Editing Paracetamol (section)

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

In clinical trials for [[osteoarthritis]], the number of participants reporting adverse effects was similar for those on paracetamol and on placebo. However, the abnormal liver function tests (meaning there was some inflammation or damage to the liver) were almost four times more likely in those on paracetamol, although the clinical importance of this effect is uncertain.<ref name="pmid30801133">{{cite journal |vauthors=Leopoldino AO, Machado GC, Ferreira PH, Pinheiro MB, Day R, McLachlan AJ, Hunter DJ, Ferreira ML |title=Paracetamol versus placebo for knee and hip osteoarthritis |journal=Cochrane Database Syst Rev |volume=2 |issue= 8|pages=CD013273 |date=February 2019 |pmid=30801133 |pmc=6388567 |doi=10.1002/14651858.CD013273}}</ref> After 13 weeks of paracetamol therapy for knee pain, a drop in hemoglobin level indicating [[gastrointestinal bleeding]] was observed in 20% of participants, this rate being similar to the ibuprofen group.<ref name="pmid25732175">{{cite journal |vauthors=Roberts E, Delgado Nunes V, Buckner S, Latchem S, Constanti M, Miller P, Doherty M, Zhang W, Birrell F, Porcheret M, Dziedzic K, Bernstein I, Wise E, Conaghan PG |title=Paracetamol: not as safe as we thought? A systematic literature review of observational studies |journal=Ann Rheum Dis |volume=75 |issue=3 |pages=552–9 |date=March 2016 |pmid=25732175 |pmc=4789700 |doi=10.1136/annrheumdis-2014-206914}}</ref>

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

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

In recommended doses, the [[Side effect|side effects]] of paracetamol are mild to non-existent.<ref name="PM: FBtCP">{{cite book | vauthors = Hughes J |title=Pain Management: From Basics to Clinical Practice |publisher=Elsevier Health Sciences |year=2008 |isbn=9780443103360}}</ref> In contrast to aspirin, it is not a [[Antiplatelet drug|blood thinner]] (and thus may be used in patients where bleeding is a concern), and it does not cause gastric irritation.<ref name="TCD">{{cite book | vauthors = Sarg M, Gross AD, Altman R |title=The Cancer Dictionary |publisher=Infobase Publishing |year=2007 |isbn=978081606-4113}}</ref> Compared to Ibuprofen—which can have adverse effects that include diarrhea, vomiting, and abdominal pain—paracetamol is well tolerated with fewer side effects.<ref>{{cite journal | vauthors = Ebrahimi S, Esfahani SA, Ghaffarian HR, Khoshneviszade M |year=2010 |title=Comparison of efficacy and safety of acetaminophen and ibuprofen administration as single dose to reduce fever in children. |url=http://journals.tums.ac.ir/abs/17188 |url-status=dead |journal=Iranian Journal of Pediatrics |volume=20 |issue=4 |pages=500–501 |archive-url=https://archive.today/20120709124051/http://journals.tums.ac.ir/abs/17188 |archive-date=2012-07-09}}</ref> Prolonged daily use may cause kidney or liver damage.<ref name="TCD" /><ref>{{cite news |date=November 23, 2003 |title=Painkillers 'cause kidney damage' |url=http://news.bbc.co.uk/2/hi/health/3271191.stm |access-date=March 27, 2010 |work=BBC News}}</ref> Paracetamol is metabolized by the liver and is [[hepatotoxic]]; side effects may be more likely in [[Alcoholism|chronic alcoholics]] or patients with liver damage.<ref name="PM: FBtCP" /><ref>{{cite book | vauthors = Dukes MN, Aronson JK |title=Meyler's Side Effects of Drugs, Vol XIV  |publisher=Elsevier |year=2000 |isbn=9780444500939}}</ref>

Until 2010 paracetamol was believed safe in pregnancy however, in a study published in October 2010 it has been linked to [[infertility]] in the adult life of the unborn.<ref>{{cite journal | vauthors = Kristensen DM, Hass U, Lesné L, Lottrup G, Jacobsen PR, Desdoits-Lethimonier C, Boberg J, Petersen JH, Toppari J, Jensen TK, Brunak S, Skakkebaek NE, Nellemann C, Main KM, Jégou B, Leffers H | title = Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat | journal = Human Reproduction | volume = 26 | issue = 1 | pages = 235–244 | date = January 2011 | pmid = 21059752 | doi = 10.1093/humrep/deq382 | doi-access = free }}</ref> Like NSAIDs and unlike opioid analgesics, paracetamol has not been found to cause euphoria or alter mood. One recent research study showed evidence that paracetamol can ease psychological pain, but more studies are needed to draw a stronger conclusion.<ref>{{cite web |date=16 July 2014 |title=Could Tylenol Ease Emotional Pain? |url=http://www.evergreen-magazine.com/2014/07/tylenol-ease-emotional-pain/ |url-status=dead |archive-url=https://web.archive.org/web/20140819090402/http://www.evergreen-magazine.com/2014/07/tylenol-ease-emotional-pain/ |archive-date=19 August 2014 |access-date=17 August 2014 |publisher=Evergreen Magazine}}</ref> Unlike aspirin, it is safe for children, as paracetamol is not associated with a risk of [[Reye syndrome]] in children with viral illnesses.<ref>{{cite journal |vauthors=Lesko SM, Mitchell AA |year=1999 |title=The safety of acetaminophen and ibuprofen among children younger than two years old |journal=Pediatrics |volume=104 |issue=4 |pages=e39 |doi=10.1542/peds.104.4.e39 |pmid=10506264 |s2cid=3107281 |doi-access=free}}</ref> Chronic users of paracetamol may have a higher risk of developing [[Hematological malignancy|blood cancer]].<ref>{{cite journal |author1=Roland B. Walter |author2=Filippo Milano |author3=Theodore M. Brasky |author4=Emily White |year=2011 |title=Long-Term Use of Acetaminophen, Aspirin, and Other Nonsteroidal Anti-Inflammatory Drugs and Risk of Hematologic Malignancies: Results From the Prospective Vitamins and Lifestyle (VITAL) Study |journal=Journal of Clinical Oncology |volume=29 |issue=17 |pages=2424–31 |doi=10.1200/JCO.2011.34.6346 |pmc=3107756 |pmid=21555699}}</ref>

===Use in pregnancy===
Paracetamol safety in pregnancy has been under increased scrutiny. There appears to be no link between paracetamol use in the first trimester and adverse pregnancy outcomes or [[birth defects]]. However, indications exist of a possible increase in the risk of asthma and developmental and reproductive disorders in the offspring of women with prolonged use of paracetamol during pregnancy.<ref name="pmid29863746"/>

Paracetamol use by the mother during pregnancy is associated with an increased risk of childhood [[asthma]],<ref>{{cite journal| vauthors=Eyers S, Weatherall M, Jefferies S, Beasley R |title=Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis|journal=Clinical and Experimental Allergy |date= April 2011|volume=41|issue=4|pages=482–9|pmid=21338428|doi=10.1111/j.1365-2222.2010.03691.x |s2cid=205275267}}</ref><ref name="pmid28237129">{{cite journal |vauthors=Fan G, Wang B, Liu C, Li D |title=Prenatal paracetamol use and asthma in childhood: A systematic review and meta-analysis |journal=Allergol Immunopathol (Madr) |volume=45 |issue=6 |pages=528–533 |date=2017 |pmid=28237129 |doi=10.1016/j.aller.2016.10.014}}</ref> but so are the maternal infections for which paracetamol may be used, and separating these influences is difficult.<ref name="pmid29863746"/> Paracetamol, in a small-scale meta-analysis was also associated with a 20{{ndash}}30% increase in [[autism spectrum disorder]], [[attention deficit hyperactivity disorder]], and [[conduct disorder]], with the association being lower in a meta-analysis where a larger demographic was used, but it is unclear whether this is a causal relationship and whether there was potential bias in the findings.<ref name="pmid29863746"/><ref name="pmid29688261">{{cite journal |vauthors=Masarwa R, Levine H, Gorelik E, Reif S, Perlman A, Matok I |title= Prenatal Exposure to Acetaminophen and Risk for Attention Deficit Hyperactivity Disorder and Autistic Spectrum Disorder: A Systematic Review, Meta-Analysis, and Meta-Regression Analysis of Cohort Studies |journal=Am J Epidemiol |volume=187 |issue=8 |pages=1817–1827 |date=August 2018 |pmid=29688261 |doi=10.1093/aje/kwy086 |doi-access= free |title-link = doi }}</ref><ref name="pmid31664451">{{cite journal |vauthors=Ji Y, Azuine RE, Zhang Y, Hou W, Hong X, Wang G, Riley A, Pearson C, Zuckerman B, Wang X |title= Association of Cord Plasma Biomarkers of In Utero Acetaminophen Exposure With Risk of Attention-Deficit/Hyperactivity Disorder and Autism Spectrum Disorder in Childhood |journal=JAMA Psychiatry |volume=77 |issue=2 |pages=180–189 |date=February 2020 |pmid=31664451 |pmc=6822099 |doi=10.1001/jamapsychiatry.2019.3259}}</ref> There is also an argument that the large number, consistency, and robust designs of the studies provide strong evidence in favor of paracetamol causing the increased risk of these neurodevelopmental disorders.<ref name="pmid29341895">{{cite journal |vauthors=Bauer AZ, Kriebel D, Herbert MR, Bornehag CG, Swan SH |title=Prenatal paracetamol exposure and child neurodevelopment: A review |journal=Horm Behav |volume=101 |issue= |pages=125–147 |date=May 2018 |pmid=29341895 |doi=10.1016/j.yhbeh.2018.01.003 |s2cid=4822468}}</ref><ref name="pmid30654621">{{cite journal |vauthors=Gou X, Wang Y, Tang Y, Qu Y, Tang J, Shi J, Xiao D, Mu D |title=Association of maternal prenatal acetaminophen use with the risk of attention deficit/hyperactivity disorder in offspring: A meta-analysis |journal=Aust N Z J Psychiatry |volume=53 |issue=3 |pages=195–206 |date=March 2019 |pmid= 30654621 |doi=10.1177/0004867418823276 |s2cid=58575048}}</ref> In animal experiments, paracetamol disrupts fetal [[testosterone]] production, and several epidemiological studies linked [[cryptorchidism]] with mother's paracetamol use for more than two weeks in the second trimester. On the other hand, several studies did not find any association.<ref name="pmid29863746"/>

The consensus recommendation appears to be to avoid prolonged use of paracetamol in pregnancy and use it only when necessary, at the lowest effective dosage, and for the shortest time.<ref name="pmid29863746"/><ref name="pmid28986045">{{cite journal |vauthors=Toda K |title=Is acetaminophen safe in pregnancy? |journal=Scand J Pain |volume=17 |issue= |pages=445–446 |date=October 2017 |pmid=28986045 |doi=10.1016/j.sjpain.2017.09.007 |s2cid=205183310}}</ref><ref name="pmid31242344">{{cite journal |vauthors=Black E, Khor KE, Kennedy D, Chutatape A, Sharma S, Vancaillie T, Demirkol A |title=Medication Use and Pain Management in Pregnancy: A Critical Review |journal=Pain Pract |volume=19 |issue=8 |pages=875–899 |date=November 2019 |pmid=31242344 |doi=10.1111/papr.12814 |s2cid=195694287}}</ref>

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