducers studied, the evidence of potentially increased liver toxicity in paracetamol overdose exists for [[phenobarbital]], [[primidone]], [[isoniazid]], and possibly [[St John's wort]].<ref name= "pmid27147854">{{cite journal |vauthors=Kalsi SS, Wood DM, Waring WS, Dargan PI |title=Does cytochrome P450 liver isoenzyme induction increase the risk of liver toxicity after paracetamol overdose? |journal=Open Access Emerg Med |volume=3 |issue= |pages=69–76 |date=2011 |pmid=27147854 |pmc=4753969 |doi=10.2147/OAEM.S24962 |doi-access=free }}</ref> On the other hand, the anti-tuberculosis drug [[isoniazid]] cuts the formation of NAPQI by 70%.<ref name="pmid15662293"/>

[[Ranitidine]] increased paracetamol [[Area under the curve (pharmacokinetics)|area under the curve]] (AUC) 1.6-fold. AUC increases are also observed with [[nizatidine]] and [[cisapride]]. The effect is explained by these drugs inhibiting [[glucuronidation]] of paracetamol.<ref name="pmid15662293"/>

Paracetamol raises plasma concentrations of [[ethinylestradiol]] by 22% by inhibiting its sulfation.<ref name="pmid15662293"/> Paracetamol increases [[Prothrombin time|INR]] during [[warfarin]] therapy and should be limited to no more than 2 g per week.<ref name="pmid23736105">{{cite journal |vauthors=Pinson GM, Beall JW, Kyle JA |title=A review of warfarin dosing with concurrent acetaminophen therapy |journal=J Pharm Pract |volume=26 |issue=5 |pages=518–21 |date=October 2013 |pmid=23736105 |doi=10.1177/0897190013488802 |s2cid=31588052}}</ref><ref name="pmid21923443">{{cite journal |vauthors=Hughes GJ, Patel PN, Saxena N |title=Effect of acetaminophen on international normalized ratio in patients receiving warfarin therapy |journal=Pharmacotherapy |volume=31 |issue=6 |pages=591–7 |date=June 2011 |pmid=21923443 |doi=10.1592/phco.31.6.591 |s2cid=28548170}}</ref><ref name="pmid21191575">{{cite journal |vauthors=Zhang Q, Bal-dit-Sollier C, Drouet L, Simoneau G, Alvarez JC, Pruvot S, Aubourg R, Berge N, Bergmann JF, Mouly S, Mahé I |title=Interaction between acetaminophen and warfarin in adults receiving long-term oral anticoagulants: a randomized controlled trial |journal=Eur J Clin Pharmacol |volume=67 |issue=3 |pages=309–14 |date=March 2011 |pmid=21191575 |doi=10.1007/s00228-010-0975-2 |s2cid=25988269}}</ref>

==Pharmacology==
===Pharmacodynamics===

Paracetamol appears to exert its effects through two mechanisms: the inhibition of [[cyclooxygenase]] (COX) and actions of its metabolite [[N-arachidonoylphenolamine|''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 drugs (NSAIDs) that act by inhibiting [[COX-1]] and [[COX-2]] enzymes and especially similar to selective [[COX-2 inhibitor]]s.<ref name="pmid23719833">{{cite journal |vauthors=Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF |title=The modern pharmacology of paracetamol: therapeutic actions, mechanism of action, metabolism, toxicity and recent pharmacological findings |journal=Inflammopharmacology |volume=21 |issue=3 |pages=201–32 |date=June 2013 |pmid=23719833 |doi=10.1007/s10787-013-0172-x |s2cid=11359488}}</ref> Paracetamol inhibits [[prostaglandin]] synthesis by reducing the active form of COX-1 and COX-2 enzymes. This occurs only when the concentration of [[arachidonic acid]] and [[Organic peroxide#Biology|peroxides]] is low. Under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under the conditions of inflammation, the concentration of peroxides is high, which counteracts the reducing effect of paracetamol. Accordingly, the anti-inflammatory action of paracetamol is slight.<ref name=Ghanem2016/><ref name="pmid23719833"/> The anti-inflammatory action of paracetamol (via COX inhibition) has also been found to primarily target the [[central nervous system]] and not peripheral areas of the body, explaining the lack of side effects associated with conventional NSAIDs such as gastric bleeding.

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 [[endocannabinoid system]] and TRPV1 may play an important role in the analgesic effect of paracetamol.<ref name=Ghanem2016/><ref name="pmid33328986">{{cite journal |vauthors=Ohashi N, Kohno T |title=Analgesic Effect of Acetaminophen: A Review of Known and Novel Mechanisms of Action |journal=Front Pharmacol |volume=11 |issue= |pages=580289 |date=2020 |pmid=33328986 |pmc=7734311 |doi=10.3389/fphar.2020.580289 |doi-access=free |title-link = doi }}</ref>

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 paracetamol is not clear. According to Suemaru ''et al''., acetaminophen and its active metabolite [[AM404]] show a dose-dependent anticonvulsant activity against pentylenetetrazol-induced seizures in mice.<ref name="Suemaru2018" />

In 2025, Maatuf ''et al.'' reported that AM404 is also produced by peripheral sensory neurons ''in vitro'' and blocks the action of pain-sensing [[Nav1.8|Na<sub>v</sub>1.8]] and [[Nav1.7|1.7]] channels at nanomolar concentrations. AM404 injected into the hind paw of rats increase the pain threshold for the treated paw, but not the untreated paw, confirming the peripheral nature of this effect. It also lowers pain responses in a few other ''in vivo'' models when injected directly into the affected area. Other tested metabolites of paracetamol do not block pain-sensing sodium channels ''in vitro''.<ref>{{cite journal | vauthors = Maatuf Y, Kushnir Y, Nemirovski A, Ghantous M, Iskimov A, Binshtok AM, Priel A | title = The analgesic paracetamol metabolite AM404 acts peripherally to directly inhibit sodium channels | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 122 | issue = 23 | pages = e2413811122 | date = June 2025 | pmid = 40465624 | doi = 10.1073/pnas.2413811122 }}</ref><ref>{{cite web |title=Does Paracetamol Block Peripheral Pain? |url=https://conexiant.com/neurology/articles/paracetamol-metabolite-blocks-pain-at-source/ |website=Conexiant |language=en |date=11 June 2025}}</ref>

===Pharmacokinetics===
After being taken by mouth, paracetamol is rapidly absorbed from the [[small intestine]], while absorption from the stomach is negligible. Thus, the rate of absorption depends on stomach emptying. Food slows the stomach's emptying and absorption, but the total amount absorbed stays the same.<ref>{{cite journal |vauthors=Prescott LF |title=Kinetics and metabolism of paracetamol and phenacetin |journal=British Journal of Clinical Pharmacology |date=October 1980 |volume=10 |issue = Suppl 2 |pages=291S–298S |pmid=7002186 |pmc=1430174 |doi=10.1111/j.1365-2125.1980.tb01812.x}}</ref> In the same subjects, the peak plasma concentration of paracetamol was reached after 20 minutes when fasting versus 90 minutes when fed. High carbohydrate (but not high protein or high fat) food decreases paracetamol peak plasma concentration by four times. Even in the fasting state, the rate of absorption of paracetamol is variable and depends on the formulation, with maximum plasma concentration being reached after 20 minutes to 1.5 hours.<ref name="pmid7039926">{{cite journal |vauthors=Forrest JA, Clements JA, Prescott LF |title=Clinical pharmacokinetics of paracetamol |journal=Clin Pharmacokinet |volume=7 |issue=2 |pages=93–107 |date=1982 |pmid=7039926 |doi=10.2165/00003088-198207020-00001 |s2cid=20946160}}</ref>

Paracetamol's [[bioavailability]] is dose-dependent: it increases from 63% for 500{{nbsp}}mg dose to 89% for 1000{{nbsp}}mg dose.<ref name="pmid7039926"/> Its plasma terminal elimination half-life is 1.9{{ndash}}2.5 hours,<ref name="pmid7039926"/> and [[volume of distribution]] is roughly 50{{nbsp}}L.<ref name=Graham_2013>{{cite journal| vauthors=Graham GG, Davies MJ, Day RO, Mohamudally A, Scott KF |title=The modern pharmacology of paracetamol: Therapeutic actions, mechanism of action, metabolism, toxicity, and recent pharmacological findings |journal=Inflammopharmacology |date=June 2013 |volume=21 |issue=3 |pages=201–232 |doi=10.1007/s10787-013-0172-x |pmid=23719833|s2cid=11359488 }}</ref> Protein binding is negligible, except under the conditions of overdose, when it may reach 15{{ndash}}21%.<ref name="pmid7039926"/> The concentration in serum after a typical dose of paracetamol usually peaks below 30{{nbsp}}μg/mL (200{{nbsp}}μmol/L).<ref name=rosen/> After 4 hours, the concentration is usually less than 10{{nbsp}}μg/mL (66{{nbsp}}μmol/L).<ref name=rosen>{{cite book|title=Rosen's Emergency Medicine – Concepts and Clinical Practice |vauthors = Marx J, Walls R, Hockberger R |publisher=Elsevier Health Sciences|year=2013|isbn=9781455749874}}</ref>

[[Image:Metabolism of paracetamol.png|class=skin-invert-image|thumb|right|upright=2|Important pathways of paracetamol metabolism]]

Paracetamol is [[drug metabolism|metabolized]] primarily in the liver, mainly by [[glucuronidation]] and [[sulfation]], and the products are then eliminated in the urine (see the Scheme on the right). Only 2{{ndash}}5% of the drug is excreted unchanged in the urine.<ref name="pmid7039926"/> Glucuronidation by [[UGT1A1]] and [[UGT1A6]] accounts for 50{{ndash}}70% of the drug metabolism. Additional 25{{ndash}}35% of paracetamol is converted to sulfate by sulfation enzymes [[SULT1A1]], [[SULT1A3]], and [[SULT1E1]].<ref name="pmid23462933">{{cite journal |vauthors=McGill MR, Jaeschke H |title=Metabolism and disposition of acetaminophen: recent advances in relation to hepatotoxicity and diagnosis |journal=Pharm Res |volume=30 |issue=9 |pages=2174–87 |date=September 2013 |pmid=23462933 |pmc=3709007 |doi=10.1007/s11095-013-1007-6}}</ref>

A minor metabolic pathway (5–15%) of oxidation by [[cytochrome P450]] enzymes, mainly by [[CYP2E1]], forms a toxic metabolite known as [[NAPQI]] (''N''-acetyl-''p''-benzoquinone imine).<ref name="pmid23462933"/> NAPQI is responsible for the liver toxicity of paracetamol. At usual doses of paracetamol, NAPQI is quickly detoxified by conjugation with [[glutathione]]. The non-toxic conjugate APAP-GSH is taken up in the bile and further degraded to mercapturic and cysteine conjugates that are excreted in the urine. In overdose, glutathione is depleted by a large amount of formed NAPQI, and NAPQI binds to [[mitochondria]] proteins of the liver cells causing [[oxidative stress]] and toxicity.<ref name="pmid23462933"/>

Yet another minor but important direction of metabolism is deacetylation of 1{{ndash}}2% of paracetamol to form [[p-Aminophenol|''p''-aminophenol]]. ''p''-Aminophenol is then converted in the brain by [[fatty acid amide hydrolase]] into [[AM404]], a compound that may be partially responsible for the analgesic action of paracetamol.<ref name=Graham_2013/>

==Chemistry==

===Synthesis===

====Classical methods====
The classical methods for the production of paracetamol involve the [[acetylation]] of [[4-aminophenol]] with [[acetic anhydride]] as the last step. They differ in how 4-aminophenol is prepared. In one method, [[nitration]] of [[phenol]] with [[nitric acid]] affords [[4-nitrophenol]], which is reduced to 4-aminophenol by [[hydrogenation]] over [[Raney nickel]]. In another method, [[nitrobenzene]] is reduced [[electrolysis|electrolytically]] giving 4-aminophenol directly. Additionally, 4-nitrophenol can be selectively reduced by [[Tin(II) chloride|Tin(II) Chloride]] in [[absolute ethanol]] or [[ethyl acetate]] to produce a 91% yield of 4-aminophenol.<ref name = Ullmann/><ref>{{cite web |url=https://patents.google.com/patent/US2998450A/en |title=US Patent 2998450 |date= |website= |publisher= |access-date= |quote= |archive-date=14 April 2021 |archive-url=https://web.archive.org/web/20210414033102/https://patents.google.com/patent/US2998450A/en |url-status=live }}</ref><ref>{{cite journal |vauthors = Bellamy FD, Ou K |date= January 1984 |title=Selective reduction of aromatic nitro compounds with stannous chloride in non acidic and non aqueous medium |journal=Tetrahedron Letters |volume=25 |issue=8 |pages=839–842 |doi=10.1016/S0040-4039(01)80041-1 |doi-access =  |title-link = doi }}</ref>
[[Image: Classic syntheses of paracetamol.png|class=skin-invert-image|thumb|center|upright=2|Classical methods for the production of paracetamol]]

====Celanese synthesis====
An alternative industrial synthesis developed at [[Celanese]] involves firstly direct acylation of phenol with acetic anhydride in the presence of [[hydrogen fluoride]] to a ketone, then the conversion of the ketone with [[hydroxylamine]] to a [[ketoxime]], and finally the acid-catalyzed [[Beckmann rearrangement]] of the cetoxime to the para-acetylaminophenol product.<ref name = Ullmann>{{Ullmann |title = Analgesics and Antipyretics |vauthors = Friderichs E, Christoph T, Buschmann H |doi = 10.1002/14356007.a02_269.pub2 |date=15 July 2007 |isbn=3-527-30673-0}}</ref><ref>{{cite patent |country = US |number = 4524217 |status = patent |title = Process for producing N-acyl-hydroxy aromatic amines |pubdate = 18 June 1985 |inventor = Davenport KG, Hilton CB |assign1 = Celanese Corporation}}</ref>

[[File: Celanese method for the preparation of paracetamol.png|class=skin-invert-image|thumb|center|upright=2|Celanese method for the preparation of paracetamol]]

===Reactions===

[[File:Парацетамол 9.jpg|thumb|right|Paracetamol crystals (crystallized from an aqueous solution) under a microscope]]
''4''-Aminophenol may be obtained by the amide [[hydrolysis]] of paracetamol. This reaction is also used to determine paracetamol in urine samples: After hydrolysis with hydrochloric acid, ''4''-aminophenol reacts in ammonia solution with a phenol derivate, e.g. salicylic acid, to form an [[indophenol]] dye under oxidization by air.<ref>{{cite journal| vauthors = Novotny PE, Elser RC| title = Indophenol method for acetaminophen in serum examined| journal = [[Clin. Chem.]]| volume = 30| issue = 6| pages = 884–6| year = 1984| doi = 10.1093/clinchem/30.6.884| pmid = 6723045| doi-access = free |title-link = doi }}</ref>

==History==
[[Image:Axelrod.jpg|thumb|[[Julius Axelrod]] ''(pictured)'' and [[Bernard Brodie (biochemist)|Bernard Brodie]] demonstrated that acetanilide and phenacetin are both metabolized to paracetamol, which is a better-tolerated analgesic.]]

[[Acetanilide]] was the first [[aniline]] derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of [[Antifebrin]] by Cahn & Hepp in 1886.<ref>{{cite journal |vauthors=Cahn A, Hepp P |title=Das Antifebrin, ein neues Fiebermittel |trans-title=Antifebrin, a new antipyretic |journal=Centralblatt für klinische Medizin |year=1886 |volume=7 |pages=561–4 |url=https://babel.hathitrust.org/cgi/pt?num=561&u=1&seq=5&view=image&size=100&id=mdp.39015009239362 |language=de |access-date=21 February 2019 |archive-date=1 September 2020 |archive-url= https://web.archive.org/web/20200901204651/https://babel.hathitrust.org/cgi/pt?num=561&u=1&seq=5&view=image&size=100&id=mdp.39015009239362 |url-status=live }}</ref> But its unacceptable toxic effects{{emdash}}the most alarming being [[cyanosis]] due to [[methemoglobinemia]], an increase of hemoglobin in its ferric [Fe<sup>3+</sup>] state, called [[methemoglobin]], which cannot bind oxygen, and thus decreases overall carriage of oxygen to tissue{{emdash}}prompted the search for less toxic aniline derivatives.<ref name=Bertolini2006rev>{{cite journal |vauthors=Bertolini A, Ferrari A, Ottani A, Guerzoni S, Tacchi R, Leone S |title=Paracetamol: New vistas of an old drug |journal= CNS Drug Reviews |volume=12 |issue=3–4 |pages=250–75 |year=2006 |pmid=17227290 |doi =10.1111/j.1527-3458.2006.00250.x|pmc=6506194 }}</ref> Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852.<ref name="ourarchive.otago.ac.nz"/><ref name="Roy_2011"/>

[[Harmon Northrop Morse]] synthesized paracetamol at [[Johns Hopkins University]] via the reduction of [[4-Nitrophenol|''p''-nitrophenol]] with [[tin]] in glacial [[acetic acid]] in 1877,<ref>{{cite journal |title=Ueber eine neue Darstellungsmethode der Acetylamidophenole |trans-title=On a new method of preparing acetylamidophenol |pages=232–233 |vauthors=Morse HN |year=1878 |doi=10.1002/cber.18780110151 |journal=[[Berichte der deutschen chemischen Gesellschaft]] |volume=11 |issue=1 |url=https://zenodo.org/record/1425148 |archive-url=https://web.archive.org/web/20230928132132/https://zenodo.org/record/1425148/files/article.pdf |url-status=live |archive-date=28 September 2023 |language=de |access-date=28 December 2023 }}</ref><ref name=badmed/> but it was not until 1887 that clinical pharmacologist [[Joseph von Mering]] tried paracetamol on humans.<ref name=Bertolini2006rev/> In 1893, von Mering published a paper reporting on the clinical results of paracetamol with [[phenacetin]], another aniline derivative.<ref>{{cite journal |vauthors = von Mering J |year=1893 |title=Beitrage zur Kenntniss der Antipyretica |journal=Ther Monatsch |volume=7 |pages=577–587 }}</ref> 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.<ref name=drugdiscov>{{cite book |title=Drug Discovery: A History |vauthors = Sneader W |publisher=Wiley |year=2005 |isbn=978-0471899808 |page=439 |location=Hoboken, NJ |url=https://books.google.com/books?id=jglFsz5EJR8C&pg=PA439 |url-status=live |archive-url=https://web.archive.org/web/20160818021904/https://books.google.com/books?id=jglFsz5EJR8C&pg=PA439 |archive-date=18 August 2016 }}</ref>

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| doi=10.1016/S0022-3565(25)05394-7 |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|url-access = subscription}}</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|doi=10.1016/S0022-3565(25)03461-5 |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 | doi = 10.1016/S0022-3565(25)03462-7 | 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| doi=10.1016/S0022-3565(25)03471-8 |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 | doi = 10.1016/S0022-3565(25)03631-6 | pmid = 18140117 | url = https://jpet.aspetjournals.org/content/97/1/58 | url-access = subscription }}</ref> This led to a "rediscovery" of paracetamol.<ref name=Bertolini2006rev/>

Paracetamol was first marketed in the United States in 1950 under the name Trigesic, a combination of paracetamol, aspirin, and caffeine.<ref name=badmed/> 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.<ref name=badmed/> The following year, 1952, paracetamol returned to the U.S. market as a prescription drug.<ref name="pmid329728"/> In the United Kingdom, marketing of paracetamol began in 1956 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.<ref name="pmid799998">{{cite journal |vauthors=Spooner JB, Harvey JG |title=The history and usage of paracetamol |journal=J Int Med Res |volume=4 |issue=4 Suppl |pages=1–6 |date=1976 |pmid=799998 |doi=10.1177/14732300760040S403 |s2cid=11289061}}</ref><ref name="LandauAchilladelis1999">{{cite book| vauthors = Landau R, Achilladelis B, Scriabine A |title=Pharmaceutical Innovation: Revolutionizing Human Health|url=https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA248|year=1999|publisher=Chemical Heritage Foundation|isbn=978-0-941901-21-5|pages=248–249|url-status=live|archive-url= https://web.archive.org/web/20160817194009/https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA248|archive-date=17 August 2016 }}</ref> 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.<ref name="pmid799998"/><ref name=badmed>{{cite book|title=Bad Medicine: The Prescription Drug Industry in the Third World |vauthors = Silverman M, Lydecker M, Lee PR |publisher= Stanford University Press |year=1992 |isbn=978-0804716697 |pages=[https://archive.org/details/badmedicinepresc0000silv/page/88 88]–90 |url= https://archive.org/details/badmedicinepresc0000silv |url-access=registration}}</ref>

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 U.S. without a prescription since 1955<ref name="pmid329728">{{cite journal |vauthors=Ameer B, Greenblatt DJ |title=Acetaminophen |journal=Ann Intern Med |volume=87 |issue=2 |pages=202–9 |date=August 1977 |pmid=329728 |doi=10.7326/0003-4819-87-2-202}}</ref> (1960, according to another source<ref>{{cite web |url=http://www.tylenol.com/news/about-us |title=Our Story |publisher=McNEIL-PPC, Inc. |access-date=8 March 2014 |url-status=dead |archive-url=https://web.archive.org/web/20140308090216/http://www.tylenol.com/news/about-us |archive-date=8 March 2014 }}</ref>), paracetamol has become a common household drug.<ref>{{cite news |url=http://www.medicinenet.com/acetaminophen/article.htm |title=Medication and Drugs |date=1996–2010 |work=MedicineNet |access-date=22 April 2010 |url-status=live |archive-url=https://web.archive.org/web/20100422200526/http://www.medicinenet.com/acetaminophen/article.htm |archive-date=22 April 2010}}</ref> In 1988, Sterling Winthrop was acquired by [[Eastman Kodak]] which sold the over the counter drug rights to [[SmithKline Beecham]] in 1994.<ref>{{cite web| url=http://www.secinfo.com/dUGc.bs.htm |title=SEC Info – Eastman Kodak Co – '8-K' for 6/30/94 |access-date=3 March 2016|url-status=dead|archive-url= https://web.archive.org/web/20160304061947/http://www.secinfo.com/dUGc.bs.htm|archive-date=4 March 2016}}</ref>

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>

In January 2011, the FDA asked manufacturers of prescription combination products containing paracetamol to limit its amount to no more than 325{{nbsp}}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.<ref name="FDA_20110113">{{cite press release| url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm| date = 13 January 2011| title = FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings| publisher = U.S. [[Food and Drug Administration]] (FDA)| access-date = 13 January 2011| url-status=dead| archive-url = https://web.archive.org/web/20110115151630/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm| archive-date = 15 January 2011}}{{PD-notice}}</ref><ref name="FDA_CDER">{{cite web| url = https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-prescription-acetaminophen-products-be-limited-325-mg-dosage-unit |title = FDA Drug Safety Communication: Prescription Acetaminophen Products to be Limited to 325 mg Per Dosage Unit; Boxed Warning Will Highlight Potential for Severe Liver Failure| date = 13 January 2011| publisher = U.S. [[Food and Drug Administration]] (FDA)| access-date = 13 January 2011| url-status=dead| archive-url = https://web.archive.org/web/20110118040527/https://www.fda.gov/Drugs/DrugSafety/ucm239821.htm| archive-date = 18 January 2011}}{{PD-notice}}</ref><ref>{{cite news| url = https://www.boston.com/lifestyle/health/articles/2011/01/13/fda_orders_lowering_pain_reliever_in_vicodin/| title = FDA orders lowering pain reliever in Vicodin |vauthors = Perrone M |agency = Associated Press| date = 13 January 2011| work = [[The Boston Globe]]| access-date = 13 January 2011| url-status= live| archive-url = https://web.archive.org/web/20121102211431/http://www.boston.com/lifestyle/health/articles/2011/01/13/fda_orders_lowering_pain_reliever_in_vicodin/ |archive-date = 2 November 2012 }}</ref><ref name="NYT_Harris">{{cite news| url = https://www.nytimes.com/2011/01/14/health/policy/14fda.html| title = F.D.A. Plans New Limits on Prescription Painkillers |vauthors = Harris G |work = [[The New York Times]]| date = 13 January 2011| access-date = 13 January 2011| url-status=live| archive-url = https://web.archive.org/web/20120609101901/http://www.nytimes.com/2011/01/14/health/policy/14fda.html| archive-date = 9 June 2012 }}</ref><ref>{{cite press release |title=FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings |website=U.S. [[Food and Drug Administration]] (FDA) |date=15 January 2011 |url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm |archive-url= https://web.archive.org/web/20110115151630/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm |archive-date=15 January 2011 |url-status=dead |access-date=23 February 2014}}{{PD-notice}}</ref> Manufacturers had three years to limit the amount of paracetamol in their prescription drug products to 325{{nbsp}}mg per dosage unit.<ref name="FDA_CDER" /><ref name="NYT_Harris" />

In November 2011, the [[Medicines and Healthcare products Regulatory Agency]] revised UK dosing of liquid paracetamol for children.<ref>{{cite web |date=14 November 2011 |url=http://www.mhra.gov.uk/home/groups/s-par/documents/websiteresources/con134921.pdf |archive-url= https://web.archive.org/web/20191028074131/http://www.mhra.gov.uk/home/groups/s-par/documents/websiteresources/con134921.pdf |url-status=dead |archive-date=28 October 2019 |title=Liquid paracetamol for children: revised UK dosing instructions introduced |publisher=[[Medicines and Healthcare products Regulatory Agency]] (MHRA) |access-date=27 October 2019}}</ref>

In September 2013, "Use Only as Directed", an episode of the radio program ''[[This American Life]]''<ref>{{cite episode |title=Use Only as Directed |url= http://www.thisamericanlife.org/radio-archives/episode/505/use-only-as-directed |access-date=24 September 2013 |series=This American Life |series-link=This American Life |network=[[Public Radio International]] |station=[[WBEZ]] |location=Chicago |date=20 September 2013 |number=505 |url-status=live |archive-url= https://web.archive.org/web/20130927121525/http://www.thisamericanlife.org/radio-archives/episode/505/use-only-as-directed |archive-date=27 September 2013 }}</ref> 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"<ref>{{cite web |vauthors = Gerth J, Miller TC |title=Use Only as Directed |url=https://www.propublica.org/article/tylenol-mcneil-fda-use-only-as-directed |publisher=[[ProPublica]] |date=20 September 2013 |access-date=24 September 2013 |url-status=live |archive-url=https://web.archive.org/web/20130924034013/http://www.propublica.org/article/tylenol-mcneil-fda-use-only-as-directed |archive-date=24 September 2013 }}</ref> and "McNeil, the maker of Tylenol, ... has repeatedly opposed safety warnings, dosage restrictions and other measures meant to safeguard users of the drug."<ref>{{cite web| vauthors = Miller TC, Gerth J |title=Dose of Confusion |url=https://www.propublica.org/article/tylenol-mcneil-fda-kids-dose-of-confusion |publisher=[[ProPublica]] |date=20 September 2013 |access-date=24 September 2013 |url-status=live |archive-url= https://web.archive.org/web/20130924033315/http://www.propublica.org/article/tylenol-mcneil-fda-kids-dose-of-confusion |archive-date=24 September 2013 }}</ref>

==Society and culture==
[[File:Read the Label! There are Risks from Taking Too Much Acetaminophen (5323869745).jpg|thumb|Awareness poster on acetaminophen abuse as issued by the FDA]]
===Naming===
''Paracetamol'' is the [[Australian Approved Name]]<ref>{{cite book |title=TGA Approved Terminology for Medicines |section=Section 1 – Chemical Substances |date=July 1999 |publisher=Therapeutic Goods Administration, Department of Health and Ageing, Australian Government |page= 97 |url=http://www.tga.gov.au/pdf/medicines-approved-terminology-chemical.pdf |archive-url= https://web.archive.org/web/20140211201639/http://www.tga.gov.au/pdf/medicines-approved-terminology-chemical.pdf |archive-date=11 February 2014}}</ref> and [[British Approved Name]]<ref name="MacintyreRowbotham2008"/> as well as the [[international nonproprietary name]] used by the WHO and in many other countries; ''acetaminophen'' is the [[United States Adopted Name]]<ref name="MacintyreRowbotham2008"/> and [[Japanese Accepted Name]] and also the name generally used in Canada,<ref name="MacintyreRowbotham2008"/> Venezuela, Colombia, and Iran.<ref name= "MacintyreRowbotham2008">{{cite book |vauthors = Macintyre P, Rowbotham D, Walker S |title=Clinical Pain Management Second Edition: Acute Pain |url= https://books.google.com/books?id=CLcsngfC9gQC&pg=PA85 |date=26 September 2008 |publisher=CRC Press |isbn=978-0-340-94009-9 |page=85 |url-status=live |archive-url= https://web.archive.org/web/20160817202730/https://books.google.com/books?id=CLcsngfC9gQC&pg=PA85 |archive-date=17 August 2016 }}</ref><ref name=INN>{{cite journal |title=International Non-Proprietary Name for Pharmaceutical Preparations (Recommended List #4) |journal=WHO Chronicle |date=March 1962 |volume=16 |issue=3 |pages=101–111 |url= https://www.who.int/medicines/publications/druginformation/innlists/RL04.pdf |access-date=21 March 2018 |archive-date=18 May 2016 |archive-url= https://web.archive.org/web/20160518192639/http://www.who.int/medicines/publications/druginformation/innlists/RL04.pdf |url-status=live }}</ref> Both ''paracetamol'' and ''acetaminophen'' are contractions of chemical names for the compound. The word "paracetamol" is a shortened form of para-acetylaminophenol,<ref>{{cite web |title=Definition of Paracetamol |url=https://www.merriam-webster.com/dictionary/paracetamol#:~:text=etymology,phenol |url-status=live |archive-url=https://web.archive.org/web/20230326071323/https://www.merriam-webster.com/dictionary/paracetamol#:~:text=etymology,phenol |archive-date=26 March 2023 |access-date=26 March 2023 |website=www.merriam-webster.com}}</ref> and was coined by Frederick Stearns & Co in 1956,<ref>{{cite web |title=A History of Paracetamol, Its Various Uses & How It Affects You |url=https://www.fevermates.com/blogs/news/a-history-of-paracetamol-and-its-various-uses |url-status=live |archive-url=https://web.archive.org/web/20230326071319/https://www.fevermates.com/blogs/news/a-history-of-paracetamol-and-its-various-uses |archive-date=26 March 2023 |access-date=26 March 2023 |website=FeverMates}}</ref> while the word "acetaminophen" is a shortened form of N-acetyl-p-aminophenol (APAP), which was coined and first marketed by McNeil Laboratories in 1955.<ref>{{cite web |title=Definition of Acetaminophen |url=https://www.merriam-webster.com/dictionary/acetaminophen |url-status=live |archive-url=https://web.archive.org/web/20230326071317/https://www.merriam-webster.com/dictionary/acetaminophen |archive-date=26 March 2023 |access-date=26 March 2023 |website=www.merriam-webster.com}}</ref> The initialism ''APAP'' is used by dispensing pharmacists in the United States.<ref>{{cite journal |vauthors=Gaunt MJ |date=8 October 2013 |title=APAP: An Error-Prone Abbreviation |url=https://www.pharmacytimes.com/view/apap-an-error-prone-abbreviation |url-status=live |journal=Pharmacy Times |series=October 2013 Diabetes |volume=79 |issue=10 |archive-url=https://web.archive.org/web/20210606002928/https://www.pharmacytimes.com/view/apap-an-error-prone-abbreviation |archive-date=6 June 2021 |access-date=6 June 2021}}</ref>

===Available forms===
{{See also|Paracetamol brand names}}

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 U.S., this combination is available only by prescription.<ref>{{cite web |title=Acetaminophen and Codeine (Professional Patient Advice) |website=Drugs.com |date=29 June 2019 |url=https://www.drugs.com/ppa/acetaminophen-and-codeine.html |access-date=25 February 2020 |archive-date=20 May 2020 |archive-url=https://web.archive.org/web/20200520011658/https://www.drugs.com/ppa/acetaminophen-and-codeine.html |url-status=live }}</ref> As of 1 February 2018, medications containing codeine also became prescription-only in Australia.<ref>{{cite web|title=Codeine information hub|url=https://www.tga.gov.au/codeine-info-hub|url-status=live|access-date=9 December 2021|website=Therapeutic Goods Administration, Australian Government|date=10 April 2018|archive-date=8 December 2021|archive-url=https://web.archive.org/web/20211208232855/https://www.tga.gov.au/codeine-info-hub}}</ref> Paracetamol is also combined with other opioids such as [[dihydrocodeine]],<ref>{{cite web |title=Acetaminophen, Caffeine, and Dihydrocodeine (Professional Patient Advice) |website=Drugs.com |date=2 October 2019 |url=https://www.drugs.com/ppa/acetaminophen-caffeine-and-dihydrocodeine.html |access-date=25 February 2020 |archive-date=19 May 2020 |archive-url=https://web.archive.org/web/20200519154515/https://www.drugs.com/ppa/acetaminophen-caffeine-and-dihydrocodeine.html |url-status=live }}</ref> referred to as [[co-dydramol]] ([[British Approved Name]] (BAN)), [[oxycodone]]<ref>{{cite web |title=Oxycodone and Acetaminophen (Professional Patient Advice) |website=Drugs.com |date=11 November 2019 |url=https://www.drugs.com/ppa/oxycodone-and-acetaminophen.html |access-date=25 February 2020 |archive-date=20 May 2020 |archive-url= https://web.archive.org/web/20200520113856/https://www.drugs.com/ppa/oxycodone-and-acetaminophen.html |url-status=live }}</ref> or [[hydrocodone]].<ref>{{cite web |title= Hydrocodone and Acetaminophen (Professional Patient Advice) |website=Drugs.com |date=2 January 2020 |url=https://www.drugs.com/ppa/hydrocodone-and-acetaminophen.html |access-date=25 February 2020 |archive-date=21 May 2020 |archive-url=https://web.archive.org/web/20200521011245/https://www.drugs.com/ppa/hydrocodone-and-acetaminophen.html |url-status=live }}</ref> Another very commonly used analgesic combination includes paracetamol in combination with [[propoxyphene napsylate]].<ref>{{cite web |title=Propoxyphene and Acetaminophen Tablets |website=Drugs.com |date=21 June 2019 |url=https://www.drugs.com/pro/propoxyphene-and-acetaminophen-tablets.html |access-date=25 February 2020 |archive-date=20 May 2020 |archive-url=https://web.archive.org/web/20200520023253/https://www.drugs.com/pro/propoxyphene-and-acetaminophen-tablets.html |url-status=live }}</ref> A combination of paracetamol, codeine, and the [[doxylamine|doxylamine succinate]] is also available.<ref>{{cite web |title=APOHealth Paracetamol Plus Codeine & Calmative |website=Drugs.com |date=3 February 2020 |url=https://www.drugs.com/international/apohealth-paracetamol-plus-codeine-calmative.html |access-date=25 February 2020 |archive-date=25 February 2020 |archive-url= https://web.archive.org/web/20200225175247/https://www.drugs.com/international/apohealth-paracetamol-plus-codeine-calmative.html |url-status=live }}</ref>

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.

{{Gallery
| align = center
| width = 220
| File:Tylenol rapid release pills.jpg|[[Tylenol (brand)|Tylenol]] 500 mg capsules
| File:Panadol.jpg|Panadol 500 mg tablets
| File:Paracetamol substance photo.jpg|For comparison: The pure drug is a colourless crystalline powder.
}}

== Research ==
Claims that paracetamol is an effective analgesic medication to treat symptoms of [[COVID-19]] were found to be unsubstantiated.<ref>{{cite journal |vauthors=Orso D, Federici N, Copetti R, Vetrugno L, Bove T |title=Infodemic and the spread of fake news in the COVID-19-era |journal=European Journal of Emergency Medicine |volume=27 |issue=5 |pages=327–328 |date=October 2020 |doi=10.1097/MEJ.0000000000000713 |pmid=32332201 |pmc=7202120}}</ref><ref>{{cite journal |vauthors=Torjesen I |title=Covid-19: ibuprofen can be used for symptoms, says UK agency, but reasons for change in advice are unclear |journal=BMJ |volume=369 |pages=m1555 |date=April 2020 |pmid=32303505 |doi=10.1136/bmj.m1555 |doi-access=free |title-link=doi}}</ref><ref>{{cite journal |vauthors=Rinott E, Kozer E, Shapira Y, Bar-Haim A, Youngster I |title=Ibuprofen use and clinical outcomes in COVID-19 patients |journal=Clinical Microbiology and Infection |volume=26 |issue=9 |pages=1259.e5–1259.e7 |date=September 2020 |doi=10.1016/j.cmi.2020.06.003 |pmid=32535147 |pmc=7289730}}</ref><ref>{{cite journal |vauthors=Day M |title=Covid-19: ibuprofen should not be used for managing symptoms, say doctors and scientists |journal=BMJ |volume=368 |pages=m1086 |date=March 2020 |pmid=32184201 |doi=10.1136/bmj.m1086 |doi-access=free |title-link=doi}}</ref>

==Veterinary use==
[[File:Brown tree snake aerial bait cartridges.jpg|thumb|[[Brown tree snake]] aerial bait cartridges consisting of dead mice with 80{{nbsp}}mg paracetamol tablets]]

===Cats===
Paracetamol is extremely toxic to cats, which lack the necessary [[UGT1A6]] enzyme to detoxify it. Initial symptoms include vomiting, salivation, and discoloration of the tongue and gums. Unlike an overdose in humans, liver damage is rarely the cause of death; instead, [[methemoglobin]] formation and the production of [[Heinz bodies]] in red blood cells inhibit oxygen transport by the blood, causing [[asphyxiation]] ([[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 [[acetylcysteine]] is recommended.<ref name="Richardson_2000" />

===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> Acetylcysteine treatment is efficacious in dogs when administered within two hours of paracetamol ingestion.<ref name="Richardson_2000"/><ref name=smallani/>

===Snakes===
Paracetamol is lethal to snakes<ref>{{cite journal |vauthors=van den Hurk P, Kerkkamp HM |title=Phylogenetic origins for severe acetaminophen toxicity in snake species compared to other vertebrate taxa |year=2019 |journal=Comp Biochem Physiol C  |volume=215 |pages=18–24 |pmid=30268769 |doi=10.1016/j.cbpc.2018.09.003|s2cid=52890371 |url=https://tigerprints.clemson.edu/cgi/viewcontent.cgi?article=1115&context=bio_pubs |url-access=subscription }}</ref> and has been suggested as a chemical control program for the invasive [[brown tree snake]] (''Boiga irregularis'') in [[Guam]].<ref>{{cite journal |vauthors=Johnston J, Savarie P, Primus T, Eisemann J, Hurley J, Kohler D |title=Risk assessment of an acetaminophen baiting program for chemical control of brown tree snakes on Guam: evaluation of baits, snake residues, and potential primary and secondary hazards |year=2002 |journal=Environ Sci Technol |volume=36 |issue=17 |pages=3827–3833 |pmid=12322757 |doi=10.1021/es015873n |bibcode=2002EnST...36.3827J}}</ref><ref>{{cite news |url=http://news.blogs.cnn.com/2010/09/07/tylenol-loaded-mice-dropped-from-air-to-control-snakes/|title=Tylenol-loaded mice dropped from air to control snakes |vauthors = Lendon B |work=CNN|date=7 September 2010|access-date=7 September 2010| url-status=dead |archive-url=https://web.archive.org/web/20100909031539/http://news.blogs.cnn.com/2010/09/07/tylenol-loaded-mice-dropped-from-air-to-control-snakes/|archive-date=9 September 2010 }}</ref> Doses of 80{{nbsp}}mg are inserted into dead mice that are scattered by helicopter<ref>{{cite magazine |url=https://www.the-scientist.com/notebook/its-raining-mice-41065 |title=It's Raining Mice |vauthors=Richards S |date=1 May 2012 |magazine=The Scientist |url-status=live |archive-url=https://web.archive.org/web/20120515060208/http://the-scientist.com/2012/05/01/its-raining-mice/ |archive-date=15 May 2012}}</ref> as lethal bait to be consumed by the snakes.

==Notes==
{{notelist}}{{clear}}

==References==
{{Reflist}}

==External links==
{{Commons category|Paracetamol}}

{{Analgesics}}
{{Cannabinoid receptor modulators}}
{{Prostanoid signaling modulators}}
{{Transient receptor potential channel modulators}}
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[[Category:Dermatoxins]]
[[Category:Drugs with unknown mechanisms of action]]
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[[Category:Haleon]]
[[Category:Hepatotoxins]]
[[Category:Drugs developed by Novartis]]
[[Category:Pesticides]]
[[Category:4-Hydroxyphenyl compounds]]
[[Category:World Health Organization essential medicines]]
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