View source for Non-steroidal anti-inflammatory drug

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[[Image:200mg ibuprofen tablets.jpg|thumb|Coated 200 mg [[ibuprofen]] tablets, a common NSAID]]
'''Nonsteroidal anti-inflammatory drugs''', usually abbreviated to '''NSAIDs''' or '''NAIDs''' - but also referred to as '''nonsteroidal anti-inflammatory agents/analgesics''' ('''NSAIAs''') or '''nonsteroidal anti-inflammatory medicines''' ('''NSAIMs''') - are [[Medication|drug]]s with [[analgesic]] and [[antipyretic]] (fever-reducing) effects and which have, in higher doses, [[anti-inflammatory]] effects.

The term "nonsteroidal" is used to distinguish these drugs from [[steroids]], which - among a broad range of other effects - have a similar [[eicosanoid]]-depressing, anti-inflammatory action. As [[analgesics]], NSAIDs are unusual in that they are non-[[narcotic]].

The most prominent members of this group of drugs are [[aspirin]], [[ibuprofen]], and [[naproxen]], all of which are available over the counter in many areas.<ref name="The Physician and Sportsmedicine 2010">{{Cite journal| author=Stuart J. Warden, PT, PhD, FACSM | title=Prophylactic Use of NSAIDs by Athletes:A Risk/Benefit Assessment | journal=The Physician and SportsMedicine. | month=April | year=2010 | pages=132–138 | volume= 38 | issue=1 | url=http://www.physsportsmed.com/index.php?article=1770 | doi=10.3810/psm.2010.04.1770 | pmid=20424410}}</ref>

==Mechanism of action==
Most NSAIDs act as nonselective inhibitors of the [[enzyme]] [[cyclooxygenase]] (COX), inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) [[isoenzyme]]s. COX catalyzes the formation of [[prostaglandin]]s and [[thromboxane]] from [[arachidonic acid]] (itself derived from the cellular [[phospholipid]] bilayer by phospholipase A<sub>2</sub>). Prostaglandins act (among other things) as messenger molecules in the process of [[inflammation]]. This [[mechanism of action]] was elucidated by [[John Vane]] (1927–2004), who later received a [[Nobel Prize]] for his work (see [[Mechanism of action of aspirin]]). Many aspects of the mechanism of action of NSAIDs remain unexplained, for this reason further COX pathways were 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.<ref name="Hinz_2008">{{Cite pmid|17884974}}</ref>

NSAIDS have antipyretic activity and can be used to treat fever.<ref name="former29">David MA, Eric GH. Antipyretics: mechanisms of action and clinical use in fever suppresion. AJ of Medicine [internet]. 2001 Sep [cited 2010 Jan 31]; 111(4):[about 1p]. Available from : http://www.amjmed.com/article/S0002-9343(01)00834-8/abstract</ref><ref name="former32">Koeberle A, Werz O. Inhibitors of the microsomal prostaglandin E(2) synthase-1 as alternative to non steroidal anti-inflammatory drugs (NSAIDs)--a critical review. Current Medicinal Chemistry 2009Volume 16 Issue 32</ref> Fever is caused by elevated levels of prostaglandin E2, which alters the firing rate of neurons within the hypothalamus that control thermoregulation.<ref name="former29"/><ref name="former30">Nabulsi M. Is combining or alternating antipyretic therapy more beneficial than monotherapy for febrile children?. BMJ [internet]. 2009 Oct [cited 2010 Feb 1]. Available from: http://www.bmj.com/cgi/content/full/339/oct01_2/b3540?view=long&pmid=19797346</ref> Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus.<ref name="former29"/><ref name="former32"/> PGE2 signals to the hypothalamus to increase the body's thermal set point.<ref name="former32"/><ref name="former33">F. Coceani, I. Bishai, J. Lees, and S. Sirko. Prostaglandin E2 and fever: a continuing debate. Yale J Biol Med. 1986 Mar–Apr; 59(2): 169–174. PMCID: PMC2590134</ref> [[Ibuprofen]] has been shown to be more effective as an antipyretic than [[acetaminophen]].<ref name="former30"/><ref name="former31">Rainsford KD. Ibuprofen: pharmacology, efficacy and safety. Inflammopharmacology [internet]. 2009 Nov 21 [cited Feb 1]</ref>
Arachidonic acid is the precursor substrate for cyclooxygenase  leading to the production of prostaglandins F,D & E.

==Classification==
NSAIDs can be broadly classified based on their chemical structure.

===Propionic acid derivatives===
* [[Ibuprofen]]<ref><nowiki>http://www.drugbank.ca/cgi-bin/getCard.cgi?CARD=APRD00372</nowiki> Drugbank Card for Ibuprofen</ref>
* [[Naproxen]]
* [[Fenoprofen]]
* [[Ketoprofen]]
* [[Flurbiprofen]]
* [[Oxaprozin]]

===Acetic acid derivatives===
* [[Indomethacin]]
* [[Sulindac]]
* [[Etodolac]]
* [[Ketorolac]]
* [[Diclofenac]] (Safety alert by FDA<ref>http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm193047.htm</ref>)
*[[Nabumetone]]

===Enolic acid (Oxicam) derivatives===
* [[Piroxicam]]
* [[Meloxicam]]
* [[Tenoxicam]]
* [[Droxicam]]
* [[Lornoxicam]]
* [[Isoxicam]]

===Fenamic acid derivatives===
* [[Mefenamic acid]]
* [[Meclofenamic acid]]
* [[Flufenamic acid]]
* [[Tolfenamic acid]]

===Selective COX-2 inhibitors (Coxibs)===
* [[Celecoxib]] (FDA alert<ref><nowiki>http://www.fda.gov/cder/drug/infopage/celebrex/celebrex-hcp.htm</nowiki>{{Dead link|date=May 2009}} FDA Alert for Practitioners on Celebrex (celecoxib)</ref>)
* [[Rofecoxib]] (withdrawn from market<ref><nowiki>http://www.fda.gov/cder/drug/infopage/vioxx/PHA_vioxx.htm</nowiki>{{Dead link|date=May 2009}}</ref>)
* [[Valdecoxib]] (withdrawn from market<ref><nowiki>http://www.fda.gov/cder/drug/InfoSheets/HCP/valdecoxibHCP.htm</nowiki>{{Dead link|date=May 2009}} Alert for Healthcare Professionals: Valdecoxib (marketed as Bextra)</ref>)
* [[Parecoxib]] FDA withdrawn
* [[Lumiracoxib]] TGA cancelled registration
* [[Etoricoxib]] FDA withdrawn
* [[Firocoxib]] used in dogs and horses

==Examples==
NSAIDs within a group will 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 tend to be with regards to dosing regimens (related to the compound's [[elimination half-life]]), route of administration, and tolerability profile. Some more common examples are given below.

===Sulphonanilides===
* [[Nimesulide]] (systemic preparations are banned by several countries for the potential risk of hepatotoxicity)

===Others===
* [[Licofelone]]
Licofelone acts by inhibiting LOX (lipooxygenase) & COX and hence known as 5-LOX/COX inhibitor.

==Uses==
NSAIDs are usually indicated for the treatment of acute or chronic conditions where [[pain]] and inflammation are present. Research continues into their potential for prevention of [[colorectal cancer]], and treatment of other conditions, such as cancer and [[cardiovascular disease]].

NSAIDs are generally indicated for the symptomatic relief of the following conditions:<ref name="isbn0-9757919-2-3">{{Cite book|editor=Simone Rossi |title=Australian medicines handbook 2006 |publisher=Australian Medicines Handbook Pty Ltd |location=[[Adelaide]] |year=2006 |pages= |isbn=0-9757919-2-3 |author=}}{{Page needed|date=August 2010}}</ref>

* [[Rheumatoid arthritis]]<ref name="pmid2702836">{{Cite journal|pmid=2702836 |year=1989 |month= March|author=Gøtzsche, Pc |title=Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal antiinflammatory drugs in rheumatoid arthritis |volume=10 |issue=1 |pages=31–56 |issn=0197-2456 |journal=Controlled clinical trials |doi=10.1016/0197-2456(89)90017-2}}</ref>
* [[Osteoarthritis]]
* Inflammatory arthropathies (e.g. [[ankylosing spondylitis]], [[psoriatic arthritis]], [[Reiter's syndrome]])
* Acute [[gout]]
* [[Dysmenorrhoea]] ([[menstruation|menstrual]] pain)
* [[Cancer|Metastatic]] bone pain
* [[Headache]] and [[migraine]]
* Postoperative pain
* Mild-to-moderate pain due to inflammation and tissue injury
* [[Pyrexia]] ([[fever]])
* [[Ileus]]
* [[Renal colic]]
* They are also given to neonate infants whose [[ductus arteriosus]] is not closed within 24 hours of birth

[[Aspirin]], the only NSAID able to irreversibly inhibit COX-1, is also indicated for inhibition of [[platelet]] aggregation.  This is useful in the management of arterial [[thrombosis]] and prevention of adverse cardiovascular events.  Aspirin inhibits platelet aggregation by inhibiting the action of thromboxane -A.

In 2001 NSAIDs accounted for 70,000,000 prescriptions and 30 billion over-the-counter doses sold annually in the [[United States]].<ref name="pmid11464731">{{Cite journal|pmid=11464731 |year=2001 |author=Green, Ga |title=Understanding NSAIDs: from aspirin to COX-2 |volume=3 |issue=5 |pages=50–60 |issn=1098-3597 |journal=Clinical cornerstone |doi=10.1016/S1098-3597(01)90069-9}}</ref>

==Pharmacokinetics==
Most nonsteroidal anti-inflammatory drugs are weak acids, 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 [[human serum albumin|albumin]], so that their [[volume of distribution]] typically approximates to plasma volume. Most NSAIDs are metabolised in the [[liver]] by oxidation and conjugation to inactive metabolites which are typically excreted in the [[urine]], although some drugs are partially excreted in [[bile]]. Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal dosage.

Ibuprofen and diclofenac have short half-lives (2–3 hours). Some NSAIDs (typically oxicams) have very long half-lives (e.g. 20–60 hours).

==Adverse effects==
The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly prevalent. The two main [[adverse drug reaction]]s (ADRs) associated with NSAIDs relate to [[gastrointestinal]] (GI) effects and [[renal]] effects of the agents.

These 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.<ref name="pmid11464731"/>

NSAIDs, like all drugs, may interact with other medications.  For example, concurrent use of NSAIDs and [[quinolone]]s may increase the risk of quinolones' adverse [[central nervous system]] effects, including seizure.<ref>
{{Cite web|first= |last= |author=Bayer HealthCare Pharmaceuticals Inc |title=CIPRO (ciprofloxacin hydrochloride) TABLETS CIPRO,(ciprofloxacin*) ORAL SUSPENSION |url=http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019537s68,19847s42,19857s49,20780s26,21473s24lbl.pdf |publisher=FDA |location=USA |format=PDF |month=September |year=2008 |accessdate=31 August 2009}}
</ref><ref>
{{Cite book|title=[[British National Formulary]] (BNF 57) |author=Royal Pharmaceutical Society of Great Britain |authorlink=Royal Pharmaceutical Society of Great Britain |publisher=BMJ Group and RPS Publishing |chapter=5 Infections |year=2009 |isbn=9780853698456 }}
</ref>

===Combinational risk===
If a COX-2 inhibitor is taken, one should not use a traditional NSAID (prescription or over-the-counter) concomitantly.<ref>http://orthoinfo.aaos.org/fact/thr_report.cfm?Thread_ID=398&topcategory=About</ref> In addition, patients on daily aspirin therapy (e.g. for reducing cardiovascular risk) need to be careful if they also use other NSAIDs, as the latter may block{{Elucidate|July 2010|date=August 2010}} the cardioprotective effects of aspirin.

===Cardiovascular===
A recent meta-analysis of all trials comparing NSAIDs found an 80% increase in the risk of myocardial infarction with both newer COX-2 antagonists and high dose traditional anti-inflammatories compared with placebo.<ref>{{Cite journal|pmid=16740558 |year=2006 |month= June|author=Kearney, Pm; Baigent, C; Godwin, J; Halls, H; Emberson, Jr; Patrono, C |title=Do selective cyclo-oxygenase-2 inhibitors and traditional nonsteroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials |volume=332 |issue=7553 |pages=1302–8 |issn=0959-8138 |pmc=1473048 |doi=10.1136/bmj.332.7553.1302 |journal=BMJ (Clinical research ed.) |url=http://bmj.com/cgi/pmidlookup?view=long&pmid=16740558 |format=Free full text}}</ref>

NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of symptomatic heart failure in patients without a history of cardiac disease. In patients with such a history, however, use of NSAIDs (aside from low-dose aspirin) was associated with more than 10-fold increase in heart failure.<ref name=page2000>{{Cite journal|pmid=10737277 |year=2000 |month= March|author=Page, J; Henry, D |title=Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem |volume=160 |issue=6 |pages=777–84 |issn=0003-9926 |journal=Archives of internal medicine |url=http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=10737277 |format=Free full text |doi=10.1001/archinte.160.6.777}}</ref> If this link is found to be causal, NSAIDs are estimated to be responsible for up to 20 percent of hospital admissions for congestive heart failure.<ref name=page2000/>

===Gastrointestinal===
The main adverse drug reactions ([[adverse drug reactions|ADRs]]) associated with use of NSAIDs relate to direct and indirect irritation of the [[gastrointestinal tract]] (GIT). NSAIDs cause a dual insult on the GIT: 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{{Clarify|July 2010|date=July 2010}} effects on epithelial mucosa.

Common gastrointestinal ADRs include:<ref name="isbn0-9757919-2-3"/>

* Nausea/Vomiting
* [[Dyspepsia]]
* [[Gastric ulcer]]ation/bleeding.<ref name="pmid7888445">{{Cite journal|pmid=7888445 |year=1995 |month= January|author=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 |volume=6 |issue=1 |pages=49–54 |issn=1044-3983 |journal=Epidemiology (Cambridge, Mass.) |doi=10.1097/00001648-199501000-00010}}</ref>
* [[Diarrhea]]

Risk of ulceration increases with duration of therapy, and with higher doses. In attempting to minimise GI ADRs, it is prudent to use the lowest effective dose for the shortest period of time, a practice which studies show is not often followed. Recent studies show that over 50% of patients taking NSAIDs have sustained damage to their small intestine.<ref name="pmid19568687">{{Cite journal|pmid=19568687 |year=2009 |month= July|author=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 |volume=44 |issue=9 |pages=879–888 |issn=1435-5922 |journal=Journal of Gastroenterology |doi=10.1007/s00535-009-0102-2}}</ref> Studies show that risk of ulceration is less with Nabumetone than with Ibuprofen alone.<ref name="pmid8239849">{{Cite journal|pmid=8239849 |year=1993|pages=2565–71|issue=22 |month= November|volume=153|author=Roth SH, Tindall EA, Jain AK, McMahon FG, April PA, Bockow BI, Cohen SB, Fleischmann RM|journal=Archives of internal medicine |title=A controlled study comparing the effects of nabumetone, ibuprofen, and ibuprofen plus misoprostol on the upper gastrointestinal tract mucosa }}</ref>

There are also some differences in the propensity of individual agents to cause gastrointestinal ADRs. [[Indomethacin]], [[ketoprofen]] and [[piroxicam]] appear to have the highest prevalence of gastric ADRs, while [[ibuprofen]] (lower doses) and [[Diclofenac]] appear to have lower rates.<ref name="isbn0-9757919-2-3"/>

Certain NSAIDs, such as aspirin, have been marketed in [[enteric coating|enteric-coated]] formulations which are claimed to reduce the incidence of gastrointestinal ADRs. Similarly, there is a belief that rectal formulations may reduce gastrointestinal ADRs. However, in consideration of the mechanism of such ADRs and indeed in clinical practice, these formulations have not been shown to have a reduced risk of GI ulceration.<ref name="isbn0-9757919-2-3"/>

Commonly, gastric (but not necessarily intestinal) adverse effects can be reduced through suppressing acid production, by concomitant use of a [[proton pump inhibitor]], e.g. [[omeprazole]], [[esomeprazole]]; or the prostaglandin analogue [[misoprostol]]. Misoprostol is itself associated with a high incidence of gastrointestinal ADRs (diarrhea). While these techniques may be effective, they prove to be expensive for maintenance therapy.

===Inflammatory bowel disease===
NSAIDs are never to be used 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.  Pain relievers such as [[paracetamol]] (also known as acetaminophen) or drugs containing [[codeine]] (which slows down bowel activity) are safer medications for pain relief in IBD.{{Citation needed|date=April 2009}}

===Renal===
NSAIDs are also associated with a relatively high incidence of renal adverse drug reactions ([[adverse drug reactions|ADRs]]). The mechanism of these renal ADRs is due to changes in renal haemodynamics (blood flow), ordinarily mediated by prostaglandins, which are affected by NSAIDs. Prostaglandins normally cause vasodilation of the [[afferent arteriole]]s of the [[glomerulus|glomeruli]].  This helps maintain normal glomerular perfusion  and [[glomerular filtration rate]] (GFR), an indicator of [[renal function]].  This is particularly important in renal 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 one it normally constricts.  Prostaglandins serve to dilate the afferent arteriole; by blocking this prostaglandin-mediated effect, particularly in renal failure, NSAIDs cause unopposed constriction of the afferent arteriole and decreased renal perfusion pressure. Horses are particularly prone to these adverse affects compared with other domestic animal species.

Common ADRs associated with altered renal function include:<ref name="isbn0-9757919-2-3"/>

* Salt and fluid retention
* [[Hypertension]] (high blood pressure)

These agents may also cause renal impairment, especially in combination with other nephrotoxic agents. Renal failure is especially a risk if the patient is also concomitantly taking an [[ACE inhibitor]] and a [[diuretic]] - the so-called "triple whammy" effect.<ref name="pmid10772593">{{Cite journal|pmid=10772593 |year=2000 |month= February|author=Thomas, Mc |title=Diuretics, ACE inhibitors and NSAIDs--the triple whammy |volume=172 |issue=4 |pages=184–5 |issn=0025-729X |journal=The Medical journal of Australia}}</ref>

In rarer instances NSAIDs may also cause more severe renal conditions:<ref name="isbn0-9757919-2-3"/>
* [[Interstitial nephritis]]
* [[Nephrotic syndrome]]
* [[Acute renal failure]]
* [[Acute tubular necrosis]]

NSAIDs in combination with excessive use of [[phenacetin]] and/or [[paracetamol]] may lead to [[analgesic nephropathy]].<ref name="pmid9459649">{{Cite journal|pmid=9459649 |year=1998 |month= February|author=De, Broe, Me; Elseviers, Mm |title=Analgesic nephropathy |volume=338 |issue=7 |pages=446–52 |issn=0028-4793 |journal=[[New England Journal of Medicine]] |doi=10.1056/NEJM199802123380707}}</ref>

===Photosensitivity===
[[Photodermatitis|Photosensitivity]] is a commonly overlooked adverse effect of many of the NSAIDs.<ref name="pmid12020173">{{Cite journal|pmid=12020173 |year=2002 |author=Moore, De |title=Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management |volume=25 |issue=5 |pages=345–72 |issn=0114-5916 |journal=Drug safety : an international journal of medical toxicology and drug experience |doi=10.2165/00002018-200225050-00004}}</ref> It is somewhat ironic that these anti-inflammatory agents may themselves produce inflammation in combination with exposure to sunlight. The 2-arylpropionic acids have proven to be the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated including [[piroxicam]], [[diclofenac]] and [[benzydamine]].

[[Benoxaprofen]], since withdrawn due to its [[hepatotoxicity]], 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]] [[functional group|moiety]]. The specific absorbance characteristics of the different [[chromophore|chromophoric]] 2-aryl substituents, affects the decarboxylation mechanism. While [[ibuprofen]] is somewhat of an exception, having weak absorption, it has been reported to be a weak photosensitising agent.

===During pregnancy===
NSAIDs are not recommended during pregnancy, particularly during the [[third trimester]]. While NSAIDs as a class are not direct [[teratogen]]s, they may cause premature closure of the fetal [[ductus arteriosus]] and renal ADRs in the fetus. Additionally, they are linked with [[premature birth]].<ref name="pmid15013926">{{Cite journal|pmid=15013926 |year=2004 |month= March|author=Østensen, Me; Skomsvoll, Jf |title=Anti-inflammatory pharmacotherapy during pregnancy |volume=5 |issue=3 |pages=571–80 |issn=1465-6566 |doi=10.1517/14656566.5.3.571 |journal=Expert opinion on pharmacotherapy}}</ref> Aspirin, however, is used together with [[heparin]] in pregnant women with [[antiphospholipid antibodies]].<ref name="pmid15485103">{{Cite journal|pmid=15485103 |year=2004 |author=Cervera, R; Balasch, J |title=The management of pregnant patients with antiphospholipid syndrome |volume=13 |issue=9 |pages=683–7 |issn=0961-2033 |journal=Lupus |doi=10.1191/0961203304lu1092oa}}</ref>

In contrast, [[paracetamol]] (acetaminophen) is regarded as being safe and well-tolerated during pregnancy.<ref name="pmid15733027">{{Cite journal|pmid=15733027 |year=2005 |author=Graham, Gg; Scott, Kf; Day, Ro |title=Tolerability of paracetamol |volume=28 |issue=3 |pages=227–40 |issn=0114-5916 |journal=Drug safety : an international journal of medical toxicology and drug experience |doi=10.2165/00002018-200528030-00004}}</ref> Doses should be taken as prescribed, due to risk of [[hepatotoxicity]] with overdoses.<ref name="pmid16351032">{{Cite journal|pmid=16351032 |year=2005 |month= November|author=Wilkes, Jm; Clark, Le; Herrera, Jl |title=Acetaminophen overdose in pregnancy |volume=98 |issue=11 |pages=1118–22 |issn=0038-4348 |journal=Southern medical journal |doi=10.1097/01.smj.0000184792.15407.51}}</ref>

In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy.<ref>{{Cite news|first=Audrey |last=Dreillard |date=2009-03-02 |title=Grossesse - Mamans attention |url=http://www.francesoir.fr/societe/2009/03/02/grossesse-mamans-attention.html |work=[[France Soir]] |accessdate=2009-06-01 |language=French}}</ref>

===Other===
Common adverse drug reactions (ADR), other than listed above, include: raised liver [[enzymes]], [[headache]], [[dizziness]].<ref name="isbn0-9757919-2-3"/> Uncommon ADRs include: [[hyperkalaemia]], confusion, [[bronchospasm]], rash.<ref name="isbn0-9757919-2-3"/> Rapid and severe swelling of the face and/or body. [[Ibuprofen]] may also rarely cause [[irritable bowel syndrome]] symptoms.

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.

In very rare cases, ibuprofen can cause aseptic meningitis.

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.<ref>{{Cite web|work=Allergy Capital|url=http://www.allergycapital.com.au/Pages/aspirin.html|title=Adverse and allergic reactions to aspirin and NSAIDS|accessdate=2009-03-23}}</ref>

===Drug Interactions===
{| class="wikitable"
|-
! Drug
! Severity
! Adverse Effect
! Recommendations
|-
| ACE Inhibitors (e.g. Benazepril Hydrochloride)
| Moderate
| May decrease antihypertensive and natriuretic effects
| Monitor blood pressure and cardiovascular function
|-
| Probenecid
| Moderate
| May result in reversal of the uricosuric effects of the other drug
| Avoid concurrent use of high-dose aspirin with probenecid
|-
| Lithium
| Moderate
| May increase lithium plasma levels and decrease its clearance renally
| Monitor for lithium toxicity
|-
| Warfarin
| Moderate
| May result in an increased risk of bleeding
| Monitor PT (prothrombin time) and INR (international normalized ratio)
|-
| Methotrexate
| Severe
| May result in increased risk of methotrexate toxicity
| DO NOT administer NSAIDs within 10 days of high dose methotrexate
|}

<ref>Drug Interactions. Micromedex. Accessed at:
http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/hcs.Interactions.WordWheel.</ref><ref>Shionoiri H. Pharmacokinetic drug interactions with ACE inhibitors. Clin Pharmacokinet. 1993 Jul;25(1):20-58. Accessed at: http://www.ncbi.nlm.nih.gov/sites/entrez.</ref><ref name="thomsonhc.com">Drug Interactions. Micromedex. Accessed at: http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/hcs.Interactions.WordWheel.</ref><ref>Lexi-Comp's Comprehensive Drug-to-Drug, Drug-to-Herb and Herb-to-Herb Interaction Analysis Program. UpToDate. Accessed at: http://www.uptodate.com/crlsql/interact/frameset.jsp.</ref><ref name="rxlist.com">Motrin Side Effects & Drug Interactions, 2007. RxList The Internet Drug Index. Accessed at: http://www.rxlist.com/ibuprofen-drug. February 1, 2009. Updated September 18, 2007.</ref><ref name="rxlist.com"/><ref name="thomsonhc.com"/><ref>Drug Interactions. Micromedex. Accessed at: http://www.thomsonhc.com/hcs/librarian/PFDefaultActionId/hcs.Interactions.WordWheel#Drug.</ref><ref>Su T., Jirgensons B.,  Optical activity studies of drug-protein complexes, the interaction of acetylsalicylic acid with human serum albumin and myeloma immunoglobulin Biochemical Pharmacology, Volume 27, Issue 7, 1 April 1978, Pages 1043-1047.</ref><ref>Yoshitane N., et.al. Gastrointestinal, Hepatic, Pulmonary, and Renal: Species Difference in the Inhibitory Effect of Nonsteroidal Anti-Inflammatory Drugs on the Uptake of Methotrexate by Human Kidney Slices. J Pharmacol Exp Ther September 2007 322:1162-1170; published ahead of print June 19, 2007, doi:10.1124/jpet.107.121491.</ref>

==Chirality==
Most NSAIDs are [[Chirality (chemistry)|chiral]] molecules ([[diclofenac]] is a notable exception). However, the majority are prepared in a [[racemic]] mixture. Typically, only a single [[enantiomer]] is pharmacologically active. For some drugs (typically profens), an [[isomerase]] [[enzyme]] exists ''in vivo'' which converts the inactive enantiomer into the active form, although its activity varies widely in individuals. This phenomenon is likely to be 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.

[[Ibuprofen]] and [[ketoprofen]] are now available in single, active 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.

==Selective COX inhibitors==
===COX-2 inhibitors===
The discovery of COX-2 in 1991 by [[Daniel L. Simmons]] at [[Brigham Young University]] raised the hope of developing an effective NSAID without the gastric problems characteristic of these agents. It was thought that selective inhibition of COX-2 would result in anti-inflammatory action without disrupting gastroprotective prostaglandins.

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. When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, these protective effects are lost and [[peptic ulcer|ulcers]] of the [[stomach]] or [[duodenum]] and potentially internal [[bleeding]] can result. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs.

The relatively selective COX-2 inhibiting oxicam, [[meloxicam]], was the first step towards developing a true [[COX-2 selective inhibitor]]. Coxibs, the newest class of NSAIDs, can be considered as true COX-2 selective inhibitors, and include [[celecoxib]], [[rofecoxib]], [[valdecoxib]], [[parecoxib]] and [[etoricoxib]].

[[Acetaminophen]] does also work mainly by blocking COX-2, unlike the newly developed COX-2 inhibitors it has weaker peripheral inhibitory activity.<ref name="Hinz_2008" />

====Controversies with COX-2 inhibitors====
While it was hoped that this COX-2 selectivity would reduce gastrointestinal adverse drug reactions (ADRs), there is little conclusive evidence that this is true. The original study touted by Searle (now part of [[Pfizer]]), showing a reduced rate of ADRs for celecoxib, was later revealed to be based on preliminary data - the final data showed no significant difference in ADRs when compared with diclofenac.

[[Rofecoxib]] however, which has since been withdrawn, had been shown to produce significantly fewer gastrointestinal ADRs compared with naproxen.<ref name="pmid11087881">{{Cite journal|pmid=11087881 |year=2000 |month= November|author=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; Vigor, Study, Group |title=Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis |volume=343 |issue=21 |pages=1520–8, 2 p following 1528 |issn=0028-4793 |journal=[[New England Journal of Medicine]] |doi=10.1056/NEJM200011233432103}}</ref> This study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs - a statistically insignificant increase in the incidence of [[myocardial infarction]]s was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a relative risk of cardiovascular events of 1.97 versus placebo - a result which resulted in the worldwide withdrawal of rofecoxib in October 2004.

===COX-3 inhibitors===
<!-- this section is a tangent into [[COX-3]] and paracetamol, which is not an NSAID;  relevance to NSAIDs is not apparent -->
[[Daniel L. Simmons|Simmons]] also co-discovered [[COX-3]] in 2002 and analyzed this new isozyme's relation to [[paracetamol]] (acetaminophen), arguably the most widely used analgesic drug in the world.<ref name="pmid12242329">{{Cite journal|pmid=12242329 |year=2002 |month= October|author=Chandrasekharan, Nv; Dai, H; Roos, Kl; Evanson, Nk; Tomsik, J; Elton, Ts; Simmons, Dl |title=COX-3, a COX-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression |volume=99 |issue=21 |pages=13926–31 |issn=0027-8424 |pmc=129799 |doi=10.1073/pnas.162468699 |journal=Proceedings of the National Academy of Sciences of the United States of America |url=http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12242329 |format=Free full text}}</ref> The authors postulated that inhibition of COX-3 could represent a primary central mechanism by which these drugs decrease pain and possibly fever.

The relevance of this research has been called into question as the putative [[COX-3]] gene encodes proteins with completely different amino acid sequences than COX-1 or COX-2. The expressed proteins do not show COX activity and it is unlikely that they play a role in prostaglandin mediated physiological responses.<ref name="pmid15879007">{{Cite journal|pmid=15879007 |year=2005 |month= October|author=Kis, B; Snipes, Ja; Busija, Dw |title=Acetaminophen and the COX-3 puzzle: sorting out facts, fictions, and uncertainties |volume=315 |issue=1 |pages=1–7 |issn=0022-3565 |doi=10.1124/jpet.105.085431 |journal=The Journal of pharmacology and experimental therapeutics |url=http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15879007 |format=Free full text}}</ref>

==Veterinary use==
Research supports the use of NSAIDs for the control of pain associated with veterinary procedures such as dehorning and castration of calves.  The best effect is obtained by combining a short-term local anesthetic such as [[lidocaine]] with an NSAID acting as a longer term analgesic.  However, most of the existing research data relates to [[ketoprofen]] while the only NSAID currently available for labelled use in the United States is [[flunixin meglumine]], indicated for conditions other than post-operative pain.

==References==
{{Commons category|Non-steroidal anti-inflammatory drugs}}
{{Reflist|2}}

==External links==
* [http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202743.html US National Library of Medicine: MedlinePlus Drug Information: Anti-inflammatory Drugs, Nonsteroidal (Systemic)]

{{Major drug groups}}
{{Anti-inflammatory and antirheumatic products}}
{{NSAIDs}}
{{Analgesics}}
{{Use dmy dates|date=August 2010}}

{{DEFAULTSORT:Nonsteroidal Anti-Inflammatory Drug}}
[[Category:Non-steroidal anti-inflammatory drugs| ]]

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[[Category:2Fix]]