The termnon-steroidal, common from around 1960, distinguishes these drugs fromcorticosteroids, another class ofanti-inflammatory drugs,[10] which during the 1950s had acquired a bad reputation due to overuse and side-effect problems after their introduction in 1948.[11][12][13]
There are two general types of NSAIDs available: non-selective andCOX-2 selective.[14] Most NSAIDs are non-selective, and inhibit the activity of both COX-1 and COX-2. These NSAIDs, while reducing inflammation, also inhibit platelet aggregation and increase the risk ofgastrointestinal ulcers and bleeds.[14] COX-2 selective inhibitors have fewer gastrointestinal side effects, but promotethrombosis, and some of these agents substantially increase the risk ofheart attack. As a result, certain COX-2 selective inhibitors—such asrofecoxib—are no longer used due to the high risk of undiagnosedvascular disease.[14] These differential effects are due to the different roles and tissue localisations of each COX isoenzyme.[14] By inhibiting physiological COX activity, NSAIDs may cause deleterious effects on kidney function,[15] and, perhaps as a result of water and sodium retention and decreases in renal blood flow, may lead to heart problems.[16] In addition, NSAIDs can blunt the production oferythropoietin, resulting inanaemia, since haemoglobin needs this hormone to be produced.
NSAIDs are often suggested for the treatment of acute or chronic conditions wherepain and inflammation are present. NSAIDs are generally used for the symptomatic relief of the following conditions:[17][18][19]
The effectiveness of NSAIDs for treating non-cancer chronic pain and cancer-related pain in children and adolescents is not clear.[27][28] There have not been sufficient numbers of high-quality randomised controlled trials conducted.[27][28]
Differences in anti-inflammatory activity between the various individual NSAIDs are small, but there is considerable variation among individual patients in therapeutic response and tolerance to these drugs. About 60% of patients will respond to any NSAID; of the others, those who do not respond to one may well respond to another. Pain relief starts soon after taking the first dose, and a full analgesic effect should normally be obtained within a week, whereas an anti-inflammatory effect may not be achieved (or may not be clinically assessable) for up to three weeks. If appropriate responses are not obtained within these times, another NSAID should be tried.[2]
Pain followingsurgery can be significant, and many people require strong pain medications such as opioids. There is some low-certainty evidence that starting NSAID painkiller medications in adults early, before surgery, may help reduce post-operative pain, and also reduce the dose or quantity of opioid medications required after surgery.[29] Any increased risk of surgical bleeding, bleeding in the gastrointestinal system, myocardial infarctions, or injury to the kidneys has not been well studied.[29] When used in combination with paracetamol, the analgesic effect on post-operative pain may be improved.[30]
NSAIDs are useful in the management of post-operativedental pain following invasive dental procedures such asdental extraction.[32] When not contra-indicated, they are favoured over the use ofparacetamol alone due to the anti-inflammatory effect they provide.[33] 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.[34]
The widespread use of NSAIDs has meant that the adverse effects of these drugs have become increasingly common. Use of NSAIDs increases the risk of a range ofgastrointestinal (GI) problems, kidney disease, and adverse cardiovascular events.[41][42] As commonly used for post-operative pain, there is evidence of increased risk of kidney complications.[43] Their use following gastrointestinal surgery remains controversial, given mixed evidence of increased risk of leakage from any bowelanastomosis created.[44][45][46]
An estimated 10–20% of people taking NSAIDs experienceindigestion. In the 1990s, high doses of prescription NSAIDs were associated with serious upper gastrointestinal adverse events, including bleeding.[47]
NSAIDs, like all medications, may interact with other medications. For example, concurrent use of NSAIDs andquinolone antibiotics may increase the risk of the adversecentral nervous system effects of quinolones including seizure.[48][49]
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 should be considered.[50] For people over the age of 65 years old, the balance between the benefits of pain-relief medications such as NSAIDs and the potential for adverse effects has not been well determined.[51]
There is some evidence suggesting that, for some people, use of NSAIDs (or other anti-inflammatories) may contribute to the initiation of chronic pain.[52]
Side 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 experiencedyspepsia, 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.[53]
Aspirin should not be taken by people who havesalicylate intolerance[54][55] or a more generalizeddrug intolerance to NSAIDs, and caution should be exercised in those withasthma orNSAID-precipitatedbronchospasm. Owing to its effect on the stomach lining, manufacturers recommend people withpeptic ulcers, milddiabetes, orgastritis seek medical advice before using aspirin.[56][57] Use of aspirin duringdengue fever is not recommended owing to increased bleeding tendency.[58] People withkidney disease,hyperuricemia, orgout should not take aspirin because it inhibits the ability of the kidneys to excreteuric acid, and thus may exacerbate these conditions.
If aCOX-2 inhibitor is taken, a traditional NSAID (prescription or over-the-counter) should not be taken at the same time.[59]
Rofecoxib (Vioxx) was shown to produce significantly fewer gastrointestinal adverse drug reactions (ADRs) compared with naproxen.[60] The study, the VIGOR trial, raised the issue of the cardiovascular safety of the coxibs (COX-2 inhibitors). A statistically significant increase in the incidence ofmyocardial 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[61]—which caused a worldwide withdrawal of rofecoxib in October 2004.[62]
Use of methotrexate together with NSAIDs inrheumatoid arthritis is safe if adequate monitoring is done.[63]
NSAIDs, aside from aspirin, increase the risk ofmyocardial infarction andstroke.[64][65] This occurs at least within a week of use.[5] They are not recommended in those who have had a previous heart attack as they increase the risk of death or recurrent MI.[66] Evidence indicates thatnaproxen may be the least harmful out of these.[65][67]
NSAIDs, aside from (low-dose) aspirin, are associated with a doubled risk ofheart failure in people without a history of cardiac disease.[67] 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.[68] 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.[69]
A 2005 Finnish survey study found an association between long-term (over three months) use of NSAIDs anderectile dysfunction.[71]
A 2011 publication[72] inThe Journal of Urology received widespread publicity.[73] According to the 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 a low original participation rate, potential participation bias, and other uncontrolled factors. The authors warned against drawing any conclusions regarding cause.[74]
The mainadverse drug reactions (ADRs) associated with NSAID use relate to direct and indirect irritation of thegastrointestinal (GI) tract. NSAIDs cause a dual assault on the GI tract: the acidic molecules directly irritate thegastric mucosa, and inhibition of COX-1 and COX-2 reduces the levels of protectiveprostaglandins.[41] Inhibition of prostaglandin synthesis in the GI tract causes increased gastric acid secretion, diminished bicarbonate secretion, diminished mucus secretion and diminished trophic effects on the epithelial mucosa.[75]
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 haveachlorhydria.[77]
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—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.[78]
The risk and rate of gastric adverse effects are different depending on the type of NSAID medication a person is taking.Indomethacin,ketoprofen, andpiroxicam use appears to lead to the highest rate of gastric adverse effects, whileibuprofen (lower doses) anddiclofenac appear to have lower rates.[17]
Certain NSAIDs, such as aspirin, have been marketed inenteric-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.[17]
Numerous "gastro-protective" drugs have been developed to prevent gastrointestinal toxicity in people who need to take NSAIDs regularly.[41] Gastric adverse effects may be reduced by taking medications that suppress acid production such asproton pump inhibitors (e.g.:omeprazole andesomeprazole), or by treatment with a drug that mimicsprostaglandin to restore the lining of the GI tract (e.g.: a prostaglandin analogmisoprostol).[41] 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 gastric ulcer while taking NSAIDs.[41] While these techniques may be effective, they are expensive for maintenance therapy.[79]
Hydrogen sulfide NSAID hybrids prevent the gastric ulceration/bleeding associated with taking the NSAIDs alone. Hydrogen sulfide is known to have a protective effect on the cardiovascular and gastrointestinal system.[80]
NSAIDs are also associated with a fairly high incidence of adverse drug reactions (ADRs) on the kidney and over time can lead tochronic kidney disease. The mechanism of these kidney ADRs is due to changes in kidney blood flow. Prostaglandins normally dilate theafferent arterioles of theglomeruli. This helps maintain normal glomerular perfusion andglomerular filtration rate (GFR), an indicator ofkidney 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.[82]
Common ADRs associated with altered kidney function include:[17]
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 anACE inhibitor (which removes angiotensin II's vasoconstriction of the efferent arteriole) and adiuretic (which drops plasma volume, and thereby RPF)—the so-called "triple whammy" effect.[83]
In rarer instances NSAIDs may also cause more severe kidney conditions:[17]
Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs.[85] The 2-arylpropionic acids are the most likely to produce photosensitivity reactions, but other NSAIDs have also been implicated includingpiroxicam,diclofenac, andbenzydamine.[86]
Benoxaprofen, since withdrawn due to itsliver toxicity, was the most photoactive NSAID observed. The mechanism of photosensitivity, responsible for the high photoactivity of the 2-arylpropionic acids, is the readydecarboxylation of thecarboxylic acidmoiety. The specific absorbance characteristics of the differentchromophoric 2-aryl substituents, affects the decarboxylation mechanism.[87]
While NSAIDs as a class are not directteratogens, use of NSAIDs in late pregnancy can cause premature closure of the fetalductus arteriosus and kidney ADRs in the fetus.[88] Thus, NSAIDs are not recommended during the third trimester of pregnancy because of the increased risk of premature constriction of the ductus arteriosus.[88] Additionally, they are linked withpremature birth[89] andmiscarriage.[90] Aspirin, however, is used together withheparin in pregnant women withantiphospholipid syndrome.[91] Additionally,indomethacin can be used in pregnancy to treatpolyhydramnios by reducing fetal urine production via inhibiting fetal renal blood flow.[92]
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.[93][94] Doses should be taken as prescribed, due to risk of liver toxicity with overdoses.[95]
In France, the country's health agency contraindicates the use of NSAIDs, including aspirin, after the sixth month of pregnancy.[96]
In October 2020, the U.S.Food and Drug Administration (FDA) required theprescribing information to be updated for all nonsteroidal anti-inflammatory medications, to describe the risk of kidney problems in unborn babies which can then lead to low amniotic fluid levels, as a result of the use of NSAIDs.[97][98] They are recommending avoiding the use of NSAIDs by pregnant women at 20 weeks or later in pregnancy.[97][98]
Allergy and allergy-like hypersensitivity reactions
A variety of allergic or allergic-likeNSAID 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.[99] Some NSAID hypersensitivity reactions are truly allergic in origin:1) repetitiveIgE-mediatedurticarial skin eruptions,angioedema, andanaphylaxis following immediately to hours after ingesting one structural type of NSAID but not after ingesting structurally unrelated NSAIDs; and2) Comparatively mild to moderately severeT cell-mediated delayed onset (usually more than 24 hour), skin reactions such asmaculopapular rash,fixed drug eruptions,photosensitivity reactions, delayedurticaria, andcontact dermatitis; or3) far more severe and potentially life-threatening t-cell-mediated delayed systemic reactions such as theDRESS syndrome,acute generalized exanthematous pustulosis, theStevens–Johnson syndrome, andtoxic 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. Affected 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 COX-1. Symptoms, which develop immediately to hours after ingesting any of various NSAIDs that inhibit COX-1, are:1) exacerbations of asthmatic and rhinitis (seeaspirin-exacerbated respiratory disease) symptoms in individuals with a history ofasthma orrhinitis and2) exacerbation or first-time development ofwheals orangioedema in individuals with or without a history of chronicurticarial lesions or angioedema.[40]
It has been hypothesized that NSAIDs may delay healing frombone andsoft-tissue injuries by inhibiting inflammation.[100] On the other hand, it has also been hypothesized that NSAIDs might speed recovery from soft tissue injuries by preventing inflammatory processes from damaging adjacent, non-injured muscles.[101]
There is moderate evidence that they delay bone healing.[102] Their overall effect on soft-tissue healing is unclear.[101][100][103]
The use of NSAIDs for analgesia following gastrointestinal surgery remains controversial, given mixed evidence of an increased risk of leakage from any bowelanastomosis created. This risk may vary according to the class of NSAID prescribed.[44][45][46]
Most NSAIDs penetrate poorly into thecentral 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.[108]
NSAIDs may increase the risk of bleeding in patients withDengue fever[109] For this reason, NSAIDs are only available with a prescription in India.[110]
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.[112]
Although small doses generally have little to no effect on the immune system, large doses of NSAIDs significantly suppress the production of immune cells.[113] As NSAIDs affect prostaglandins, they affect the production of most fast-growing cells.[113] This includes immune cells.[113] Unlikecorticosteroids, they do not directly suppress the immune system, and so their effect on the immune system is not immediately obvious.[113] They suppress the production of new immune cells, but leave existing immune cells functional.[113] Large doses slowly reduce the immune response as the immune cells are renewed at a much lower rate.[113] Causing a gradual reduction of the immune system, much slower and less noticeable than the immediate effect of Corticosteroids.[113] The effect significantly increases with dosage, at a nearly exponential rate.[113] Doubling of dose reduced cells by nearly four times.[113] Increasing the dose by five times reduced cell counts to only a few percent of normal levels.[113] This is likely why the effect was not immediately obvious in low-dose trials, as the effect is not apparent until much higher dosages are tested.[113]
NSAIDs may interfere and reduce effectiveness ofSSRI antidepressants through inhibitingTNFα andIFNγ, both of which are cytokine derivatives.[117][118] NSAIDs, when used in combination with SSRIs, increase the risk of adverse gastrointestinal effects.[119] NSAIDs, when used in combination with SSRIs, increase the risk of internal bleeding and brain hemorrhages.[120]
NSAIDs may reduce the effectiveness ofantibiotics. Anin-vitro study on culturedbacteria found that adding NSAIDs to antibiotics reduced their effectiveness by around 20%.[122]
COX-1 is a constitutively expressed enzyme with a "house-keeping" role in regulating many normal physiological processes. One of these is in thestomach lining, where prostaglandins serve a protective role, preventing the stomachmucosa 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.[127]
When nonselective COX-1/COX-2 inhibitors (such as aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels,ulcers of the stomach orduodenum and internalbleeding can result.[128] 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.[129]
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.[130]
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.[8]
However, many aspects of the mechanism of action of NSAIDs remain unexplained, and for this reason, further COX pathways are hypothesized. TheCOX-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.[8]
NSAIDs haveantipyretic activity and can be used to treat fever.[135][136] Fever is caused by elevated levels ofprostaglandin E2 (PGE2), which alters the firing rate of neurons within thehypothalamus that control thermoregulation.[135][137] Antipyretics work by inhibiting the enzyme COX, which causes the general inhibition ofprostanoid biosynthesis (PGE2) within the hypothalamus.[135][136] PGE2 signals to the hypothalamus to increase the body's thermal setpoint.[136][138]Ibuprofen has been shown more effective as anantipyretic thanparacetamol (acetaminophen).[137][139]Arachidonic acid is the precursor substrate for cyclooxygenase leading to the production of prostaglandins F, D, and E.[140]
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.[141]
Most NSAIDs arechiral molecules;diclofenac and theoxicams are exceptions. However, the majority are prepared asracemic mixtures. Typically, only a singleenantiomer is pharmacologically active. For some drugs (typically profens), anisomeraseenzymein 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.[153]
Ibuprofen andketoprofen are now available in single-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.[154]
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.[155] Rather, differences among compounds usually relate to dosing regimens (related to the compound'selimination half-life), route of administration, and tolerability profile.[medical citation needed]
Regarding adverse effects, selectiveCOX-2 inhibitors have a lower risk of gastrointestinal bleeding.[155] Except fornaproxen, nonselective NSAIDs increase the risk of having a heart attack.[155] Some data also supports that the partially selectivenabumetone is less likely to cause gastrointestinal events.[155]
A consumer report noted thatibuprofen, naproxen, andsalsalate are less expensive than other NSAIDs, and essentially as effective and safe when used appropriately to treat osteoarthritis and pain.[156]
Most nonsteroidal anti-inflammatory drugs are weak acids,[157] with a pKa of 3–5. They are absorbed well from thestomach and intestinal mucosa. They are highly protein-bound in plasma (typically >95%), usually toalbumin, so that theirvolume of distribution typically approximates to plasma volume. Most NSAIDs are metabolized in theliver byoxidation and conjugation to inactive metabolites that typically are excreted in theurine, though some drugs are partially excreted inbile. Metabolism may be abnormal in certain disease states, and accumulation may occur even with normal dosage.[medical citation needed]
NSAIDs can also be divided into short-acting (plasma half-life less than 6 h) such as aspirin, diclofenac and ibuprofen and long-acting (half-life approximately greater than 10 h) such as naproxen, celecoxib.[158]
One of the first advertisements for Bayer Aspirin, published inThe New York Times in 1917
It is widely believed that naturally occurring salicin inwillow trees and other plants was used by the ancients as a form of analgesic or anti-inflammatory drug,[159] but this story, although compelling, is not entirely true.[160][161] Hippocrates does not mention willow at all.[162]Dioscorides'sDe materia medica was arguably the most influential herbal from Roman to Medieval times but, if he mentions willow at all (there is doubt about the identity of 'Itea'), then he used the ashes, steeped in vinegar, as a treatment for corns,[163] which corresponds well with modern uses ofsalicylic acid.
Willow bark (from trees of theSalix genus) was widely known to be used as a medicine by multiple First Nations communities.[164] The bark would be chewed or steeped in water for its pain relieving and antipyretic effects. The effects are a result of the bark's salicin content. Meadowsweet, another plant to contain salicin, has strong roots in British folk medicine for the same maladies. Willow bark was first reported in Western science by Edward Stone in 1763 as a treatment forague (fever) according to the pseudoscientificdoctrine of signatures.[165]
In the body, salicin is turned into salicylic acid, which produces the antipyretic and analgesic effects that the plants are known for.
By 1897, the German chemistFelix Hoffmann and theBayer company prompted a new age of pharmacology by converting salicylic acid into acetylsalicylic acid—namedaspirin byHeinrich Dreser. Other NSAIDs likeibuprofen were developed from the 1950s forward.[166]In 2001, NSAIDs accounted for 70,000,000 prescriptions and 30billionover-the-counter doses sold annually in theUnited States.[47]
Research supports the use of NSAIDs for the control of pain associated with veterinary procedures such as dehorning and castration of calves.[citation needed] The best effect is obtained by combining a short-term local anesthetic such aslidocaine with an NSAID acting as a longer term analgesic.[citation needed] 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.[citation needed]
In the United States,meloxicam is approved for use only in canines, whereas (due to concerns about kidney damage) it carries warnings against its use in cats[171][172] except for one-time use during surgery.[173] In spite of these warnings, meloxicam is frequently prescribed "off-label" for non-canine animals including cats and livestock species.[174] In other countries, for exampleThe European Union (EU), there is a label claim for use in cats.[175]
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