The term nonsteroidal distinguishes these drugs from steroids, which while having a similar eicosanoid-depressing, anti-inflammatory action, have a broad range of other effects. First used in 1960, the term served to distance these medications from steroids.
There are two types of NSAID available: non-selective and COX-2 selective. Most NSAIDs are non-selective, and inhibit the activity of both COX-1 and COX-2. These NSAIDs, while reducing inflammation, also thin the blood (especially aspirin) and increase the risk of gastrointestinal ulcers/bleeds. COX-2 selective inhibitors have less gastrointestinal side effects, but promote thrombosis and substantially increase the risk of heart attack. As a result, COX-2 selective inhibitors are generally contraindicated due to the high risk of undiagnosed vascular disease. These differential effects are due to the different roles and tissue localisations of each COX isoenzyme. By inhibiting physiological COX activity, all NSAIDs increase the risk of kidney disease and, through a related mechanism, heart attack.
The most prominent NSAIDs are aspirin, ibuprofen and naproxen, all available over the counter in most countries.Paracetamol (acetaminophen) is generally not considered an NSAID because it has only 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.
In a more specific application, the reduction in prostaglandins is used to close a patent ductus arteriosus in neonates if it has not done so physiologically after 24 hours.
NSAIDs are useful in the management of post-operative dental pain following invasive dental procedures such as dental extraction. When not contra-indicated they are favoured over the use of paracetamol alone due to the anti-inflammatory effect they provide. When used in combination with paracetamol the analgesic effect has been proven to be improved. There is weak evidence suggesting that taking pre-operative analgesia can reduce the length of post operative pain associated with placing orthodontic spacers under local anaesthetic. Combination of NSAIDs with pregabalin as preemptive analgesia has shown promising results for decreasing post operative pain intensity.
The effectiveness of NSAID's for treating non-cancer chronic pain and cancer-related pain in children and adolescents is not clear. There have not been sufficient numbers of high-quality randomized controlled trials conducted.
NSAIDs may be used with caution by people with the following conditions:
The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly common. Use of NSAIDs increases risk of a range of gastrointestinal (GI) problems, kidney disease and adverse cardiovascular events. As commonly used for post-operative pain, there is evidence of increased risk of kidney complications. Their use following gastrointestinal surgery remains controversial, given mixed evidence of increased risk of leakage from any bowel anastomosis created.
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. Over the past decade,[when?] 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.
There is an argument over the benefits and risks of NSAIDs for treating chronic musculoskeletal pain. Each drug has a benefit-risk profile and balancing the risk of no treatment with the competing potential risks of various therapies is the clinician's responsibility.
If a COX-2 inhibitor is taken, a traditional NSAID (prescription or over-the-counter) should not be taken at the same time. 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 (Vioxx) was shown to produce significantly fewer gastrointestinal adverse drug reactions (ADRs) compared with naproxen. This study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs. A statistically significant increase in the incidence of myocardial infarctions was observed in patients on rofecoxib. Further data, from the APPROVe trial, showed a statistically significant relative risk of cardiovascular events of 1.97 versus placebo—which caused a worldwide withdrawal of rofecoxib in October 2004.
NSAIDs, aside from aspirin, increase the risk of myocardial infarction and stroke. This occurs at least within a week of use. They are not recommended in those who have had a previous heart attack as they increase the risk of death or recurrent MI. Evidence indicates that naproxen may be the least harmful out of these.
NSAIDs aside from (low-dose) aspirin are associated with a doubled risk of heart failure in people without a history of cardiac disease. In people with such a history, use of NSAIDs (aside from low-dose aspirin) was associated with a more than 10-fold increase in heart failure. 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.
On 9 July 2015, the FDA toughened warnings of increased heart attack and stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAID). Aspirin is an NSAID but is not affected by the new warnings.
Possible erectile dysfunction risk
A 2005 Finnish study linked long term (over 3 months) use of NSAIDs with an increased risk of erectile dysfunction. This study was correlational only, and depended solely on self-reports (questionnaires).
A 2011 publication in The Journal of Urology received widespread publicity. According to this study, men who used NSAIDs regularly were at significantly increased risk of erectile dysfunction. A link between NSAID use and erectile dysfunction still existed after controlling for several conditions. However, the study was observational and not controlled, with low original participation rate, potential participation bias, and other uncontrolled factors. The authors warned against drawing any conclusion regarding cause.
The main adverse drug reactions (ADRs) associated with NSAID use relate to direct and indirect irritation of the gastrointestinal (GI) tract. NSAIDs cause a dual assault on the GI tract: the acidic molecules directly irritate the gastric mucosa, and inhibition of COX-1 and COX-2 reduces the levels of protective prostaglandins. Inhibition of prostaglandin synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished mucus secretion and diminished trophic[clarification needed] effects on the epithelial mucosa.
Clinical NSAID ulcers are related to the systemic effects of NSAID administration. Such damage occurs irrespective of the route of administration of the NSAID (e.g., oral, rectal, or parenteral) and can occur even in people who have achlorhydria.
Ulceration risk increases with therapy duration, and with higher doses. To minimize GI side effects, it is prudent to use the lowest effective dose for the shortest period of time—a practice that studies show is often not followed. Over 50% of patients who take NSAIDs have sustained some mucosal damage to their small intestine.
The risk and rate of gastric adverse effects is different depending on the type of NSAID medication a person is taking. Indomethacin, ketoprofen and piroxicam use appear to lead to the highest rate of gastric adverse effects, while ibuprofen (lower doses) and diclofenac appear to have lower rates.
Certain NSAIDs, such as aspirin, have been marketed in enteric-coated formulations that manufacturers claim reduce the incidence of gastrointestinal ADRs. Similarly, some believe that rectal formulations may reduce gastrointestinal ADRs. However, consistent with the systemic mechanism of such ADRs, and in clinical practice, these formulations have not demonstrated a reduced risk of GI ulceration.
Numerous "gastro-protective" drugs have been developed with the goal of preventing gastrointestinal toxicity in people who need to take NSAIDS on a regular basis. Gastric adverse effects may be reduced by taking medications that suppress acid production such as proton pump inhibitors (e.g.: omeprazole and esomeprazole), or by treatment with a drug that mimics prostaglandin in order to restore the lining of the GI tract (e.g.: a prostaglandin analog misoprostol). Diarrhea is a common side effect of misoprostol, however, higher doses of misoprostol have been shown to reduce the risk of a person having a complication related to a gastic ulcer while taking NSAIDS. While these techniques may be effective, they are expensive for maintenance therapy.
Hydrogen sulfide NSAID hybrids prevent the gastric ulceration/bleeding associated with taking the NSAIDs alone. Hydrogen sulphide is known to have a protective effect on the cardiovascular and gastrointestinal system.
NSAIDs are also associated with a fairly high incidence of adverse drug reactions (ADRs) on the kidney and over time can lead to chronic kidney disease. The mechanism of these kidney ADRs is due to changes in kidney blood flow. Prostaglandins normally dilate the afferent arterioles of the glomeruli. This helps maintain normal glomerular perfusion and glomerular filtration rate (GFR), an indicator of kidney function. This is particularly important in kidney failure where the kidney is trying to maintain renal perfusion pressure by elevated angiotensin II levels. At these elevated levels, angiotensin II also constricts the afferent arteriole into the glomerulus in addition to the efferent arteriole it normally constricts. Since NSAIDs block this prostaglandin-mediated effect of afferent arteriole dilation, particularly in kidney failure, NSAIDs cause unopposed constriction of the afferent arteriole and decreased RPF (renal perfusion flow) and GFR.
Common ADRs associated with altered kidney function include:
These agents may also cause kidney impairment, especially in combination with other nephrotoxic agents. Kidney failure is especially a risk if the patient is also concomitantly taking an ACE inhibitor (which removes angiotensin II's vasoconstriction of the efferent arteriole) and a diuretic (which drops plasma volume, and thereby RPF)—the so-called "triple whammy" effect.
In rarer instances NSAIDs may also cause more severe kidney conditions:
Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. 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 liver toxicity, was the most photoactive NSAID observed. The mechanism of photosensitivity, responsible for the high photoactivity of the 2-arylpropionic acids, is the ready decarboxylation of the carboxylic acidmoiety. The specific absorbance characteristics of the different chromophoric 2-aryl substituents, affects the decarboxylation mechanism.
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. Doses should be taken as prescribed, due to risk of liver toxicity with overdoses.
In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy.
Allergy/allergy-like hypersensitivity reactions
A variety of allergic or allergic-like NSAID hypersensitivity reactions follow the ingestion of NSAIDs. These hypersensitivity reactions differ from the other adverse reactions listed here which are toxicity reactions, i.e. unwanted reactions that result from the pharmacological action of a drug, are dose-related, and can occur in any treated individual; hypersensitivity reactions are idiosyncratic reactions to a drug. Some NSAID hypersensitivity reactions are truly allergic in origin: 1) repetitive IgE-mediated urticarial skin eruptions, angioedema, and anaphylaxis following immediately to hours after ingesting one structural type of NSAID but not after ingesting structurally unrelated NSAIDs; and 2) Comparatively mild to moderately severe T cell-mediated delayed onset (usually more than 24 hour), skin reactions such as maculopapular rash, fixed drug eruptions, photosensitivity reactions, delayed urticaria, and contact dermatitis; or 3) far more severe and potentially life-threatening t-cell-mediated delayed systemic reactions such as the DRESS syndrome, acute generalized exanthematous pustulosis, the Stevens–Johnson syndrome, and toxic epidermal necrolysis. Other NSAID hypersensitivity reactions are allergy-like symptoms but do not involve true allergic mechanisms; rather, they appear due to the ability of NSAIDs to alter the metabolism of arachidonic acid in favor of forming metabolites that promote allergic symptoms. Afflicted individuals may be abnormally sensitive to these provocative metabolites or overproduce them and typically are susceptible to a wide range of structurally dissimilar NSAIDs, particularly those that inhibit COX1. Symptoms, which develop immediately to hours after ingesting any of various NSAIDs that inhibit COX-1, are: 1) exacerbations of asthmatic and rhinitis (see aspirin-induced asthma) symptoms in individuals with a history of asthma or rhinitis and 2) exacerbation or first-time development of wheals or angioedema in individuals with or without a history of chronic urticarial lesions or angioedema.
The use of NSAIDS for analgesia following gastrointestinal surgery remains controversial, given mixed evidence of an increased risk of leakage from any bowel anastomosis created. This risk may vary according to the class of NSAID prescribed.
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.
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.
COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes. One of these is in the stomach lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by its own acid. COX-2 is an enzyme facultatively expressed in inflammation, and it is inhibition of COX-2 that produces the desirable effects of NSAIDs.
When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, ulcers of the stomach or duodenum internal bleeding can result.
NSAIDs have been studied in various assays to understand how they affect each of these enzymes. While the assays reveal differences, unfortunately, different assays provide differing ratios.
The discovery of COX-2 led to research to the development of selective COX-2 inhibiting drugs that do not cause gastric problems characteristic of older NSAIDs.
Paracetamol (acetaminophen) is not considered an NSAID because it has little anti-inflammatory activity. It treats pain mainly by blocking COX-2 mostly in the central nervous system, but not much in the rest of the body.
However, many aspects of the mechanism of action of NSAIDs remain unexplained, and for this reason, further COX pathways are hypothesized. The COX-3 pathway was believed to fill some of this gap but recent findings make it appear unlikely that it plays any significant role in humans and alternative explanation models are proposed.
NSAIDs 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.
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 isomeraseenzymein 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.
Main practical differences
NSAIDs within a group tend to have similar characteristics and tolerability. There is little difference in clinical efficacy among the NSAIDs when used at equivalent doses. Rather, differences among compounds usually relate to dosing regimens (related to the compound's elimination half-life), route of administration, and tolerability profile.
Regarding adverse effects, selective COX-2 inhibitors have lower risk of gastrointestinal bleeding, and there is no significant increase in risk of myocardial infarction. With the exception of naproxen, nonselective NSAIDs increase the risk of having a heart attack. Some data also supports that the partially selective nabumetone is less likely to cause gastrointestinal events.
A consumer report noted that ibuprofen, naproxen, and salsalate are less expensive than other NSAIDs, and essentially as effective and safe when used appropriately to treat osteoarthritis and pain.
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 metabolized in the liver by oxidation and conjugation to inactive metabolites that typically are excreted in the urine, though some drugs are partially excreted in bile. Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal dosage.
Ibuprofen and diclofenac have short half-lives (2–3 hours). Some NSAIDs (typically oxicams) have very long half-lives (e.g. 20–60 hours).
One of the first advertisements for Bayer Aspirin, published in The New York Times in 1917
From the era of Greek 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 expansive pharmacopeia of the time. Myrtle leaves were in use by 1500 BCE. Hippocrates (460–377 BCE) first reported using willow bark and in 30 BCE Celsus described the signs of inflammation and also used willow bark to mitigate them. On 25 April 1763, Edward Stone wrote to the Royal Society describing his observations on the use of willow bark-based medicines in febrile patients. 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.
While studies have been conducted to see if various NSAIDs can improve behavior in transgenic mouse models of Alzheimer's disease and observational studies in humans have shown promise, there is no good evidence from randomized clinical trials that NSAIDs can treat or prevent Alzheimer's in humans; clinical trials of NSAIDs for treatment of Alzheimer's have found more harm than benefit. NSAIDs coordinate with metal ions affecting cellular function.
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 cats except for one-time use during surgery. In spite of these warnings, meloxicam is frequently prescribed "off-label" for non-canine animals including cats and livestock species. In other countries, for example The European Union (EU), there is a label claim for use in cats.
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