100-425: Diclofenac , sold under the brand name Voltaren among others, is a nonsteroidal anti-inflammatory drug (NSAID) used to treat pain and inflammatory diseases such as gout . It can be taken orally (swallowed by mouth), inserted rectally as a suppository , injected intramuscularly , injected intravenously , applied to the skin topically , or through eye drops . Improvements in pain last up to eight hours. It
200-465: 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: NSAIDs in combination with excessive use of phenacetin or paracetamol (acetaminophen) may lead to analgesic nephropathy . Photosensitivity is a commonly overlooked adverse effect of many of the NSAIDs. The 2-arylpropionic acids are
300-441: A case called, University of Rochester v. G.D. Searle & Co. , 358 F.3d 916 (Fed. Cir. 2004). The court ruled in favor of Searle in 2004, holding in essence that the university had claimed a method requiring, yet provided no written description of, a compound that could inhibit COX-2 and therefore the patent was invalid. In the course of the search for a specific inhibitor of the negative effects of prostaglandins that spared
400-709: A crowded country like India, whereas vultures' digestive systems safely destroy many species of such pathogens. Vultures are long-lived and slow to breed. They start breeding only at the age of six and only 50% of their young survive. Even if the government ban is fully implemented, it will take many years to revive the vulture population. The loss of vultures has had a social impact on the Indian Zoroastrian Parsi community , who traditionally use vultures to dispose of human corpses in Towers of Silence , but are now compelled to seek alternative methods of disposal. Despite
500-591: 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,
600-404: 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
700-511: A more generalized drug intolerance to NSAIDs, and caution should be exercised in those with asthma or NSAID -precipitated bronchospasm . Owing to its effect on the stomach lining, manufacturers recommend people with peptic ulcers , mild diabetes , or gastritis seek medical advice before using aspirin. Use of aspirin during dengue fever is not recommended owing to increased bleeding tendency. People with kidney disease , hyperuricemia , or gout should not take aspirin because it inhibits
800-457: A prescription. Use of diclofenac for animals is controversial due to toxicity when eaten by scavenging birds that eat dead animals; the medication has been banned for veterinary use in several countries. Use of diclofenac in animals has been reported to have led to a sharp decline in the vulture population in the Indian subcontinent – a 95% decline by 2003 and a 99.9% decline by 2008. The mechanism
900-440: 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
1000-470: A relative increased rate of heart disease of 1.63 compared to nonusers. Professor Peter Weissberg, medical director of the British Heart Foundation said, "However, the increased risk is small, and many patients with chronic debilitating pain may well feel that this small risk is worth taking to relieve their symptoms". Only aspirin was found not to increase the risk of heart disease; however, this
1100-501: A significant increase in heart attacks and strokes, with some drugs in the class having worse risks than others. Rofecoxib (sold under the brand name Vioxx) was taken off the market in 2004 because of these concerns, while celecoxib (sold under the brand name Celebrex) and traditional NSAIDs received boxed warnings on their labels. Many COX-2–specific inhibitors have been removed from the US market. As of December 2011, only Celebrex (celecoxib)
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#17328847596451200-507: A single dose to treat pain after surgery. In this role etoricoxib appears as good as, if not better than, other pain medications, and celecoxib appears to be about as useful as ibuprofen . NSAIDs are often used in treatment of acute gout attacks. COX-2 inhibitors appear to work as well as nonselective NSAIDs, such as aspirin. They have not been compared to other treatment options such as colchicine or glucocorticoids . COX-2 appears to be related to cancers and abnormal growths in
1300-412: A study including coxib, diclofenac, ibuprofen and naproxen . Upper gastrointestinal complications were also reported. Major adverse cardiovascular events were increased by about a third by diclofenac, chiefly due to an increase in major coronary events. Compared with placebo, of 1000 patients allocated to diclofenac for a year, three more had major vascular events, one of which was fatal. Vascular death
1400-456: A type of nonsteroidal anti-inflammatory drug (NSAID) that directly target cyclooxygenase-2 ( COX-2 ), an enzyme responsible for inflammation and pain . Targeting selectivity for COX-2 reduces the risk of peptic ulceration and is the main feature of celecoxib , rofecoxib , and other members of this drug class. After several COX-2–inhibiting drugs were approved for marketing, data from clinical trials revealed that COX-2 inhibitors caused
1500-463: A year, three more had major vascular events, one of which was fatal. Vascular death was increased by diclofenac (1·65). Following the identification of increased risks of heart attacks with the selective COX-2 inhibitor rofecoxib in 2004, attention has focused on all the other members of the nonsteroidal anti-inflammatory drug group, including diclofenac. Research results are mixed, with a meta-analysis of papers and reports up to April 2006 suggesting
1600-405: Is also available as the fixed-dose combination diclofenac/misoprostol (Arthrotec) to help protect the stomach. Common side effects include abdominal pain , gastrointestinal bleeding , nausea, dizziness, headache, and swelling. Serious side effects may include heart disease , stroke , kidney problems , and stomach ulceration . Use is not recommended in the third trimester of pregnancy . It
1700-499: Is also available in topical forms and is useful for osteoarthritis but not other types of long-term musculoskeletal pain. Diclofenac may also help with actinic keratosis and with acute pain caused by minor strains, sprains and contusions . In many countries, eye drops are sold to treat acute and chronic nonbacterial inflammation of the anterior part of the eyes (such as postoperative states). The eye drops have also been used to manage pain for traumatic corneal abrasion . Diclofenac
1800-571: 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 people taking NSAIDs experience indigestion . In the 1990s, high doses of prescription NSAIDs were associated with serious upper gastrointestinal adverse events, including bleeding. NSAIDs, like all medications, may interact with other medications. For example, concurrent use of NSAIDs and quinolone antibiotics may increase
1900-552: Is increased significantly by diclofenac. In October 2020, the US Food and Drug Administration (FDA) required the prescription label to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in fetuses that result in low amniotic fluid. In 2013, a study found major vascular events were increased by about a third by diclofenac, chiefly due to an increase in major coronary events. Compared with placebo, of 1000 people allocated to diclofenac for
2000-553: Is known to have a higher rate of gastric ulceration than diclofenac. As of January 2015, the MHRA announced that diclofenac would be reclassified as a prescription-only medicine (POM) due to the risk of cardiovascular adverse events. A subsequent large study of 74,838 Danish users of nonsteroidal anti-inflammatory drugs or coxibs found no additional cardiovascular risk from diclofenac use. A very large study of 1,028,437 Danish users of various nonsteroidal anti-inflammatory drugs or coxibs found
2100-622: Is likely safe during breastfeeding . Diclofenac is believed to work by decreasing the production of prostaglandins , like other drugs in this class. In 2022, it was the 51st most commonly prescribed medication in the United States, with more than 12 million prescriptions. It is available as its acid or in two salts, as either diclofenac sodium or potassium. Diclofenac is used to treat pain related to arthritis , dysmenorrhea , rheumatic diseases and other inflammatory disorders , kidney stones and gallstones . An additional indication
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#17328847596452200-518: Is not effective for the treatment or prevention of Alzheimer's disease . NSAIDs may be used with caution by people with the following conditions: NSAIDs should usually be avoided 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
2300-408: Is often used to treat chronic pain associated with cancer , especially if inflammation is present. Diclofenac is contraindicated for pregnant women; for people with active stomach and/or duodenal ulceration or gastrointestinal bleeding ; and for people undergoing coronary artery bypass surgery . Diclofenac consumption has been associated with significantly increased vascular and coronary risk in
2400-506: 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
2500-615: Is presumed to be kidney failure ; however, toxicity may be due to direct inhibition of uric acid secretion in vultures. Vultures eat the carcasses of livestock that have been administered veterinary diclofenac, and are poisoned by the accumulated chemical, as vultures do not have a particular enzyme to break down diclofenac. At a meeting of the National Wildlife Board in March 2005, the Government of India announced it intended to phase out
2600-416: 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
2700-416: 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. In October 2020,
2800-435: Is safe, if adequate monitoring is done. 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
2900-428: 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. Any increase risk of surgical bleeding, bleeding in the gastrointestinal system, myocardial infarctions, or injury to the kidneys has not been well studied. When used in combination with paracetamol,
3000-564: Is still available for purchase in the United States. In the European Union, celecoxib, parecoxib , and etoricoxib have been approved for use by the European Medicines Agency . Paracetamol (acetaminophen) inhibits COX-2 almost exclusively within the brain and only minimally in the rest of the body, although it is not considered an NSAID, since it has only minor anti-inflammatory activity. Some COX-2 inhibitors are used in
3100-659: Is the most potent NSAID on a broad basis. Marked differences exist among nonsteroidal anti-inflammatory drugs in their selective inhibition of the two subtypes of cyclooxygenase, COX-1, and COX-2. Drug developers have focused on selective COX-2 inhibition, particularly as a way to minimize the gastrointestinal side effects of nonsteroidal anti-inflammatory drugs. In practice, the use of some COX-2 inhibitors with their adverse effects has led to massive numbers of lawsuits alleging wrongful death by heart attack , yet other significantly COX-selective nonsteroidal anti-inflammatory drugs, such as diclofenac, have been well tolerated by most of
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3200-419: Is the treatment of acute migraines . Diclofenac is used to treat mild to moderate postoperative or post-traumatic pain, in particular when inflammation is also present. Diclofenac ophthalmic is indicated for the treatment of postoperative inflammation in people who have undergone cataract extraction and for the temporary relief of pain and photophobia in people undergoing corneal refractive surgery. Diclofenac
3300-415: Is unknown. Studies have shown that COX-2 inhibitors block the phosphorylation of HDM2 preventing its activation. In vitro, the use of COX-2 inhibitors lowers the level of active HDM2 found in neuroblastoma cells. The exact process of how COX-2 inhibitors block HDM2 phosphorylation is unknown, but this mediated reduction in active HDM2 concentration level restores the cellular p53 levels. After treatment with
3400-457: Is ≈170-fold more potent in inhibiting COX-1 than COX-2. Studies of meloxicam 7.5 mg per day for 23 days find a level of gastric injury similar to that of a placebo , and for meloxicam 15 mg per day a level of injury lower than that of other NSAIDs; however, in clinical practice meloxicam can still cause some ulcer complications. Valdecoxib and rofecoxib were about 300 times more potent at inhibiting COX-2 than COX-1, but too toxic for
3500-519: The Food and Drug Administration (FDA) toughened warnings of increased heart attack and stroke risk associated with nonsteroidal anti-inflammatory drugs (NSAIDs) other than aspirin . A 2005 Finnish survey study found an association between long term (over three months) use of NSAIDs and erectile dysfunction . A 2011 publication in The Journal of Urology received widespread publicity. According to
3600-506: The cytosol . When cellular DNA is damaged beyond repair, p53 is transported to the nucleus where it promotes p53 mediated apoptosis. Two of the metabolites of COX-2, prostaglandin A2 (PGA2) and A1 (PGA1), when present in high quantities, bind to p53 in the cytosol and inhibit its ability to cross into the nucleus. This essentially sequesters p53 in the cytosol and prevents apoptosis. Coxibs such as Celebrex (celecoxib), by selectively inhibiting
3700-461: 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 effects on
3800-442: The gastrointestinal tract , while prostaglandins whose synthesis involves the cyclooxygenase-II enzyme, or COX-2, are responsible for inflammation and pain. The existing nonsteroidal anti-inflammatory drugs ( NSAIDs ) differ in their relative specificities for COX-2 and COX-1; while aspirin and ibuprofen inhibit COX-2 and COX-1 enzymes, other NSAIDs appear to have partial COX-2 specificity, particularly meloxicam ( Mobic ). Aspirin
3900-407: The turkey vulture , can tolerate at least 100 times the level of diclofenac that is lethal to Gyps species. "The loss of tens of millions of vultures over the last decade has had major ecological consequences across the Indian subcontinent that pose a potential threat to human health. In many places, populations of feral dogs have increased sharply from the disappearance of Gyps vultures as
4000-502: The "Use of the nonselective NSAID diclofenac and the selective cyclooxygenase-2 inhibitor rofecoxib was associated with an increased risk of cardiovascular death ( odds ratio , 1.91; 95% confidence interval, 1.62 to 2.42; and odds ratio, 1.66; 95% confidence interval, 1.06 to 2.59, respectively), with a dose-dependent increase in risk." Diclofenac is similar in COX-2 selectivity to celecoxib . As with other nonsteroidal anti-inflammatory drugs,
4100-619: The Celecoxib Long-term Arthritis Safety Study (CLASS) in JAMA , and the Vioxx Gastrointestinal Outcomes Research (VIGOR). The VIGOR trial was later proven to have been based on faulty data, and Vioxx was eventually withdrawn from the market. The VIGOR (Vioxx Gastrointestinal Outcomes Research) trial, "which was the making of Merck's drug rofecoxib (Vioxx)," was at the center of a dispute about
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4200-462: The Reuben studies were removed, the conclusions in the majority of them remained unchanged. The review found that the key Reuben claims that needed to be re-examined were "the absence of detrimental effects of coxibs on bone healing after spine surgery , the beneficial long-term outcome after preemptive administration of coxibs including an allegedly decreased incidence of chronic pain after surgery, and
4300-491: The U.S. Food and Drug Administration (FDA) required the drug label 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. They are recommending avoiding the use of NSAIDs by pregnant women at 20 weeks or later in pregnancy. COX-2 inhibitor Cyclooxygenase-2 inhibitors ( COX-2 inhibitors ), also known as coxibs , are
4400-674: The United States Food and Drug Administration (FDA) sent a warning letter to the CEO of Merck, stating, "Your promotional campaign discounts the fact that in the VIGOR study, patients on Vioxx were observed to have a four to five fold increase in myocardial infarctions (MIs) compared to patients on the comparator nonsteroidal anti-inflammatory drug (NSAID), Naprosyn (naproxen)." This led to the introduction, in April 2002, of warnings on Vioxx labeling concerning
4500-506: The United States, 1% diclofenac gel was approved by the FDA in 2007 as a prescription drug for the temporary relief of the pain of osteoarthritis of joints in the hands, knees, and feet. In 2020, the FDA approved the gel formulation for nonprescription use. In January 2015, diclofenac oral preparations were reclassified as prescription-only medicines in the UK. The topical preparations are available without
4600-658: The ability of all these compounds to kill tumor cells in cell culture was investigated, it turned out that the antitumor potency did not at all depend on whether or not the respective compound could inhibit COX-2, showing that inhibition of COX-2 was not required for the anticancer effects. One of these compounds, 2,5-dimethyl-celecoxib, which entirely lacks the ability to inhibit COX-2, actually turned out to display stronger anticancer activity than celecoxib itself and this anticancer effect could also be verified in highly drug-resistant tumor cells and in various animal tumor models. Analysis of clinical trial data revealed that there
4700-467: The activity of cyclooxygenase enzymes (the COX-1 and COX-2 isoenzymes ). In cells, these enzymes are involved in the synthesis of key biological mediators, namely prostaglandins , which are involved in inflammation , and thromboxanes , which are involved in blood clotting . There are two general types of NSAIDs available: non-selective and COX-2 selective . Most NSAIDs are non-selective, and inhibit
4800-443: The activity of both COX-1 and COX-2. These NSAIDs, while reducing inflammation, also inhibit platelet aggregation and increase the risk of gastrointestinal ulcers and bleeds. COX-2 selective inhibitors have fewer gastrointestinal side effects, but promote thrombosis , and some of these agents substantially increase the risk of heart attack . As a result, certain COX-2 selective inhibitors—such as rofecoxib —are no longer used due to
4900-422: 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
5000-452: The analgesic effect on post-operative pain may be improved. Aspirin , the only NSAID able to irreversibly inhibit COX-1 , is also indicated for antithrombosis through inhibition of platelet aggregation . This is useful for the management of arterial thrombosis , and prevention of adverse cardiovascular events like heart attacks. Aspirin inhibits platelet aggregation by inhibiting the action of thromboxane A 2 . NSAIDs are useful in
5100-600: The analgesic efficacy of ketorolac or clonidine when added to local anesthetics for intravenous regional anesthesia ." Celebrex (and other brand names for celecoxib) was introduced in 1999 and rapidly became the most frequently prescribed new drug in the United States. By October 2000, its US sales exceeded 100 million prescriptions per year for $ 3 billion, and was still rising. Sales of Celebrex alone reached $ 3.1 billion in 2001. A Spanish study found that between January 2000 and June 2001, 7% of NSAID prescriptions and 29% of NSAID expenditures were for COX-2 inhibitors. Over
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#17328847596455200-645: The anticancer effects of celecoxib in the absence of COX-2. Moreover, a recent study with various malignant tumor cells showed that celecoxib could inhibit the growth of these cells, even though some of these cancer cells didn't even contain COX-2. Additional support for the idea that other targets besides COX-2 are important for celecoxib's anticancer effects has come from studies with chemically modified versions of celecoxib. Several dozen analogs of celecoxib were generated with small alterations in their chemical structures . Some of these analogs retained COX-2 inhibitory activity, whereas many others didn't. However, when
5300-437: The benefits of pain-relief medications such as NSAIDS and the potential for adverse effects has not been well determined. There is some evidence suggesting that, for some people, use of NSAIDs (or other anti-inflammatories) may contribute to the initiation of chronic pain. Side effects are dose-dependent, and in many cases severe enough to pose the risk of ulcer perforation, upper gastrointestinal bleeding, and death, limiting
5400-547: The brain, and only minimally in the rest of the body. NSAIDs are often suggested for the treatment of acute or chronic conditions where pain and inflammation are present. NSAIDs are generally used for the symptomatic relief of the following conditions: The effectiveness of NSAIDs 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 randomised controlled trials conducted. Differences in anti-inflammatory activity between
5500-492: The cardiovascular problems became, and remains, a subject of intensive research. As of 2012 results have been converging on the hypothesis that the adverse cardiovascular effects are most likely due to inhibition of COX-2 in blood vessels , which leads to a decrease in the production of prostacyclin in them. Prostacyclin usually prevents platelet aggregation and vasoconstriction , so its inhibition can lead to excess clot formation and higher blood pressure. The COX-2 enzyme
5600-551: The cardiovascular safety of the coxibs (COX-2 inhibitors). 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. Use of methotrexate together with NSAIDs in rheumatoid arthritis
5700-400: The different chromophoric 2-aryl substituents, affects the decarboxylation mechanism. While NSAIDs as a class are not direct teratogens , use of NSAIDs in late pregnancy can cause premature closure of the fetal ductus arteriosus and kidney ADRs in the fetus. Thus, NSAIDs are not recommended during the third trimester of pregnancy because of the increased risk of premature constriction of
5800-400: The ductus arteriosus. Additionally, they are linked with premature birth and miscarriage . Aspirin, however, is used together with heparin in pregnant women with antiphospholipid syndrome . Additionally, indomethacin can be used in pregnancy to treat polyhydramnios by reducing fetal urine production via inhibiting fetal renal blood flow. In contrast, paracetamol (acetaminophen)
5900-478: The epithelial mucosa. Common gastrointestinal side effects include: 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
6000-505: The ethics of medical journals. In the VIGOR trial, over 8,000 patients were randomized to receive either naproxen or rofecoxib (Vioxx). Both studies concluded that COX-2 specific NSAIDs were associated with significantly fewer adverse gastrointestinal effects. In the CLASS trial which compared Celebrex 800 mg/day to ibuprofen 2400 mg/day and diclofenac 150 mg/day for osteoarthritis or rheumatoid arthritis for six months, Celebrex
6100-440: 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. 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. NSAIDs are also associated with
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#17328847596456200-541: The gills, kidneys and liver. Diclofenac is used for livestock; such use was responsible for the Indian vulture crisis , during which in a few years 95% of the country's vulture population was killed, and in many countries, agricultural use is now forbidden. Diclofenac is approved as a veterinary medication in some countries for the treatment of pets as well as in livestock. In some species of birds, diclofenac causes accumulation of uric acid crystals in internal organs—especially
6300-465: The heart, suggesting the possibility of relief from pain and inflammation without gastrointestinal irritation, and promising to be a boon for those who had previously experienced adverse effects or had comorbidities that could lead to such complications. Celecoxib is approximately 30 times more potent at inhibiting COX-2 than COX-1, with etoricoxib being 106 times more potent. Between 1996 and 2009, Scott Reuben purportedly conducted clinical research on
6400-405: 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, NSAIDs may cause deleterious effects on kidney function, and, perhaps as a result of water and sodium retention and decreases in renal blood flow, may lead to heart problems. In addition, NSAIDs can blunt
6500-493: 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
6600-474: The increased risk of cardiovascular events (heart attack and stroke). By 2005 The New England Journal of Medicine published an editorial accusing the Bombardier et al. of deliberately withholding data. Claire Bombardier, a University of Toronto rheumatologist, had claimed that the VIGOR trial showed that Vioxx 50 mg/day had benefits over naproxen for rheumatoid arthritis, specifically that Vioxx reduced
6700-1021: The intestinal tract. Overexpression of COX-2 produces excess prostaglandins, which have been shown to increase the possibility of colorectal cancer . COX inhibitors have been shown to reduce the occurrence of cancers and precancerous growths. The National Cancer Institute has done some studies on COX-2 and cancer. COX-2 can act as an anti-tumor enzyme, but only in specific cases. The FDA has approved Celebrex for treatment of familial adenomatous polyposis (FAP). COX-2 inhibitors are currently being studied in breast cancer and appear to be beneficial. COX-2 inhibitors have been found to be effective in suppressing inflammatory neurodegenerative pathways, with beneficial results in animal studies for major depressive disorder , as well as schizophrenia , bipolar disorder , and obsessive-compulsive disorder . These need to be confirmed in human clinical trials. Current studies support an association of disorders such as these with chronic inflammation, which appears to decrease with
6800-400: The kidneys' ability to excrete uric acid , and thus may exacerbate these conditions. If a COX-2 inhibitor is taken, a traditional NSAID (prescription or over-the-counter) should not be taken at the same time. Rofecoxib (Vioxx) was shown to produce significantly fewer gastrointestinal adverse drug reactions ( ADRs ) compared with naproxen. The study, the VIGOR trial, raised the issue of
6900-406: 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 gastric ulcer while taking NSAIDs. While these techniques may be effective, they are expensive for maintenance therapy. Hydrogen sulfide NSAID hybrids prevent
7000-503: The liver and kidneys—resulting in visceral gout , as well as cellular damage and necrosis . In South Asia in the 2000s, vulture populations were decimated after feeding on carcasses of livestock that had been treated with diclofenac. Nonsteroidal anti-inflammatory drug Non-steroidal anti-inflammatory drugs ( NSAID ) are members of a therapeutic drug class which reduces pain , decreases inflammation , decreases fever , and prevents blood clots . Side effects depend on
7100-427: The main scavenger of wild and domestic ungulate carcasses. Associated with the rise in dog numbers is an increased risk of rabies " and casualties of almost 50,000 people. The Government of India cites this as one of the major consequences of a vulture species extinction. A major shift in the transfer of corpse pathogens from vultures to feral dogs and rats could lead to a disease pandemic, causing millions of deaths in
7200-510: 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. 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. Based on observational studies and randomized controlled trials , NSAID use
7300-471: 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 acid moiety . The specific absorbance characteristics of
7400-672: The number of deaths would be quite small. A paper published in 2021 identified the first authenticated death of a vulture from diclofenac in Spain, a cinereous vulture . Diclofenac is on the European Union's watch list because it pollutes the Baltic Sea. When the substance enters freshwater, it has an environmental impact and is considered more difficult to remove in wastewater treatment plants than, for example, ibuprofen. Harmful residues have been found in blue mussels and fish, among others, where it has been found to cause damage to internal organs such as
7500-480: The overexpressed COX-2, allow p53 to work properly. Functional p53 allows DNA damaged neuroblastoma cells to commit suicide through apoptosis, halting tumor growth. COX-2 up-regulation has also been linked to the phosphorylation and activation of the E3 ubiquitin ligase HDM2 , a protein that mediates p53 ligation and tagged destruction, through ubiquitination . The mechanism for this neuroblastoma HDM2 hyperactivity
7600-479: The patients given rofecoxib (0.4%) compared with those given naproxen (0.1%)" and "patients given naproxen experienced 121 side effects compared with 56 in the patients taking rofecoxib," a "marvellous result for Merck" which "contributed to huge sales of rofecoxib." Merck's scientists incorrectly interpreted the finding as a protective effect of naproxen, telling the FDA that the difference in heart attacks "is primarily due to" this protective effect. In September 2001,
7700-624: The period of the study, COX-2 inhibitors rose from 10.03% of total NSAIDs prescribed by specialty physicians to 29.79%, and from 1.52% to 10.78% of NSAIDs prescribed by primary care physicians (98.23% of NSAIDs and 94.61% of COX-2 inhibitors were prescribed by primary care physicians). For specialty physicians, rofecoxib and celecoxib were third and fifth most frequently prescribed NSAIDs but first and second in cost, respectively; for primary-care physicians they were ninth and twelfth most frequently prescribed NSAIDs and first and fourth in cost. Sales and marketing efforts were supported by two large trials,
7800-482: The population. Besides the COX-inhibition, several other molecular targets of diclofenac possibly contributing to its pain-relieving actions have recently been identified. These include: The duration of action (i.e., duration of pain relief) of a single dose is longer (6 to 8 h ) than the drug's 1.2–2 h half-life. This could be partly because it persists for over 11 hours in synovial fluids . Diclofenac
7900-429: The positive effects, it was discovered that prostaglandins could indeed be separated into two general classes that could loosely be regarded as "good prostaglandins" and "bad prostaglandins", according to the structure of a particular enzyme involved in their biosynthesis , cyclooxygenase . Prostaglandins whose synthesis involves the cyclooxygenase-I enzyme, or COX-1, are responsible for maintenance and protection of
8000-498: The primary mechanism responsible for its anti-inflammatory , antipyretic and analgesic action is thought to be inhibition of prostaglandin synthesis through COX -inhibition. The main target in the inhibition of prostaglandin synthesis appears to be the transiently expressed prostaglandin-endoperoxide synthase-2 (PGES-2), also known as cycloxygenase-2 (COX-2). That is, diclofenac is partially selective for COX-2. The reported selectivity for COX-2 varies from 1.5 to 30 depending on
8100-479: The production of erythropoietin , resulting in anaemia, since haemoglobin needs this hormone to be produced. The most prominent NSAIDs are aspirin , ibuprofen , and naproxen ; all available over the counter (OTC) in most countries. Paracetamol (acetaminophen) is generally not considered an NSAID because it has only minor anti-inflammatory activity. Paracetamol treats pain mainly by blocking COX-2 and inhibiting endocannabinoid reuptake almost exclusively within
8200-406: 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 should be considered. For people over the age of 65 years old, the balance between
8300-451: The risk of symptomatic ulcers and clinical upper gastrointestinal events ( perforations , obstructions and bleeding ) by 54%, to 1.4% from 3%, the risk of complicated upper gastrointestinal events (complicated perforations, obstructions and bleeding in the upper gastrointestinal tract ) by 57%, and the risk of bleeding from anywhere in the gastrointestinal tract by 62%. An enormous marketing effort capitalized on these publications; Vioxx
8400-564: The sodium salt of diclofenac. In the United Kingdom, Voltarol can be supplied with either the sodium salt or the potassium salt, while Cataflam, sold in some other countries, is the potassium salt only. However, Voltarol Emulgel contains diclofenac diethylammonium 1.16%, being equivalent to 1% sodium salt. In 2016, Voltarol was one of the biggest selling branded over-the-counter medications sold in Great Britain, with sales of £39.3 million. In
8500-415: The source. The drug may be bacteriostatic via inhibiting bacterial DNA synthesis. Diclofenac has a relatively high lipid solubility, making it one of the few nonsteroidal anti-inflammatory drugs that are able to enter the brain by crossing the blood-brain barrier . As in the rest of the body, it is thought to exert its effect in the brain through inhibition of COX-2. In addition, it may have effects inside
8600-473: The specific drug, its dose and duration of use, but largely include an increased risk of gastrointestinal ulcers and bleeds , heart attack , and kidney disease . The term non-steroidal , common from around 1960, distinguishes these drugs from corticosteroids , another class of anti-inflammatory drugs, which during the 1950s had acquired a bad reputation due to overuse and side-effect problems after their introduction in 1948. NSAIDs work by inhibiting
8700-411: The spinal cord. Diclofenac may be a unique member of the nonsteroidal anti-inflammatory drugs in other aspects. Some evidence indicates it inhibits the lipoxygenase pathways, thus reducing the formation of leukotrienes (also pro-inflammatory autacoids ). It also may inhibit phospholipase A2 , which may be relevant to its mechanism of action. These additional actions may explain its high potency – it
8800-546: 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 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
8900-402: The time of Simmons's work. A settlement was reached in April 2012 in which Pfizer agreed to pay $ 450 million. The other litigation is based on United States Pat. No. 6,048,850 owned by University of Rochester , which claimed a method to treat pain without causing gastro-intestinal distress by selectively inhibiting COX-2. When the patent issued, the university sued Searle (later Pfizer) in
9000-418: The use of COX-2 inhibitors, often in combination with gabapentin or pregabalin , for the prevention and treatment of postoperative pain , research which was found in 2009 to have been faked. Reuben pleaded guilty, paid fines, and served six months in jail, and lost his medical license . A 2009 review of meta-articles used in evidence-based medicine found that while some reviews were no longer valid when
9100-518: The use of COX-2 inhibitors. The inhibition of COX-2 is paramount for the anti-inflammatory and analgesic function of the selective COX-2 inhibitor celecoxib. However, with regard to this drug's promise for the therapy of advanced cancers, it is unclear whether the inhibition of COX-2 plays a dominant role, and this has become a controversial and intensely researched issue. In recent years, several additional intracellular components (besides COX-2) were discovered that appear to be important for mediating
9200-546: The use of NSAID therapy. An estimated 10–20% of NSAID patient's 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. Aspirin should not be taken by people who have salicylate intolerance or
9300-734: 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. Pain following surgery can be significant, and many people require strong pain medications such as opioids. There
9400-492: The veterinary use of diclofenac. Meloxicam is a safer alternative to replace use of diclofenac. It is more expensive than diclofenac, but the cost is dropping as more pharmaceutical companies are beginning to manufacture it. Steppe eagles have the same vulnerability to diclofenac as Old World vultures and are therefore at a similar risk from its effects. Diclofenac has been shown also to harm freshwater fish species such as rainbow trout. In contrast, New World vultures , such as
9500-538: The vulture crisis, diclofenac remains available in other countries including many in Europe. It was controversially approved for veterinary use in Spain in 2013 and continues to be available, despite Spain being home to around 90% of the European vulture population and an independent simulation showing that the drug could reduce the population of vultures by 1–8% annually. Spain's medicine agency presented simulations suggesting that
9600-496: Was a significant increase in the rate of vascular events like myocardial infarction or stroke with COX-2 inhibitors compared with placebo . These results led Merck to voluntarily withdraw (rofecoxib) from the market in September 2004 and to regulatory authorities imposing a boxed warning on the label of celecoxib. Traditional NSAIDs were also found to have cardiovascular risks, leading to similar boxed warnings . The cause of
9700-492: Was associated with significantly fewer upper gastrointestinal complications (0.44% vs. 1.27%, p = 0.04), with no significant difference in incidence of cardiovascular events in patients not taking aspirin for cardiovascular prophylaxis . The VIGOR trial results were published in 2000 in the New England Journal of Medicine Bombardier and his research team claimed that there was "an increase in myocardial infarction in
9800-411: Was discovered in 1988 by Daniel Simmons, a Brigham Young University researcher. The mouse COX-2 gene was cloned by UCLA scientist Harvey Herschman, a finding published in 1991. The basic research leading to the discovery of COX-2 inhibitors has been the subject of at least two lawsuits. Brigham Young University has sued Pfizer , alleging breach of contract from relations BYU had with the company at
9900-549: Was first synthesized by Alfred Sallmann and Rudolf Pfister in 1973. The name "diclofenac" derives from its chemical name: 2-(2,6- dichlo ranilino) phen yl ac etic acid. It was patented in Germany in 1978 by Ciba-Geigy (now Novartis ). It came into medical use in the United States in 1988. GlaxoSmithKline purchased the rights in 2015. It is available as a generic medication . Diclofenac formulations are available worldwide under many different brand names. Voltaren and Voltarol contain
10000-410: Was the most heavily advertised prescription drug in 2000, and Celebrex the seventh, according to IMS Health . Small tumors of the sympathetic nervous system ( neuroblastoma ) appear to have abnormal levels of COX-2 expressed. These studies report that overexpression of the COX-2 enzyme has an adverse effect on the tumor suppressor, p53 . p53 is an apoptosis transcription factor normally found in
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