Coated 200 mg
Ibuprofen tablets, a common NSAID
Nonsteroidal anti-inflammatory drugs, usually abbreviated to NSAIDs, but also referred to as nonsteroidal anti-inflammatory agents/analgesics (NSAIAs) or nonsteroidal anti-inflammatory medicines (NSAIMs), are drugs 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.[1][2]
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:[3]
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.
In 2001 NSAIDs accounted for 70,000,000 prescriptions and 30 billion over-the-counter doses sold annually in the United States.[5]
The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly prevalent. The two main adverse drug reactions (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.[5]
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.[6][7]
If a COX-2 inhibitor is taken, one should not use a traditional NSAID (prescription or over-the-counter) concomitantly.[8] In addition, people 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[further explanation needed] the cardioprotective effects of aspirin.
NSAIDs aside from aspirin, both newer COX-2 antagonists and traditional anti-inflammatories, increase the risk of myocardial infarction and stroke.[9][10] They are not recommended in those who have had a previous heart attack as they increase the risk of death and / or recurrent MI.[11] Naproxen seems least harmful.[10]
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.[12] 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. In people with heart failure, NSAIDs increase mortality risk by approximately 1.2-1.3 for naproxen and ibuprofen, 1.7 for rofecoxib and celecoxib, and 2.1 for diclofenac.[13]
A 2005 study linked long term (over 3 months) use of NSAIDs, including ibuprofen, with a 1.4 times increased risk of erectile dysfunction.[14][15] 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".[16] 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".[15]
The main adverse drug reactions (ADRs) associated with use of NSAIDs relate to direct and indirect irritation of the gastrointestinal (GI) tract. NSAIDs cause a dual assault on the GI tract: the acidic molecules directly irritate the gastric mucosa, and inhibition of COX-1 and COX-2 reduces the levels of protective prostaglandins. Inhibition of prostaglandin synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished mucus secretion and diminished trophic[clarification needed] effects on epithelial mucosa.
Common gastrointestinal ADRs include:[3]
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.[18]
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 some mucosal damage to their small intestine.[19] Studies show that risk of ulceration is less with nabumetone than with ibuprofen alone.[20]
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.[3]
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.[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.
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 (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. Horses are particularly prone to these adverse effects compared with other domestic animal species.
Common ADRs associated with altered renal function include:[3]
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.[21]
In rarer instances NSAIDs may also cause more severe renal conditions:[3]
NSAIDs in combination with excessive use of phenacetin and/or paracetamol (acetaminophen) may lead to analgesic nephropathy.[22]
Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs.[23] 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 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 to be 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 birth[24] and miscarriage.[25][26] Aspirin, however, is used together with heparin in pregnant women with antiphospholipid antibodies.[27]. 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.[28] Doses should be taken as prescribed, due to risk of hepatotoxicity with overdoses.[29]
In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy.[30]
Common adverse drug reactions (ADR), other than listed above, include: raised liver enzymes, headache, dizziness.[3] Uncommon ADRs include: hyperkalaemia, confusion, bronchospasm, rash.[3] 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.
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.[31]
NSAIDs reduce renal blood flow and thereby decrease the efficacy of diuretics, and inhibit the elimination of lithium and methotrexate.[32]
NSAIDs cause hypocoagulability, which may be serious when combined with other drugs that also decrease blood clotting, such as warfarin.[32]
NSAIDs may aggravate hypertension (high blood pressure) and thereby antagonize the effect of antihypertensives,[32] such as ACE Inhibitors.[33]
NSAIDs may interfere and reduce efficiency of SSRI antidepressants[34][35]
Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase (COX), inhibiting both the cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) isoenzymes. 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). Many aspects of the mechanism of action of NSAIDs remain unexplained, 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.[36] NSAIDs are also used in the acute pain caused by gout because they inhibit urate crystal phagocytosis besides inhibition of prostaglandin synthase.[37]
NSAIDS have antipyretic activity and can be used to treat fever.[38][39] Fever is caused by elevated levels of prostaglandin E2, which alters the firing rate of neurons within the hypothalamus that control thermoregulation.[38][40] Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition of prostanoid biosynthesis (PGE2) within the hypothalamus.[38][39] PGE2 signals to the hypothalamus to increase the body's thermal set point.[39][41] Ibuprofen has been shown to be more effective as an antipyretic than acetaminophen.[40][42] 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.
- 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
A related drug, Paracetamol or ""acetaminophen" is often considered in the same category as NSAIDS due to its use as a non-narcotic analgesic and fever-reducing agent, but is not classified as a NSAID because it only has weak anti-inflammatory effect.
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.[48] 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.
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.[48] Some data also supports that the partially selective nabumetone is less likely to cause gastrointestinal events.[48] The nonselective naproxen appears to be risk-neutral with regard to cardiovascular events.[48]
A consumer report noted ibuprofen, naproxen and salsalate to be less expensive than other NSAIDs and to be essentially as effective and safe as any of them when used appropriately in treating osteoarthritis and pain.[49]
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 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).
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 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.
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 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.[36]
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.[50] 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 placebo[51] - a result which resulted in the worldwide withdrawal of rofecoxib in October 2004.
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.[52] 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.[53]
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 the specific species studied, and the relevant government agency in one area will sometimes prohibit uses which are 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 treating 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 cats[54][55] except for one-time use during surgery.[56] In spite of these warnings, meloxicam is frequently prescribed "off-label" for non-canine animals including cats and livestock species.[57] In other countries (for example EU and CAN), by contrast, there is a label claim for use in cats.[citation needed]
- ^ Stuart J. Warden, PT, PhD, FACSM (April 2010). "Prophylactic Use of NSAIDs by Athletes:A Risk/Benefit Assessment". The Physician and SportsMedicine. 38 (1): 132–138. DOI:10.3810/psm.2010.04.1770. PMID 20424410. http://www.physsportsmed.com/index.php?article=1770.
- ^ Some Common Medications That Contain Acetaminophen, Acetaminophen is also a common NSAID.
- ^ a b c d e f g h Simone Rossi, ed. (2006). Australian medicines handbook 2006. Adelaide: Australian Medicines Handbook Pty Ltd. ISBN 0-9757919-2-3. [page needed]
- ^ 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.
- ^ a b 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.
- ^ "CIPRO (ciprofloxacin hydrochloride) TABLETS CIPRO,(ciprofloxacin*) ORAL SUSPENSION" (PDF). USA: FDA. September 2008. http://www.accessdata.fda.gov/drugsatfda_docs/label/2008/019537s68,19847s42,19857s49,20780s26,21473s24lbl.pdf. 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.
- ^ http://orthoinfo.aaos.org/fact/thr_report.cfm?Thread_ID=398&topcategory=About
- ^ 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. http://bmj.com/cgi/pmidlookup?view=long&pmid=16740558.
- ^ a b 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. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3019238.
- ^ 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.
- ^ 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. http://archinte.ama-assn.org/cgi/pmidlookup?view=long&pmid=10737277.
- ^ Gislason, G. H.; Rasmussen, J. N.; Abildstrom, S. Z.; Schramm, T. K.; Hansen, M. L.; Fosbol, E. L.; Sorensen, R.; Folke, F. et al. (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. edit
- ^ Shiri et al (Received 2005-05-21). "Effect of Nonsteroidal Anti-Inflammatory Drug Use on the Incidence of Erectile Dysfunction". Journal of Urology 175 (5): 1812–1816. http://www.jurology.com/article/S0022-5347%2805%2901000-1/abstract. Retrieved 12 June 2011.
- ^ a b "Non-steroidal anti-inflammatory drugs linked to increased risk of erectile dysfunction". sciencedaily.com. 2 March 2011. http://www.sciencedaily.com/releases/2011/03/110302152811.htm. Retrieved 7 June 2011.
- ^ Mary Brophy Marcus (March, 2011). "New study links pain relievers to erectile dysfunction". USA Today. http://yourlife.usatoday.com/health/story/2011/03/New-study-links-pain-relievers-to-erectile-dysfunction/44363996/1.
- ^ 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. http://www.springerlink.com/content/p637716362731058/.
- ^ Roth SH, Tindall EA, Jain AK, McMahon FG, April PA, Bockow BI, Cohen SB, Fleischmann RM (November 1993). "A controlled study comparing the effects of nabumetone, ibuprofen, and ibuprofen plus misoprostol on the upper gastrointestinal tract mucosa". Archives of Internal Medicine 153 (22): 2565–71. DOI:10.1001/archinte.153.22.2565. PMID 8239849.
- ^ 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:10.1517/14656566.5.3.571. 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. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=3193112.
- ^ 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. http://www.cmaj.ca/content/early/2011/09/06/cmaj.110454.full.pdf+html. 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.
- ^ 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" (in French). France Soir. http://www.francesoir.fr/societe/2009/03/02/grossesse-mamans-attention.html. Retrieved 1 June 2009.
- ^ "Adverse and allergic reactions to aspirin and NSAIDS". Allergy Capital. http://www.allergycapital.com.au/Pages/aspirin.html. Retrieved 23 March 2009. [dead link]
- ^ a b c MedicineNet > Nonsteroidal Antiinflammatory Drugs (NSAIDs) By Omudhome Ogbru. Last Editorial Review: 12/17/2008
- ^ 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.
- ^ 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
- ^ a b 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. edit
- ^ http://www.pharmacology2000.com/Hemo/Inflammation/inflam5.htm
- ^ a b c 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.
- ^ a b c 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.
- ^ a b 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. //www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2590134.
- ^ 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
- ^ http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm193047.htm
- ^ 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.htm[dead link]
- ^ http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124649.htm Alert for Healthcare Professionals: Valdecoxib (marketed as Bextra)
- ^ a b c d 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
- ^ 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.
- ^ Chandrasekharan, Nv; Dai, H; Roos, Kl; Evanson, Nk; Tomsik, J; Elton, Ts; Simmons, Dl (October 2002). "COX-3, a COX-1 variant inhibited by acetaminophen and other analgesic/antipyretic drugs: cloning, structure, and expression" (Free full text). Proceedings of the National Academy of Sciences of the United States of America 99 (21): 13926–31. DOI:10.1073/pnas.162468699. ISSN 0027-8424. PMC 129799. PMID 12242329. http://www.pnas.org/cgi/pmidlookup?view=long&pmid=12242329.
- ^ Kis, B; Snipes, Ja; Busija, Dw (October 2005). "Acetaminophen and the COX-3 puzzle: sorting out facts, fictions, and uncertainties" (Free full text). The Journal of Pharmacology and Experimental Therapeutics 315 (1): 1–7. DOI:10.1124/jpet.105.085431. ISSN 0022-3565. PMID 15879007. http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=15879007.
- ^ "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. April 15, 2003. http://www.fda.gov/downloads/AnimalVeterinary/Products/ApprovedAnimalDrugProducts/FOIADrugSummaries/ucm118006.pdf. 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 October 28, 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.
