Nonsteroidal anti-inflammatory drug

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:{{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}}{{Citation|author1=Consumer Reports Health Best Buy Drugs|author1-link=Consumer Reports|date=July 2013|title=NSAIDs|publisher=Consumer Reports|location=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}}{{cite journal |last1=Machado |first1=Gustavo C |last2=Maher |first2=Chris G |last3=Ferreira |first3=Paulo H |last4=Day |first4=Richard O |last5=Pinheiro |first5=Marina B |last6=Ferreira |first6=Manuela L |title=Non-steroidal anti-inflammatory drugs for spinal pain: a systematic review and meta-analysis |journal=Annals of the Rheumatic Diseases |date=July 2017 |volume=76 |issue=7 |pages=1269–1278 |doi=10.1136/annrheumdis-2016-210597 |pmid=28153830 }}{{Div col|colwidth=25em}}

• Osteoarthritis{{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}}{{cite journal |last1=Derry |first1=Sheena |last2=Conaghan |first2=Philip |last3=Da Silva |first3=José António P |last4=Wiffen |first4=Philip J |last5=Moore |first5=R Andrew |title=Topical NSAIDs for chronic musculoskeletal pain in adults |journal=Cochrane Database of Systematic Reviews |date=22 April 2016 |volume=2020 |issue=2 |pages=CD007400 |doi=10.1002/14651858.CD007400.pub3 |pmid=27103611 |pmc=6494263 }}
• Rheumatoid arthritis{{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}}
• Mild-to-moderate pain due to inflammation and tissue injury
• Low back pain{{Citation|vauthors=Roelofs PD, Deyo RA, Koes BW, Scholten RJ, van Tulder MW|year=2008|title=Cochrane Database of Systematic Reviews|journal=The Cochrane Database of Systematic Reviews|volume=2008 |issue=1|pages=CD000396|pmid=18253976|doi=10.1002/14651858.CD000396.pub3|pmc=10220428 }}
• Inflammatory arthropathies (e.g., ankylosing spondylitis, psoriatic arthritis, reactive arthritis)
• Tennis elbow{{Citation|vauthors=Pattanittum P, Turner T, Green S, Buchbinder R|date=2013|title=Cochrane Database of Systematic Reviews|journal=The Cochrane Database of Systematic Reviews|volume=5|issue=5|pages=CD003686|pmid=23728646|doi=10.1002/14651858.CD003686.pub2|pmc=7173751}}
• Headache
• Migraine
• Acute gout
• Dysmenorrhea (menstrual pain)
• Metastatic bone pain
• Postoperative pain
• Muscle stiffness and pain due to Parkinson's disease
• Pyrexia (fever)
• Ileus
• Renal colic
• Macular edema{{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}}
• Traumatic injury{{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}}{{Div col end}}

The effectiveness of NSAIDs for treating non-cancer chronic pain and cancer-related pain in children and adolescents is not clear.{{Cite journal|vauthors=Eccleston C, Cooper TE, Fisher E, Anderson B, Wilkinson NM|date=August 2017|title=Non-steroidal anti-inflammatory drugs (NSAIDs) for chronic non-cancer pain in children and adolescents|journal=The Cochrane Database of Systematic Reviews|volume=8|issue=8 |pages=CD012537|pmid=28770976|pmc=6460508|doi=10.1002/14651858.CD012537.pub2}}{{Cite journal|vauthors=Cooper TE, Heathcote LC, Anderson B, Grégoire MC, Ljungman G, Eccleston C|date=July 2017|title=Non-steroidal anti-inflammatory drugs (NSAIDs) for cancer-related pain in children and adolescents|journal=The Cochrane Database of Systematic Reviews|volume=7|issue=10|pages=CD012563|pmid=28737843|pmc=6484396|doi=10.1002/14651858.CD012563.pub2}} There have not been sufficient numbers of high-quality randomised controlled trials conducted.

Differences in anti-inflammatory activity between the various individual NSAIDs are small, but there is considerable variation among individual patients in therapeutic response and tolerance to these drugs. About 60% of patients will respond to any NSAID; of the others, those who do not respond to one may well respond to another. Pain relief starts soon after taking the first dose, and a full analgesic effect should normally be obtained within a week, whereas an anti-inflammatory effect may not be achieved (or may not be clinically assessable) for up to three weeks. If appropriate responses are not obtained within these times, another NSAID should be tried.

Pain following surgery can be significant, and many people require strong pain medications such as opioids. There is some low-certainty evidence that starting NSAID painkiller medications in adults early, before surgery, may help reduce post-operative pain, and also reduce the dose or quantity of opioid medications required after surgery.{{cite journal | vauthors = Doleman B, Leonardi-Bee J, Heinink TP, Boyd-Carson H, Carrick L, Mandalia R, Lund JN, Williams JP | title = Pre-emptive and preventive NSAIDs for postoperative pain in adults undergoing all types of surgery | journal = The Cochrane Database of Systematic Reviews | volume = 2021 | issue = 6 | pages = CD012978 | date = June 2021 | pmid = 34125958 | pmc = 8203105 | doi = 10.1002/14651858.CD012978.pub2 }} Any increase risk of surgical bleeding, bleeding in the gastrointestinal system, myocardial infarctions, or injury to the kidneys has not been well studied. When used in combination with paracetamol, the analgesic effect on post-operative pain may be improved.{{cite journal | vauthors = Moore RA, Derry S, Aldington D, Wiffen PJ | title = Single dose oral analgesics for acute postoperative pain in adults - an overview of Cochrane reviews | journal = The Cochrane Database of Systematic Reviews | issue = 9 | pages = CD008659 | date = September 2015 | volume = 2015 | pmid = 26414123 | pmc = 6485441 | doi = 10.1002/14651858.CD008659.pub3 }}

Aspirin, the only NSAID able to irreversibly inhibit COX-1, is also indicated for antithrombosis through inhibition of platelet aggregation. This is useful for the management of arterial thrombosis, and prevention of adverse cardiovascular events like heart attacks. Aspirin inhibits platelet aggregation by inhibiting the action of thromboxane A₂.{{Cite book|vauthors=Mutschler E|date=2013|title=Arzneimittelwirkungen|language=German|trans-title=Pharmaceuticals|publisher=Wissenschaftliche Verlagsgesellschaft Stuttgart|isbn=978-3-8047-2898-1|page=473}}

NSAIDs are useful in the management of post-operative dental pain following invasive dental procedures such as dental extraction.{{Cite web |title=Oral Analgesics for Acute Dental Pain |url=https://www.ada.org/resources/ada-library/oral-health-topics/oral-analgesics-for-acute-dental-pain#:~:text=An%20overview%20of%20systematic%20reviews,than%20any%20opioid-containing%20regimen |access-date=2025-03-28 |website=www.ada.org |language=en}} When not contra-indicated, they are favoured over the use of paracetamol alone due to the anti-inflammatory effect they provide.{{cite web |title=DCEP Drug Prescribing for Dentistry 3rd edition |url=https://www.sdcep.org.uk/wp-content/uploads/2016/03/SDCEP-Drug-Prescribing-for-Dentistry-3rd-edition.pdf |website=Scottish Dental Clinical Effectiveness Programme |publisher=NHS Education for Scotland |access-date=16 November 2024 |archive-url=https://web.archive.org/web/20200705073013/https://www.sdcep.org.uk/wp-content/uploads/2016/03/SDCEP-Drug-Prescribing-for-Dentistry-3rd-edition.pdf |archive-date=2020-07-05 |pages=49–54 |date=January 2016}} There is weak evidence suggesting that taking pre-operative analgesia can reduce the length of post operative pain associated with placing orthodontic spacers under local anaesthetic.{{cite journal |last1=Ashley |first1=Paul F |last2=Parekh |first2=Susan |last3=Moles |first3=David R |last4=Anand |first4=Prabhleen |last5=MacDonald |first5=Laura CI |title=Preoperative analgesics for additional pain relief in children and adolescents having dental treatment |journal=Cochrane Database of Systematic Reviews |date=8 August 2016 |volume=2016 |issue=8 |pages=CD008392 |doi=10.1002/14651858.CD008392.pub3 |pmid=27501304 |pmc=8568367 }}

Based on observational studies and randomized controlled trials, NSAID use is not effective for the treatment or prevention of Alzheimer's disease.{{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 |journal=Acta Neurobiologiae Experimentalis |volume=83 |issue=4 |pages=386–394 |doi=10.55782/ane-2023-2467 |pmid=38224283 |doi-access=free }}{{Cite journal |last1=Miguel-Álvarez |first1=Marina |last2=Santos-Lozano |first2=Alejandro |last3=Sanchis-Gomar |first3=Fabian |last4=Fiuza-Luces |first4=Carmen |last5=Pareja-Galeano |first5=Helios |last6=Garatachea |first6=Nuria |last7=Lucia |first7=Alejandro |date=Feb 2015 |title=Non-steroidal anti-inflammatory drugs as a treatment for Alzheimer's disease: a systematic review and meta-analysis of treatment effect |journal=Drugs & Aging |volume=32 |issue=2 |pages=139–147 |doi=10.1007/s40266-015-0239-z |pmid=25644018 }}

NSAIDs may be used with caution by people with the following conditions:

• Persons who are over age 50, and who have a family history of gastrointestinal (GI) problems
• Persons who have had previous gastrointestinal problems from NSAID use

NSAIDs should usually be avoided by people with the following conditions:

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• Peptic ulcer or stomach bleeding
• Uncontrolled hypertension
• Kidney disease
• People with inflammatory bowel disease{{Medical citation needed|date=March 2024}}
• Past transient ischemic attack (excluding aspirin)
• Past stroke (excluding aspirin)
• Past myocardial infarction (excluding aspirin)
• Coronary artery disease (excluding aspirin)
• Undergoing coronary artery bypass surgery
• Congestive heart failure (excluding low-dose aspirin){{Cite journal|vauthors=Danelich IM, Wright SS, Lose JM, Tefft BJ, Cicci JD, Reed BN|date=May 2015|title=Safety of non-steroidal anti-inflammatory drugs in patients with cardiovascular disease|journal=Pharmacotherapy|volume=35|issue=5|pages=520–35|pmid=25940579|doi=10.1002/phar.1584 |doi-access=free}}
• In third trimester of pregnancy
• Persons who have undergone gastric bypass surgery{{Cite journal|vauthors=Wilson JA, Romagnuolo J, Byrne TK, Morgan K, Wilson FA|date=October 2006|title=Predictors of endoscopic findings after Roux-en-Y gastric bypass|journal=The American Journal of Gastroenterology|volume=101|issue=10|pages=2194–9|doi=10.1111/j.1572-0241.2006.00770.x|pmid=17032183 }}{{Cite web|title=Long term medical issues associated after Roux-en-Y Gastric Bypass Procedure (RYGBP)|url=http://www.SSMHealth.com/weightloss/documents/infosheet-pcp-longterm-medissues.pdf|website=www.SSMHealth.com|publisher=SSMHealth|access-date=18 October 2015|url-status=dead|archive-url=https://web.archive.org/web/20160304061302/http://www.ssmhealth.com/weightloss/documents/infosheet-pcp-longterm-medissues.pdf|archive-date=4 March 2016}}
• Persons who have a history of allergic or allergic-like NSAID hypersensitivity reactions, e.g. aspirin-exacerbated respiratory disease{{Cite journal|vauthors=Kowalski ML, Asero R, Bavbek S, Blanca M, Blanca-Lopez N, Bochenek G, Brockow K, Campo P, Celik G, Cernadas J, Cortellini G, Gomes E, Niżankowska-Mogilnicka E, Romano A, Szczeklik A, Testi S, Torres MJ, Wöhrl S, Makowska J|date=October 2013|title=Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs|journal=Allergy|volume=68|issue=10|pages=1219–32|pmid=24117484|doi=10.1111/all.12260 }}{{Div col end}}

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 gastrointestinal (GI) problems, kidney disease and adverse cardiovascular events.{{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 }}{{cite news|url=https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/medications-non-steroidal-anti-inflammatory-drugs|title=Medications - non-steroidal anti-inflammatory drugs|publisher=U.S. Department of Health & Human Services|access-date=2 February 2018|language=en|archive-date=2 February 2018|archive-url=https://web.archive.org/web/20180202190249/https://www.betterhealth.vic.gov.au/health/conditionsandtreatments/medications-non-steroidal-anti-inflammatory-drugs|url-status=live}} As commonly used for post-operative pain, there is evidence of increased risk of kidney complications.{{cite journal | vauthors = Lee A, Cooper MG, Craig JC, Knight JF, Keneally JP | title = Effects of nonsteroidal anti-inflammatory drugs on postoperative renal function in adults with normal renal function | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD002765 | date = April 2007 | volume = 2018 | pmid = 17443518 | pmc = 6516878 | doi = 10.1002/14651858.CD002765.pub3 }} Their use following gastrointestinal surgery remains controversial, given mixed evidence of increased risk of leakage from any bowel anastomosis created.{{cite journal | author = StarSurg Collaborative | title = Safety of Nonsteroidal Anti-inflammatory Drugs in Major Gastrointestinal Surgery: A Prospective, Multicenter Cohort Study | journal = World Journal of Surgery | volume = 41 | issue = 1 | pages = 47–55 | date = January 2017 | pmid = 27766396 | doi = 10.1007/s00268-016-3727-3 }}{{cite journal | author = StarSurg Collaborative | title = Impact of postoperative non-steroidal anti-inflammatory drugs on adverse events after gastrointestinal surgery | journal = The British Journal of Surgery | volume = 101 | issue = 11 | pages = 1413–23 | date = October 2014 | pmid = 25091299 | doi = 10.1002/bjs.9614 | doi-access = free }}{{cite journal | vauthors = Bhangu A, Singh P, Fitzgerald JE, Slesser A, Tekkis P | title = Postoperative nonsteroidal anti-inflammatory drugs and risk of anastomotic leak: meta-analysis of clinical and experimental studies | journal = World Journal of Surgery | volume = 38 | issue = 9 | pages = 2247–57 | date = September 2014 | pmid = 24682313 | doi = 10.1007/s00268-014-2531-1 }}

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.

NSAIDs, like all medications, may interact with other medications. For example, concurrent use of NSAIDs and quinolone antibiotics may increase the risk of quinolones' adverse central nervous system effects, including seizure.{{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 }}{{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}}

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.{{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-access = free }} 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.{{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 }}

There is some evidence suggesting that, for some people, use of NSAIDs (or other anti-inflammatories) may contribute to the initiation of chronic pain.{{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 }}

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 patients 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.{{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 |pmid=11464731}}

Aspirin should not be taken by people who have salicylate intolerance{{cite journal |last1=Raithel |first1=M. |last2=Baenkler |first2=H. W. |last3=Naegel |first3=A. |last4=Buchwald |first4=F. |last5=Schultis |first5=H. W. |last6=Backhaus |first6=B. |last7=Kimpel |first7=S. |last8=Koch |first8=H. |last9=Mach |first9=K. |last10=Hahn |first10=E. G. |last11=Konturek |first11=P. C. |title=Significance of salicylate intolerance in diseases of the lower gastrointestinal tract |journal=Journal of Physiology and Pharmacology|date=September 2005 |volume=56 Suppl 5 |pages=89–102 |pmid=16247191 |url=https://www.jpp.krakow.pl/journal/archive/09_05_s5/pdf/89_09_05_s5_article.pdf }}{{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}} 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 ulcers, mild diabetes, or gastritis seek medical advice before using aspirin.{{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}}{{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}} Use of aspirin during dengue fever is not recommended owing to increased bleeding tendency.{{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|publisher=Centers for Disease Control and Prevention}} 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.

If a COX-2 inhibitor is taken, a traditional NSAID (prescription or over-the-counter) should not be taken at the same time.{{cite web |title=What Are NSAIDs? |url=http://orthoinfo.aaos.org/fact/thr_report.cfm?Thread_ID=398&topcategory=About |url-status= dead |archive-url=https://web.archive.org/web/20070129065844/http://orthoinfo.aaos.org/fact/thr_report.cfm?Thread_ID=398&topcategory=About |archive-date= 29 January 2007}}

Rofecoxib (Vioxx) was shown to produce significantly fewer gastrointestinal adverse drug reactions (ADRs) compared with naproxen.{{cite journal | vauthors = Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ | title = Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group | journal = The New England Journal of Medicine | volume = 343 | issue = 21 | pages = 1520–8, 2 p following 1528 | date = November 2000 | pmid = 11087881 | doi = 10.1056/NEJM200011233432103 | doi-access = free }} The study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs (COX-2 inhibitors). A statistically significant increase in the incidence of myocardial infarctions was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a statistically significant relative risk of cardiovascular events of 1.97 versus placebo{{cite journal | vauthors = Baron JA, Sandler RS, Bresalier RS, Lanas A, Morton DG, Riddell R, Iverson ER, Demets DL | title = Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial | journal = The Lancet | volume = 372 | issue = 9651 | pages = 1756–64 | date = November 2008 | pmid = 18922570 | doi = 10.1016/S0140-6736(08)61490-7 }}—which caused a worldwide withdrawal of rofecoxib in October 2004.{{cite journal | vauthors = Sibbald B | title = Rofecoxib (Vioxx) voluntarily withdrawn from market | journal = CMAJ | volume = 171 | issue = 9 | pages = 1027–8 | date = October 2004 | pmid = 15505253 | pmc = 526313 | doi = 10.1503/cmaj.1041606 }}

Use of methotrexate together with NSAIDs in rheumatoid arthritis is safe, if adequate monitoring is done.{{cite journal | vauthors = Colebatch AN, Marks JL, Edwards CJ | title = Safety of non-steroidal anti-inflammatory drugs, including aspirin and paracetamol (acetaminophen) in people receiving methotrexate for inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis) | journal = The Cochrane Database of Systematic Reviews | issue = 11 | pages = CD008872 | date = November 2011 | pmid = 22071858 | doi = 10.1002/14651858.CD008872.pub2 }}

NSAIDs, aside from aspirin, increase the risk of myocardial infarction and stroke.{{cite journal | vauthors = Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C | title = Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials | journal = BMJ | volume = 332 | issue = 7553 | pages = 1302–8 | date = June 2006 | pmid = 16740558 | pmc = 1473048 | doi = 10.1136/bmj.332.7553.1302 }} This occurs at least within a week of use. They are not recommended in those who have had a previous heart attack as they increase the risk of death or recurrent MI.{{cite journal | vauthors = Schjerning Olsen AM, Fosbøl EL, Lindhardsen J, Folke F, Charlot M, Selmer C, Lamberts M, Bjerring Olesen J, Køber L, Hansen PR, Torp-Pedersen C, Gislason GH | title = Duration of treatment with nonsteroidal anti-inflammatory drugs and impact on risk of death and recurrent myocardial infarction in patients with prior myocardial infarction: a nationwide cohort study | journal = Circulation | volume = 123 | issue = 20 | pages = 2226–35 | date = May 2011 | pmid = 21555710 | doi = 10.1161/CIRCULATIONAHA.110.004671 | doi-access = free }} Evidence indicates that naproxen may be the least harmful out of these.{{cite journal | vauthors = Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, Egger M, Jüni P | title = Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis | journal = BMJ | volume = 342 | issue = jan11 1 | pages = c7086 | date = January 2011 | pmid = 21224324 | pmc = 3019238 | doi = 10.1136/bmj.c7086 }}{{cite journal | vauthors = Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Baron JA, Bombardier C, Cannon C, Farkouh ME, FitzGerald GA, Goss P, Halls H, Hawk E, Hawkey C, Hennekens C, Hochberg M, Holland LE, Kearney PM, Laine L, Lanas A, Lance P, Laupacis A, Oates J, Patrono C, Schnitzer TJ, Solomon S, Tugwell P, Wilson K, Wittes J, Baigent C | title = Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials | journal = The Lancet | volume = 382 | issue = 9894 | pages = 769–79 | date = August 2013 | pmid = 23726390 | pmc = 3778977 | doi = 10.1016/S0140-6736(13)60900-9 }}

NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of heart failure in people without a history of cardiac disease. 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.{{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 }} 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.{{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 }}

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.{{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 }}

A 2005 Finnish survey study found an association between long term (over three months) use of NSAIDs and erectile dysfunction.{{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 }}

A 2011 publication{{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 }} in The Journal of Urology received widespread publicity.{{cite web |url=http://www.medscape.org/viewarticle/738584 |title=Regular NSAID Use Linked to Erectile Dysfunction |vauthors=Barclay L |date=8 March 2011 |website=Medscape |access-date=21 July 2014 |archive-date=16 October 2014 |archive-url=https://web.archive.org/web/20141016003907/http://www.medscape.org/viewarticle/738584 |url-status=live }} According to the study, men who used NSAIDs regularly were at significantly increased risk of erectile dysfunction. A link between NSAID use and erectile dysfunction still existed after controlling for several conditions. However, the study was observational and not controlled, with low original participation rate, potential participation bias, and other uncontrolled factors. The authors warned against drawing any conclusion regarding cause.{{cite web |url=https://www.medpagetoday.org/urology/erectiledysfunction/25204 |title=NSAID Use Tied to Men's Sexual Performance |vauthors=Neale T |date=5 March 2011 |website=MedPage Today |access-date=21 July 2014 |archive-date=28 July 2020 |archive-url=https://web.archive.org/web/20200728022615/https://www.medpagetoday.org/urology/erectiledysfunction/25204?vpass=1 |url-status=live }}

The main adverse drug reactions (ADRs) associated with NSAID use relate to direct and indirect irritation of the gastrointestinal (GI) tract. NSAIDs cause a dual assault on the GI tract: the acidic molecules directly irritate the gastric mucosa, and inhibition of COX-1 and COX-2 reduces the levels of protective prostaglandins. Inhibition of prostaglandin synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished mucus secretion and diminished trophic effects on the epithelial mucosa.{{cite journal | vauthors = Wallace JL | title = Prostaglandins, NSAIDs, and gastric mucosal protection: why doesn't the stomach digest itself? | journal = Physiological Reviews | volume = 88 | issue = 4 | pages = 1547–1565 | date = October 2008 | pmid = 18923189 | doi = 10.1152/physrev.00004.2008 }}

Common gastrointestinal side effects include:

• Nausea or vomiting
• Indigestion
• Gastric ulceration or bleeding{{cite journal | vauthors = Traversa G, Walker AM, Ippolito FM, Caffari B, Capurso L, Dezi A, Koch M, Maggini M, Alegiani SS, Raschetti R | title = Gastroduodenal toxicity of different nonsteroidal antiinflammatory drugs | journal = Epidemiology | volume = 6 | issue = 1 | pages = 49–54 | date = January 1995 | pmid = 7888445 | doi = 10.1097/00001648-199501000-00010 | doi-access = free }}
• Diarrhea

Clinical NSAID ulcers are related to the systemic effects of NSAID administration. Such damage occurs irrespective of the route of administration of the NSAID (e.g., oral, rectal, or parenteral) and can occur even in people who have achlorhydria.Textbook of Gastroenterology, Tadataka Yamada, 2008, Ch.40, Peptic Ulcer Disease, page 941

Ulceration risk increases with therapy duration, and with higher doses. To minimize GI side effects, it is prudent to use the lowest effective dose for the shortest period of time—a practice that studies show is often not followed. Over 50% of patients who take NSAIDs have sustained some mucosal damage to their small intestine.{{cite journal | vauthors = Higuchi K, Umegaki E, Watanabe T, Yoda Y, Morita E, Murano M, Tokioka S, Arakawa T | title = Present status and strategy of NSAIDs-induced small bowel injury | journal = Journal of Gastroenterology | volume = 44 | issue = 9 | pages = 879–88 | date = July 2009 | pmid = 19568687 | doi = 10.1007/s00535-009-0102-2 | doi-access = free }}

The risk and rate of gastric adverse effects is different depending on the type of NSAID medication a person is taking. Indomethacin, ketoprofen, and piroxicam use appear to lead to the highest rate of gastric adverse effects, while ibuprofen (lower doses) and diclofenac appear to have lower rates.

Certain NSAIDs, such as aspirin, have been marketed in enteric-coated formulations that manufacturers claim reduce the incidence of gastrointestinal ADRs. Similarly, some believe that rectal formulations may reduce gastrointestinal ADRs. However, consistent with the systemic mechanism of such ADRs, and in clinical practice, these formulations have not demonstrated a reduced risk of GI ulceration.

Numerous "gastro-protective" drugs have been developed with the goal of preventing gastrointestinal toxicity in people who need to take NSAIDs on a regular basis. Gastric adverse effects may be reduced by taking medications that suppress acid production such as proton pump inhibitors (e.g.: omeprazole and esomeprazole), or by treatment with a drug that mimics prostaglandin in order to restore the lining of the GI tract (e.g.: a prostaglandin analog misoprostol). Diarrhea is a common side effect of misoprostol; however, higher doses of misoprostol have been shown to reduce the risk of a person having a complication related to a gastric ulcer while taking NSAIDs. While these techniques may be effective, they are expensive for maintenance therapy.{{cite journal | vauthors = Scarpignato C, Gatta L, Zullo A, Blandizzi C | title = Effective and safe proton pump inhibitor therapy in acid-related diseases - A position paper addressing benefits and potential harms of acid suppression | journal = BMC Medicine | volume = 14 | issue = 1 | pages = 179 | date = November 2016 | pmid = 27825371 | pmc = 5101793 | doi = 10.1186/s12916-016-0718-z | first15 = the Italian Association of Hospital Gastroenterologists, and the Italian Federation of General Practitioners | doi-access = free }}

Hydrogen sulfide NSAID hybrids prevent the gastric ulceration/bleeding associated with taking the NSAIDs alone. Hydrogen sulfide is known to have a protective effect on the cardiovascular and gastrointestinal system.{{cite journal | vauthors = Guo W, Cheng ZY, Zhu YZ | title = Hydrogen sulfide and translational medicine | language = En | journal = Acta Pharmacologica Sinica | volume = 34 | issue = 10 | pages = 1284–91 | date = October 2013 | pmid = 24096643 | pmc = 3791558 | doi = 10.1038/aps.2013.127 }}

NSAIDs should be used with caution in individuals with inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) due to their tendency to cause gastric bleeding and form ulceration in the gastric lining.{{cite journal | vauthors = Long MD, Kappelman MD, Martin CF, Chen W, Anton K, Sandler RS | title = Role of Nonsteroidal Anti-Inflammatory Drugs in Exacerbations of Inflammatory Bowel Disease | journal = Journal of Clinical Gastroenterology | volume = 50 | issue = 2 | pages = 152–6 | date = February 2016 | pmid = 26485106 | pmc = 4703528 | doi = 10.1097/MCG.0000000000000421 }}

NSAIDs are also associated with a fairly high incidence of adverse drug reactions (ADRs) on the kidney and over time can lead to chronic kidney disease. The mechanism of these kidney ADRs is due to changes in kidney blood flow. Prostaglandins normally dilate the afferent arterioles of the glomeruli. This helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of kidney function. This is particularly important in kidney failure where the kidney is trying to maintain renal perfusion pressure by elevated angiotensin II levels. At these elevated levels, angiotensin II also constricts the afferent arteriole into the glomerulus in addition to the efferent arteriole it normally constricts. Since NSAIDs block this prostaglandin-mediated effect of afferent arteriole dilation, particularly in kidney failure, NSAIDs cause unopposed constriction of the afferent arteriole and decreased RPF (renal perfusion flow) and GFR.{{cite journal | vauthors = Hörl WH | title = Nonsteroidal Anti-Inflammatory Drugs and the Kidney | journal = Pharmaceuticals | volume = 3 | issue = 7 | pages = 2291–2321 | date = July 2010 | pmid = 27713354 | pmc = 4036662 | doi = 10.3390/ph3072291 | doi-access = free }}

Common ADRs associated with altered kidney function include:

• Sodium and fluid retention
• Hypertension (high blood pressure)

These agents may also cause kidney impairment, especially in combination with other nephrotoxic agents. Kidney failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor (which removes angiotensin II's vasoconstriction of the efferent arteriole) and a diuretic (which drops plasma volume, and thereby RPF)—the so-called "triple whammy" effect.{{cite journal | vauthors = Thomas MC | title = Diuretics, ACE inhibitors and NSAIDs--the triple whammy | journal = The Medical Journal of Australia | volume = 172 | issue = 4 | pages = 184–5 | date = February 2000 | pmid = 10772593 | doi = 10.5694/j.1326-5377.2000.tb125548.x }}

In rarer instances NSAIDs may also cause more severe kidney conditions:

• Interstitial nephritis
• Nephrotic syndrome
• Acute kidney injury
• Acute tubular necrosis
• Renal papillary necrosis

NSAIDs in combination with excessive use of phenacetin or paracetamol (acetaminophen) may lead to analgesic nephropathy.{{cite journal | vauthors = De Broe ME, Elseviers MM | title = Analgesic nephropathy | journal = The New England Journal of Medicine | volume = 338 | issue = 7 | pages = 446–52 | date = February 1998 | pmid = 9459649 | doi = 10.1056/NEJM199802123380707 }}

Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs.{{cite journal | vauthors = Moore DE | title = Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management | journal = Drug Safety | volume = 25 | issue = 5 | pages = 345–372 | year = 2002 | pmid = 12020173 | doi = 10.2165/00002018-200225050-00004 }} The 2-arylpropionic acids are the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including piroxicam, diclofenac, and benzydamine.{{cite journal | vauthors = Lozzi F, Di Raimondo C, Lanna C, Diluvio L, Mazzilli S, Garofalo V, Dika E, Dellambra E, Coniglione F, Bianchi L, Campione E | title = Latest Evidence Regarding the Effects of Photosensitive Drugs on the Skin: Pathogenetic Mechanisms and Clinical Manifestations | journal = Pharmaceutics | volume = 12 | issue = 11 | pages = 1104 | date = November 2020 | pmid = 33213076 | pmc = 7698592 | doi = 10.3390/pharmaceutics12111104 | doi-access = free }}

Benoxaprofen, since withdrawn due to its liver toxicity, was the most photoactive NSAID observed. The mechanism of photosensitivity, responsible for the high photoactivity of the 2-arylpropionic acids, is the ready decarboxylation of the carboxylic acid moiety. The specific absorbance characteristics of the different chromophoric 2-aryl substituents, affects the decarboxylation mechanism.{{cite journal | vauthors = Musa KA, Eriksson LA | title = Computational Studies of the Photodegradation Mechanism of the Highly Phototoxic Agent Benoxaprofen | journal = ACS Omega | volume = 7 | issue = 33 | pages = 29475–29482 | date = August 2022 | pmid = 36033698 | pmc = 9404164 | doi = 10.1021/acsomega.2c03118 }}

While NSAIDs as a class are not direct teratogens, use of NSAIDs in late pregnancy can cause premature closure of the fetal ductus arteriosus and kidney ADRs in the fetus.{{cite journal | vauthors = Koren G, Florescu A, Costei AM, Boskovic R, Moretti ME | title = Nonsteroidal antiinflammatory drugs during third trimester and the risk of premature closure of the ductus arteriosus: a meta-analysis | journal = The Annals of Pharmacotherapy | volume = 40 | issue = 5 | pages = 824–829 | date = May 2006 | pmid = 16638921 | doi = 10.1345/aph.1G428 }} Thus, NSAIDs are not recommended during the third trimester of pregnancy because of the increased risk of premature constriction of the ductus arteriosus. Additionally, they are linked with premature birth{{cite journal | vauthors = Østensen ME, Skomsvoll JF | title = Anti-inflammatory pharmacotherapy during pregnancy | journal = Expert Opinion on Pharmacotherapy | volume = 5 | issue = 3 | pages = 571–580 | date = March 2004 | pmid = 15013926 | doi = 10.1517/14656566.5.3.571 }} and miscarriage.{{cite journal | vauthors = Nakhai-Pour HR, Broy P, Sheehy O, Bérard A | title = Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion | journal = CMAJ | volume = 183 | issue = 15 | pages = 1713–1720 | date = October 2011 | pmid = 21896698 | pmc = 3193112 | doi = 10.1503/cmaj.110454 }} Aspirin, however, is used together with heparin in pregnant women with antiphospholipid syndrome.{{cite journal | vauthors = Cervera R, Balasch J | title = The management of pregnant patients with antiphospholipid syndrome | journal = Lupus | volume = 13 | issue = 9 | pages = 683–687 | year = 2004 | pmid = 15485103 | doi = 10.1191/0961203304lu1092oa }} Additionally, indomethacin can be used in pregnancy to treat polyhydramnios by reducing fetal urine production via inhibiting fetal renal blood flow.{{cite journal | vauthors = Hamza A, Herr D, Solomayer EF, Meyberg-Solomayer G | title = Polyhydramnios: Causes, Diagnosis and Therapy | language = de | journal = Geburtshilfe und Frauenheilkunde | volume = 73 | issue = 12 | pages = 1241–1246 | date = December 2013 | pmid = 24771905 | pmc = 3964358 | doi = 10.1055/s-0033-1360163 }}

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.{{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 }}{{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 }} Doses should be taken as prescribed, due to risk of liver toxicity with overdoses.{{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 }}

In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy.{{cite news |vauthors=Dreillard A |date=2 March 2009 |title=Grossesse – Mamans attention |url=http://www.francesoir.fr/societe/2009/03/02/grossesse-mamans-attention.html |work=France Soir |access-date=1 June 2009 |language=fr |url-status=dead |archive-url=https://web.archive.org/web/20090609142802/http://www.francesoir.fr/societe/2009/03/02/grossesse-mamans-attention.html |archive-date=9 June 2009 }}

In October 2020, the U.S. Food and Drug Administration (FDA) required the drug label to be updated for all nonsteroidal anti-inflammatory medications, to describe the risk of kidney problems in unborn babies which can then lead to low amniotic fluid levels, as a result of the use of NSAIDs.{{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 }}}}{{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 }}}} They are recommending avoiding the use of NSAIDs by pregnant women at 20 weeks or later in pregnancy.

A variety of allergic or allergic-like NSAID hypersensitivity reactions follow the ingestion of NSAIDs. These hypersensitivity reactions differ from the other adverse reactions listed here which are toxicity reactions, i.e. unwanted reactions that result from the pharmacological action of a drug, are dose-related, and can occur in any treated individual; hypersensitivity reactions are idiosyncratic reactions to a drug.{{cite journal | vauthors = Kowalski ML, Makowska JS | title = Seven steps to the diagnosis of NSAIDs hypersensitivity: how to apply a new classification in real practice? | journal = Allergy, Asthma & Immunology Research | volume = 7 | issue = 4 | pages = 312–20 | date = July 2015 | pmid = 25749768 | pmc = 4446629 | doi = 10.4168/aair.2015.7.4.312 | doi-access = free }} Some NSAID hypersensitivity reactions are truly allergic in origin: 1) repetitive IgE-mediated urticarial skin eruptions, angioedema, and anaphylaxis following immediately to hours after ingesting one structural type of NSAID but not after ingesting structurally unrelated NSAIDs; and 2) Comparatively mild to moderately severe T cell-mediated delayed onset (usually more than 24 hour), skin reactions such as maculopapular rash, fixed drug eruptions, photosensitivity reactions, delayed urticaria, and contact dermatitis; or 3) far more severe and potentially life-threatening t-cell-mediated delayed systemic reactions such as the DRESS syndrome, acute generalized exanthematous pustulosis, the Stevens–Johnson syndrome, and toxic epidermal necrolysis. Other NSAID hypersensitivity reactions are allergy-like symptoms but do not involve true allergic mechanisms; rather, they appear due to the ability of NSAIDs to alter the metabolism of arachidonic acid in favor of forming metabolites that promote allergic symptoms. Affected individuals may be abnormally sensitive to these provocative metabolites or overproduce them and typically are susceptible to a wide range of structurally dissimilar NSAIDs, particularly those that inhibit COX1. Symptoms, which develop immediately to hours after ingesting any of various NSAIDs that inhibit COX-1, are: 1) exacerbations of asthmatic and rhinitis (see aspirin-exacerbated respiratory disease) symptoms in individuals with a history of asthma or rhinitis and 2) exacerbation or first-time development of wheals or angioedema in individuals with or without a history of chronic urticarial lesions or angioedema.

It has been hypothesized that NSAIDs may delay healing from bone and soft-tissue injuries by inhibiting inflammation.{{cite journal | vauthors = Constantinescu DS, Campbell MP, Moatshe G, Vap AR | title = Effects of Perioperative Nonsteroidal Anti-inflammatory Drug Administration on Soft Tissue Healing: A Systematic Review of Clinical Outcomes After Sports Medicine Orthopaedic Surgery Procedures | journal = Orthopaedic Journal of Sports Medicine | volume = 7 | issue = 4 | pages = 2325967119838873 | date = April 2019 | pmid = 31019986 | pmc = 6469280 | doi = 10.1177/2325967119838873 }} On the other hand, it has also been hypothesized that NSAIDs might speed recovery from soft tissue injuries by preventing inflammatory processes from damaging adjacent, non-injured muscles.{{cite journal | vauthors = Morelli KM, Brown LB, Warren GL | title = Effect of NSAIDs on Recovery From Acute Skeletal Muscle Injury: A Systematic Review and Meta-analysis | journal = The American Journal of Sports Medicine | volume = 46 | issue = 1 | pages = 224–233 | date = January 2018 | pmid = 28355084 | doi = 10.1177/0363546517697957 | doi-access = free }}

There is moderate evidence that they delay bone healing.{{cite journal| vauthors = Ali MU, Usman M, Patel K |date=Apr 2020|title=Effects of NSAID use on bone healing: A meta-analysis of retrospective case–control and cohort studies within clinical settings|journal=Trauma |volume=22|issue=2|pages=94–111|doi=10.1177/1460408619886211 }} Their overall effect on soft-tissue healing is unclear.{{cite journal | vauthors = Ghosh N, Kolade OO, Shontz E, Rosenthal Y, Zuckerman JD, Bosco JA, Virk MS | title = Nonsteroidal Anti-Inflammatory Drugs (NSAIDs) and Their Effect on Musculoskeletal Soft-Tissue Healing: A Scoping Review | language = en-US | journal = JBJS Reviews | volume = 7 | issue = 12 | pages = e4 | date = December 2019 | pmid = 31851037 | doi = 10.2106/JBJS.RVW.19.00055 }}

Long-term use of NSAID analgesics and paracetamol is associated with an increased risk of hearing loss.{{cite journal | vauthors = Lin BM, Curhan SG, Wang M, Eavey R, Stankovic KM, Curhan GC | title = Duration of Analgesic Use and Risk of Hearing Loss in Women | journal = American Journal of Epidemiology | volume = 185 | issue = 1 | pages = 40–47 | date = January 2017 | pmid = 27974293 | pmc = 5209586 | doi = 10.1093/aje/kww154 }}{{cite journal | vauthors = Curhan SG, Shargorodsky J, Eavey R, Curhan GC | title = Analgesic use and the risk of hearing loss in women | journal = American Journal of Epidemiology | volume = 176 | issue = 6 | pages = 544–54 | date = September 2012 | pmid = 22933387 | pmc = 3530351 | doi = 10.1093/aje/kws146 }}{{cite journal | vauthors = Curhan SG, Eavey R, Shargorodsky J, Curhan GC | title = Analgesic use and the risk of hearing loss in men | journal = The American Journal of Medicine | volume = 123 | issue = 3 | pages = 231–7 | date = March 2010 | pmid = 20193831 | pmc = 2831770 | doi = 10.1016/j.amjmed.2009.08.006 }}

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.

Common adverse drug reactions (ADR), other than listed above, include: raised liver enzymes, headache, dizziness. Uncommon ADRs include an abnormally high level of potassium in the blood, confusion, spasm of the airways, and rash. Ibuprofen may also rarely cause irritable bowel syndrome symptoms. NSAIDs are also implicated in some cases of Stevens–Johnson syndrome.{{cite book |last1=Ershad |first1=Muhammed |last2=Ameer |first2=Muhammad Atif |last3=Chen |first3=Richard J. |last4=Vearrier |first4=David |title=StatPearls |date=2025 |publisher=StatPearls Publishing |chapter-url=http://www.ncbi.nlm.nih.gov/books/NBK526078/ |chapter=Ibuprofen Toxicity |pmid=30252334 }}

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.{{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 }}

NSAIDs may increase the risk of bleeding in patients with Dengue fever{{cite web|title=Dengue|url=https://wwwnc.cdc.gov/travel/diseases/dengue|publisher=United States Centers for Disease Control and Prevention|access-date=27 April 2018|date=28 March 2016|quote=Use acetaminophen. Do not take pain relievers that contain aspirin and ibuprofen (Advil), it may lead to a greater tendency to bleed.|archive-date=24 March 2018|archive-url=https://web.archive.org/web/20180324100419/https://wwwnc.cdc.gov/travel/diseases/dengue|url-status=live}} For this reason, NSAIDs are only available with a prescription in India.{{cite news|title=Delhi government bans over the counter sale of NSAIDs without prescription|newspaper=The Economic Times|year=2015|url=https://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/delhi-government-bans-over-the-counter-sale-of-nsaids-without-prescription/articleshow/48441880.cms|access-date=6 November 2019|archive-date=15 April 2021|archive-url=https://web.archive.org/web/20210415214556/https://economictimes.indiatimes.com/industry/healthcare/biotech/pharmaceuticals/delhi-government-bans-over-the-counter-sale-of-nsaids-without-prescription/articleshow/48441880.cms|url-status=live}}

In very rare cases, ibuprofen can cause aseptic meningitis.{{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 |series=Handbook of Clinical Neurology |volume=119 |pages=577–84 |date=2014 |pmid=24365321 |doi=10.1016/B978-0-7020-4086-3.00038-2|isbn=978-0-7020-4086-3 }}

As with other drugs, 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.{{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 }}

Although small doses generally have little to no effect on the immune system, large doses of NSAIDs significantly suppress the production of immune cells. As NSAIDs affect prostaglandins, they affect the production of most fast growing cells. This includes immune cells. Unlike corticosteroids, they do not directly suppress the immune system and so their effect on the immune system is not immediately obvious. They suppress the production of new immune cells, but leave existing immune cells functional. Large doses slowly reduce the immune response as the immune cells are renewed at a much lower rate. Causing a gradual reduction of the immune system, much slower and less noticeable than the immediate effect of Corticosteroids. The effect significantly increases with dosage, in a nearly exponential rate. Doubling of dose reduced cells by nearly four times. Increasing dose by five times reduced cell counts to only a few percent of normal levels. This is likely why the effect was not immediately obvious in low dose trials, as the effect is not apparent until much higher dosages are tested.{{cite journal | vauthors = Bancos S, Bernard MP, Topham DJ, Phipps RP | title = Ibuprofen and other widely used non-steroidal anti-inflammatory drugs inhibit antibody production in human cells | journal = Cellular Immunology | volume = 258 | issue = 1 | pages = 18–28 | date = 2009 | pmid = 19345936 | pmc = 2693360 | doi = 10.1016/j.cellimm.2009.03.007 }}

NSAIDs reduce kidney blood flow and thereby decrease the efficacy of diuretics, and inhibit the elimination of lithium and methotrexate.{{cite web |date=17 December 2008 |title=Nonsteroidal Antiinflammatory Drugs (NSAIDs) |url=https://www.medicinenet.com/nonsteroidal_antiinflammatory_drugs/article.htm |work=MedicineNet |vauthors=Ogbru O |access-date=29 January 2020 |archive-date=10 April 2021 |archive-url=https://web.archive.org/web/20210410233828/https://www.medicinenet.com/nonsteroidal_antiinflammatory_drugs/article.htm |url-status=live }}

NSAIDs cause 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.

NSAIDs may aggravate hypertension (high blood pressure) and thereby antagonize the effect of antihypertensives, such as ACE inhibitors.{{cite journal |last1=Shionoiri |first1=Hiroshi |title=Pharmacokinetic Drug Interactions with ACE Inhibitors |journal=Clinical Pharmacokinetics |date=July 1993 |volume=25 |issue=1 |pages=20–58 |doi=10.2165/00003088-199325010-00003 |pmid=8354016 }}

NSAIDs may interfere and reduce effectiveness of SSRI antidepressants through inhibiting TNFα and IFNγ, both of which are cytokine derivatives.{{cite web |title=Why Painkillers Interfere with Anti-depressants |url=https://www.healthcentral.com/article/why-painkillers-interfere-with-anti-depressants |url-status=dead |archive-url=https://web.archive.org/web/20200129065429/https://www.healthcentral.com/article/why-painkillers-interfere-with-anti-depressants |archive-date=29 January 2020 |access-date=29 January 2020 |publisher=healthcentral.com}}{{cite journal |vauthors=Warner-Schmidt JL, Vanover KE, Chen EY, Marshall JJ, Greengard P |date=May 2011 |title=Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans |journal=Proceedings of the National Academy of Sciences of the United States of America |volume=108 |issue=22 |pages=9262–7 |bibcode=2011PNAS..108.9262W |doi=10.1073/pnas.1104836108 |pmc=3107316 |pmid=21518864 |doi-access=free}} NSAIDs, when used in combination with SSRIs, increase the risk of adverse gastrointestinal effects.{{cite journal |vauthors=de Jong JC, van den Berg PB, Tobi H, de Jong-van den Berg LT |date=June 2003 |title=Combined use of SSRIs and NSAIDs increases the risk of gastrointestinal adverse effects |journal=British Journal of Clinical Pharmacology |volume=55 |issue=6 |pages=591–5 |doi=10.1046/j.0306-5251.2002.01770.x |pmc=1884264 |pmid=12814454}} NSAIDs, when used in combination with SSRIs, increase the risk of internal bleeding and brain hemorrhages.{{cite journal |vauthors=Shin JY, Park MJ, Lee SH, Choi SH, Kim MH, Choi NK, Lee J, Park BJ |date=July 2015 |title=Risk of intracranial haemorrhage in antidepressant users with concurrent use of non-steroidal anti-inflammatory drugs: nationwide propensity score matched study |journal=BMJ (Clinical Research Ed.) |volume=351 |issue= |pages=h3517 |doi=10.1136/bmj.h3517 |pmc=4501372 |pmid=26173947}}

Various widely used NSAIDs enhance endocannabinoid signaling by blocking the anandamide-degrading membrane enzyme fatty acid amide hydrolase (FAAH).{{cite journal |vauthors=Bertolacci L, Romeo E, Veronesi M, Magotti P, Albani C, Dionisi M, Lambruschini C, Scarpelli R, Cavalli A, De Vivo M, Piomelli D, Garau G |date=January 2013 |title=A binding site for nonsteroidal anti-inflammatory drugs in fatty acid amide hydrolase |journal=Journal of the American Chemical Society |volume=135 |issue=1 |pages=22–5 |doi=10.1021/ja308733u |pmc=3562592 |pmid=23240907|bibcode=2013JAChS.135...22B }}

NSAIDs may reduce the effectiveness of antibiotics. An in-vitro study on cultured bacteria found that adding NSAIDs to antibiotics reduced their effectiveness by around 20%.{{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 |pmc=6806810 |pmid=32258617 }}

The concomitant use of NSAIDs with alcohol and/or tobacco products significantly increases the already elevated risk of peptic ulcers during NSAID therapy.{{cite journal |last1=Agrawal |first1=N |title=Risk factors for gastrointestinal ulcers caused by nonsteroidal anti-inflammatory drugs (NSAIDs). |journal=The Journal of Family Practice |date=June 1991 |volume=32 |issue=6 |pages=619–24 |pmid=2040888 }}{{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}}

Most NSAIDs act as nonselective inhibitors of the cyclooxygenase (COX) enzymes, inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. This inhibition is competitively reversible (albeit at varying degrees of reversibility), as opposed to the mechanism of aspirin, which is irreversible inhibition.{{cite journal |last1=Knights |first1=Kathleen M |last2=Mangoni |first2=Arduino A |last3=Miners |first3=John O |title=Defining the COX inhibitor selectivity of NSAIDs: implications for understanding toxicity |journal=Expert Review of Clinical Pharmacology |date=November 2010 |volume=3 |issue=6 |pages=769–776 |doi=10.1586/ecp.10.120 |pmid=22111779 }} COX catalyzes the formation of prostaglandins and thromboxane from arachidonic acid (itself derived from the cellular phospholipid bilayer by phospholipase A₂). 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).{{cite journal |last1=Vane |first1=J.R |last2=Botting |first2=R.M |title=The mechanism of action of aspirin |journal=Thrombosis Research |date=June 2003 |volume=110 |issue=5–6 |pages=255–258 |doi=10.1016/S0049-3848(03)00379-7 |pmid=14592543 }}{{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 }}

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.{{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 }}

When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, ulcers of the stomach or duodenum and internal bleeding can result.{{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 }} 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.{{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 }}

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.{{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 }}

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.

However, many aspects of the mechanism of action of NSAIDs remain unexplained, and for this reason, further COX pathways are hypothesized. The COX-3 pathway was believed to fill some of this gap but recent findings make it appear unlikely that it plays any significant role in humans and alternative explanation models are proposed.

NSAIDs interact with the endocannabinoid system and its endocannabinoids, as COX2 have been shown to utilize endocannabinoids as substrates, and may have a key role in both the therapeutic effects and adverse effects of NSAIDs, as well as in NSAID-induced placebo responses.{{cite journal | vauthors = Fowler CJ | title = The contribution of cyclooxygenase-2 to endocannabinoid metabolism and action | journal = British Journal of Pharmacology | volume = 152 | issue = 5 | pages = 594–601 | date = November 2007 | pmid = 17618306 | pmc = 2190012 | doi = 10.1038/sj.bjp.0707379 }}{{cite journal | vauthors = Rouzer CA, Marnett LJ | title = Non-redundant functions of cyclooxygenases: oxygenation of endocannabinoids | journal = The Journal of Biological Chemistry | volume = 283 | issue = 13 | pages = 8065–9 | date = March 2008 | pmid = 18250160 | pmc = 2417164 | doi = 10.1074/jbc.R800005200 | doi-access = free }}{{cite journal | vauthors = Hamza M, Dionne RA | title = Mechanisms of non-opioid analgesics beyond cyclooxygenase enzyme inhibition | journal = Current Molecular Pharmacology | volume = 2 | issue = 1 | pages = 1–14 | date = January 2009 | pmid = 19779578 | pmc = 2749259 | doi = 10.2174/1874-470210902010001 }}

NSAIDs are also used in the acute pain caused by gout because they inhibit urate crystal phagocytosis besides inhibition of prostaglandin synthase.{{cite journal | vauthors = Cronstein BN, Sunkureddi P | title = Mechanistic aspects of inflammation and clinical management of inflammation in acute gouty arthritis | journal = Journal of Clinical Rheumatology | volume = 19 | issue = 1 | pages = 19–29 | date = January 2013 | pmid = 23319019 | pmc = 3551244 | doi = 10.1097/RHU.0b013e31827d8790 }}

NSAIDs have antipyretic activity and can be used to treat fever.{{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 }}{{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 }} Fever is caused by elevated levels of prostaglandin E2 (PGE2), which alters the firing rate of neurons within the hypothalamus that control thermoregulation.{{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 }} Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus. PGE2 signals to the hypothalamus to increase the body's thermal setpoint.{{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 }} Ibuprofen has been shown more effective as an antipyretic than paracetamol (acetaminophen).{{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 }}

Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D, and E.{{cite book |doi=10.1016/B978-1-4377-1738-9.00024-4 |chapter=Prostaglandins, Leukotrienes, and Related Compounds |title=Kelley's Textbook of Rheumatology |date=2013 |pages=340–357 |isbn=978-1-4377-1738-9 | vauthors = Zurier RB }}

File:Burana600.jpg package]]

NSAIDs can be classified based on their chemical structure or mechanism of action. Older NSAIDs were known long before their mechanism of action was elucidated and were for this reason classified by chemical structure or origin. Newer substances are more often classified by mechanism of action.{{cite journal | vauthors = Bindu S, Mazumder S, Bandyopadhyay U | title = Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective | journal = Biochemical Pharmacology | volume = 180 | pages = 114147 | date = October 2020 | pmid = 32653589 | pmc = 7347500 | doi = 10.1016/j.bcp.2020.114147 }}

{{Div col|colwidth=25em}}

• Aspirin (acetylsalicylic acid)
• Diflunisal (Dolobid)
• Ethenzamide
• Salicylamide
• Salicylic acid and its salts
• Salsalate (Disalcid)
• Choline salicylate
• Methyl salicylate
• Sodium salicylate

{{Div col end}}

{{main|Profen (drug class)}}

{{Div col|colwidth=25em}}

• Ibuprofen{{cite web |url=https://www.drugbank.ca/drugs/DB01050 |title=Ibuprofen |publisher=DrugBank |access-date=29 January 2020 |archive-date=21 July 2014 |archive-url=https://web.archive.org/web/20140721050937/http://www.drugbank.ca/drugs/db01050 |url-status=live }}
• Dexibuprofen
• Naproxen
• Fenoprofen
• Ketoprofen
• Dexketoprofen
• Flurbiprofen
• Oxaprozin
• Loxoprofen
• Pelubiprofen
• Zaltoprofen
• Fenbufen
• Tiaprofenic acid
• Carprofen

{{Div col end}}

{{Div col|colwidth=25em}}

• Indomethacin
• Acemetacin
• Tolmetin
• Sulindac
• Etodolac
• Ketorolac
• Diclofenac
• Fenclofenac
• Aceclofenac
• Bromfenac
• Fentiazac
• Nabumetone (drug itself is non-acidic but the active, principal metabolite has a carboxylic acid group)

{{Div col end}}

{{Div col|colwidth=25em}}

• Piroxicam
• Ampiroxicam
• Meloxicam
• Tenoxicam
• Droxicam
• Lornoxicam
• Isoxicam (withdrawn from market 1985{{cite book |title=Consolidated list of products whose consumption and / or sale have been banned, withdrawn, severely restricted or not approved by Governments.: 15th issue (New data only), (June 2007-June 2009),: Chemicals |date=2009 |publisher=UN Department of Economic and Social Affairs |isbn=978-92-1-130277-6 |page=123 |url=https://digitallibrary.un.org/record/708141 }}{{cite journal | vauthors = Fung M, Thornton A, Mybeck K, Wu JH, Hornbuckle K, Muniz E |title=Evaluation of the Characteristics of Safety Withdrawal of Prescription Drugs from Worldwide Pharmaceutical Markets-1960 to 1999 |journal=Therapeutic Innovation & Regulatory Science |date=1 January 2001 |volume=35 |issue=1 |pages=293–317 |doi=10.1177/009286150103500134 }})
• Phenylbutazone (Bute)

{{Div col end}}

The following NSAIDs are derived from fenamic acid, which is a derivative of anthranilic acid,Sriram D, Yogeeswari P. [https://books.google.com/books?id=tUSLclf_NoQC&pg=PA235 Medicinal Chemistry, 2nd Edition]. Pearson Education India, 2010. {{ISBN|9788131731444}}{{rp|235}} which in turn is a nitrogen isostere of salicylic acid, which is the active metabolite of aspirin.{{rp|235}}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 }}{{rp|17}}

{{Div col|colwidth=25em}}

• Mefenamic acid
• Meclofenamic acid
• Flufenamic acid
• Tolfenamic acid
• Etofenamate

{{Div col end}}

{{Div col|colwidth=25em}}

• Celecoxib (FDA alert{{cite web |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124655.htm |title=Information for Healthcare Professionals: Celecoxib (marketed as Celebrex) |publisher=Food and Drug Administration (FDA) |access-date=8 March 2017 |url-status=dead |archive-url=https://web.archive.org/web/20101119075404/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124655.htm |archive-date=19 November 2010}})
• Rofecoxib (withdrawn from market{{cite web |url=https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm106274.htm |title=Safety of Vioxx |work=FDA Public Health Advisory |publisher=Food and Drug Administration (FDA) |access-date=8 March 2017 |url-status=dead |archive-url=https://web.archive.org/web/20140527230004/https://www.fda.gov/drugs/drugsafety/postmarketdrugsafetyinformationforpatientsandproviders/ucm106274.htm |archive-date=27 May 2014}})
• Valdecoxib (withdrawn from market{{cite web |url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124649.htm |title=Information for Healthcare Professionals: Valdecoxib (marketed as Bextra) |publisher=Food and Drug Administration (FDA) |access-date=8 March 2017 |url-status=dead |archive-url=https://web.archive.org/web/20120202220606/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124649.htm |archive-date=2 February 2012}})
• Parecoxib FDA withdrawn, licensed in the EU
• Lumiracoxib TGA cancelled registration
• 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}}

• Nimesulide (systemic preparations are banned by several countries for the potential risk of hepatotoxicity){{cite journal | vauthors = McNaughton R, Huet G, Shakir S | title = An investigation into drug products withdrawn from the EU market between 2002 and 2011 for safety reasons and the evidence used to support the decision-making | journal = BMJ Open | volume = 4 | issue = 1 | pages = e004221 | date = January 2014 | pmid = 24435895 | pmc = 3902466 | doi = 10.1136/bmjopen-2013-004221 }}

• Benzydamine (commonly branded as Tantum Verde or Difflam) is an indazole derivative with local anaesthetic and analgesic properties
• Clonixin
• Licofelone acts by inhibiting LOX (lipooxygenase) and COX and hence known as 5-LOX/COX inhibitor
• H-harpagide in figwort{{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 }} or devil's claw{{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 }}
• Some NSAIDs are also given intravenously, such as Ketorolac and Diclofenac sodium.

Most NSAIDs are chiral molecules; diclofenac and the oxicams are exceptions. However, the majority are prepared as racemic mixtures. Typically, only a single enantiomer is pharmacologically active. For some drugs (typically profens), an isomerase enzyme in vivo converts the inactive enantiomer into the active form, although its activity varies widely in individuals. This phenomenon is likely responsible for the poor correlation between NSAID efficacy and plasma concentration observed in older studies when specific analysis of the active enantiomer was not performed.{{Cite book |last=Rainsford |first=K. D. |title=Ibuprofen: Pharmacology, Therapeutics and Side Effects |date=2013-02-01 |publisher=Springer Science+Business Media |isbn=978-3-0348-0496-7 |edition=1st |language=en |doi=10.1007/978-3-0348-0496-7}}

Ibuprofen and ketoprofen are now available in single-enantiomer preparations (dexibuprofen and dexketoprofen), which purport to offer quicker onset and an improved side-effect profile. Naproxen has always been marketed as the single active enantiomer.{{Cite book |last1=Evers |first1=Alex S. |url=https://www.cambridge.org/core/books/anesthetic-pharmacology/1464D1AD12B6F8A7A94445AF2DFDC7B6 |title=Anesthetic Pharmacology |last2=Mazes |first2=Mervyn |last3=Kharasch |first3=Evan D. |publisher=Cambridge University Press |year=2011 |isbn=9780511781933 |edition=2nd |pages=548–562 |language=en |chapter=34 |doi=10.1017/CBO9780511781933 |chapter-url=https://www.cambridge.org/core/books/abs/anesthetic-pharmacology/nonsteroidal-antiinflammatory-drugs/1E7F3A9599F43F0BB11AB34085DBB88E}}

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. 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 inhibitors have lower risk of gastrointestinal bleeding.{{cite book |vauthors=Dean L |date=1 May 2011 |chapter=Comparing NSAIDs |title=PubMed Clinical Q&A |publisher=National Center for Biotechnology Information |chapter-url=https://www.ncbi.nlm.nih.gov/books/NBK45590/ }} With the exception of naproxen, nonselective NSAIDs increase the risk of having a heart attack. Some data also supports that the partially selective nabumetone is less likely to cause gastrointestinal events.

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.[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

{{Unreferenced section|date=July 2019}}

Most nonsteroidal anti-inflammatory drugs are weak acids,{{cite journal | vauthors = Ellis GA, Blake DR | title = Why are non-steroidal anti-inflammatory drugs so variable in their efficacy? A description of ion trapping | journal = Annals of the Rheumatic Diseases | volume = 52 | issue = 3 | pages = 241–243 | date = March 1993 | pmid = 8484682 | pmc = 1005027 | doi = 10.1136/ard.52.3.241 }} with a pKa of 3–5. They are absorbed well from the stomach and intestinal mucosa. They are highly protein-bound in plasma (typically >95%), usually to albumin, so that their volume of distribution typically approximates to plasma volume. Most NSAIDs are metabolized in the liver by oxidation and conjugation to inactive metabolites that typically are excreted in the urine, though some drugs are partially excreted in bile. Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal dosage.{{medical citation needed|date=July 2020}}

NSAIDs can also be divided into short-acting (plasma half-life less than 6 h) such as aspirin, diclofenac and ibuprofen and long-acting (half-life approximately greater than 10 h) such as naproxen, celecoxib.{{Cite journal |last1=Bindu |first1=Samik |last2=Mazumder |first2=Somnath |last3=Bandyopadhyay |first3=Uday |date=October 2020 |title=Non-steroidal anti-inflammatory drugs (NSAIDs) and organ damage: A current perspective |journal=Biochemical Pharmacology |language=en |volume=180 |pages=114147 |doi=10.1016/j.bcp.2020.114147 |pmc=7347500 |pmid=32653589}}

File:Bayer Aspirin ad, NYT, February 19, 1917.jpg 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,{{cite book |last1=Jeffreys |first1=Diarmuid |title=Aspirin: The Remarkable Story of a Wonder Drug |date=2008 |publisher=Chemical Heritage Foundation |isbn=978-1-59691-816-0 }}{{page needed|date=January 2025}} but this story, although compelling, is not entirely true.{{cite web |vauthors=Propatier S |title=The Mythology of Aspirin |url=https://skeptoid.com/blog/2014/05/22/the-mythology-of-asprin/ |access-date=12 January 2022 |archive-date=10 January 2022 |archive-url=https://web.archive.org/web/20220110104133/https://skeptoid.com/blog/2014/05/22/the-mythology-of-asprin/ |url-status=live }}{{cite web |vauthors=Martyr P |title=Hippocrates and willow bark? What you know about the history of aspirin is probably wrong |date=18 October 2020 |url=https://theconversation.com/hippocrates-and-willow-bark-what-you-know-about-the-history-of-aspirin-is-probably-wrong-148087 |access-date=12 January 2022 |archive-date=27 July 2023 |archive-url=https://web.archive.org/web/20230727005149/https://theconversation.com/hippocrates-and-willow-bark-what-you-know-about-the-history-of-aspirin-is-probably-wrong-148087 |url-status=live }} Hippocrates does not mention willow at all.{{cite web |title=Works by Hippocrates |url=http://classics.mit.edu/Browse/browse-Hippocrates.html |website=The Internet Classics Archive |access-date=12 January 2022 |archive-date=6 January 2011 |archive-url=https://web.archive.org/web/20110106091330/http://classics.mit.edu/Browse/browse-Hippocrates.html |url-status=dead }} Dioscorides's De materia medica was arguably the most influential herbal from Roman to Medieval times but, if he mentions willow at all (there is doubt about the identity of 'Itea'), then he used the ashes, steeped in vinegar, as a treatment for corns,{{cite web | vauthors = Dioscorides P |title=De Materia Medica |url=https://archive.org/details/de-materia-medica |access-date=12 January 2022}} which corresponds well with modern uses of salicylic acid.

Willow bark (from trees of the Salix genus) was widely known to be used as a medicine by multiple First Nations communities.{{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}} 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 ague (fever) according to the pseudoscientific doctrine of signatures.{{Cite journal |vauthors=Szczeklik A |date=2013 |title=The History of Aspirin: The Discoveries That Changed Contemporary Medicine |url=https://www.pas.va/content/dam/casinapioiv/pas/pdf-volumi/acta/acta18pas.pdf#page=243 |journal=Paths of Discovery |volume=18 |pages=175–184 |access-date=12 July 2022 |archive-date=2 July 2022 |archive-url=https://web.archive.org/web/20220702005135/https://www.pas.va/content/dam/casinapioiv/pas/pdf-volumi/acta/acta18pas.pdf#page=243 |url-status=live }}

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.{{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.}} By hydrolysis, salicin releases glucose and salicyl alcohol which can be converted into salicylic acid, both in vivo and through chemical methods.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}} In 1869, Hermann Kolbe synthesised salicylic acid, although it was too acidic for the gastric mucosa. The reaction used to synthesise aromatic acid from a phenol in the presence of {{CO2}} is known as the Kolbe-Schmitt reaction.{{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 }}{{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 }}{{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)

File:Kolbe-Schmitt-reaction-mechanism.png

By 1897, the German chemist Felix Hoffmann and the Bayer company prompted a new age of pharmacology by converting salicylic acid into acetylsalicylic acid—named aspirin by Heinrich Dreser. Other NSAIDs like ibuprofen were developed from the 1950s forward.

In 2001, NSAIDs accounted for 70,000,000 prescriptions and 30{{nbsp}}billion over-the-counter doses sold annually in the United States.{{cite journal | vauthors = Green GA | title = Understanding NSAIDs: from aspirin to COX-2 | journal = Clinical Cornerstone | volume = 3 | issue = 5 | pages = 50–60 | year = 2001 | pmid = 11464731 | doi = 10.1016/S1098-3597(01)90069-9 }}

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{{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}}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. except for one-time use during surgery.[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}} In spite of these warnings, meloxicam is frequently prescribed "off-label" for non-canine animals including cats and livestock species.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. In other countries, for example The European Union (EU), there is a label claim for use in cats.{{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 | pmc = 11148972 }}

• Discovery and development of cyclooxygenase 2 inhibitors

{{Reflist}}

{{Commons category|Non-steroidal anti-inflammatory drugs}}

• {{cite web | title=Nonsteroidal Anti-inflammatory Drugs (NSAIDs) | website=U.S. Food and Drug Administration (FDA) | date=30 December 2020 | url=https://www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/nonsteroidal-anti-inflammatory-drugs-nsaids }}

{{Anti-inflammatory products}}

{{Prostanoid signaling modulators}}

{{Portal bar|Medicine}}

{{Authority control}}

Category:Dermatoxins

Category:Hepatotoxins