{{Short description|Medication for pain and fever}} {{Redirect|Paracetam|the drug used in vertigo and some dementias|Piracetam}} {{More medical citations needed|reason=Excess of primary studies, some (few) justified, most inappropriate|date=September 2025}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Use dmy dates|date=November 2025}} {{Infobox drug | image = Paracetamol-skeletal.svg | image_class = skin-invert-image | width = 210 | alt = | caption = | imageL = Paracetamol-from-xtal-3D-balls.png | image_classL = bg-transparent | imageR = Paracetamol-from-xtal-3D-vdW.png | image_classR = bg-transparent | 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, Panadol, 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 | date = 14 June 2019 | website = Drugs.com | 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 = By mouth, intravenous, 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 = / Rx-only<ref>{{cite web | title = Regulatory Decision Summary – Acetaminophen Injection | date = 23 October 2014 | url = https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?lang=en&linkID=RDS00565 | website = Health Canada | 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 = / Rx-only<ref>{{cite web | title = Tylenol Regular Strength- acetaminophen tablet, film coated | date = 6 August 2025 | website = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=398d8996-b522-a3cd-e063-6394a90ac2c8 | access-date = 28 September 2025 }}</ref><ref>{{cite web | title = Acetaminophen injection | date = 18 August 2025 | website = DailyMed | url = https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=88c29438-3648-4b09-bd43-70ad7a35bcb5 | access-date = 28 September 2025 }}</ref> | legal_UN = <!-- N I, II, III, IV / P I, II, III, IV--> | legal_UN_comment = | legal_status = CN: OTC
<!-- Pharmacokinetic data -->| bioavailability = 63–89%<ref>{{cite book | vauthors = ((Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine)) | veditors = Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J | title = Acute Pain Management: Scientific Evidence | location = Melbourne | year = 2015 | isbn = 978-0-9873236-7-5 | edition = 4th | publisher = Australian and New Zealand College of Anaesthetists (ANZCA), Faculty of Pain Medicine (FPM) | 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="Forrest_1982" /> | metabolism = Predominantly in the liver<ref name="TGA">{{cite web | title = Codapane Forte Paracetamol and codeine phosphate product information | date = 29 April 2013 | work = TGA eBusiness Services | publisher = Alphapharm Pty Limited | 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 gluc, APAP sulfate, APAP 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: 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="Forrest_1982" /> | duration_of_action = | excretion = Kidney<ref name="Forrest_1982" />
<!-- Identifiers -->| CAS_number = 103-90-2 | CAS_supplemental = | PubChem = 1983 | IUPHAR_ligand = 5239 | DrugBank = DB00316 | ChemSpiderID = 1906 | UNII = 362O9ITL9D | KEGG = D00217 | ChEBI = 46195 | 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 = 1S/C8H9NO2/c1-6(10)9-7-2-4-8(11)5-3-7/h2-5,11H,1H3,(H,9,10) | StdInChI_comment = | StdInChIKey = RZVAJINKPMORJF-UHFFFAOYSA-N | density = 1.293 | density_notes = | melting_point = 169 | melting_high = | melting_notes = <ref>{{cite journal | vauthors = Karthikeyan M, Glen RC, Bender A | title = General Melting Point Prediction Based on a Diverse Compound Data Set and Artificial Neural Networks | journal = Journal of Chemical Information and Modeling | volume = 45 | issue = 3 | pages = 581–590 | year = 2005 | pmid = 15921448 | doi = 10.1021/ci0500132 | s2cid = 13017241 }}</ref><ref>{{cite web | title = melting point data for paracetamol | url = http://lxsrv7.oru.edu/~alang/meltingpoints/meltingpointof.php?csid=1906 | 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="Granberg_1999">{{cite journal | vauthors = Granberg RA, Rasmuson AC | title = Solubility of paracetamol in pure solvents | journal = Journal of Chemical & Engineering Data | volume = 44 | issue = 6 | pages = 1391–1395 | year = 1999 | doi = 10.1021/je990124v }}</ref> | 8.21{{nbsp}}g/kg (5{{nbsp}}°C)<ref name="Granberg_1999" /> | 9.44{{nbsp}}g/kg (10{{nbsp}}°C)<ref name="Granberg_1999" /> | 10.97{{nbsp}}g/kg (15{{nbsp}}°C)<ref name="Granberg_1999" /> | 12.78{{nbsp}}g/kg (20{{nbsp}}°C)<ref name="Granberg_1999" /> | ~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 an analgesic and antipyretic agent used to treat fever and mild to moderate pain.<ref name="Warwick_2008" /><ref name="Saragiotto_2019" /> It is a widely available over-the-counter drug sold generically or 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="Stephens_2016" /> The aspirin/paracetamol/caffeine combination also helps with both conditions when the pain is mild and is recommended as a first-line treatment for them.<ref name="Mayans_2018" /> At a standard dose, paracetamol slightly reduces fever,<ref name="Warwick_2008" /><ref name="Chiumello_2017" /><ref name="de_Martino_2015" /> though it is inferior to ibuprofen in that respect<ref name="Pierce_2010" /> and the benefits of its use for fever are unclear, particularly in the context of fever of viral origins.<ref name="Ludwig_2019" /> Paracetamol is effective for pain after wisdom tooth extraction, but it is less effective than ibuprofen.<ref name="Bailey_2013" /> The combination of paracetamol and ibuprofen provides greater analgesic efficacy than either drug alone.<ref name="Bailey_2013" /><ref name="Moore_2013" /> The pain relief paracetamol provides in osteoarthritis is small and clinically insignificant.<ref name="Saragiotto_2019" /><ref name="Kolasinski_2020" /> Evidence supporting its use in low back pain, cancer pain, and neuropathic pain is insufficient.<ref name="Saragiotto_2019" /><ref name="Machado_2015" /><ref name="Qaseem_2017" /><ref name="Saragiotto_2016" /><ref name="Wiffen_2017" /><ref name="Wiffen_2016" /> Paracetamol is the first-line treatment for pain and fever in pregnancy; no causal association with neurodevelopmental disorders has been established, while untreated pain and fever can harm the mother and fetus.<ref name="hc">{{cite web | title = Public advisory: Acetaminophen is a recommended treatment for fever and pain during pregnancy | date = 23 September 2025 | url = https://recalls-rappels.canada.ca/en/alert-recall/acetaminophen-recommended-treatment-fever-and-pain-during-pregnancy | publisher = Health Canada, Government of Canada | access-date = 24 September 2025 }}</ref><ref name="sogc">{{cite web | title = SOGC Position Statement on the use of Acetaminophen for Analgesia and Fever in Pregnancy | date = 12 September 2025 | publisher = Society of Obstetricians and Gynaecologists of Canada | url = https://sogc.org/common/Uploaded%20files/Position%20Statements/SOGC%20Position%20Statement%20Acetamenophin_EN_20250911.pdf | access-date = 24 September 2025 }}</ref><ref name="WHO_2025">{{cite press release | title = WHO statement on autism-related issues | url = https://www.who.int/news/item/24-09-2025-who-statement-on-autism-related-issues | access-date = 25 September 2025 | publisher = World Health Organization (WHO) }}</ref>
In support of existing recommendations for its safe use during pregnancy, a 2026 review found that there were no clinically significant increases in the occurrence of autism, attention deficit hyperactivity disorder, or intellectual disability in the children of pregnant women who used paracetamol as directed.<ref>{{Cite journal | vauthors = D'Antonio F, Flacco ME, Valle LD, Prasad S, Manzoli L, Samara A, Khalil A | title = Prenatal paracetamol exposure and child neurodevelopment: a systematic review and meta-analysis | journal = The Lancet: Obstetrics, Gynaecology, & Women's Health | date = 2026-01-16 | doi = 10.1016/S3050-5038(25)00211-0 | url = https://linkinghub.elsevier.com/retrieve/pii/S3050503825002110 | language = en | doi-access = free }}</ref>
<!-- Side effects and mechanism--> When used as directed, at a recommended maximum daily dose for an adult of three to four grams,<ref name="Machado_2015" /><ref name="UK2017">{{cite web | title = Paracetamol for adults: painkiller to treat aches, pains and fever | url = https://www.nhs.uk/medicines/paracetamol-for-adults/ | 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> paracetamol is safe and effective in the short term,<ref>{{cite web | title = Acetaminophen | date = 11 October 2012 | 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> with uncommon adverse effects similar to those of 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> It is often used in patients who cannot tolerate nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen,<ref name="Moore_2016">{{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="Conaghan_2019" /> than which paracetamol is typically safer in 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> However, chronic consumption of paracetamol may result in a drop in hemoglobin level, indicating possible gastrointestinal bleeding,<ref name="Roberts_2016" /> and abnormal liver function tests, and 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="Daly_2008">{{cite journal | vauthors = Daly FF, Fountain JS, Murray L, Graudins A, Buckley NA | 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 | date = March 2008 | pmid = 18312195 | doi = 10.5694/j.1326-5377.2008.tb01625.x | s2cid = 9505802 }}</ref><ref name="Hawkins_2007">{{cite journal | vauthors = Hawkins LC, Edwards JN, Dargan PI | 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 = 465–479 | year = 2007 | pmid = 17536874 | doi = 10.2165/00002018-200730060-00002 | s2cid = 36435353 }}</ref><ref name="Larson_2005">{{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)) | title = Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study | journal = Hepatology | volume = 42 | issue = 6 | pages = 1364–1372 | date = Dec 2005 | pmid = 16317692 | doi = 10.1002/hep.20948 | s2cid = 24758491 | 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 | location = Philadelphia, Pennsylvania | pages = 39 | date = 2005 | publisher = F.A. Davis | isbn = 978-0-8036-2027-8 | 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="Eyers_2012">{{cite thesis | vauthors = Eyers SJ | title = The effect of regular paracetamol on bronchial responsiveness and asthma control in mild to moderate asthma | date = April 2012 | 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 | title = An introduction to pharmaceutical sciences: production, chemistry, techniques and technology | location = Oxford | pages = 270 | date = 2011 | chapter-url = https://books.google.com/books?id=0IdmAgAAQBAJ&pg=PA270 | publisher = Biohealthcare | 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 | pages = 814 | date = 22 October 2010 | url = https://books.google.com/books?id=HnbKaRQAXOIC&pg=PA814 | publisher = Jones & Bartlett Publishers | isbn = 978-1-4496-1846-9 | 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 World Health Organization's List of Essential Medicines.<ref name="World_Health_Organization_2025">{{cite book | vauthors = ((World Health Organization)) | title = The selection and use of essential medicines, 2025: WHO Model List of Essential Medicines, 24th list | location = Geneva | year = 2025 | doi = 10.2471/B09474 | hdl = 10665/382243 | author-link = World Health Organization | publisher = World Health Organization | hdl-access = free | doi-access = free | id = License: CC BY-NC-SA 3.0 IGO }}</ref> Paracetamol is available as a generic medication, with brand names including Tylenol and Panadol, among others.<ref>{{cite book | vauthors = Hamilton RJ | title = Tarascon pocket pharmacopeia: 2013 classic shirt-pocket edition | location = Burlington, Massachusetts | pages = 12 | date = 2013 | publisher = Jones & Bartlett Learning | isbn = 978-1-4496-6586-9 | 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 2023, it was the 112th most commonly prescribed medication in the United States, with more than 5{{nbsp}}million prescriptions.<ref name="Top300Drugs">{{cite web | title = Top 300 of 2023 | url = https://clincalc.com/DrugStats/Top300Drugs.aspx | website = ClinCalc | access-date = 12 August 2025 | archive-date = 12 August 2025 | archive-url = https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status = live }}</ref><ref>{{cite web | title = Acetaminophen Drug Usage Statistics, United States, 2014 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Acetaminophen | access-date = 18 August 2025 }}</ref> {{TOC limit}}
==Medical uses==
===Fever=== Paracetamol is used for reducing fever.<ref name="Prescott_2000">{{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> However, there has been a lack of research on its antipyretic properties, particularly in adults, and thus its benefits are unclear.<ref name="Warwick_2008" /> As a result, it has been described as over-prescribed for this application.<ref name="Warwick_2008">{{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 | doi = 10.1177/1466424008092794 | s2cid = 25702228 }}</ref> In addition, low-quality clinical data indicates that when used for the common cold, paracetamol may relieve a stuffed or runny nose, but not other cold symptoms such as sore throat, malaise, sneezing, or cough.<ref name="Li_2013">{{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 | date = July 2013 | pmid = 23818046 | pmc = 7389565 | doi = 10.1002/14651858.CD008800.pub2 | article-number = CD008800 }}</ref>
For people in critical care, paracetamol decreases body temperature by only 0.2{{ndash}}0.3{{nbsp}}°C more than control interventions and does not affect their mortality.<ref name="Chiumello_2017">{{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 | 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="de_Ridder_2017">{{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="Chiumello_2017" /> 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="Deen_2019">{{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="Ludwig_2019">{{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 | volume = 2002 | issue = 2 | year = 2002 | pmid = 12076499 | pmc = 6532671 | doi = 10.1002/14651858.CD003676 | article-number = CD003676 }}</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 | title = Fever in under 5s: assessment and initial management | date = 7 November 2019 | publisher = NICE | url = https://www.nice.org.uk/guidance/ng143/chapter/Recommendations | access-date = 28 September 2025 }}</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 | 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="Warwick_2008" /> Based on this, some physicians advocate using higher doses that may decrease the temperature by as much as 0.7{{nbsp}}°C.<ref name="de_Martino_2015">{{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 = 149–168 | 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="Narayan_2017">{{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="Tan_2020">{{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 | date = October 2020 | pmid = 33125495 | pmc = 7599455 | doi = 10.1001/jamanetworkopen.2020.22398 | article-number = e2022398 }}</ref> with equivalent safety.<ref name="Pierce_2010">{{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="Sherbash_2020">{{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 | date = March 2020 | pmid = 32293369 | pmc = 7087361 | doi = 10.1186/s12890-020-1102-5 | article-number = 72 | doi-access = free }}</ref>
===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="Bertolini_2006">{{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 = 250–275 | 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="Saragiotto_2019">{{cite journal | vauthors = Saragiotto BT, Abdel Shaheed C, Maher CG | title = Paracetamol for pain in adults | journal = BMJ | volume = 367 | date = December 2019 | pmid = 31892511 | doi = 10.1136/bmj.l6693 | article-number = l6693 | s2cid = 209524643 }}</ref>
====Musculoskeletal pain==== The benefits of paracetamol in musculoskeletal conditions, such as osteoarthritis and backache, are uncertain.<ref name="Saragiotto_2019" />
It appears to provide only small and not clinically important benefits in osteoarthritis.<ref name="Saragiotto_2019" /><ref name="Machado_2015">{{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 | volume = 350 | date = March 2015 | pmid = 25828856 | pmc = 4381278 | doi = 10.1136/bmj.h1225 | article-number = h1225 }}</ref> American College of Rheumatology and Arthritis Foundation guideline for the management of osteoarthritis notes that the effect size in clinical trials of paracetamol has been very small, which suggests that for most individuals it is ineffective.<ref name="Kolasinski_2020">{{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 | pmc = 11488261 | doi = 10.1002/acr.24131 | 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="Kolasinski_2020" /> Essentially the same recommendation was issued by European League Against Rheumatism (EULAR) for hand osteoarthritis.<ref name="Kloppenburg_2019">{{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="Bruyere_2019">{{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="Saragiotto_2019" /><ref name="Qaseem_2017">{{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 back pain, and the evidence in favor of paracetamol is lacking.<ref name="Saragiotto_2016">{{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 | volume = 2016 | issue = 6 | date = June 2016 | pmid = 27271789 | pmc = 6353046 | doi = 10.1002/14651858.CD012230 | article-number = CD012230 }}</ref><ref name="Machado_2015" /><ref name="Qaseem_2017" />
====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 = 2013 | issue = 4 | date = Apr 2013 | pmid = 23633349 | pmc = 4161111 | doi = 10.1002/14651858.CD008040.pub3 | article-number = CD008040 }}</ref> The aspirin/paracetamol/caffeine combination also "has strong evidence of effectiveness and can be used as a first-line treatment for migraine".<ref name="Mayans_2018">{{cite journal | vauthors = Mayans L, Walling A | title = Acute Migraine Headache: Treatment Strategies | journal = Am Fam Physician | volume = 97 | issue = 4 | pages = 243–251 | date = February 2018 | pmid = 29671521 | url = https://www.aafp.org/pubs/afp/issues/2018/0215/p243.html }}</ref> Paracetamol on its own only slightly alleviates episodic tension headache in those who have them frequently.<ref name="Stephens_2016">{{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 = 2016 | issue = 6 | date = June 2016 | pmid = 27306653 | pmc = 6457822 | doi = 10.1002/14651858.CD011889.pub2 | article-number = CD011889 }}</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="Diener_2014">{{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 | date = November 2014 | pmid = 25406671 | pmc = 4256978 | doi = 10.1186/1129-2377-15-76 | article-number = 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="Haag_2011">{{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="Pergolizzi_2020">{{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="Bailey_2013">{{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 = 2013 | issue = 12 | date = December 2013 | pmid = 24338830 | pmc = 11561150 | doi = 10.1002/14651858.CD004624.pub2 | article-number = CD004624 }}</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="Hersh_2020">{{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 | pmc = 7313348 | doi = 10.1177/0022034520914254 }}</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="Bailey_2013" /><ref name="Moore_2013">{{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="Derry_2013">{{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 = 2013 | issue = 6 | date = June 2013 | pmid = 23794268 | pmc = 6485825 | doi = 10.1002/14651858.CD010210.pub2 | article-number = CD010210 }}</ref><ref name="Daniels_2018">{{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="Moore_2013" />
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="Toms_2009">{{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 | date = January 2009 | pmid = 19160199 | pmc = 4171965 | doi = 10.1002/14651858.CD001547.pub2 | article-number = CD001547 }}</ref>
====Other pain====
Paracetamol fails to relieve procedural pain in newborn babies.<ref name="Allegaert_2020">{{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 | date = 2020 | pmid = 32257982 | pmc = 7093493 | doi = 10.3389/fped.2020.00089 | article-number = 89 | 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 | issue = 1 | date = January 2020 | pmid = 31985830 | pmc = 6984663 | doi = 10.1002/14651858.CD011219.pub4 | article-number = CD011219 }}</ref> For perineal pain postpartum paracetamol appears to be less effective than nonsteroidal anti-inflammatory drugs (NSAIDs).<ref name="Wuytack_2021">{{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 | date = January 2021 | pmid = 33427305 | pmc = 8092572 | doi = 10.1002/14651858.CD011352.pub3 | article-number = CD011352 }}</ref>
The studies to support or refute the use of paracetamol for cancer pain and neuropathic pain are lacking.<ref name="Wiffen_2017">{{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 = 7 | date = July 2017 | pmid = 28700092 | pmc = 6369932 | doi = 10.1002/14651858.CD012637.pub2 | article-number = CD012637 }}</ref><ref name="Wiffen_2016">{{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 = 12 | date = December 2016 | pmid = 28027389 | pmc = 6463878 | doi = 10.1002/14651858.CD012227.pub2 | article-number = CD012227 }}</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 = 543–553 | 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 | veditors = Derry S | title = Caffeine as an analgesic adjuvant for acute pain in adults | journal = The Cochrane Database of Systematic Reviews | volume = 3 | issue = 3 | date = March 2012 | pmid = 22419343 | doi = 10.1002/14651858.CD009281.pub2 | article-number = CD009281 | s2cid = 205199173 }}</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="Jasani_2022">{{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 | issue = 12 | date = December 2022 | pmid = 36519620 | pmc = 6984659 | doi = 10.1002/14651858.CD010061.pub5 | article-number = CD010061 }}</ref> Its use for extremely low birth weight and gestational age infants, however, requires further study.<ref name="Jasani_2022" />
== Use in pregnancy and breastfeeding ==
=== Pregnancy === Paracetamol has long been established as a safe medication to treat short-term fever and significant pain in pregnant patients. Regulatory agencies, including the European Medicines Agency (EMA),<ref>{{cite web | title = Use of paracetamol during pregnancy unchanged in the EU | date = 23 September 2025 | publisher = European Medicines Agency | url = https://www.ema.europa.eu/en/news/use-paracetamol-during-pregnancy-unchanged-eu }}</ref> the Medicines and Healthcare products Regulatory Agency (MHRA),<ref>{{cite web | title = MHRA confirms taking paracetamol during pregnancy remains safe and there is no evidence it causes autism in children | date = 23 September 2025 | url = https://www.gov.uk/government/news/mhra-confirms-taking-paracetamol-during-pregnancy-remains-safe-and-there-is-no-evidence-it-causes-autism-in-children | website = GOV.UK }}</ref> the World Health Organization (WHO),<ref>{{cite press release | title = WHO statement on autism-related issues | url = https://www.who.int/news/item/24-09-2025-who-statement-on-autism-related-issues | access-date = 30 September 2025 | publisher = World Health Organization (WHO) }}</ref> and the U.S. Food and Drug Administration (FDA)<ref>{{cite web | title = Drug Safety Communication: Acetaminophen use during pregnancy | date = 2025 | publisher = U.S. Food and Drug Administration | url = https://www.fda.gov/news-events/press-announcements/fda-responds-evidence-possible-association-between-autism-and-acetaminophen-use-during-pregnancy }}</ref> recommend paracetamol as a first-line analgesic and antipyretic in pregnancy, with use limited to situations where necessary, at the lowest effective dose, and for the shortest duration.
Some observational studies have suggested a possible association between prenatal paracetamol use and neurodevelopmental disorders, including ADHD and autism. However, these studies are limited by confounding factors such as maternal fever and infection, and do not demonstrate causation.<ref name="Pearson_2025">{{cite journal | vauthors = Pearson H, Ledford H | title = Trump links autism and Tylenol: is there any truth to it? | journal = Nature | volume = 646 | issue = 8083 | pages = 13–14 | date = October 2025 | pmid = 40999085 | doi = 10.1038/d41586-025-02876-1 | bibcode = 2025Natur.646...13P }}</ref><ref name="auto">{{cite journal | vauthors = Ahlqvist VH, Sjöqvist H, Dalman C, Karlsson H, Stephansson O, Johansson S, Magnusson C, Gardner RM, Lee BK | title = Acetaminophen Use During Pregnancy and Children's Risk of Autism, ADHD, and Intellectual Disability | journal = JAMA | volume = 331 | issue = 14 | pages = 1205–1214 | date = April 2024 | pmid = 38592388 | pmc = 11004836 | doi = 10.1001/jama.2024.3172 }}</ref><ref name="Okubo_2025">{{cite journal | vauthors = Okubo Y, Hayakawa I, Sugitate R, Nariai H | title = Maternal Acetaminophen Use and Offspring's Neurodevelopmental Outcome: A Nationwide Birth Cohort Study | journal = Paediatric and Perinatal Epidemiology | date = September 2025 | volume = 40 | issue = 1 | pmid = 40898607 | doi = 10.1111/ppe.70071 | article-number = ppe.70071 }}</ref><ref name="Damkier_2025">{{cite journal | vauthors = Damkier P, Gram EB, Ceulemans M, Panchaud A, Cleary B, Chambers C, Weber-Schoendorfer C, Kennedy D, Hodson K, Grant KS, Diav-Citrin O, Običan SG, Shechtman S, Alwan S | title = Acetaminophen in Pregnancy and Attention-Deficit and Hyperactivity Disorder and Autism Spectrum Disorder | journal = Obstetrics and Gynecology | volume = 145 | issue = 2 | pages = 168–176 | date = February 2025 | pmid = 39637384 | doi = 10.1097/AOG.0000000000005802 | url = https://portal.findresearcher.sdu.dk/da/publications/449b9743-50d5-41cd-9426-8b66046e7b81 }}</ref>
Large, well-controlled studies, including sibling-controlled analyses, find no causal link after adjusting for maternal conditions.<ref name="Pearson_2025" /><ref name="auto"/><ref name="Okubo_2025" /><ref name="Damkier_2025" />
Untreated pain and fever can harm mother and fetus.<ref name="sogc" /><ref name="hc" />
=== Breastfeeding === Paracetamol is excreted in breast milk at measurable concentrations (milk/plasma ratio approximately 1), but the amount ingested by the infant is much lower than paediatric therapeutic doses and rarely associated with clinical effects.<ref name="Tamaki_2024">{{cite journal | vauthors = Tamaki R, Noshiro K, Furugen A, Nishimura A, Asano H, Watari H, Kobayashi M, Umazume T | title = Breast milk concentrations of acetaminophen and diclofenac - unexpectedly high mammary transfer of the general-purpose drug acetaminophen | journal = BMC Pregnancy and Childbirth | volume = 24 | issue = 1 | date = January 2024 | pmid = 38287321 | pmc = 10826108 | doi = 10.1186/s12884-024-06287-4 | doi-access = free | article-number = 90 }}</ref><ref name="LactMed2025">{{cite book | chapter = Acetaminophen | title = Drugs and Lactation Database (LactMed). | date = 2025 | publisher = U.S. National Library of Medicine. | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK501922/ }}></ref> Use during breastfeeding is considered compatible at recommended doses, with extra caution for preterm infants or infants with liver disease.<ref name="EMA2025">{{cite web | title = Paracetamol and breastfeeding: safety communication. | date = 2025 | work = European Medicines Agency (EMA) | url = https://www.ema.europa.eu/en/news/paracetamol-breastfeeding-safety-communication }}{{Dead link|date=May 2026 |bot=InternetArchiveBot }}</ref>
==Adverse effects== Gastrointestinal adverse effects such as nausea and abdominal pain are extremely uncommon, and their frequency is substantially lower than with ibuprofen use.<ref name="Conaghan_2019" /> 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="FDA_2013">{{cite web | title = FDA Drug Safety Communication: FDA warns of rare but serious skin reactions with the pain reliever/fever reducer acetaminophen | date = 1 August 2013 | website = U.S. Food and Drug Administration (FDA) | 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="FDA_2013" /><ref name="LebrunVignes_2018">{{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="Leopoldino_2019">{{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 = 2 | date = February 2019 | pmid = 30801133 | pmc = 6388567 | doi = 10.1002/14651858.CD013273 | article-number = 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="Roberts_2016">{{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 = 552–559 | date = March 2016 | pmid = 25732175 | pmc = 4789700 | doi = 10.1136/annrheumdis-2014-206914 }}</ref>
Due to the absence of controlled studies, most of the information about the long-term safety of paracetamol comes from observational studies.<ref name="Conaghan_2019">{{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 as well as cardiovascular (stroke, myocardial infarction), gastrointestinal (ulcers, bleeding) and renal adverse effects with increased dose of paracetamol.<ref name="Roberts_2016" /><ref name="Conaghan_2019" /><ref name="Choueiri_2014">{{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 = 384–396 | 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="Conaghan_2019" /> 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="McCrae_2018" /> Meta-analyses suggest that paracetamol may increase the risk of kidney impairment by 23%<ref name="Kanchanasurakit_2020">{{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="Choueiri_2014" /> Paracetamol slightly but significantly increases blood pressure and heart rate.<ref name="Conaghan_2019" /> A review of available research has suggested that an increase in systolic blood pressure and increased risk of gastrointestinal bleeding associated with chronic paracetamol use shows a degree of dose dependence.<ref name="McCrae_2018">{{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="LouridoCebreiro_2017">{{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 | volume = 54 | issue = 1 | pages = 32–38 | date = January 2017 | pmid = 27575940 | doi = 10.1080/02770903.2016.1194431 | 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 | volume = 100 | issue = 1 | pages = 81–89 | date = January 2015 | pmid = 25429049 | doi = 10.1136/archdischild-2012-303043 | 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="Sherbash_2020" />
In recommended doses, the 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 | year = 2008 | publisher = Elsevier Health Sciences | isbn = 978-0-443-10336-0 }}</ref> In contrast to aspirin, it is not a blood thinner (and thus may be used in patients where bleeding is a concern), and it does not cause gastric irritation.<ref name="Sarg_2007">{{cite book | vauthors = Sarg M, Gross AD, Altman R | title = The Cancer Dictionary | year = 2007 | publisher = Infobase Publishing }}</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 | title = Comparison of efficacy and safety of acetaminophen and ibuprofen administration as single dose to reduce fever in children. | journal = Iranian Journal of Pediatrics | volume = 20 | issue = 4 | pages = 500–501 | year = 2010 | url = http://journals.tums.ac.ir/abs/17188 | url-status = dead | archive-url = https://archive.today/20120709124051/http://journals.tums.ac.ir/abs/17188 | archive-date = 9 July 2012 }}</ref> Prolonged daily use may cause kidney or liver damage.<ref name="Sarg_2007" /><ref>{{cite news | title = Painkillers 'cause kidney damage' | date = 23 November 2003 | url = http://news.bbc.co.uk/2/hi/health/3271191.stm | access-date = 27 March 2010 | work = BBC News }}</ref> Paracetamol is metabolized by the liver and is hepatotoxic; side effects may be more likely in 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 | year = 2000 | publisher = Elsevier | isbn = 978-0-444-50093-9 }}</ref>
==Overdose== {{Main|Paracetamol poisoning}}
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 liver damage.<ref>{{cite web | title = Acetaminophen Information | date = 14 November 2017 | website = U.S. Food and Drug Administration | 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 | date = 26 February 2018 | website = U.S. Food and Drug Administration (FDA) | 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 mg, doses should be taken no sooner than four hours apart, and no more than four doses (4000 mg) in 24 hours.<ref name="UK2017" /> While a majority of adult overdoses are linked to suicide attempts, many cases are accidental, often due to the use of more than one paracetamol-containing product over an extended period.<ref>{{cite journal | vauthors = Amar PJ, Schiff ER | title = Acetaminophen safety and hepatotoxicity--where do we go from here? | journal = Expert Opinion on Drug Safety | volume = 6 | issue = 4 | pages = 341–355 | date = July 2007 | pmid = 17688378 | doi = 10.1517/14740338.6.4.341 | s2cid = 20399748 }}</ref>
Paracetamol is hepatotoxic and depletes the stock of the antioxidant glutathione in the liver as glutathione is consumed much faster than it can be replenished.
Paracetamol toxicity had become the foremost cause of acute liver failure in the United States by 2003,<ref name="Larson_2005" /> 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 }}</ref> As of 2004, paracetamol overdose resulted in more calls to poison control centers in the U.S. than overdose of any other pharmacological substance.<ref name="Lee_2004">{{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 | date = Jul 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 | title = Prescription Drug Products Containing Acetaminophen: Actions to Reduce Liver Injury from Unintentional Overdose | date = 14 January 2011 | publisher = US Food and Drug Administration | website = regulations.gov | url = http://www.regulations.gov/#!documentDetail;D=FDA-2011-N-0021-0001 | 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 use of prescription opioids, as these opioids are most often combined with paracetamol.<ref>{{cite news | vauthors = Yan H | title = FDA: Acetaminophen doses over 325 mg may lead to liver damage | date = 16 January 2014 | url = https://www.cnn.com/2014/01/15/health/fda-acetaminophen-dosage/index.html | publisher = CNN | access-date = 18 February 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="Lee_2017">{{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 symptoms. The first symptoms of overdose usually begin several hours after ingestion, with nausea, vomiting, sweating, and pain as acute liver failure starts.<ref name="Rumack_1975">{{cite journal | vauthors = Rumack B, Matthew H | title = Acetaminophen poisoning and toxicity | journal = Pediatrics | volume = 55 | issue = 6 | pages = 871–876 | date = Jun 1975 | pmid = 1134886 | doi = 10.1542/peds.55.6.871 | 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="Mehta_2012">{{cite web | vauthors = Mehta S | title = Metabolism of Paracetamol (Acetaminophen), Acetanilide and Phenacetin | date = 25 August 2012 | website = PharmaXChange.info | 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="Mehta_2012" /> 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="Daly_2008" /><ref>{{cite web | title = Highlights of Prescribing Information | url = http://acetadote.com/Acetadote21-539-12_PI_Clean_June2013.pdf | 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 is usually given following a treatment nomogram for patients with an acute overdose at a known time of ingestion.<ref name="Dart_2023">{{cite journal | vauthors = Dart RC, Mullins ME, Matoushek T, Ruha AM, Burns MM, Simone K, Beuhler MC, Heard KJ, Mazer-Amirshahi M, Stork CM, Varney SM, Funk AR, Cantrell LF, Cole JB, Banner W, Stolbach AI, Hendrickson RG, Lucyk SN, Sivilotti ML, Su MK, Nelson LS, Rumack BH | title = Management of Acetaminophen Poisoning in the US and Canada: A Consensus Statement | journal = JAMA Network Open | volume = 6 | issue = 8 | pages = e2327739 | date = August 2023 | pmid = 37552484 | doi = 10.1001/jamanetworkopen.2023.27739 | doi-access = free }}</ref> Patients with unknown time of ingestion, unreliable history, or repeat supratherapeutic ingestion are treated based on risk assessment.<ref name="Dart_2023" /> Toxicity of paracetamol is due to its quinone metabolite NAPQI and NAC also helps in neutralizing it.<ref name="Mehta_2012" /> Kidney failure is also a possible side effect.<ref name="Lee_2017" />
==Interactions==
Prokinetic agents such as metoclopramide accelerate gastric emptying, shorten time (t<sub>max</sub>) to paracetamol 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="Nimmo_1973">{{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 = 587–589 | date = March 1973 | pmid = 4694406 | pmc = 1589913 | doi = 10.1136/bmj.1.5853.587 }}</ref><ref name="Toes_2005">{{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="Toes_2005" />
There have been suspicions that 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="Toes_2005" /> 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="Kalsi_2011">{{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 | 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="Toes_2005" />
Ranitidine increased paracetamol 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="Toes_2005" />
Paracetamol raises plasma concentrations of ethinylestradiol by 22% by inhibiting its sulfation.<ref name="Toes_2005" /> Paracetamol increases INR during warfarin therapy and should be limited to no more than 2 g per week.<ref name="Pinson_2013">{{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 = 518–521 | date = October 2013 | pmid = 23736105 | doi = 10.1177/0897190013488802 | s2cid = 31588052 }}</ref><ref name="Hughes_2011">{{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 = 591–597 | date = June 2011 | pmid = 21923443 | doi = 10.1592/phco.31.6.591 | s2cid = 28548170 }}</ref><ref name="Zhang_2011">{{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 = 309–314 | 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 (AM404).<ref name="Ghanem_2016">{{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 = 119–131 | 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 inhibitors,<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 | volume = 21 | issue = 3 | pages = 201–232 | 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 peroxides is low; under these conditions, COX-2 is the predominant form of cyclooxygenase, which explains the apparent COX-2 selectivity of paracetamol. Under typical inflammation conditions, the concentration of peroxides is high, which counteracts the reducing anti-inflammatory effect of paracetamol, rendering it negligible; in situations where peroxide levels are low, such as for COX-2 in the CNS, this inhibition and its resulting anti-inflammatory effect remain high.<ref name="Ghanem_2016" /><ref name="Graham_2013" />
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="Ghanem_2016" /><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 | 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="Ghanem_2016" /> AM404 is a weak agonist of cannabinoid receptors CB1 and CB2, an inhibitor of endocannabinoid transporter, and a potent activator of TRPV1 receptor.<ref name="Ghanem_2016" /> This and other research indicate that the endocannabinoid system and TRPV1 may play an important role in the analgesic effect of paracetamol.<ref name="Ghanem_2016" /><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 | date = 2020 | pmid = 33328986 | pmc = 7734311 | doi = 10.3389/fphar.2020.580289 | article-number = 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="Suemaru_2018">{{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 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="Suemaru_2018" />
In 2025, Maatuf ''et al.'' reported that AM404 is also produced by peripheral sensory neurons ''in vitro'' and blocks the action of pain-sensing Na<sub>v</sub>1.8 and 1.7 channels at nanomolar concentrations. AM404 injected into the hind paw of rats increases 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 | date = June 2025 | pmid = 40465624 | pmc = 12168006 | doi = 10.1073/pnas.2413811122 | article-number = e2413811122 | bibcode = 2025PNAS..12213811M }}</ref><ref>{{cite web | title = Does Paracetamol Block Peripheral Pain? | date = 11 June 2025 | url = https://conexiant.com/neurology/articles/paracetamol-metabolite-blocks-pain-at-source/ | website = Conexiant }}</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 | volume = 10 | issue = Suppl 2 | pages = 291S–298S | date = October 1980 | pmid = 7002186 | pmc = 1430174 | doi = 10.1111/j.1365-2125.1980.tb01812.x }}</ref> In the same subjects, the time to reach peak plasma concentration of paracetamol was 20 minutes in a fasting state, compared to 90 minutes in a fed state. Furthermore, a high-carbohydrate meal reduced the peak plasma concentration by approximately fourfold, an effect not observed with high-protein or high-fat meals.<ref name="Forrest_1982">{{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="Forrest_1982" /> Its plasma terminal elimination half-life is 1.9{{ndash}}2.5 hours,<ref name="Forrest_1982" /> and volume of distribution is roughly 50{{nbsp}}L.<ref name="Graham_2013a">{{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 = 201–232 | date = June 2013 | pmid = 23719833 | doi = 10.1007/s10787-013-0172-x | s2cid = 11359488 }}</ref> Protein binding is negligible, except under the conditions of overdose, when it may reach 15{{ndash}}21%.<ref name="Forrest_1982" /> 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 | vauthors = Marx J, Walls R, Hockberger R | title = Rosen's Emergency Medicine – Concepts and Clinical Practice | year = 2013 | publisher = Elsevier Health Sciences | isbn = 978-1-4557-4987-4 }}</ref>
class=skin-invert-image|thumb|right|upright=1.6|Important pathways of paracetamol metabolism
Paracetamol is metabolized primarily in the liver, mainly by glucuronidation and sulfation, and the products are then eliminated in the urine (see the Scheme on the right). Only 2{{ndash}}5% of the drug is excreted unchanged in the urine.<ref name="Forrest_1982" /> 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="McGill_2013">{{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 = 2174–2187 | 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="McGill_2013" /> 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="McGill_2013" />
Yet another minor but important direction of metabolism is deacetylation of 1{{ndash}}2% of paracetamol to form ''p''-aminophenol. ''p''-Aminophenol is then converted in the brain by fatty acid amide hydrolase into AM404, a compound that may be partially responsible for the analgesic action of paracetamol.<ref name="Graham_2013a" />
==Chemistry==
===Synthesis===
====Classical methods==== The classical methods for the production of paracetamol involve the acetylation of 4-aminophenol with acetic anhydride as the last step. They differ in how 4-aminophenol is prepared. In one method, nitration of phenol with nitric acid affords 4-nitrophenol, which is reduced to 4-aminophenol by hydrogenation over Raney nickel. In another method, nitrobenzene is reduced electrolytically giving 4-aminophenol directly. Additionally, 4-nitrophenol can be selectively reduced by Tin(II) Chloride in absolute ethanol or ethyl acetate to produce a 91% yield of 4-aminophenol.<ref name="Friderichs_2007" /><ref>{{cite web | title = US Patent 2998450 | url = https://patents.google.com/patent/US2998450A/en | 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 | 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 | date = January 1984 | doi = 10.1016/S0040-4039(01)80041-1 | title-link = doi | bibcode = 1984TetL...25..839B }}</ref> 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 give a methyl ketone, then the conversion of the ketone with hydroxylamine to a ketoxime, and finally the acid-catalysed Beckmann rearrangement of the oxime to the amide in the para-acetylaminophenol product.<ref name="Friderichs_2007">{{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 | title = Process for producing N-acyl-hydroxy aromatic amines | issue = 4524217 | country = US | status = patent | pubdate = 18 June 1985 | inventor = Davenport KG, Hilton CB | assign1 = Celanese Corporation }}</ref>
class=skin-invert-image|thumb|center|upright=2|Celanese method for the preparation of paracetamol
===Reactions===
thumb|right|Paracetamol crystals (crystallized from an aqueous solution) under a microscope thumb|right|Close-up image of Paracetamol crystals produced by acetylation of 4-aminophenol ''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 = 884–886 | date = Jun 1984 | pmid = 6723045 | doi = 10.1093/clinchem/30.6.884 | doi-access = free | title-link = doi }}</ref>
==History== [[Image:Axelrod.jpg|thumb|Julius Axelrod ''(pictured)'' and Bernard Brodie demonstrated that acetanilide and phenacetin are both metabolized to paracetamol, which is a better-tolerated analgesic.]]
Acetanilide was the first aniline derivative serendipitously found to possess analgesic as well as antipyretic properties, and was quickly introduced into medical practice under the name of Antifebrin by Cahn & Hepp in 1886.<ref>{{cite journal | vauthors = Cahn A, Hepp P | title = Das Antifebrin, ein neues Fiebermittel | journal = Centralblatt für Klinische Medizin | volume = 7 | pages = 561–564 | year = 1886 | trans-title = Antifebrin, a new antipyretic | 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="Bertolini_2006a">{{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 = 250–275 | year = 2006 | pmid = 17227290 | pmc = 6506194 | doi = 10.1111/j.1527-3458.2006.00250.x }}</ref> Some reports state that Cahn & Hepp or a French chemist called Charles Gerhardt first synthesized paracetamol in 1852.<ref name="Eyers_2012" /><ref name="Roy_2011" />
Harmon Northrop Morse synthesized paracetamol at Johns Hopkins University via the reduction of ''p''-nitrophenol with tin in glacial acetic acid in 1877,<ref>{{cite journal | vauthors = Morse HN | title = Ueber eine neue Darstellungsmethode der Acetylamidophenole | journal = berichte der Deutschen Chemischen Gesellschaft | volume = 11 | issue = 1 | pages = 232–233 | year = 1878 | doi = 10.1002/cber.18780110151 | trans-title = On a new method of preparing acetylamidophenol | 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="Silverman_1992" /> but it was not until 1887 that clinical pharmacologist Joseph von Mering tried paracetamol on humans.<ref name="Bertolini_2006a" /> 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 | title = Beitrage zur Kenntniss der Antipyretica | journal = Ther Monatsch | volume = 7 | pages = 577–587 | year = 1893 }}</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="Sneader_2005">{{cite book | vauthors = Sneader W | title = Drug Discovery: A History | location = Hoboken, NJ | pages = 439 | year = 2005 | publisher = Wiley | isbn = 978-0-470-01552-0 | 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 analysed the metabolism of acetanilide and phenacetin.<ref name="Sneader_2005" /> In 1947, David Lester and Leon Greenberg found strong evidence that paracetamol was a major metabolite of acetanilide in human blood, and in a subsequent study, they reported that large doses of paracetamol given to albino rats did not cause methemoglobinemia.<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. | volume = 90 | issue = 1 | pages = 68–75 | date = May 1947 | pmid = 20241897 | doi = 10.1016/S0022-3565(25)05394-7 }}</ref> In 1948, Bernard Brodie, Julius Axelrod and Frederick Flinn confirmed that paracetamol was the major metabolite of acetanilide in humans, and established that it was just as efficacious an analgesic as its precursor.<ref>{{cite journal | vauthors = Brodie BB, Axelrod J | 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. | volume = 94 | issue = 1 | pages = 22–28 | date = Sep 1948 | pmid = 18885610 | doi = 10.1016/S0022-3565(25)03461-5 | author-link2 = Julius Axelrod }}</ref><ref>{{cite journal | vauthors = Brodie BB, Axelrod J | title = The fate of acetanilide in man | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 94 | issue = 1 | pages = 29–38 | date = September 1948 | pmid = 18885611 | doi = 10.1016/S0022-3565(25)03462-7 | author-link2 = Julius Axelrod | url = http://profiles.nlm.nih.gov/HH/A/A/A/D/_/hhaaad.pdf | url-status = dead | 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. | volume = 94 | issue = 1 | pages = 76–77 | date = Sep 1948 | pmid = 18885618 | doi = 10.1016/S0022-3565(25)03471-8 }}</ref> They also suggested that methemoglobinemia is produced in humans mainly by another metabolite, phenylhydroxylamine. A follow-up paper by Brodie and Axelrod in 1949 established that phenacetin was also metabolized to paracetamol.<ref>{{cite journal | vauthors = Brodie BB, Axelrod J | title = The fate of acetophenetidin in man and methods for the estimation of acetophenetidin and its metabolites in biological material | journal = The Journal of Pharmacology and Experimental Therapeutics | volume = 97 | issue = 1 | pages = 58–67 | date = September 1949 | pmid = 18140117 | doi = 10.1016/S0022-3565(25)03631-6 }}</ref> This led to a "rediscovery" of paracetamol.<ref name="Bertolini_2006a" />
Paracetamol was first marketed in the United States in 1950 under the name Trigesic, a combination of paracetamol, aspirin, and caffeine.<ref name="Silverman_1992" /> 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="Silverman_1992" /> 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="Landau_1999">{{cite book | vauthors = Landau R, Achilladelis B, Scriabine A | title = Pharmaceutical Innovation: Revolutionizing Human Health | pages = 248–249 | year = 1999 | url = https://books.google.com/books?id=IH4lPs6S1bMC&pg=PA248 | publisher = Chemical Heritage Foundation | isbn = 978-0-941901-21-5 | 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="Silverman_1992">{{cite book | vauthors = Silverman M, Lydecker M, Lee PR | title = Bad Medicine: The Prescription Drug Industry in the Third World | pages = [https://archive.org/details/badmedicinepresc0000silv/page/88 88]–90 | year = 1992 | publisher = Stanford University Press | 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="Bertolini_2006a" /> 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 = 202–209 | date = August 1977 | pmid = 329728 | doi = 10.7326/0003-4819-87-2-202 }}</ref> (1960, according to another source<ref>{{cite web | title = Our Story | url = http://www.tylenol.com/news/about-us | 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.{{cn|date=October 2025}} 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 | title = SEC Info – Eastman Kodak Co – '8-K' for 6/30/94 | url = http://www.secinfo.com/dUGc.bs.htm | 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 | title = FDA May Restrict Acetaminophen | date = 1 July 2009 | url = http://www.webmd.com/pain-management/news/20090701/fda-may-restrict-acetaminophen | publisher = Webmd | 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 | title = FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings | date = 13 January 2011 | url = https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm | 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 | 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 | url = https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-prescription-acetaminophen-products-be-limited-325-mg-dosage-unit | 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 | vauthors = Perrone M | title = FDA orders lowering pain reliever in Vicodin | date = 13 January 2011 | url = https://archive.boston.com/lifestyle/health/articles/2011/01/13/fda_orders_lowering_pain_reliever_in_vicodin/ | agency = Associated Press | 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="Harris_2011">{{cite news | vauthors = Harris G | title = F.D.A. Plans New Limits on Prescription Painkillers | date = 13 January 2011 | url = https://www.nytimes.com/2011/01/14/health/policy/14fda.html | work = The New York Times | 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 | date = 15 January 2011 | website = U.S. Food and Drug Administration (FDA) | 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="Harris_2011" />
In November 2011, the Medicines and Healthcare products Regulatory Agency revised UK dosing of liquid paracetamol for children.<ref>{{cite web | title = Liquid paracetamol for children: revised UK dosing instructions introduced | 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 | 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 | location = Chicago | issue = 505 | date = 20 September 2013 | 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 | 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 | date = 20 September 2013 | url = https://www.propublica.org/article/tylenol-mcneil-fda-use-only-as-directed | publisher = ProPublica | 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 | date = 20 September 2013 | url = https://www.propublica.org/article/tylenol-mcneil-fda-kids-dose-of-confusion | publisher = ProPublica | 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>
In September 2025, US President Donald Trump and HHS Secretary Robert F. Kennedy Jr. claimed that Tylenol may cause autism and urged pregnant women to avoid it; medical experts, major health organizations, and international studies strongly dispute any causal link, emphasizing that the drug remains safe for treating pain and fever in pregnancy.<ref name="Halpert_2025">{{cite web | vauthors = Halpert M, Yousif N | title = Trump urges pregnant women to avoid Tylenol over unproven autism link | date = 22 September 2025 | website = BBC News | url = https://www.bbc.co.uk/news/articles/cx20d4lr67lo | access-date = 23 September 2025 }}</ref>
==Society and culture== 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 | pages = 97 | date = July 1999 | section = Section 1 – Chemical Substances | publisher = Therapeutic Goods Administration, Department of Health and Ageing, Australian Government | 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 the British Approved Name<ref name="Macintyre_2008" /> as well as the international nonproprietary name that is used by the World Health Organization (WHO); acetaminophen is the United States Adopted Name<ref name="Macintyre_2008" /> and the Japanese Accepted Name.<ref name="Macintyre_2008">{{cite book | vauthors = Macintyre P, Rowbotham D, Walker S | title = Clinical Pain Management Second Edition: Acute Pain | pages = 85 | date = 26 September 2008 | url = https://books.google.com/books?id=CLcsngfC9gQC&pg=PA85 | publisher = CRC Press | isbn = 978-0-340-94009-9 | 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 | volume = 16 | issue = 3 | pages = 101–111 | date = March 1962 | 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 | url-status = live | archive-url = https://web.archive.org/web/20230326071323/https://www.merriam-webster.com/dictionary/paracetamol | archive-date = 26 March 2023 | access-date = 26 March 2023 | website = Merriam-Webster }}</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 | title = APAP: An Error-Prone Abbreviation | journal = Pharmacy Times | volume = 79 | issue = 10 | date = 8 October 2013 | url = https://www.pharmacytimes.com/view/apap-an-error-prone-abbreviation | url-status = live | series = October 2013 Diabetes | 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 | location = Montvale, N.J. | pages = 1915–1916 | date = 2009 | publisher = Physicians' Desk Reference | isbn = 978-1-56363-703-2 | oclc = 276871036 | edition = 63rd }}</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 (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) | date = 29 June 2019 | website = Drugs.com | 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 | date = 10 April 2018 | url = https://www.tga.gov.au/codeine-info-hub | url-status = live | access-date = 9 December 2021 | website = Therapeutic Goods Administration, Australian Government | 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) | date = 2 October 2019 | website = Drugs.com | 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) | date = 11 November 2019 | website = Drugs.com | 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) | date = 2 January 2020 | website = Drugs.com | 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 | date = 21 June 2019 | website = Drugs.com | 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 succinate is also available.<ref>{{cite web | title = APOHealth Paracetamol Plus Codeine & Calmative | date = 3 February 2020 | website = Drugs.com | 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 also available combined with butalbital and caffeine as a treatment for tension and migraine headaches.<ref>{{cite web | title = Fioricet Uses, Dosage, Side Effects & Warnings | url = https://www.drugs.com/fioricet.html | access-date = 6 July 2025 | website = Drugs.com }}</ref>
Paracetamol is sometimes combined with phenylephrine hydrochloride.<ref name="Atkinson_2014">{{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 | pages = 1171–1172 | date = Mar 2014 | pmid = 24645960 | doi = 10.1056/NEJMc1313942 | doi-access = free | hdl = 2292/34799 | hdl-access = free }}</ref> Sometimes a third active ingredient, such as ascorbic acid,<ref name="Atkinson_2014" /><ref>{{cite web | title = Ascorbic acid/Phenylephrine/Paracetamol | url = http://www.nhs.uk/medicine-guides/pages/selectorshow.aspx?medicine=Ascorbic%20acid/Phenylephrine/Paracetamol | publisher = National Health Service | work = NHS Choices | 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 | title = Phenylephrine/Caffeine/Paracetamol dual relief | url = http://www.nhs.uk/medicine-guides/pages/MedicineOverview.aspx?medicine=Phenylephrine/Caffeine/Paracetamol%20dual%20relief | 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 | title = Beechams Decongestant Plus With Paracetamol | url = http://www.nhs.uk/Conditions/Painkillers-paracetamol/Pages/MedicineOverview.aspx?medicine=Beechams%20Decongestant%20Plus%20With%20Paracetamol | 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> chlorpheniramine maleate,<ref name="Senyuva_2002">{{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 | pages = 97–100 | date = Feb 2002 | pmid = 11881712 | doi = 10.1093/chromsci/40.2.97 | doi-access = free | title-link = doi }}</ref> or guaifenesin<ref name="Janin_2014">{{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 | pages = 347–359 | date = Apr 2014 | pmid = 24553480 | doi = 10.1177/0300060513503762 | 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 | title = Phenylephrine/Guaifenesin/Paracetamol | url = http://www.nhs.uk/Conditions/Flu/Pages/selectorshow.aspx?medicine=Phenylephrine/Guaifenesin/Paracetamol | publisher = National Health Service | work = NHS Choices | 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 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. }}
==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 (methaemoglobinaemia and haemolytic anaemia).<ref name="Allen_2003">{{cite journal | vauthors = Allen AL | title = The diagnosis of acetaminophen toxicosis in a cat | journal = The Canadian Veterinary Journal | volume = 44 | issue = 6 | pages = 509–510 | date = June 2003 | pmid = 12839249 | pmc = 340185 }}</ref> Acetylcysteine is used to treat cats with toxicity arising from paracetamol.<ref name="Papich_2016">{{cite book | vauthors = Papich M | title = Saunders Handbook of Veterinary Drugs | date = 2016 | publisher = Elsevier | isbn = 978-0-323-24485-5 | edition = 4th }}</ref>
===Dogs=== Paracetamol has been reported to be as effective as aspirin in the treatment of musculoskeletal pain in dogs.<ref name="Maddison_2002">{{cite book | vauthors = Maddison JE, Page SW, Church D | title = Small Animal Clinical Pharmacology | pages = 260–261 | year = 2002 | publisher = Elsevier Health Sciences }}</ref> Paracetamol is considered a weak analgesic and is usually combined with codeine, although the efficacy of this formulation has not been evaluated.<ref name="Papich_2016" />
The main effect of toxicity in dogs is liver damage, and GI ulceration has been reported.<ref name="Richardson_2000">{{cite journal | vauthors = Richardson JA | title = Management of acetaminophen and ibuprofen toxicoses in dogs and cats | 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="Villar_1998">{{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 = 156–162 | 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="Maddison_2002" />
===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 | journal = Comp Biochem Physiol C | volume = 215 | pages = 18–24 | date = Jan 2019 | 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 }}</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 | journal = Environ Sci Technol | volume = 36 | issue = 17 | pages = 3827–3833 | date = Sep 2002 | pmid = 12322757 | doi = 10.1021/es015873n | bibcode = 2002EnST...36.3827J }}</ref><ref>{{cite news | vauthors = Lendon B | title = Tylenol-loaded mice dropped from air to control snakes | date = 7 September 2010 | url = http://news.blogs.cnn.com/2010/09/07/tylenol-loaded-mice-dropped-from-air-to-control-snakes/ | work = CNN | 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 | vauthors = Richards S | title = It's Raining Mice | date = 1 May 2012 | url = https://www.the-scientist.com/notebook/its-raining-mice-41065 | 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}}
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