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|Pronounce= {{IPAc-en|ˈ|ɛ|n|s|ɛ|d}} {{respell|EN|sed}}
|Synonyms = {{plainlist}}
* Cyclooxygenase inhibitor<ref name="stat">{{Citation |last1=Ghlichloo |first1=Ida |title=Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) |date=1 May 2023 |work=StatPearls |url=http://www.ncbi.nlm.nih.gov/books/NBK547742/ |access-date=2024-03-31 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31613522 |last2=Gerriets |first2=Valerie |archive-date=23 April 2024 |archive-url=https://web.archive.org/web/20240423114005/https://ncbi.nlm.nih.gov/books/NBK547742/ |url-status=live }}</ref>
* Cyclooxygenase enzyme inhibitor<ref name=
* Non-steroidal anti-inflammatory agent/analgesic (NSAIA)
{{endplainlist}}
<!-- Class identifiers -->
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'''Non-steroidal anti-inflammatory drugs'''<ref name=OED>{{Cite web|title=non-steroidal anti-inflammatory drug|url=https://www.lexico.com/definition/non-steroidal_anti-inflammatory_drug|website=www.Lexico.com|publisher=[[Oxford English Dictionary]]|date=2022|access-date=4 February 2022|archive-date=5 February 2022|archive-url=https://web.archive.org/web/20220205104155/https://www.lexico.com/definition/non-steroidal_anti-inflammatory_drug|url-status=dead}}</ref><ref name=BNF-NICE>{{Cite web|title=Non-steroidal anti-inflammatory drugs|url=https://BNF.NICE.org.uk/treatment-summary/non-steroidal-anti-inflammatory-drugs.html|website=BNF.NICE.org.uk|publisher=[[British National Formulary]] (BNF), [[National Institute for Health and Care Excellence]] (NICE)|date=2022|access-date=4 February 2022}}</ref> ('''NSAID''')<ref name=OED/> are members of a [[Indication (medicine)|therapeutic]] [[drug class]] which [[Analgesic|reduces pain]],<ref>{{Cite journal |last=Mallinson |first=Tom Edward |date=2017-12-02 |title=A review of ketorolac as a prehospital analgesic |journal=Journal of Paramedic Practice |language=en |volume=9 |issue=12 |pages=522–526 |doi=10.12968/jpar.2017.9.12.522 |issn=1759-1376|doi-access=free }}</ref> [[Anti-inflammatory|decreases inflammation]], [[Antipyretic|decreases fever]],<ref name=OED/> and [[Antithrombotic|prevents blood clots]]. Side effects depend on the specific drug, its dose and duration of use, but largely include an increased risk of [[Stomach ulcers|gastrointestinal ulcers and bleeds]], [[heart attack]], and [[kidney disease]].<ref name="Risk of acute myocardial infarction">{{Cite journal|vauthors=Bally M, Dendukuri N, Rich B, Nadeau L, Helin-Salmivaara A, Garbe E, Brophy JM|date=May 2017|title=Risk of acute myocardial infarction with NSAIDs in real world use: bayesian meta-analysis of individual patient data|journal=[[The BMJ]]|volume=357|pages=j1909|pmid=28487435|pmc=5423546|doi=10.1136/bmj.j1909}}</ref><ref>{{Cite journal|vauthors=Lanas A, Chan FK|date=August 2017|title=Peptic ulcer disease|journal=[[The Lancet]]|volume=390|issue=10094|pages=613–624|pmid=28242110|doi=10.1016/S0140-6736(16)32404-7|s2cid=4547048}}</ref>
The term ''non-steroidal'', common from around 1960, distinguishes these drugs from [[corticosteroids]], another class of anti-inflammatory drugs,<ref name=":12">{{cite journal |vauthors=Liu D, Ahmet A, Ward L, Krishnamoorthy P, Mandelcorn ED, Leigh R, Brown JP, Cohen A, Kim H |date=August 2013 |title=A practical guide to the monitoring and management of the complications of systemic corticosteroid therapy |journal=Allergy, Asthma, and Clinical Immunology |volume=9 |issue=1 |pages=30 |doi=10.1186/1710-1492-9-30 |pmc=3765115 |pmid=23947590 |doi-access=free}}</ref> which during the 1950s had acquired a bad reputation due to overuse and side-effect problems after their
NSAIDs work by inhibiting the activity of [[cyclooxygenase]] enzymes (the [[COX-1]] and [[COX-2]] [[isozyme|isoenzyme]]s). In cells, these enzymes are involved in the synthesis of key biological mediators, namely [[prostaglandin]]s, which are involved in [[inflammation]], and [[thromboxane]]s, which are involved in [[Coagulation|blood clotting]].
There are two general types of NSAIDs available: non-selective
The most prominent NSAIDs are [[aspirin]], [[ibuprofen]], and [[naproxen]]; all available [[Over-the-counter drug|over the counter]] (OTC) in most countries.<ref name="The Physician and Sportsmedicine 20103">{{Cite journal|vauthors=Warden SJ|date=April 2010|title=Prophylactic use of NSAIDs by athletes: a risk / benefit assessment|journal=The Physician and Sportsmedicine|volume=38|issue=1|pages=132–8|pmid=20424410|doi=10.3810/psm.2010.04.1770|s2cid=44567896}}</ref> [[Paracetamol]] (acetaminophen) is generally not considered an NSAID because it has only minor anti-inflammatory activity. Paracetamol treats pain mainly by blocking COX-2 and inhibiting [[endocannabinoid]] reuptake almost exclusively within the brain, and only minimally in the rest of the body.<ref name="Hinz_20083">{{Cite journal|vauthors=Hinz B, Cheremina O, Brune K|date=February 2008|title=Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man|journal=FASEB Journal|volume=22|issue=2|pages=383–90|pmid=17884974|doi=10.1096/fj.07-8506com|doi-access=free |s2cid=9633350}}</ref><ref name=integrada>{{Cite book| vauthors = Page CP, Curtis MJ, Sutter M, Walker M, Hoffman B |date=1998|url=https://books.google.com/books?id=h7cxH6XH4-sC|title=Farmacología integrada|language=Spanish|publisher=[[Elsevier]] España|isbn=84-8174-340-2|via=Google Books}}</ref>
==Medical uses==
NSAIDs are often suggested for the treatment of acute or chronic conditions where [[pain]] and inflammation are present. NSAIDs are generally used for the symptomatic relief of the following conditions:<ref name="isbn0-9757919-2-3">{{Cite book|editor=Simone Rossi|date=2006|title=Australian medicines handbook 2006|publisher=Australian Medicines Handbook Pty Ltd|location=Adelaide|isbn=978-0-9757919-2-9}}{{Page needed|date=August 2010}}</ref><ref name=BBDNSAIDs>{{Citation|author1=Consumer Reports Health Best Buy Drugs|author1-link=Consumer Reports|date=July 2013|title=NSAIDs|publisher=Consumer Reports|location=[[Yonkers, New York|Yonkers]], New York|url=http://consumerhealthchoices.org/catalog/nsaids/|contribution=The Nonsteroidal Anti-Inflammatory Drugs: Treating Osteoarthritis and Pain. Comparing effectiveness, safety, and price.|contribution-url=http://consumerhealthchoices.org/wp-content/uploads/2012/02/BBD-NSAIDs-Full.pdf|access-date=12 February 2014|url-status=dead|archive-url=https://web.archive.org/web/20140222204921/http://consumerhealthchoices.org/catalog/nsaids/|archive-date=22 February 2014}}</ref><ref>{{Cite journal|vauthors=Machado GC, Maher CG, Ferreira PH, Day RO, Pinheiro MB, Ferreira ML|date=July 2017|title=Non-steroidal anti-inflammatory drugs for spinal pain: a systematic review and meta-analysis|journal=Annals of the Rheumatic Diseases|volume=76|issue=7|pages=1269–1278|pmid=28153830|doi=10.1136/annrheumdis-2016-210597|url=https://ard.bmj.com/content/76/7/1269|s2cid=22850331|access-date=29 January 2020|archive-date=4 May 2021|archive-url=https://web.archive.org/web/20210504053409/https://ard.bmj.com/content/76/7/1269|url-status=live}}</ref>{{Div col|colwidth=25em}}
*[[Osteoarthritis]]<ref name="BBDNSAIDs"/><ref name="TowheedMaxwell2006">{{Cite journal|vauthors=Towheed TE, Maxwell L, Judd MG, Catton M, Hochberg MC, Wells G|date=January 2006|title=Acetaminophen for osteoarthritis|journal=The Cochrane Database of Systematic Reviews|issue=1|pages=CD004257|volume=2010|pmid=16437479|doi=10.1002/14651858.CD004257.pub2|pmc=8275921}}</ref><ref name=Derry2016>{{Cite journal|vauthors=Derry S, Conaghan P, Da Silva JA, Wiffen PJ, Moore RA|date=April 2016|title=Topical NSAIDs for chronic musculoskeletal pain in adults|journal=The Cochrane Database of Systematic Reviews|volume=4|issue=4 |pages=CD007400|pmid=27103611|pmc=6494263|doi=10.1002/14651858.CD007400.pub3}}</ref>
*[[Rheumatoid arthritis]]<ref name="pmid2702836">{{Cite journal|vauthors=Gøtzsche PC|date=March 1989|title=Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal antiinflammatory drugs in rheumatoid arthritis|journal=Controlled Clinical Trials|volume=10|issue=1|pages=31–56|pmid=2702836|doi=10.1016/0197-2456(89)90017-2}}</ref>
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*[[Renal colic]]<ref name="isbn0-9757919-2-3"/>
*[[Macular edema]]<ref>{{Cite journal|vauthors=Lim BX, Lim CH, Lim DK, Evans JR, Bunce C, Wormald R|date=November 2016|title=Prophylactic non-steroidal anti-inflammatory drugs for the prevention of macular oedema after cataract surgery|journal=The Cochrane Database of Systematic Reviews|volume=2016|issue=11 |pages=CD006683|pmid=27801522|pmc=6464900|doi=10.1002/14651858.CD006683.pub3}}</ref>
*Traumatic injury<ref name=Mallinson>{{Cite journal|vauthors=Mallinson TE|date=2017|title=A review of ketorolac as a prehospital analgesic|journal=Journal of Paramedic Practice|volume=9|issue=12|pages=522–526|url=https://www.researchgate.net/publication/321640488|access-date=2 June 2018|doi=10.12968/jpar.2017.9.12.522|doi-access=free|archive-date=5 June 2018|archive-url=https://web.archive.org/web/20180605033254/https://www.researchgate.net/publication/321640488_A_review_of_ketorolac_as_a_prehospital_analgesic|url-status=live}}</ref>{{Div col end}}
===Chronic pain and cancer-related pain===
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===Dentistry===
NSAIDs are useful in the management of post-operative [[Toothache|dental pain]] following invasive dental procedures such as [[dental extraction]]. When not contra-indicated, they are favoured over the use of [[paracetamol]] alone due to the anti-inflammatory effect they provide.<ref>{{Cite web|title=Drug Prescribing for Dentistry|url=https://www.
=== Alzheimer's disease ===
Based on [[Observational study|observational studies]] and [[Randomized controlled trial|randomized controlled trials]], NSAID use is not effective for the treatment or prevention of [[Alzheimer's disease]].<ref>{{Cite journal |last1=Asthana |first1=Akash |last2=Tripathi |first2=Shashank |last3=Agarwal |first3=Rachna |date=2023-12-04 |title=Systematic review and meta‑analysis of observational studies to check the protective role of non‑steroidal anti‑inflammatory drugs in Alzheimer's disease
==Contraindications==
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==Adverse effects==
The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly common. Use of NSAIDs increases risk of a range of [[human gastrointestinal tract|gastrointestinal]] (GI) problems, kidney disease and adverse cardiovascular events.<ref name="RostomDube2002">{{cite journal | vauthors = Rostom A, Dube C, Wells G, Tugwell P, Welch V, Jolicoeur E, McGowan J | title = Prevention of NSAID-induced gastroduodenal ulcers | journal = The Cochrane Database of Systematic Reviews | issue = 4 | pages = CD002296 | year = 2002 | volume = 2011 | pmid = 12519573 | doi = 10.1002/14651858.CD002296 | pmc = 8439413 }}</ref><ref>{{cite news|url=https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/medications-non-steroidal-anti-inflammatory-drugs|title=Medications - non-steroidal anti-inflammatory drugs
An estimated 10–20% of people taking NSAIDs experience [[indigestion]]. In the 1990s high doses of prescription NSAIDs were associated with serious upper gastrointestinal adverse events, including bleeding.<ref name="pmid11464731"/>
NSAIDs, like all medications, may interact with other medications. For example, concurrent use of NSAIDs and [[quinolone antibiotic]]s may increase the risk of quinolones' adverse [[central nervous system]] effects, including seizure.<ref>{{cite web |author=Bayer HealthCare Pharmaceuticals Inc |title=Cipro Medication Guide |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019537s68,19847s42,19857s49,20780s26,21473s24lbl.pdf |publisher=[[Food and Drug Administration]] (FDA) |date=September 2008 |access-date=31 August 2009 |archive-date=14 December 2010 |archive-url=https://web.archive.org/web/20101214110353/http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019537s68,19847s42,19857s49,20780s26,21473s24lbl.pdf |url-status=live }}</ref><ref>{{cite book |title=British National Formulary (BNF 57) |author=Royal Pharmaceutical Society of Great Britain |author-link=Royal Pharmaceutical Society of Great Britain |publisher=BMJ Group and RPS Publishing |chapter=5 Infections |year=2009 |isbn=978-0-85369-845-6|title-link=British National Formulary}}</ref>
There is an argument over the benefits and risks of NSAIDs for treating chronic musculoskeletal pain. Each drug has a benefit-risk profile and balancing the risk of no treatment with the competing potential risks of various therapies should be considered.<ref name="van Walsem et al 2015">{{cite journal | vauthors = van Walsem A, Pandhi S, Nixon RM, Guyot P, Karabis A, Moore RA | title = Relative benefit-risk comparing diclofenac to other traditional non-steroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors in patients with osteoarthritis or rheumatoid arthritis: a network meta-analysis | journal = Arthritis Research & Therapy | volume = 17 | issue = 1 | pages = 66 | date = March 2015 | pmid = 25879879 | pmc = 4411793 | doi = 10.1186/s13075-015-0554-0 | doi-broken-date = 19 March 2024 | doi-access = free }}</ref> For people over the age of 65 years old, the balance between the benefits of pain-relief medications such as NSAIDS and the potential for adverse effects has not been well determined.<ref>{{cite journal | vauthors = Jones P, Lamdin R, Dalziel SR | title = Oral non-steroidal anti-inflammatory drugs versus other oral analgesic agents for acute soft tissue injury | journal = The Cochrane Database of Systematic Reviews | volume = 2020 | issue = 8 | pages = CD007789 | date = August 2020 | pmid = 32797734 | pmc = 7438775 | doi = 10.1002/14651858.CD007789.pub3 }}</ref>
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There is some evidence suggesting that, for some people, use of NSAIDs (or other anti-inflammatories) may contribute to the initiation of chronic pain.<ref>{{cite journal | vauthors = Parisien M, et al. | title = Acute inflammatory response via neutrophil activation protects against the development of chronic pain | journal = Science Translational Medicine | volume = 14 | issue = 644 | date = 11 May 2022 | pages = eabj9954 | doi = 10.1126/scitranslmed.abj9954 | pmid=35544595 | pmc = 10317000 | s2cid = 248736062 }}</ref>
Side effects are dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting the use of NSAID therapy. An estimated 10-20% of NSAID patient's experience [[dyspepsia]], and NSAID-associated upper gastrointestinal adverse events are estimated to result in 103,000 hospitalizations and 16,500 deaths per year in the United States, and represent 43% of drug-related emergency visits. Many of these events are avoidable; a review of physician visits and prescriptions estimated that unnecessary prescriptions for NSAIDs were written in 42% of visits.<ref name="pmid114647312">{{Cite journal |author=Green, Ga |year=2001 |title=Understanding NSAIDs: from aspirin to COX-2 |journal=Clinical Cornerstone |volume=3 |issue=5 |pages=50–60 |doi=10.1016/S1098-3597(01)90069-9 |issn=1098-3597 |pmid=11464731}}</ref>
Aspirin should not be taken by people who have [[salicylate intolerance]]<ref name="pmid16247191">{{Cite journal |author=Raithel M |author2=Baenkler HW |author3=Naegel A |last4=Buchwald |first4=F |last5=Schultis |first5=HW |last6=Backhaus |first6=B |last7=Kimpel |first7=S |last8=Koch |first8=H |last9=Mach |first9=K |date=September 2005 |title=Significance of salicylate intolerance in diseases of the lower gastrointestinal tract |url=http://www.jpp.krakow.pl/journal/archive/09_05_s5/pdf/89_09_05_s5_article.pdf |journal=J. Physiol. Pharmacol. |volume=56 |issue=Suppl 5 |pages=89–102 |pmid=16247191 |access-date=8 May 2024 |archive-date=9 April 2011 |archive-url=https://web.archive.org/web/20110409093851/http://www.jpp.krakow.pl/journal/archive/09_05_s5/pdf/89_09_05_s5_article.pdf |url-status=live }}</ref><ref name="pmid8566739">{{Cite journal |vauthors=Senna GE, Andri G, Dama AR, Mezzelani P, Andri L |year=1995 |title=Tolerability of imidazole salycilate in aspirin-sensitive patients |journal=Allergy Proc |volume=16 |issue=5 |pages=251–4 |doi=10.2500/108854195778702675 |pmid=8566739}}</ref> or a more generalized [[drug intolerance]] to NSAIDs, and caution should be exercised in those with [[asthma]] or [[NSAID]]-precipitated [[bronchospasm]]. Owing to its effect on the stomach lining, manufacturers recommend people with [[Peptic ulcer|peptic ulcers]], mild [[diabetes]], or [[gastritis]] seek medical advice before using aspirin.<ref name="mercksource">{{cite web |title=PDR Guide to Over the Counter (OTC) Drugs |url=http://www.mercksource.com/pp/us/cns/cns_hl_pdr.jspzQzpgzEzzSzppdocszSzuszSzcnszSzcontentzSzpdrotczSzotc_fullzSzdrugszSzfgotc036zPzhtm |url-status=live |archive-url=https://web.archive.org/web/20080410223441/http://www.mercksource.com/pp/us/cns/cns_hl_pdr.jspzQzpgzEzzSzppdocszSzuszSzcnszSzcontentzSzpdrotczSzotc_fullzSzdrugszSzfgotc036zPzhtm |archive-date=10 April 2008 |access-date=28 April 2008}}</ref><ref>{{Cite book |author=Frank B. Livingstone. |url=https://books.google.com/books?id=OjqNeJERhWwC&q=0195036344 |title=Frequencies of hemoglobin variants: thalassemia, the glucose-6-phosphate dehydrogenase deficiency, G6PD variants, and ovalocytosis in human populations |publisher=Oxford University Press |year=1985 |isbn=0-19-503634-4 |access-date=7 May 2011}}</ref> Use of aspirin during [[dengue fever]] is not recommended owing to increased bleeding tendency.<ref>{{cite web |title=Dengue and Dengue Hemorrhagic Fever: Information for Health Care Practitioners |url=https://www.cdc.gov/NCIDOD/dvbid/dengue/dengue-hcp.htm |url-status=dead |archive-url=https://web.archive.org/web/20080317070305/http://www.cdc.gov/Ncidod/dvbid/dengue/dengue-hcp.htm |archive-date=17 March 2008 |access-date=28 April 2008}}</ref> People with [[kidney disease]], [[hyperuricemia]], or [[gout]] should not take aspirin because it inhibits the kidneys' ability to excrete [[uric acid]], and thus may exacerbate these conditions.
===Combinational risk===
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NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of [[heart failure]] in people without a history of cardiac disease.<ref name=Bha2013/> In people with such a history, use of NSAIDs (aside from low-dose aspirin) was associated with a more than 10-fold increase in heart failure.<ref name=page2000>{{cite journal | vauthors = Page J, Henry D | title = Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem | journal = Archives of Internal Medicine | volume = 160 | issue = 6 | pages = 777–84 | date = March 2000 | pmid = 10737277 | doi = 10.1001/archinte.160.6.777 | doi-access = free }}</ref> If this link is proven causal, researchers estimate that NSAIDs would be responsible for up to 20 percent of hospital admissions for congestive heart failure. In people with heart failure, NSAIDs increase mortality risk ([[hazard ratio]]) by approximately 1.2–1.3 for naproxen and ibuprofen, 1.7 for rofecoxib and celecoxib, and 2.1 for diclofenac.<ref>{{cite journal | vauthors = Gislason GH, Rasmussen JN, Abildstrom SZ, Schramm TK, Hansen ML, Fosbøl EL, Sørensen R, Folke F, Buch P, Gadsbøll N, Rasmussen S, Poulsen HE, Køber L, Madsen M, Torp-Pedersen C | title = Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure | journal = Archives of Internal Medicine | volume = 169 | issue = 2 | pages = 141–9 | date = January 2009 | pmid = 19171810 | doi = 10.1001/archinternmed.2008.525 | doi-access = free }}</ref>
On 9 July 2015, the [[Food and Drug Administration]] (FDA) toughened warnings of increased [[heart attack]] and [[stroke]] risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs) ''other than [[aspirin]]''.<ref name="FDA-20150709">{{cite web |author=Staff |title=FDA Strengthens Warning of Heart Attack and Stroke Risk for Non-Steroidal Anti-Inflammatory Drugs |url=https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm453610.htm |date=9 July 2015 |publisher=[[Food and Drug Administration]] (FDA) |access-date=9 July 2015 |archive-date=23 April 2019 |archive-url=https://web.archive.org/web/20190423055137/https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm453610.htm |url-status=live }}</ref>
===Possible erectile dysfunction risk===
A 2005 Finnish survey study found an association between long term (over three months) use of NSAIDs and [[erectile dysfunction]].<ref>{{cite journal | vauthors = Shiri R, Koskimäki J, Häkkinen J, Tammela TL, Auvinen A, Hakama M | title = Effect of nonsteroidal anti-inflammatory drug use on the incidence of erectile dysfunction | journal = The Journal of Urology | volume = 175 | issue = 5 | pages = 1812–5; discussion 1815–6 | date = May 2006 | pmid = 16600768 | doi = 10.1016/S0022-5347(05)01000-1 | url = http://www.jurology.com/article/S0022-5347%2805%2901000-1/abstract | access-date = 17 October 2011 | archive-date = 5 October 2013 | archive-url = https://web.archive.org/web/20131005000331/http://www.jurology.com/article/S0022-5347(05)01000-1/abstract | url-status = live }}</ref>
A 2011 publication<ref>{{cite journal | vauthors = Gleason JM, Slezak JM, Jung H, Reynolds K, Van den Eeden SK, Haque R, Quinn VP, Loo RK, Jacobsen SJ | title = Regular nonsteroidal anti-inflammatory drug use and erectile dysfunction | journal = The Journal of Urology | volume = 185 | issue = 4 | pages = 1388–93 | date = April 2011 | pmid = 21334642 | doi = 10.1016/j.juro.2010.11.092 | url = http://www.jurology.com/article/S0022-5347(10)05203-1/abstract | access-date = 21 July 2014 | archive-date = 28 July 2020 | archive-url = https://web.archive.org/web/20200728022613/https://www.auajournals.org/article/S0022-5347%2810%2905203-1/abstract | url-status = live }}</ref> in ''[[The Journal of Urology]]'' received widespread publicity.<ref>{{cite web |url=http://www.medscape.org/viewarticle/738584 |title=Regular NSAID Use Linked to Erectile Dysfunction |
===Gastrointestinal===
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In contrast, [[paracetamol]] (acetaminophen) is regarded as being safe and well tolerated during pregnancy, but Leffers et al. released a study in 2010, indicating that there may be associated male infertility in the unborn.<ref name="pmid15733027">{{cite journal | vauthors = Graham GG, Scott KF, Day RO | title = Tolerability of paracetamol | journal = Drug Safety | volume = 28 | issue = 3 | pages = 227–40 | year = 2005 | pmid = 15733027 | doi = 10.2165/00002018-200528030-00004 | s2cid = 20083476 }}</ref><ref name="pmid21059752">{{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 = 235–44 | date = January 2011 | pmid = 21059752 | doi = 10.1093/humrep/deq323 | doi-access = free }}</ref> Doses should be taken as prescribed, due to risk of liver toxicity with overdoses.<ref name="pmid16351032">{{cite journal | vauthors = Wilkes JM, Clark LE, Herrera JL | title = Acetaminophen overdose in pregnancy | journal = Southern Medical Journal | volume = 98 | issue = 11 | pages = 1118–22 | date = November 2005 | pmid = 16351032 | doi = 10.1097/01.smj.0000184792.15407.51 | s2cid = 21464381 }}</ref>
In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy.<ref>{{cite news |
In October 2020, the U.S. [[Food and Drug Administration]] (FDA) required the [[Drug labelling|drug label]] to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.<ref name="FDA PR 20201015">{{citation-attribution|{{cite press release | title=FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications | website=U.S. [[Food and Drug Administration]] (FDA) | date=15 October 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-warns-using-type-pain-and-fever-medication-second-half-pregnancy-could-lead-complications | access-date=15 October 2020 | archive-date=16 October 2020 | archive-url=https://web.archive.org/web/20201016180003/https://www.fda.gov/news-events/press-announcements/fda-warns-using-type-pain-and-fever-medication-second-half-pregnancy-could-lead-complications | url-status=live }}}}</ref><ref name="FDA safety 20201015">{{citation-attribution|{{cite web | title=NSAIDs may cause rare kidney problems in unborn babies | website=U.S. Food and Drug Administration | date=21 July 2017 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic | access-date=15 October 2020 | archive-date=17 October 2020 | archive-url=https://web.archive.org/web/20201017014419/https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic | url-status=live }}}}</ref> They are recommending avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.<ref name="FDA PR 20201015" /><ref name="FDA safety 20201015" />
===Allergy and allergy-like hypersensitivity reactions===
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The use of NSAIDs for analgesia following gastrointestinal surgery remains controversial, given mixed evidence of an increased risk of leakage from any bowel [[anastomosis]] created. This risk may vary according to the class of NSAID prescribed.<ref name="STARSurg2017"/><ref name="STARSurg2014"/><ref name="Bhangu2014"/>
Common adverse drug reactions (ADR), other than listed above, include: raised liver [[enzymes]], [[headache]], [[dizziness]].<ref name="isbn0-9757919-2-3"/> Uncommon ADRs include an [[hyperkalaemia|abnormally high level of potassium in the blood]], confusion, [[bronchospasm|spasm of the airways]], and rash.<ref name="isbn0-9757919-2-3"/> Ibuprofen may also rarely cause [[irritable bowel syndrome]] symptoms. NSAIDs are also implicated in some cases of [[Stevens–Johnson syndrome]].<ref>{{cite book |
Most NSAIDs penetrate poorly into the [[central nervous system]] (CNS). However, the COX enzymes are expressed constitutively in some areas of the CNS, meaning that even limited penetration may cause adverse effects such as somnolence and dizziness.<ref>{{cite journal | vauthors = Zarghi A, Arfaei S | title = Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships | journal = Iranian Journal of Pharmaceutical Research | volume = 10 | issue = 4 | pages = 655–683 | date = 2011 | pmid = 24250402 | pmc = 3813081 }}</ref>
NSAIDs may increase the risk of bleeding in patients with [[Dengue fever]]<ref name=USCDC_Dengue>{{cite web
In very rare cases, ibuprofen can cause [[aseptic meningitis]].<ref name="pmid24365321">{{cite book |vauthors=Auriel E, Regev K, Korczyn AD |title=Neurologic Aspects of Systemic Disease Part I |chapter=Nonsteroidal anti-inflammatory drugs exposure and the central nervous system |
As with other drugs, [[allergy|allergies]] to NSAIDs might exist. While many allergies are specific to one NSAID, up to 1 in 5 people may have unpredictable cross-reactive allergic responses to other NSAIDs as well.<ref name="pmid23639711">{{cite journal | vauthors = Woessner KM, Castells M | title = NSAID single-drug-induced reactions | journal = Immunology and Allergy Clinics of North America | volume = 33 | issue = 2 | pages = 237–49 | date = May 2013 | pmid = 23639711 | doi = 10.1016/j.iac.2012.12.002 }}</ref>
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== Interactions ==
NSAIDs reduce kidney blood flow and thereby decrease the efficacy of [[diuretic]]s, and inhibit the elimination of [[lithium pharmacology|lithium]] and [[methotrexate]].<ref name="Ogbru">{{cite web |date=17 December 2008 |title=Nonsteroidal Antiinflammatory Drugs (NSAIDs)
NSAIDs cause [[hypocoagulability|decreased ability to form blood clots]], which can increase the risk of bleeding when combined with other drugs that also decrease blood clotting, such as [[warfarin]].<ref name="Ogbru" />
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NSAIDs may reduce the effectiveness of [[Antibiotic|antibiotics]]. An [[In vitro|in-vitro]] study on cultured [[bacteria]] found that adding NSAIDs to antibiotics reduced their effectiveness by around 20%.<ref>{{Cite journal |last1=Bhattacharya |first1=S. |last2=Akula |first2=Y. |last3=Mitongo |first3=G. M. |last4=Khorram |first4=Q. |date=2017 |title=Comparison between effects of antibiotics, NSAIDs and their mixture on the growth of microorganisms: PS151 |journal=Porto Biomedical Journal |volume=2 |issue=5 |pages=176–177 |doi=10.1016/j.pbj.2017.07.006 |issn=2444-8672 |pmc=6806810 |pmid=32258617}}</ref>
The concomitant use of NSAIDs with [[Alcoholic beverage|alcohol]] and/or [[tobacco]] products significantly increases the already elevated risk of [[Peptic ulcer|peptic ulcers]] during NSAID therapy.<ref>{{Cite journal |last=Agrawal |first=N. |date=June 1991 |title=Risk factors for gastrointestinal ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs) |url=https://pubmed.ncbi.nlm.nih.gov/2040888/ |journal=The Journal of Family Practice |volume=32 |issue=6 |pages=619–624 |issn=0094-3509 |pmid=2040888 |access-date=21 March 2024 |archive-date=21 March 2024 |archive-url=https://web.archive.org/web/20240321184819/https://pubmed.ncbi.nlm.nih.gov/2040888/ |url-status=live }}</ref>{{Better source needed|reason=The current source is old (1996) and only an abstract is available for it, making it impossible to verify its claims|date=March 2024}}
==Mechanism of action==
Most NSAIDs act as nonselective inhibitors of the [[cyclooxygenase]] (COX) [[enzyme]]s, inhibiting both the cyclooxygenase-1 ([[COX-1]]) and cyclooxygenase-2 ([[COX-2]]) [[isoenzyme]]s. This inhibition is competitively [[reversible inhibition#Reversible inhibitors|reversible]] (albeit at varying degrees of reversibility), as opposed to the mechanism of [[aspirin]], which is irreversible inhibition.<ref>{{cite journal | vauthors = Knights KM, Mangoni AA, Miners JO | title = Defining the COX inhibitor selectivity of NSAIDs: implications for understanding toxicity | journal = Expert Review of Clinical Pharmacology | volume = 3 | issue = 6 | pages = 769–76 | date = November 2010 | pmid = 22111779 | doi = 10.1586/ecp.10.120 | url = https://www.medscape.com/viewarticle/733075_5 | access-date = 17 February 2013 | publisher = Web MD LLC | s2cid = 207209534 | archive-date = 10 May 2013 | archive-url = https://web.archive.org/web/20130510184705/http://www.medscape.com/viewarticle/733075_5 | url-status = live }}</ref> COX catalyzes the formation of [[prostaglandin]]s and [[thromboxane]] from [[arachidonic acid]] (itself derived from the cellular [[phospholipid]] bilayer by [[phospholipase A2|phospholipase A<sub>2</sub>]]). Prostaglandins act (among other things) as messenger molecules in the process of [[inflammation]]. This [[mechanism of action]] was elucidated in 1970 by [[John Vane]] (1927–2004), who received a [[Nobel Prize]] for his work (see [[Mechanism of action of aspirin]]).<ref>{{Cite journal |last1=Vane |first1=J.R |last2=Botting |first2=R.M |date=June 2003 |title=The mechanism of action of aspirin |url=https://linkinghub.elsevier.com/retrieve/pii/S0049384803003797 |journal=Thrombosis Research |language=en |volume=110 |issue=5–6 |pages=255–258 |doi=10.1016/S0049-3848(03)00379-7 |pmid=14592543 |access-date=30 June 2023 |archive-date=8 March 2023 |archive-url=https://web.archive.org/web/20230308064703/https://linkinghub.elsevier.com/retrieve/pii/S0049384803003797 |url-status=live }}</ref><ref>{{Cite web |title=Sir John Vane, FRS |url=https://www.williamharveyresearch.com/about-us/sir-john-vane-frs |access-date=30 June 2023 |website=www.williamharveyresearch.com |language=english |archive-date=30 June 2023 |archive-url=https://web.archive.org/web/20230630175356/https://www.williamharveyresearch.com/about-us/sir-john-vane-frs |url-status=live }}</ref>
COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes. One of these is in the [[stomach]] lining, where prostaglandins serve a protective role, preventing the stomach [[mucosa]] from being eroded by its own acid. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs.<ref>{{cite journal | vauthors = Zarghi A, Arfaei S | title = Selective COX-2 Inhibitors: A Review of Their Structure-Activity Relationships | journal = Iranian Journal of Pharmaceutical Research | volume = 10 | issue = 4 | pages = 655–83 | date = 2011 | pmid = 24250402 | pmc = 3813081 }}</ref>
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When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, [[peptic ulcer disease|ulcers]] of the stomach or [[duodenum]] and internal [[bleeding]] can result.<ref>{{cite journal | vauthors = Lim YJ, Yang CH | title = Non-steroidal anti-inflammatory drug-induced enteropathy | journal = Clinical Endoscopy | volume = 45 | issue = 2 | pages = 138–144 | date = June 2012 | pmid = 22866254 | pmc = 3401617 | doi = 10.5946/ce.2012.45.2.138 }}</ref> The discovery of COX-2 led to research to the development of selective COX-2 inhibiting drugs that do not cause gastric problems characteristic of older NSAIDs.<ref>{{cite journal | vauthors = Wright JM | title = The double-edged sword of COX-2 selective NSAIDs | journal = CMAJ | volume = 167 | issue = 10 | pages = 1131–1137 | date = November 2002 | pmid = 12427705 | pmc = 134294 }}</ref>
NSAIDs have been studied in various assays to understand how they affect each of these enzymes. While the assays reveal differences, unfortunately, different assays provide differing ratios.<ref>{{cite journal | vauthors = Botting RM | title = Inhibitors of cyclooxygenases: mechanisms, selectivity and uses | journal = Journal of Physiology and Pharmacology | volume = 57 | issue = Suppl 5 | pages = 113–24 | date = November 2006 | pmid = 17218763 | url = http://www.jpp.krakow.pl/journal/archive/11_06_s5/pdf/113_11_06_s5_article.pdf | access-date = 10 June 2012 | archive-date = 27 February 2021 | archive-url = https://web.archive.org/web/20210227070439/http://www.jpp.krakow.pl/journal/archive/11_06_s5/pdf/113_11_06_s5_article.pdf | url-status = live }}</ref>
[[Paracetamol]] (acetaminophen) is not considered an NSAID because it has little anti-inflammatory activity. It treats pain mainly by blocking COX-2 mostly in the central nervous system, but not much in the rest of the body.<ref name="Hinz_20083"/>
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NSAIDs have [[antipyretic]] activity and can be used to treat fever.<ref name="former29">{{cite journal | vauthors = Aronoff DM, Neilson EG | title = Antipyretics: mechanisms of action and clinical use in fever suppression | journal = The American Journal of Medicine | volume = 111 | issue = 4 | pages = 304–15 | date = September 2001 | pmid = 11566461 | doi = 10.1016/S0002-9343(01)00834-8 }}</ref><ref name="former32">{{cite journal | vauthors = Koeberle A, Werz O | title = Inhibitors of the microsomal prostaglandin E(2) synthase-1 as alternative to non steroidal anti-inflammatory drugs (NSAIDs)--a critical review | journal = Current Medicinal Chemistry | volume = 16 | issue = 32 | pages = 4274–96 | year = 2009 | pmid = 19754418 | doi = 10.2174/092986709789578178 }}</ref> Fever is caused by elevated levels of [[prostaglandin E2]] (PGE2), which alters the firing rate of neurons within the [[hypothalamus]] that control thermoregulation.<ref name="former29"/><ref name="former30">{{cite journal | vauthors = Nabulsi M | title = Is combining or alternating antipyretic therapy more beneficial than monotherapy for febrile children? | journal = BMJ | volume = 339 | pages = b3540 | date = October 2009 | pmid = 19797346 | doi = 10.1136/bmj.b3540 | s2cid = 44269305 }}</ref> Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of [[prostanoid]] biosynthesis (PGE2) within the hypothalamus.<ref name="former29"/><ref name="former32"/> PGE2 signals to the hypothalamus to increase the body's thermal setpoint.<ref name="former32"/><ref name="former33">{{cite journal | vauthors = Coceani F, Bishai I, Lees J, Sirko S | title = Prostaglandin E2 and fever: a continuing debate | journal = The Yale Journal of Biology and Medicine | volume = 59 | issue = 2 | pages = 169–74 | year = 1986 | pmid = 3488620 | pmc = 2590134 }}</ref> [[Ibuprofen]] has been shown more effective as an [[antipyretic]] than [[paracetamol]] (acetaminophen).<ref name="former30"/><ref name="former31">{{cite journal | vauthors = Rainsford KD | title = Ibuprofen: pharmacology, efficacy and safety | journal = Inflammopharmacology | volume = 17 | issue = 6 | pages = 275–342 | date = December 2009 | pmid = 19949916 | doi = 10.1007/s10787-009-0016-x | s2cid = 10135223 }}</ref>
[[Arachidonic acid]] is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D, and E.<ref>{{Cite web |title=Prostaglandin Synthase - an overview {{!}} ScienceDirect Topics |url=https://www.sciencedirect.com/topics/medicine-and-dentistry/prostaglandin-synthase |access-date=19 October 2022 |website=www.sciencedirect.com |archive-date=19 October 2022 |archive-url=https://web.archive.org/web/20221019144455/https://www.sciencedirect.com/topics/medicine-and-dentistry/prostaglandin-synthase |url-status=live }}</ref>
==Classification==
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* [[Salsalate]] (Disalcid)
* [[Choline salicylate]]
* [[
* [[Sodium salicylate]]
{{Div col end}}
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{{main|Profen (drug class)}}
{{Div col|colwidth=25em}}
* [[Ibuprofen]]<ref name="urlDrugBank: Ibuprofen (DB01050)">{{cite web |url=https://www.drugbank.ca/drugs/DB01050 |title
* [[Dexibuprofen]]
* [[Naproxen]]
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{{Div col|colwidth=25em}}
* [[Piroxicam]]
* [[Ampiroxicam]]
* [[Meloxicam]]
* [[Tenoxicam]]
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===Anthranilic acid derivatives (Fenamates)===
The following NSAIDs are derived from [[fenamic acid]], which is a derivative of [[anthranilic acid]],<ref name=Sriram>Sriram D, Yogeeswari P. [https://books.google.com/books?id=tUSLclf_NoQC&pg=PA235 Medicinal Chemistry, 2nd Edition]. Pearson Education India, 2010. {{ISBN|9788131731444}}</ref>{{rp|235}} which in turn is a nitrogen [[isostere]] of [[salicylic acid]], which is the [[active metabolite]] of [[aspirin]].<ref name=Sriram/>{{rp|235}}<ref>Auburn University course material. Jack DeRuiter, Principles of Drug Action 2, Fall 2002 1: [http://www.auburn.edu/~deruija/nsaids_2002.pdf Non-Steroidal Antiinflammatory Drugs (NSAIDs)] {{Webarchive|url=https://web.archive.org/web/20180920104528/http://www.auburn.edu/~deruija/nsaids_2002.pdf |date=20 September 2018 }}</ref>{{rp|17}}
{{Div col|colwidth=25em}}
* [[Mefenamic acid]]
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* [[Etoricoxib]] not FDA approved, licensed in the EU
* [[Firocoxib]] used in dogs and horses
* [[Deracoxib]] labeled for use in dogs
* [[Robenacoxib]] labeled for use in dogs and cats
{{Div col end}}
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* [[Licofelone]] acts by inhibiting LOX (lipooxygenase) and COX and hence known as 5-LOX/COX inhibitor
* H-harpagide in [[Scrophularia|figwort]]<ref name="pmid22414102">{{cite journal | vauthors = Viljoen A, Mncwangi N, Vermaak I | title = Anti-inflammatory iridoids of botanical origin | journal = Current Medicinal Chemistry | volume = 19 | issue = 14 | pages = 2104–27 | year = 2012 | pmid = 22414102 | pmc = 3873812 | doi = 10.2174/092986712800229005 }}</ref> or [[Harpagophytum|devil's claw]]<ref name="pmid21775152">{{cite journal | vauthors = Zhang L, Feng L, Jia Q, Xu J, Wang R, Wang Z, Wu Y, Li Y | title = Effects of β-glucosidase hydrolyzed products of harpagide and harpagoside on cyclooxygenase-2 (COX-2) in vitro | journal = Bioorganic & Medicinal Chemistry | volume = 19 | issue = 16 | pages = 4882–6 | date = August 2011 | pmid = 21775152 | doi = 10.1016/j.bmc.2011.06.069 }}</ref>
* ''Some NSAIDs are also given [[Intravenous therapy|Intravenously]] such as [[Ketorolac]] and [[Diclofenac sodium]].''
===Chirality===
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NSAIDs within a group tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses.<ref name=dean/> Rather, differences among compounds usually relate to dosing regimens (related to the compound's [[elimination half-life]]), route of administration, and tolerability profile.{{medical citation needed|date=July 2020}}
Regarding adverse effects, selective [[COX-2 inhibitor]]s have lower risk of gastrointestinal bleeding.<ref name=dean>{{cite book |
A consumer report noted that [[ibuprofen]], naproxen, and [[salsalate]] are less expensive than other NSAIDs, and essentially as effective and safe when used appropriately to treat osteoarthritis and pain.<ref>[http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/Nsaids2.pdf Treating Osteoarthritis and Pain: The Non-Steroidal Anti-Inflammatory Drugs Comparing Effectiveness, Safety, and Price] {{Webarchive|url=https://web.archive.org/web/20161110043556/http://www.consumerreports.org/health/resources/pdf/best-buy-drugs/Nsaids2.pdf |date=10 November 2016 }}
Consumers Union 2005 {{dead link|date=July 2019}}</ref>
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==History==
[[File:Bayer Aspirin ad, NYT, February 19, 1917.jpg|thumb|200px|right|One of the first advertisements for Bayer Aspirin, published in ''[[The New York Times]]'' in 1917]]
It is widely believed that naturally occurring salicin in [[willow]] trees and other plants was used by the ancients as a form of analgesic or anti-inflammatory drug,<ref>{{cite book | vauthors = Jeffreys D |title=Aspirin: the story of a wonder drug |date=2004 |publisher=Bloomsbury |location=London}}</ref> but this story, although compelling, is not entirely true.<ref>{{cite web |
Willow bark (from trees of the [[Willow|''Salix'']] genus) was widely known to be used as a medicine by multiple First Nations communities.<ref>{{Cite book | vauthors = Keoke ED, Porterfield KM|url=http://worldcat.org/oclc/249349540 |title=American Indian contributions to the world: 15,000 years of inventions and innovations |date=2003 |publisher=Checkmark Books |isbn=0-8160-4052-4 |oclc=249349540}}</ref> The bark would be chewed or steeped in water for its pain relieving and antipyretic effects. The effects are a result of the bark's salicin content. Meadowsweet, another plant to contain salicin, has strong roots in British folk medicine for the same maladies. Willow bark was first reported in Western science by Edward Stone in 1763 as a treatment for [[fever|ague]] (fever) according to the pseudoscientific [[doctrine of signatures]].<ref>{{Cite journal |
In the body, salicin is turned into salicylic acid, which produces the antipyretic and analgesic effects that the plants are known for.
Salicin was first isolated by [[Johann Andreas Buchner]] in 1827. By 1829, French chemist Henri Leroux had improved the extraction process to obtain about 30g of purified salicin from 1.5{{nbsp}}kg of willow bark.<ref name="goodman">{{cite book | vauthors = Hardman JG, Limbird LE, Gilman GA |title=Goodman & Gilman, las bases farmacológicas de la terapéutica. |edition=9 |year=1996 |publisher=Ed. McGraw-Hill Interamericana |location= México |isbn=978-0-07-026266-9 |chapter=Capítulo 27: Analgésicos-antipiréticos, antiinflamatorios y fármacos que se utilizan en el tratamiento de la gota.}}</ref> By [[hydrolysis]], salicin releases [[glucose]] and [[salicyl alcohol]] which can be converted into [[salicylic acid]], both [[in vivo]] and through chemical methods.<ref name="organica">John McMurry. [https://books.google.com/books?id=LZ4xXyz8Qy4C Química Orgánica] {{Webarchive|url=https://web.archive.org/web/20230113023612/https://books.google.com/books?id=LZ4xXyz8Qy4C |date=13 January 2023 }} (in Spanish). Published by Cengage Learning Editores, 2005. {{ISBN|970-686-354-0}}</ref> In 1869, [[Hermann Kolbe]] synthesised salicylic acid, although it was too acidic for the [[gastric mucosa]].<ref name="organica" /> The reaction used to synthesise [[aromatic hydrocarbon|aromatic]] acid from a [[phenol]] in the presence of {{CO2}} is known as the [[Kolbe-Schmitt reaction]].<ref>{{cite journal |title=Ueber Synthese der Salicylsäure |author=Hermann Kolbe |journal=[[Annalen der Chemie und Pharmacie]] |year=1860 |volume=113 |issue=1 |pages=125–27 |doi=10.1002/jlac.18601130120 |author-link=Adolph Wilhelm Hermann Kolbe |url=https://zenodo.org/record/1427141 |access-date=28 June 2019 |archive-date=28 July 2020 |archive-url=https://web.archive.org/web/20200728022645/https://zenodo.org/record/1427141 |url-status=live }}</ref><ref>{{cite journal |title=Beitrag zur Kenntniss der Kolbe'schen Salicylsäure Synthese |author=R. Schmitt |journal=[[Journal für Praktische Chemie]] |year=1885 |volume=31 |issue=1 |pages=397–411 |doi=10.1002/prac.18850310130 |url=https://zenodo.org/record/1427904 |access-date=28 June 2019 |archive-date=28 July 2020 |archive-url=https://web.archive.org/web/20200728022700/https://zenodo.org/record/1427904 |url-status=live }}</ref><ref>{{cite journal | vauthors = Lindsey AS, Jeskey H |title=The Kolbe-Schmitt Reaction |year=1957 |journal=[[Chem. Rev.]] |volume=57 |issue=4 |pages=583–620 |doi=10.1021/cr50016a001}} (Review)</ref>
[[File:Kolbe-Schmitt-reaction-mechanism.png|700px|center|Kolbe–Schmitt reaction mechanism]]
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Research supports the use of NSAIDs for the control of pain associated with veterinary procedures such as dehorning and castration of calves.{{Citation needed|date=January 2018}} The best effect is obtained by combining a short-term local anesthetic such as [[lidocaine]] with an NSAID acting as a longer term analgesic.{{Citation needed|date=July 2019}} However, as different species have varying reactions to different medications in the NSAID family, little of the existing research data can be extrapolated to animal species other than those specifically studied, and the relevant government agency in one area sometimes prohibits uses approved in other jurisdictions.{{citation needed|date=July 2020}}
In the United States, [[meloxicam]] is approved for use only in canines, whereas (due to concerns about liver damage) it carries warnings against its use in cats<ref>{{cite web |url=http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118006.pdf |title=NADA 141–213: New Animal Drug Application Approval (for Metacam (meloxicam) 0.5 mg/mL and 1.5 mg/mL Oral Suspension) |date=15 April 2003 |publisher=Food and Drug Administration (FDA) |access-date=24 July 2010 |url-status=dead |archive-url=https://web.archive.org/web/20121015015305/http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118006.pdf |archive-date=15 October 2012}}</ref><ref name="ProdInsert">Metacam [https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/DrugLabels/UCM050394.pdf Client Information Sheet] {{Webarchive|url=https://web.archive.org/web/20110411123756/https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/DrugLabels/UCM050394.pdf |date=11 April 2011}}, product description: "Non-steroidal anti-inflammatory drug for oral use in dogs only", and in the "What Is Metacam" section in bold-face type: "Do not use in cats.", January 2005.</ref> except for one-time use during surgery.<ref>[https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118027.pdf Metacam 5 mg/mL Solution for Injection, Supplemental Approval] 28 October 2004. {{Webarchive|url=https://web.archive.org/web/20110819114026/https://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118027.pdf |date=19 August 2011}}</ref> In spite of these warnings, meloxicam is frequently prescribed "off-label" for non-canine animals including cats and livestock species.<ref>Off-label use discussed in: Arnold Plotnick MS, DVM, ACVIM, ABVP, [http://www.manhattancats.com/Articles/pain.html Pain Management using Metacam] {{webarchive|url=https://web.archive.org/web/20110714025604/http://www.manhattancats.com/Articles/pain.html |date=14 July 2011 }}, and Stein, Robert, [http://www.vasg.org/perioperative_pain_management_part_iv.htm Perioperative Pain Management] {{Webarchive|url=https://web.archive.org/web/20100418035553/http://www.vasg.org/perioperative_pain_management_part_iv.htm |date=18 April 2010 }} Part IV, Looking Beyond Butorphanol, September 2006.</ref> In other countries, for example [[European Union|The European Union]] (EU), there is a label claim for use in cats.<ref>{{cite journal | vauthors = Rhodes L | title = Put a label (claim) on it: Getting non-surgical contraceptives approved for use in cats and dogs | journal = Journal of Feline Medicine and Surgery | volume = 17 | issue = 9 | pages = 783–9 | date = September 2015 | pmid = 26323803 | doi = 10.1177/1098612x15594993 | s2cid = 25045757 | pmc = 11148972 }}</ref>
==See also==
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