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