Non-steroidal anti-inflammatory drug 22071 224973430 2008-07-11T07:11:25Z CERminator 6756741 +bs '''Non-steroidal anti-inflammatory drugs''', usually abbreviated to '''NSAID'''s, are [[Medication|drug]]s with [[analgesic]], [[antipyretic]] and, in higher doses, [[anti-inflammatory]] effects - they reduce [[Pain|pain]], [[fever]] and [[inflammation]]. The term "non-steroidal" is used to distinguish these drugs from [[glucocorticoid|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]]. NSAIDs are sometimes also referred to as '''non-steroidal anti-inflammatory agents/analgesics''' ('''NSAIAs''') or '''non-steroidal anti-inflammatory medicines''' ('''NSAIMs'''). The most prominent members of this group of drugs are [[aspirin]], [[ibuprofen]], and [[naproxen]] partly because they are available over-the-counter in many areas. [[Paracetamol]] (acetaminophen) has negligible anti-inflammatory activity, and is not an NSAID. Beginning in 1829, with the isolation of [[salicin]] from the [[folk remedy]] [[white willow]] bark, NSAIDs have become an important part of the pharmaceutical treatment of pain (at low doses) and inflammation (at higher doses). Part of the popularity of NSAIDs is that, unlike [[opioid]]s, they do not produce sedation or respiratory depression and have a very low addiction rate. NSAIDs, however, are not without their own problems (see below). Certain NSAIDs, including ibuprofen and aspirin, have become accepted as relatively safe and are available over-the-counter without prescription. == Mode of action == Most NSAIDs act as non-selective inhibitors of the [[enzyme]] [[cyclooxygenase]], inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) [[isoenzyme]]s. Cyclooxygenase 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]], who later received a [[Nobel Prize]] for his work (see [[Mechanism of action of aspirin]]). A newly discovered [[COX-3]] may also have some role. == Examples == NSAIDs can be broadly classified based on their chemical structure. 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 tended 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. [[Paracetamol]] (acetaminophen) is sometimes grouped with the NSAIDs; however, it is not an NSAID and does not have any significant anti-inflammatory properties. Though the mechanism of action is unclear, it is suspected that the lack of anti-inflammatory action may be due to inhibition of cyclooxygenase predominantly in the [[central nervous system]].{{Fact|date=December 2007}} There is also some speculation that paracetamol acts through the inhibition of the recently discovered COX-3 isoform (see below). It is believed as well that NSAIDs act centrally, possibly within the spinal cord.{{Fact|date=December 2007}} However, the mechanism of action in this case is not well-characterized. === [[Salicylic acid|Salicylates]] === * [[Aspirin|Acetylsalicylic acid]] (Aspirin) * [[Amoxiprin]] * [[Benorylate|Benorylate/Benorilate]] * [[Choline magnesium salicylate]] * [[Diflunisal]] * [[Ethenzamide]] * [[Faislamine]] * [[Methyl salicylate]] * [[Magnesium salicylate]] * [[Salicin|Salicyl salicylate]] * [[Salicylamide]] === Arylalkanoic acids === * [[Diclofenac]] * [[Aceclofenac]] * [[Acemetacin]] * [[Alclofenac]] * [[Bromfenac]] * [[Etodolac]] * [[Indometacin]] * [[Nabumetone]] * [[Oxametacin]] * [[Proglumetacin]] * [[Sulindac]] * [[Tolmetin]] === 2-Arylpropionic acids (profens) === * [[Ibuprofen]] * [[Alminoprofen]] * [[Benoxaprofen]] (withdrawn from the market) * [[Carprofen]] * [[Dexibuprofen]] * [[Dexketoprofen]] * [[Fenbufen]] * [[Fenoprofen]] * [[Flunoxaprofen]] * [[Flurbiprofen]] * [[Ibuproxam]] * [[Indoprofen]] * [[Ketoprofen]] (Actron, at least, has been withdrawn from the market.) * [[Ketorolac]] * [[Loxoprofen]] * [[Naproxen]] * [[Oxaprozin]] * [[Pirprofen]] * [[Suprofen]] * [[Tiaprofenic acid]] === ''N''-Arylanthranilic acids ([[fenamic acid]]s) === * [[Mefenamic acid]] * [[Flufenamic acid]] * [[Meclofenamic acid]] * [[Tolfenamic acid]] === [[Pyrazolidine]] derivatives === * [[Phenylbutazone]] * [[Ampyrone]] * [[Azapropazone]] * [[Clofezone]] * [[Kebuzone]] * [[Metamizole]] * [[Mofebutazone]] * [[Oxyphenbutazone]] * [[Phenazone]] * [[Phenylbutazone]] * [[Sulfinpyrazone]] === [[Oxicam]]s === * [[Piroxicam]] * [[Droxicam]] * [[Lornoxicam]] * [[Meloxicam]] * [[Tenoxicam]] === [[Cyclooxygenase|COX]][[COX-2 inhibitor|-2 inhibitors]] === * [[Celecoxib]] (FDA alert <ref>[http://www.fda.gov/cder/drug/infopage/celebrex/celebrex-hcp.htm FDA Alert for Practitioners on Celebrex (celecoxib)<!-- Bot generated title -->]</ref>) * [[Etoricoxib]] FDA withdrawn * [[Lumiracoxib]] TGA cancelled registration * [[Parecoxib]] FDA withdrawn * [[Rofecoxib]] (withdrawn from market <ref>http://www.fda.gov/cder/drug/infopage/vioxx/PHA_vioxx.htm</ref>) * [[Valdecoxib]] (withdrawn from market <ref>[http://www.fda.gov/cder/drug/InfoSheets/HCP/valdecoxibHCP.htm Alert for Healthcare Professionals: Valdecoxib (marketed as Bextra)<!-- Bot generated title -->]</ref>) === Sulphonanilides === * [[Nimesulide]] (banned by several countries for the potential risk of hepatotoxicity) === Others === * [[Licofelone]] * [[Omega-3 fatty acid]]s Licofelone acts by inhibiting LOX (lipooxygenase) & COX (cyclooxygenase)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: (Rossi, 2006)<ref name=Rossi2006>Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3</ref> * [[Rheumatoid arthritis]] * [[Osteoarthritis]] * Inflammatory arthropathies (e.g. [[ankylosing spondylitis]], [[psoriatic arthritis]], [[Reiter's syndrome]]) * Acute [[gout]] * [[Dysmenorrhoea]] (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.; an indication useful in the management of arterial [[thrombosis]] and prevention of adverse cardiovascular events.It shows inhibition of platelet aggregation because it inhibits 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]] (Green, 2001). With the aging of the [[Baby Boomer]] generation and the associated rise in the incidence of osteoarthritis and other such conditions for which NSAIDs are indicated, the use of NSAIDs may increase further still. One study has suggested that taking NSAIDs (or [[cyclooxygenase|COX]] inhibitors in general) while smoking [[marijuana]] may prevent the [[neurotoxicity|death of brain cells]] resulting from [[tetrahydrocannabinol|THC]] intoxication.<ref>[http://www.jneurosci.org/cgi/content/abstract/18/14/5322 Hippocampal Neurotoxicity of Delta 9-Tetrahydrocannabinol - Chan et al. 18 (14): 5322 - Journal of Neuroscience]</ref> However, neurotoxicity of marijuana is still a [[Health issues and the effects of cannabis#Memory|matter of dispute]]. == Pharmacokinetics == Most NSAIDs 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 relatively safe 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. (Green, 2001) === Combinational risk === If a COX-2 inhibitor is taken, one should not use a traditional NSAID (prescription or over-the-counter) concomitantly.[http://orthoinfo.aaos.org/fact/thr_report.cfm?Thread_ID=398&topcategory=About] In addition, patients on daily aspirin therapy (as for reducing cardiovascular risk or colon cancer risk) need to be careful if they also use other NSAIDs, as the latter may block the cardioprotective effects of aspirin. === Cardiovascular risk === 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. (Kearney et al., BMJ 2006;332:1302-1308) NSAIDs aside from 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. [http://archinte.ama-assn.org/cgi/content/full/160/6/777] 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. [http://archinte.ama-assn.org/cgi/content/full/160/6/777] === Gastrointestinal ADRs === The main ADRs (adverse drug reactions) 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 reduces the levels of protective [[prostaglandins]]. Common gastrointestinal ADRs include: (Rossi, 2006)<ref name=Rossi2006>Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3</ref> * Nausea/Vomiting * [[Dyspepsia]] * [[Gastric ulcer]]ation/bleeding * [[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. 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. (Rossi, 2006)<ref name=Rossi2006>Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3</ref> Certain NSAIDs, such as aspirin, have been marketed in [[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. (Rossi, 2006)<ref name=Rossi2006>Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3</ref> Commonly, gastrointestinal adverse effects can be reduced through suppressing acid production, by concomitant use of a [[proton pump inhibitor]], e.g. [[omeprazole]]; or the prostaglandin analogue [[misoprostol]]. Misoprostol is itself associated with a high incidence of gastrointestinal ADRs (diarrhoea). While these techniques may be effective, they prove to be expensive for maintenance therapy. === Inflammatory Bowel Disease (IBD) === NSAIDs are never to be used in individuals with Inflammatory Bowel Disease (IBD-Crohn's Disease and Ulcerative Colitis) due to its ability to cause gastric bleeding and form ulceration in the gastric lining. Drugs such as Advil should be avoided in persons afflicted with IBD. Pain relievers such as Tylenol (containing acetaminophen) or drugs containing Codeine (which slows down bowel activity) are safer methods than Ibuprofen for pain relief in IBD. === Renal ADRs === NSAIDs are also associated with a relatively high incidence of [[renal]] 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]]. By blocking this prostaglandin-mediated effect, NSAIDs ultimately may cause renal impairment. Horses are particularly prone to these adverse affects compared to other domestic animal species. Common ADRs associated with altered renal function include: (Rossi, 2006)<ref name=Rossi2006>Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3</ref> * 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. (Thomas, 2000) In rarer instances NSAIDs may also cause more severe renal conditions: (Rossi, 2006)<ref name=Rossi2006>Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3</ref> * [[Interstitial nephritis]] * [[Nephrotic syndrome]] * [[Acute renal failure]] * [[Acute tubular necrosis]] === Photosensitivity === [[Photodermatitis|Photosensitivity]] is a commonly overlooked adverse effect of many of the NSAIDs. (Moore, 2002) 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]] (Ostensen & Skomsvoll, 2004). Aspirin, however, is used together with [[heparin]] in pregnant women with [[antiphospholipid antibodies]] (Cervera & Balasch, 2004). In contrast, [[paracetamol]] (acetaminophen) is regarded as being safe and well-tolerated during pregnancy (Graham et al., 2005). Doses should be taken as prescribed, due to risk of [[hepatotoxicity]] with overdoses (Wilkes et al., 2005). === Other ADRs === Common ADRs, other than listed above, include: raised liver enzymes, headache, dizziness (Rossi, 2006). Uncommon ADRs include: [[hyperkalaemia]], confusion, [[bronchospasm]], rash (Rossi, 2006). 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. == 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. == Newer NSAIDs: 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 non-selective 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]]. ==== 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 to naproxen. (Bombardier et al, 2000). 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 === 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. (Chandrasekharan et al, 2002). 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. (Kis, 2005) The clinical ramifications and knowledge of COX isozymes are rapidly expanding{{weasel-inline}} and may offer significant hope for future treatments of pain, inflammation, and fever.{{Or|date=July 2008}} == Veterinary Use == === NSAID Analgesia === 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 meglamine, indicated for conditions other than post-operative pain. == References == {{reflist}} * Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, et al. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. [[N Engl J Med]] 2000;343(21):1520-8. PMID 11087881 * Cervera R, Balasch J. The management of pregnant patients with antiphospholipid syndrome. Lupus 2004;13(9):683-7. PMID 15485103 * Chandrasekharan NV, Dai H, Roos KL, Evanson NK, Tomsik J, Elton TS, Simmons DL. COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression. Proc Natl Acad Sci U S A 2002;99:13926-31. PMID 12242329 * Graham GG, Scott KF, Day RO. Tolerability of paracetamol. Drug Saf 2005;28(3):227-40. PMID 15733027 * Green GA. Understanding NSAIDS: from aspirin to COX-2. Clin Cornerstone 2001;3(5):50-59. PMID 11464731 * Moore DE. Drug-induced cutaneous photosensitivity. Drug Safety 2002;25:345-72. PMID 12020173 * Ostensen ME, Skomsvoll JF. Anti-inflammatory pharmacotherapy during pregnancy. Expert Opin Pharmacother 2004;5(3):571-80. PMID 15013926 * Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006. ISBN 0-9757919-2-3 * Thomas MC. Diuretics, ACE inhibitors and NSAIDs – the triple whammy. Med J Aust 2000;172:184-185. PMID 10772593 * Wilkes JM, Clark LE, Herrera JL. Acetaminophen overdose in pregnancy. South Med J 2005;98(11):1118-22. PMID 16351032 * Kis B, Snipes, JA, Busija DW. Acetaminophen and the Cyclooxygenase-3 Puzzle: Sorting out Facts, Fictions, and Uncertainties. JPET 2005;315:1-7. PMID 15879007 == 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)] {{Anti-inflammatory and antirheumatic products}} {{NSAIDs}} {{Analgesics}} [[Category:Analgesics]] [[Category:Non-steroidal anti-inflammatory drugs| ]] [[bs:Nesteroidni antiupalni lijekovi]] [[ca:Antiinflamatori no esteroïdal]] [[cs:Antirevmatikum]] [[de:Nichtsteroidales Antirheumatikum]] [[es:Antiinflamatorio no esteroideo]] [[fr:Anti-inflammatoire non stéroïdien]] [[it:FANS]] [[hu:Nem-szteroid gyulladáscsökkentő gyógyszerek]] [[nl:NSAID]] [[ja:非ステロイド性抗炎症薬]] [[no:Ikkesteroid antiinflammatorisk middel]] [[pl:Niesteroidowe leki przeciwzapalne]] [[pt:Antiinflamatórios não-esteróides]] [[ru:Нестероидные противовоспалительные препараты]] [[sk:Nesteroidné antiflogistikum]] [[fi:Tulehduskipulääke]] [[sv:NSAID]] [[th:เอ็นเซด]] [[vi:Thuốc chống viêm không steroid]] [[tr:Non steroidal antienflamatuar ilaçlar]] [[zh:非類固醇消炎止痛藥]]