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Diclofenac

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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.<ref name="Voltaren FDA label" /><ref name=AHFS2018>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name=AHFS2018/><ref name=inject>Template:Cite journal</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Improvements in pain last up to eight hours.<ref name=AHFS2018/> It is also available as the fixed-dose combination diclofenac/misoprostol (Arthrotec) to help protect the stomach; however, proton pump inhibitors such as omeprazole are typically first-line since they are at least as effective as misoprostol, but with better tolerability.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref name=BNF74/><ref>Template:Cite journal</ref>

Common side effects include abdominal pain, gastrointestinal bleeding, nausea, dizziness, headache, and swelling.<ref name=AHFS2018/> Serious side effects may include heart disease, stroke, kidney problems, and stomach ulceration.<ref name=BNF74/><ref name=AHFS2018/> Use is not recommended in the third trimester of pregnancy.<ref name=AHFS2018/> It is likely safe during breastfeeding.<ref name=BNF74/> Diclofenac is believed to work by decreasing the production of prostaglandins, like other drugs in this class.<ref>Template:Cite book</ref>

In 2022, it was the 51st most commonly prescribed medication in the United States, with more than 12Template:Nbspmillion prescriptions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> It is available as its acid or in two salts, as either diclofenac sodium or potassium.<ref name=BNF74>Template:Cite book</ref>

Medical usesEdit

Diclofenac is used to treat pain related to arthritis, dysmenorrhea, rheumatic diseases and other inflammatory disorders,<ref name=AHFS2018/> kidney stones and gallstones. An additional indication is the treatment of acute migraines.<ref name="Cambia FDA label" /> 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Diclofenac is also available in topical forms and is useful for osteoarthritis but not other types of long-term musculoskeletal pain.<ref name=Dutta2007>Template:Cite journal</ref> Diclofenac may also help with actinic keratosis and with acute pain caused by minor strains, sprains and contusions.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

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).<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> The eye drops have also been used to manage pain for traumatic corneal abrasion.<ref name="Wakai">Template:Cite journal</ref>

Diclofenac is often used to treat chronic pain associated with cancer, especially if inflammation is present.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

  • Voltaren tablets.jpg

    Voltaren (diclofenac) 50 mg enteric coated tablets

  • Diclofenac sodium IV 75mg.jpg

    Dyloject (diclofenac) 2 ml for IV and IM administration

  • Diclofenac sodium 100mg.jpg

    Sintofarm (diclofenac) for suppository administration

  • Diclofenac Topical Gel.jpg

    150 gram tube diclofenac topical gel U.S. package generic

ContraindicationsEdit

Diclofenac is contraindicated for pregnant women; for people with active stomach or duodenal ulceration or gastrointestinal bleeding; and for people undergoing coronary artery bypass surgery.<ref name=AHFS2018 /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Adverse effectsEdit

Template:See also

Diclofenac consumption has been associated with significantly increased vascular and coronary risk in a study including coxib, diclofenac, ibuprofen and naproxen.<ref name="BhalaEmbersonEtAl">Template:Cite journal</ref> Upper gastrointestinal complications were also reported.<ref name="BhalaEmbersonEtAl" /> Major adverse cardiovascular events were increased by about a third by diclofenac, chiefly due to an increase in major coronary events.<ref name="BhalaEmbersonEtAl" /> Compared with placebo, of 1000 patients allocated to diclofenac for a year, three more had major vascular events, one of which was fatal.<ref name="BhalaEmbersonEtAl" /> Vascular death is increased significantly by diclofenac.<ref name="BhalaEmbersonEtAl" />

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.<ref name="FDA PR 20201015">Template:Cite press release Template:PD-notice</ref><ref name="FDA safety 20201015">{{#invoke:citation/CS1|citation |CitationClass=web }} Template:PD-notice</ref>

HeartEdit

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.<ref name="BhalaEmbersonEtAl" /> Compared with placebo, of 1000 people allocated to diclofenac for a year, three more had major vascular events, one of which was fatal.<ref name="BhalaEmbersonEtAl" /> Vascular death was increased by diclofenac (1·65).<ref name="BhalaEmbersonEtAl" />

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 a relative increased rate of heart disease of 1.63 compared to nonusers.<ref name="BMJ2006-Kearney">Template:Cite journal</ref> 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 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.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

A subsequent large study of 74,838 Danish users of nonsteroidal anti-inflammatory drugs or coxibs found no additional cardiovascular risk from diclofenac use.<ref name="ArthritisRheum2006-Solomon">Template:Cite journal</ref> A very large study of 1,028,437 Danish users of various nonsteroidal anti-inflammatory drugs or coxibs found 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."<ref name="pmid20530789">Template:Cite journal</ref>

Diclofenac is similar in COX-2 selectivity to celecoxib.<ref name="pmid11496855">Template:Cite journal</ref>Template:Contradictory inline

GastrointestinalEdit

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  • Gastrointestinal complaints are most often noted. Most patients receive a gastro-protective drug as prophylaxis during long-term treatment (misoprostol, ranitidine, or omeprazole).

LiverEdit

  • Liver damage occurs infrequently, and is usually reversible. Hepatitis may occur rarely without any warning symptoms and may be fatal. Patients with osteoarthritis more often develop symptomatic liver disease than patients with rheumatoid arthritis. If used for the short-term treatment of pain or fever, diclofenac has not been found more hepatotoxic than other nonsteroidal anti-inflammatory drugs.Template:Medical citation needed
  • Template:As of, Endo, Novartis, and the US FDA notified healthcare professionals to add new warnings and precautions about the potential for elevation in liver function tests during treatment with all products containing diclofenac sodium.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

  • Cases of drug-induced hepatotoxicity have been reported in the first month but can occur at any time during treatment with diclofenac. Postmarketing surveillance has reported cases of severe hepatic reactions, including liver necrosis, jaundice, fulminant hepatitis with and without jaundice, and liver failure. Some of these reported cases resulted in fatalities or liver transplantation.Template:Medical citation needed

KidneyEdit

  • Nonsteroidal anti-inflammatory drugs "are associated with adverse renal [kidney] effects caused by the reduction in synthesis of renal prostaglandins"<ref name="Brater2002">Template:Cite journal</ref> in sensitive persons or animal species, and potentially during long-term use in nonsensitive persons if resistance to side effects decreases with age. However, this side effect cannot be avoided merely by using a COX-2 selective inhibitor because, "Both isoforms of COX, COX-1, and COX-2, are expressed in the kidney...

Mental healthEdit

  • Mental health side effects have been reported. These symptoms are rare but exist in significant enough numbers to include as potential side effects. These include depression, anxiety, irritability, nightmares, and psychotic reactions.<ref>{{#invoke:citation/CS1|citation

|CitationClass=web }}</ref>

PharmacologyEdit

As with other nonsteroidal anti-inflammatory drugs, 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 the source.<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref><ref>Template:Cite journal</ref>

The drug may be bacteriostatic via inhibiting bacterial DNA synthesis.<ref name="Dutta2000">Template:Cite journal</ref>

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.<ref name="Diclofenac: novità su tollerabilità">Template:Cite journal</ref> As in the rest of the body, it is thought to exert its effect in the brain through inhibition of COX-2.<ref name="Diclofenac: novità su tollerabilità"/> In addition, it may have effects inside the spinal cord.<ref>Template:Cite journal</ref>

Diclofenac may be a unique member of the nonsteroidal anti-inflammatory drugs in other aspects. Some evidence indicates it inhibits the lipoxygenase pathways,<ref>Template:Cite journal</ref><ref>Template:Cite journal</ref> 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 is the most potent NSAID on a broad basis.<ref name="pmid3085490">Template:Cite journal</ref>

Marked differences exist among nonsteroidal anti-inflammatory drugs in their selective inhibition of the two subtypes of cyclooxygenase, COX-1, and COX-2.<ref name="Cryer1998">Template:Cite journal</ref> 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 the population.Template:Citation needed

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.<ref name="pmid6628528">Template:Cite journal</ref>

HistoryEdit

Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pfister in 1973.<ref name=":1">Template:Cite journal</ref><ref>Template:Cite journal</ref> The name "diclofenac" derives from its chemical name: 2-(2,6-dichloranilino) phenylacetic acid. It was patented in Germany in 1978 by Ciba-Geigy (now Novartis).<ref name=Fischer2006>Template:Cite book</ref><ref>Template:Cite patent Template:Webarchive</ref> It came into medical use in the United States in 1988.<ref name=AHFS2018/> GlaxoSmithKline purchased the rights in 2015.<ref name=":1" /> It is available as a generic medication.<ref name=AHFS2018/>

Formulations and brand namesEdit

Diclofenac formulations are available worldwide under many different brand names.<ref name=tn>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Voltaren and Voltarol contain 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.<ref name=Connelly2017>Template:Cite news</ref>

In 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.<ref name=FDAswitch/>

In January 2015, diclofenac oral preparations were reclassified as prescription-only medicines in the UK. The topical preparations are available without a prescription.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Template:AnchorEcological effectsEdit

Template:Missing information {{#invoke:Labelled list hatnote|labelledList|Main article|Main articles|Main page|Main pages}}

Use of diclofenac in animals has environmental effects: It is toxic to scavenging birds – these consume animal carcases in which the drug is present;<ref name="vulture1" /><ref name="Moreno-Opo_2021">Template:Cite journal</ref> residues of the drug are found in marine and freshwater organisms, contaminated by agricultural runoff containing diclofenac.Template:R The medication has been banned for veterinary use in several countries;<ref name="vulture2" /><ref name="vulture3" /> India restricted its use in 2006.<ref>Template:Cite magazine</ref><ref>Template:Cite news</ref> Meloxicam is an alternative to diclofenac, one which is safer for wildlife.<ref name="Swan_2006">Template:Cite journal</ref><ref>Template:Cite journal</ref>

Veterinary use in livestock resulted in a sharp decline in the vulture population in the Indian subcontinent – a 95% decline by 2003<ref name="Oaks2004">Template:Cite journal</ref> and a 99.9% decline by 2008. 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 Indian government ban is fully implemented, it will take many years to revive the vulture population.<ref name="The Indian Express">Template:Cite news</ref>

The mechanism of toxicity in vultures is presumed to be kidney failure;<ref>Template:Cite journal</ref> however, toxicity may be due to direct inhibition of uric acid secretion in vultures.<ref name="pmid18727958">Template:Cite journal</ref> Vultures eat the carcasses of livestock that have been administered veterinary diclofenac, and are poisoned by the accumulated chemical,<ref name="BBC3">Template:Cite news</ref> 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 the veterinary use of diclofenac.<ref name="PIB2005">Template:Cite press release</ref>

Steppe eagles have the same vulnerability to diclofenac as Old World vultures and are therefore at similar risk from its effects.<ref>Template:Cite news</ref> In contrast, New World vultures, such as the turkey vulture, can tolerate at least 100 times the level of diclofenac that is lethal to Gyps species.<ref>Template:Cite journal</ref>

Despite the vulture crisis, diclofenac remains available in other countries including many in Europe.<ref name="European Parliament">{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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 medicines agency presented simulations suggesting that the number of deaths would be quite small.<ref name=Becker2016/><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> A paper published in 2021 identified the first authenticated death of a vulture from diclofenac in Spain, a cinereous vulture.<ref name="Moreno-Opo_2021" /><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Diclofenac is on the European Union's watch list because it pollutes the Baltic Sea. When the substance enters fresh water, it has an environmental impact and is considered more difficult to remove in wastewater treatment plants than, for example, ibuprofen.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> Diclofenac has been shown also to harm freshwater fish species such as rainbow trout.<ref name="Schwaiger">Template:Cite journal</ref><ref name="Triebskorn">Template:Cite journal</ref><ref>Template:Cite journal</ref><ref name="pmid17216161">Template:Cite journal</ref> Harmful residues have been found in fish, blue mussels, and other aquatic organisms, where it has been found to cause damage to internal organs such as the gills, kidneys and liver.<ref>Template:Cite news</ref>

Human impactEdit

A major shift in the transfer of corpse pathogens from vultures to feral dogs and rats could lead to disease pandemics, causing millions of deaths in a densely-populated country like India, whereas vultures' digestive systems safely destroy many species of such pathogens.Template:R

The drastic decline of tens of millions of vultures over the past decade has significantly disrupted the ecological balance across the Indian subcontinent, creating potential risks for human health.<ref name="Swan_2006" /> In many regions, the collapse of Gyps vulture populations—the primary scavengers of wild and domestic ungulate carcasses—has led to a sharp increase in feral dog populations. This rise in dog numbers has also been linked to a heightened threat of rabies.<ref name="Swan_2006" /> The Government of India cites rising deaths from rabies as one of the major consequences of vulture species near-extinction.<ref name="PIB2005"/> An increase of almost 50,000 human deaths due to rabies has been estimated,<ref>Template:Cite news</ref> with an extra 500,000 deaths between 2000 and 2005 attributed to all health effects related to the vulture population crash.<ref>Template:Cite magazine Citing:

The loss of vultures has had a social impact on the Indian Zoroastrian Parsi community, who for religious reasons traditionally use vultures to dispose of human corpses in Towers of Silence, but are now compelled to seek alternative methods of disposal.<ref name="Swan_2006" />

Veterinary useEdit

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. In many countries, agricultural use is now forbidden.<ref name=vulture1>Template:Cite journal</ref><ref name="Moreno-Opo_2021" /><ref name=vulture2>Template:Citation</ref><ref name=vulture3>Template:Cite news</ref>

Diclofenac is approved as a veterinary medication in some countries<ref name=vulture1/><ref name="Moreno-Opo_2021" /><ref name=vulture2/><ref name=vulture3/> 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 the liver and kidneys—resulting in visceral gout, as well as cellular damage and necrosis.<ref name=Hussain2008>Template:Cite journal</ref> In South Asia in the 2000s, vulture populations were decimated after feeding on carcasses of livestock that had been treated with diclofenac.<ref name=Becker2016>Template:Cite journal</ref>

ReferencesEdit

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External linksEdit

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Template:Other dermatological preparations Template:Anti-inflammatory and antirheumatic products Template:Topical products for joint and muscular pain {{#invoke:navbox|navbox 

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  | list4 =

  | group5 = Fenamates
  | list5 =

  | group6 = Salicylates
  | list6 =

  | group7 = Pyrazolones
  | list7 =

  | group8 = Others
  | list8 =

}}

| group4 = Cannabinoids
| list4 =

| group5 = Ion channel
modulators
| list5 = {{#invoke:navbox|navbox|child

  | group1 = Calcium blockers
  | list1 =

  | group2 = Sodium blockers
  | list2 =

  | group3 = Potassium openers
  | list3 =

}}

| group6 = Myorelaxants
| list6 =

| group7 = Others
| list7 =

| list8 =

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