Non-steroidal anti-inflammatory drug
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs // EN-sed—but also referred to as nonsteroidal anti-inflammatory agents/analgesics (NSAIAs) or nonsteroidal anti-inflammatory medicines (NSAIMs)—are a class of drugs that provides analgesic (pain-killing) and antipyretic (fever-reducing) effects, and, in higher doses, anti-inflammatory effects.
The term nonsteroidal distinguishes 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 and thus are used as a non-addictive alternative to narcotics.
The most prominent members of this group of drugs, aspirin, ibuprofen and naproxen, are all available over the counter in most countries.1 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.2
NSAIDs inhibit the activity of both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2), and thereby, the synthesis of prostaglandins and thromboxanes. It is thought that inhibiting COX-2 leads to the anti-inflammatory, analgesic and antipyretic effects and that those NSAIDs also inhibiting COX-1, particularly aspirin, may cause gastrointestinal bleeding and ulcers.3 For this reason, the advantages of COX-2 selective inhibitors may be indicated.
- 1 Medical uses
- 2 Contraindications
- 3 Adverse effects
- 4 Mechanism of action
- 5 Classification
- 6 Pharmacokinetics
- 7 History
- 8 Veterinary use
- 9 References
- Rheumatoid arthritis7
- Mild-to-moderate pain due to inflammation and tissue injury5
- Low back pain58
- Inflammatory arthropathies (e.g., ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome)
- Tennis elbow9
- Acute gout4
- Dysmenorrhoea (menstrual pain)4
- Metastatic bone pain4
- Postoperative pain4
- Muscle stiffness and pain due to Parkinson's disease4
- Pyrexia (fever)4
- Renal colic4
- They are also given to neonate infants whose ductus arteriosus is not closed within 24 hours of birth4
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 A2.
NSAIDs may be used with caution by people with the following conditions:5
- Irritable bowel syndrome5
- Persons who are over age 50, and who have a family history of GI problems5
- Persons who have had past GI problems from NSAID use5
NSAIDs should usually be avoided by people with the following conditions:5
The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly prevalent. Use of NSAIDs increases risk of having a range of gastrointestinal (GI) problems.10 When NSAIDs are used for pain management after surgery they cause increased risk of kidney problems.11
An estimated 10-20% of NSAID patients experience dyspepsia. In the 1990s high doses of prescription NSAIDs were associated with serious upper gastrointestinal adverse events, including bleeding.12 Over the past decade, deaths associated with gastric bleeding have declined.
NSAIDs, like all drugs, may interact with other medications. For example, concurrent use of NSAIDs and quinolones may increase the risk of quinolones' adverse central nervous system effects, including seizure.1314
If a COX-2 inhibitor is taken, a traditional NSAID (prescription or over-the-counter) should not be taken at the same time.15not in citation given In addition, people on daily aspirin therapy (e.g., for reducing cardiovascular risk) must be careful if they also use other NSAIDs, as these may inhibit the cardioprotective effects of aspirin.
Rofecoxib was shown to produce significantly fewer gastrointestinal ADRs compared with naproxen.16 This study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs. A statistically insignificant 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 placebo17—which caused a worldwide withdrawal of rofecoxib in October 2004.
NSAIDs aside from aspirin, both newer selective COX-2 inhibitors and traditional anti-inflammatories, increase the risk of myocardial infarction and stroke.1819 They are not recommended in those who have had a previous heart attack as they increase the risk of death and / or recurrent MI.20 Naproxen seems least harmful.1921
NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of heart failure in people without a history of cardiac disease.21 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.22 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.23
A 2005 study linked long term (over 3 months) use of NSAIDs, including ibuprofen, with an average of 1.4 times (40%) increased relative-risk of erectile dysfunction.2425 The report by Kaiser Permanente and published in the Journal of Urology, considered that "regular non-steroidal anti-inflammatory drug use is associated with erectile dysfunction beyond what would be expected due to age and other condition".26 The director of research for Kaiser Permanente added that "There are many proven benefits of non steroidals in preventing heart disease and for other conditions. People shouldn't stop taking them based on this observational study. However, if a man is taking this class of drugs and has ED, it's worth a discussion with his doctor".25
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 trophicclarification needed effects on epithelial mucosa.
Common gastrointestinal ADRs include:4
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 patients with achlorhydria.28
Ulceration risk increases with therapy duration, and with higher doses. To minimise GI ADRs, it is prudent to use the lowest effective dose for the shortest period of time—a practice that studies show is often not followed. Recent studies show that over 50% of patients who take NSAIDs have sustained some mucosal damage to their small intestine.29
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.4
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, considering the mechanism of such ADRs, and in clinical practice, these formulations have not demonstrated a reduced risk of GI ulceration.4
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 are expensive for maintenance therapy.
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. 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
NSAIDs are also associated with a relatively high incidence of renal adverse drug reactions (ADRs). The mechanism of these renal ADRs is due to changes in renal haemodynamics (kidney blood flow), ordinarily mediated by prostaglandins, which are affected by NSAIDs. Prostaglandins normally cause vasodilation of the afferent arterioles of the 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 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.
Common ADRs associated with altered renal function include:4
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 (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.30
In rarer instances NSAIDs may also cause more severe renal conditions:4
Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs.32 The 2-arylpropionic acids are 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 moiety. The specific absorbance characteristics of the different chromophoric 2-aryl substituents, affects the decarboxylation mechanism. While ibuprofen has weak absorption, it has been reported as a weak photosensitising agent.citation needed
NSAIDs are not recommended during pregnancy, particularly during the third trimester. While NSAIDs as a class are not direct teratogens, they may cause premature closure of the fetal ductus arteriosus and renal ADRs in the fetus. Additionally, they are linked with premature birth33 and miscarriage.3435 Aspirin, however, is used together with heparin in pregnant women with antiphospholipid antibodies.36 Additionally, Indomethacin is used in pregnancy to treat polyhydramnios by reducing fetal urine production via inhibiting fetal renal blood flow.
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.3738 Doses should be taken as prescribed, due to risk of hepatotoxicity with overdoses.39
In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy.40
Common adverse drug reactions (ADR), other than listed above, include: raised liver enzymes, headache, dizziness.4 Uncommon ADRs include: hyperkalaemia, confusion, bronchospasm, rash.4 Rapid and severe swelling of the face and/or body. Ibuprofen may also rarely cause irritable bowel syndrome symptoms. NSAIDs are also implicated in some cases of Stevens–Johnson syndrome.
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.41
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.42
Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), 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.47 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 by John Vane (1927–2004), who received a Nobel Prize for his work (see Mechanism of action of aspirin).
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 was discovered in 1991 by Daniel L. Simmons at Brigham Young University. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs.
The discovery of COX-2 led to research to development of selective COX-2 inhibiting drugs that do not cause gastric problems characteristic of older NSAIDs.
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.2
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.2
NSAIDS have antipyretic activity and can be used to treat fever.5152 Fever is caused by elevated levels of prostaglandin E2, which alters the firing rate of neurons within the hypothalamus that control thermoregulation.5153 Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus.5152 PGE2 signals to the hypothalamus to increase the body's thermal set point.5254 Ibuprofen has been shown more effective as an antipyretic than paracetamol (acetaminophen).5355 Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D & E.
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.
- Aspirin (acetylsalicylic acid)
- Choline Magnesium Trisalicylate(Trilisate™)
- Diclofenac (Safety alert by FDA57)
- Nabumetone (drug itself is non-acidic but the active, principal metabolite has a carboxylic acid group)
- Celecoxib (FDA alert58)
- Rofecoxib (withdrawn from market59)
- Valdecoxib (withdrawn from market60)
- Parecoxib FDA withdrawn, licenced in the EU
- Lumiracoxib TGA cancelled registration
- Etoricoxib not FDA approved, licenced in the EU
- Firocoxib used in dogs and horses
- Nimesulide (systemic preparations are banned by several countries for the potential risk of hepatotoxicity)
- Licofelone acts by inhibiting LOX (lipooxygenase) & COX and hence known as 5-LOX/COX inhibitor
Most NSAIDs are 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 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.
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.
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.63 Rather, differences among compounds usually relate to dosing regimens (related to the compound's elimination half-life), route of administration, and tolerability profile.
Regarding adverse effects, selective COX-2 inhibitors have lower risk of gastrointestinal bleeding, but a substantially more increased risk of myocardial infarction than the increased risk from nonselective inhibitors.63 Some data also supports that the partially selective nabumetone is less likely to cause gastrointestinal events.63 The nonselective naproxen appears risk-neutral with regard to cardiovascular events.63
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 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 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.
Ibuprofen and diclofenac have short half-lives (2–3 hours). Some NSAIDs (typically oxicams) have very long half-lives (e.g. 20–60 hours).
From the era of Greek philosophical medicine to the mid-19th century, the discovery of medicinal agents was classed as an empirical art; folklore and mythological guidance were combined in deploying the vegetable and mineral products that made up the meagre pharmacopoeia of the time. Myrtle leaves were in use by 1500 BCE. Hippocrates (460 - 377 BCE) first reported using willow bark65 and in 30 BCE Celsus described the signs of inflammation and also used willow bark to mitigate them. On April 25, 1763, Edward Stone wrote to the Royal Society describing his observations on the use of willow bark-based medicines in febrile patients.66 The active ingredient of willow bark, a glycoside called 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 kg of bark.66
By hydrolysis, salicin releases glucose and salicylic alcohol which can be converted into salicylic acid, both in vivo and through chemical methods.65 The acid is more effective than salicin and, in addition to its fever-reducing properties, is anti-inflammatory and analgesic. In 1869, Hermann Kolbe synthesised salicylate, although it was too acidic for the gastric mucosa.65 The reaction used to synthesise aromatic acid from a phenol in the presence of CO2 is known as the Kolbe-Schmitt reaction.676869
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 were developed from the 1950s forward.66
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, 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.
For example, ketoprofen's effects have been studied in horses more than in ruminants but, due to controversy over its use in racehorses, veterinarians who treat livestock in the United States more commonly prescribe flunixin meglumine, which, while labeled for use in such animals, is not indicated for post-operative pain.
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 cats7071 except for one-time use during surgery.72 In spite of these warnings, meloxicam is frequently prescribed "off-label" for non-canine animals including cats and livestock species.73 In other countries, for example The European Union (EU), there is a label claim for use in cats.citation needed
- Warden, Stuart J. (April 2010). "Prophylactic Use of NSAIDs by Athletes: A Risk/Benefit Assessment". The Physician and Sports Medicine 38 (1): 132–138. doi:10.3810/psm.2010.04.1770. PMID 20424410.
- Hinz, B.; Cheremina, O.; Brune, K. (2008). "Acetaminophen (paracetamol) is a selective cyclooxygenase-2 inhibitor in man.". The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 22 (2): 383–390. doi:10.1096/fj.07-8506com. PMID 17884974.
- Clive P. Page, Michael J. Curtis, Morley Sutter, Michael Walker, Brian Hoffman. Farmacología integrada (in Spanish). Published by Elsevier España, 1998. ISBN 84-8174-340-2
- Simone Rossi, ed. (2006). Australian medicines handbook 2006. Adelaide: Australian Medicines Handbook Pty Ltd. ISBN 0-9757919-2-3.page needed
- Consumer Reports Health Best Buy Drugs (July 2013). "The Nonsteroidal Anti-Inflammatory Drugs: Treating Osteoarthritis and Pain. Comparing effectiveness, safety, and price.". NSAIDs. Yonkers, New York: Consumer Reports. Retrieved 12 February 2014
- Towheed, Tanveer; Maxwell, Lara; Judd, Maria; Catton, Michelle; Hochberg, Marc C; Wells, George A; Towheed, Tanveer (2006). "Acetaminophen for osteoarthritis". Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD004257.pub2.
- Gøtzsche, Pc (March 1989). "Methodology and overt and hidden bias in reports of 196 double-blind trials of nonsteroidal antiinflammatory drugs in rheumatoid arthritis". Controlled clinical trials 10 (1): 31–56. doi:10.1016/0197-2456(89)90017-2. ISSN 0197-2456. PMID 2702836.
- Roelofs, P. D. M.; Deyo, R. A.; Koes, B. W.; Scholten, R. J. M.; Van Tulder, M. W. (2008). "Non-steroidal anti-inflammatory drugs for low back pain". Cochrane Database of Systematic Reviews (1). pp. CD000396. doi:10.1002/14651858.CD000396.pub3. PMID 18253976.
- Pattanittum, Porjai; Turner, Tari; Green, Sally; Buchbinder, Rachelle; Buchbinder, Rachelle (2013). "Non-steroidal anti-inflammatory drugs (NSAIDs) for treating lateral elbow pain in adults". Cochrane Database of Systematic Reviews 5. pp. CD003686. doi:10.1002/14651858.CD003686.pub2. PMID 23728646.
- Rostom, Alaa; Dube, Catherine; Wells, George A; Tugwell, Peter; Welch, Vivian; Jolicoeur, Emilie; McGowan, Jessie; Lanas, Angel; Rostom, Alaa (2002). "Prevention of NSAID-induced gastroduodenal ulcers". Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD002296.
- Lee, Anna; Cooper, Michael G; Craig, Jonathan C; Knight, John F; Keneally, John P; Lee, Anna (2007). "Effects of nonsteroidal anti-inflammatory drugs on postoperative renal function in adults with normal renal function". Cochrane Database of Systematic Reviews. doi:10.1002/14651858.CD002765.pub3.
- Green, Ga (2001). "Understanding NSAIDs: from aspirin to COX-2". Clinical cornerstone 3 (5): 50–60. doi:10.1016/S1098-3597(01)90069-9. ISSN 1098-3597. PMID 11464731.
- Bayer HealthCare Pharmaceuticals Inc (September 2008). "CIPRO (ciprofloxacin hydrochloride) TABLETS CIPRO,(ciprofloxacin*) ORAL SUSPENSION" (PDF). USA: FDA. Retrieved 31 August 2009.
- Royal Pharmaceutical Society of Great Britain (2009). "5 Infections". British National Formulary (BNF 57). BMJ Group and RPS Publishing. ISBN 978-0-85369-845-6.
- 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 (November 2000). "Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis". New England Journal of Medicine 343 (21): 1520–8, 2 p following 1528. doi:10.1056/NEJM200011233432103. ISSN 0028-4793. PMID 11087881.
- Baron, JA; Sandler, RS, Bresalier, RS, Lanas, A, Morton, DG, Riddell, R, Iverson, ER, Demets, DL (15 November 2008). "Cardiovascular events associated with rofecoxib: final analysis of the APPROVe trial". Lancet 372 (9651): 1756–64. doi:10.1016/S0140-6736(08)61490-7. PMID 18922570.
- Kearney, Pm; Baigent, C; Godwin, J; Halls, H; Emberson, Jr; Patrono, C (June 2006). "Do selective cyclo-oxygenase-2 inhibitors and traditional nonsteroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials" (Free full text). BMJ (Clinical research ed.) 332 (7553): 1302–8. doi:10.1136/bmj.332.7553.1302. ISSN 0959-8138. PMC 1473048. PMID 16740558.
- Trelle, S; Reichenbach, S, Wandel, S, Hildebrand, P, Tschannen, B, Villiger, PM, Egger, M, Jüni, P (11 January 2011). "Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis.". BMJ (Clinical research ed.) 342 (jan11 1): c7086. doi:10.1136/bmj.c7086. PMC 3019238. PMID 21224324.
- 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 (9 May 2011). "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.". Circulation 123 (20): 2226–35. doi:10.1161/CIRCULATIONAHA.110.004671. PMID 21555710.
- Coxib and traditional NSAID Trialists' (CNT), Collaboration; 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 (Aug 31, 2013). "Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials.". Lancet 382 (9894): 769–79. doi:10.1016/S0140-6736(13)60900-9. PMC 3778977. PMID 23726390.
- Page, J; Henry, D (March 2000). "Consumption of NSAIDs and the development of congestive heart failure in elderly patients: an underrecognized public health problem" (Free full text). Archives of Internal Medicine 160 (6): 777–84. doi:10.1001/archinte.160.6.777. ISSN 0003-9926. PMID 10737277.
- Gislason, G. H.; Rasmussen, J. N.; Abildstrom, S. Z.; Schramm, T. K.; Hansen, M. L.; Fosbøl, E. L.; Sørensen, R.; Folke, F.; Buch, P.; Gadsbøll, N.; Rasmussen, S.; Poulsen, H. E.; Køber, L.; Madsen, M.; Torp-Pedersen, C. (2009). "Increased Mortality and Cardiovascular Morbidity Associated with Use of Nonsteroidal Anti-inflammatory Drugs in Chronic Heart Failure". Archives of Internal Medicine 169 (2): 141–149. doi:10.1001/archinternmed.2008.525. PMID 19171810.
- Shiri et al, R.; Koskimäki, J.; Häkkinen, J.; Tammela, T.L.J.; Auvinen, A.; Hakama, M. (May 2006). "Effect of Nonsteroidal Anti-Inflammatory Drug Use on the Incidence of Erectile Dysfunction". Journal of Urology 175 (5): 1812–1816. doi:10.1016/S0022-5347(05)01000-1. PMID 16600768. Retrieved 12 June 2011.
- "Non-steroidal anti-inflammatory drugs linked to increased risk of erectile dysfunction". sciencedaily.com. 2 March 2011. Retrieved 7 June 2011.
- Mary Brophy Marcus (March 2011). "New study links pain relievers to erectile dysfunction". USA Today.
- Traversa, G; Walker, Am; Ippolito, Fm; Caffari, B; Capurso, L; Dezi, A; Koch, M; Maggini, M; Alegiani, Ss; Raschetti, R (January 1995). "Gastroduodenal toxicity of different nonsteroidal antiinflammatory drugs". Epidemiology (Cambridge, Mass.) 6 (1): 49–54. doi:10.1097/00001648-199501000-00010. ISSN 1044-3983. PMID 7888445.
- Textbook of Gastroenterology, Tadataka Yamada, 2008, Ch.40, Peptic Ulcer Disease, page 941
- Higuchi K, Umegaki E, Watanabe T, Yoda Y, Morita E, Murano M, Tokioka S, Arakawa T (July 2009). "Present status and strategy of NSAIDs-induced small bowel injury". Journal of Gastroenterology 44 (9): 879–888. doi:10.1007/s00535-009-0102-2. ISSN 1435-5922. PMID 19568687.
- Thomas, Mc (February 2000). "Diuretics, ACE inhibitors and NSAIDs—the triple whammy". The Medical journal of Australia 172 (4): 184–5. ISSN 0025-729X. PMID 10772593.
- De, Broe, Me; Elseviers, Mm (February 1998). "Analgesic nephropathy". New England Journal of Medicine 338 (7): 446–52. doi:10.1056/NEJM199802123380707. ISSN 0028-4793. PMID 9459649.
- Moore, De (2002). "Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention and management". Drug safety: an international journal of medical toxicology and drug experience 25 (5): 345–72. doi:10.2165/00002018-200225050-00004. ISSN 0114-5916. PMID 12020173.
- Østensen, Me; Skomsvoll, Jf (March 2004). "Anti-inflammatory pharmacotherapy during pregnancy". Expert opinion on pharmacotherapy 5 (3): 571–80. doi:10.1517/146565220.127.116.111. ISSN 1465-6566. PMID 15013926.
- Hamid Reza Nakhai-Pour MD PhD, Perrine Broy BSc, Odile Sheehy MSc, Anick Bérard PhD (September 2011). "Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion". Canadian Medical Association Journal 183 (15): 1713–20. doi:10.1503/cmaj.110454. PMC 3193112. PMID 21896698.
- Reza Nakhai-Pour MD PhD,, Hamid. "Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion". Canadian Medical Association Journal. Retrieved 7 September 2011.
- Cervera, R; Balasch, J (2004). "The management of pregnant patients with antiphospholipid syndrome". Lupus 13 (9): 683–7. doi:10.1191/0961203304lu1092oa. ISSN 0961-2033. PMID 15485103.
- Graham, Gg; Scott, Kf; Day, Ro (2005). "Tolerability of paracetamol". Drug safety: an international journal of medical toxicology and drug experience 28 (3): 227–40. doi:10.2165/00002018-200528030-00004. ISSN 0114-5916. PMID 15733027.
- Leffers, A.; et al (2010). "Intrauterine exposure to mild analgesics is a risk factor for development of male reproductive disorders in human and rat". Human Reproduction 25 (1): 235–244. doi:10.1093/humrep/deq382.
- Wilkes, Jm; Clark, Le; Herrera, Jl (November 2005). "Acetaminophen overdose in pregnancy". Southern Medical Journal 98 (11): 1118–22. doi:10.1097/01.smj.0000184792.15407.51. ISSN 0038-4348. PMID 16351032.
- Dreillard, Audrey (2 March 2009). "Grossesse - Mamans attention". France Soir (in French). Retrieved 1 June 2009.
- Auriel E et al. Nonsteroidal anti-inflammatory drugs exposure and the central nervous system Handb Clin Neurol. 2014;119:577-84. doi: 10.1016/B978-0-7020-4086-3.00038-2. PMID 24365321
- Woessner KM, Castells M. NSAID single-drug-induced reactions. Immunol Allergy Clin North Am. 2013 May;33(2):237-49. PMID 23639711
- MedicineNet > Nonsteroidal Antiinflammatory Drugs (NSAIDs) By Omudhome Ogbru. Last Editorial Review: 17 December 2008
- Shionoiri, H (July 1993). "Pharmacokinetic drug interactions with ACE inhibitors". Clinical pharmacokinetics 25 (1): 20–58. doi:10.2165/00003088-199325010-00003. PMID 8354016. Retrieved 30 November 2012.
- Why Painkillers Interfere with Anti-depressants
- J.L. Warner-Schmidt et.al "Antidepressant effects of selective serotonin reuptake inhibitors (SSRIs) are attenuated by antiinflammatory drugs in mice and humans" PNAS 2011
- Knights, Kathleen. "Defining the COX Inhibitor Selectivity of NSAIDs: Implications for Understanding Toxicity". Web MD LLC. Retrieved 17 February 2013.
- dead link
- "INHIBIT ORS OF CYCLOOXYGENASES: MECHANISMS, SELECTIVITY AND USES". Journal of Physiology and Pharmacology. Retrieved 2014-03-16.
- "Inflammation page 5". Pharmacology2000.com. Retrieved 2012-11-30.
- Aronoff DM, Neilson EG (September 2001). "Antipyretics: mechanisms of action and clinical use in fever suppression". Am. J. Med. 111 (4): 304–15. doi:10.1016/S0002-9343(01)00834-8. PMID 11566461.
- Koeberle A, Werz O (2009). "Inhibitors of the microsomal prostaglandin E(2) synthase-1 as alternative to non steroidal anti-inflammatory drugs (NSAIDs)–a critical review". Curr. Med. Chem. 16 (32): 4274–96. doi:10.2174/092986709789578178. PMID 19754418.
- Nabulsi M (2009). "Is combining or alternating antipyretic therapy more beneficial than monotherapy for febrile children?". BMJ 339: b3540. doi:10.1136/bmj.b3540. PMID 19797346.
- Coceani F, Bishai I, Lees J, Sirko S (1986). "Prostaglandin E2 and fever: a continuing debate". Yale J Biol Med 59 (2): 169–74. PMC 2590134. PMID 3488620.
- Rainsford KD (December 2009). "Ibuprofen: pharmacology, efficacy and safety". Inflammopharmacology 17 (6): 275–342. doi:10.1007/s10787-009-0016-x. PMID 19949916.
- http://www.drugbank.ca/cgi-bin/getCard.cgi?CARD=APRD00372 Drugbank Card for Ibuprofen
- "Voltaren Gel (diclofenac sodium topical gel) 1% - Hepatic Effects Labeling Changes". Fda.gov. 2009-12-04. Retrieved 2012-11-30.
- Information for Healthcare Professionals: Celecoxib (marketed as Celebrex) http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124655.htm
- http://www.fda.gov/cder/drug/infopage/vioxx/PHA_vioxx.htmdead link
- Alert for Healthcare Professionals: Valdecoxib (marketed as Bextra)
- Viljoen A, Mncwangi N, Vermaak I. (2012). Anti-inflammatory iridoids of botanical origin. Curr Med Chem. 2012;19(14):2104-27.
- Liuqiang Zhanga, Li Fenga, Qi Jiaa, Jinwen Xub, Rui Wanga, Zhengtao Wangc, Yingchun Wua, Yiming Lia. (2011). Effects of β-glucosidase hydrolyzed products of harpagide and harpagoside on cyclooxygenase-2 (COX-2) in vitro. Bioorganic & Medicinal ChemistryVolume 19, Issue 16, 15 August 2011, Pages 4882–4886
- Comparing NSAIDs - Summaries of key questions from the Drug Effectiveness Review Project (DERP), Oregon Health & Science University. By Laura Dean, National Center of Biotechnology Information (NCBI)
- Treating Osteoarthritis and Pain: The Non-Steroidal Anti-Inflammatory Drugs Comparing Effectiveness, Safety, and Price Consumers Union 2005
- John McMurry. Química Orgánica (in Spanish). Published by Cengage Learning Editores, 2005. ISBN 970-686-354-0
- Hardman, Joel G.; Limbird, Lee E.; Goodman Gilman, Alfred (1996). "Capítulo 27: Analgésicos-antipiréticos, antiinflamatorios y fármacos que se utilizan en el tratamiento de la gota.". Goodman & Gilman, las bases farmacológicas de la terapéutica. (9 ed.). México, D. F.: Ed. McGraw-Hill Interamericana. ISBN 0-07-026266-7.
- Hermann Kolbe (1860). "Ueber Synthese der Salicylsäure". Annalen der Chemie und Pharmacie 113 (1): 125–27. doi:10.1002/jlac.18601130120.
- R. Schmitt (1885). "Beitrag zur Kenntniss der Kolbe'schen Salicylsäure Synthese". Journal für Praktische Chemie 31 (1): 397–411. doi:10.1002/prac.18850310130.
- A. S. Lindsey and H. Jeskey (1957). "The Kolbe-Schmitt Reaction". Chem. Rev. 57 (4): 583–620. doi:10.1021/cr50016a001. (Review)
- "NADA 141-213: New Animal Drug Application Approval (for Metacam® (meloxicam) 0.5 mg/mL and 1.5 mg/mL Oral Suspension)". US Food and Drug Administration. 15 April 2003. Retrieved 24 July 2010.
- Metacam Client Information Sheet, 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.
- Metacam 5 mg/mL Solution for Injection, Supplemental Approval 28 October 2004.
- Off-label use discussed in: Arnold Plotnick MS, DVM, ACVIM, ABVP, Pain Management using Metacam, and Stein, Robert, Perioperative Pain Managemment Part IV, Looking Beyond Butorphanol, September 2006.