In 2023, it was the 73rd most commonly prescribed medication in the United States, with more than 9million prescriptions.[17][18] It is available as its acid or in two salts, as either diclofenac sodium or potassium.[14]
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.[19]
Diclofenac is also available in topical forms and is useful forosteoarthritis but not other types of long-term musculoskeletal pain.[20] Diclofenac may also help withactinic keratosis and with acute pain caused by minor strains, sprains andcontusions.[21]
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).[22] The eye drops have also been used to manage pain fortraumatic corneal abrasion.[23]
Diclofenac consumption has been associated with significantly increased vascular and coronary risk in a study includingCOX-2 inhibitors, diclofenac,ibuprofen andnaproxen.[27] Upper gastrointestinal complications were also reported.[27]Major adverse cardiovascular events were increased by about a third by diclofenac, chiefly due to an increase in major coronary events.[27] Compared with placebo, of 1000 patients allocated to diclofenac for a year, three more had major vascular events, one of which was fatal.[27] Vascular death is increased significantly by diclofenac.[27]
In October 2020, the USFood and Drug Administration (FDA) required theprescribing information to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in fetuses that result in low amniotic fluid.[28][29]
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.[27] Compared with placebo, of 1000 people allocated to diclofenac for a year, three more had major vascular events, one of which was fatal.[27] Vascular death was increased by diclofenac (1·65).[27]
Following the identification of increased risks of heart attacks with the selectiveCOX-2 inhibitorrofecoxib 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.[30] 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". Onlyaspirin 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.[31]
A subsequent large study of 74,838 Danish users of nonsteroidal anti-inflammatory drugs orcoxibs found no additional cardiovascular risk from diclofenac use.[32] 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."[33]
Gastrointestinal complaints are most often noted. Most patients receive a gastro-protective drug as prophylaxis during long-term treatment (misoprostol,ranitidine, oromeprazole).
Liver damage occurs infrequently, and is usually reversible.Hepatitis may occur rarely without any warning symptoms and may be fatal. Patients withosteoarthritis 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.[medical citation needed]
As of December 2009[update], 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.[35]
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.[medical citation needed]
Nonsteroidal anti-inflammatory drugs "are associated with adverse renal [kidney] effects caused by the reduction in synthesis of renalprostaglandins"[36] 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 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.[37]
As with other nonsteroidal anti-inflammatory drugs, the primarymechanism responsible for itsanti-inflammatory,antipyretic andanalgesic action is thought to be inhibition of prostaglandin synthesis throughCOX-inhibition.
The main target in the inhibition of prostaglandin synthesis appears to be the transiently expressed prostaglandin-endoperoxide synthase-2 (PGES-2), also known ascycloxygenase-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.[38][39][40][41]
The drug may be bacteriostatic via inhibiting bacterial DNA synthesis.[42]
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 theblood-brain barrier.[43] As in the rest of the body, it is thought to exert its effect in the brain through inhibition of COX-2.[43] In addition, it may have effects inside the spinal cord.[44]
Diclofenac may be a unique member of the nonsteroidal anti-inflammatory drugs in other aspects. Some evidence indicates it inhibits thelipoxygenase pathways,[45][46] thus reducing the formation ofleukotrienes (also pro-inflammatoryautacoids). It also may inhibitphospholipase 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.[47]
Marked differences exist among nonsteroidal anti-inflammatory drugs in their selective inhibition of the two subtypes of cyclooxygenase, COX-1, and COX-2.[48] Drug developers have focused on selective COX-2 inhibition, particularly as a way to minimize the gastrointestinal side effects of nonsteroidal anti-inflammatory drugs. However, the cardiovascularadverse effects of someCOX-2 inhibitors has led to lawsuits alleging wrongful death byheart attack. Yet, other significantly COX-selective nonsteroidal anti-inflammatory drugs, such as diclofenac, have been well tolerated by most of the population.[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:
Blockage of voltage-dependentsodium channels (after activation of the channel, diclofenac inhibits its reactivation, also known as phase inhibition)[49][50]
Positive allosteric modulation of KCNQ- and BK-potassium channels (diclofenac opens these channels, leading to hyperpolarization of the cell membrane)[52][50]
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 may be partly due to its persistence for over 11 hours insynovial fluids.[53]
Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pfister in 1973.[54][55] The name "diclofenac" derives from its chemical name: 2-(2,6-dichloranilino)phenylacetic acid. It was patented in Germany in 1978 by Ciba-Geigy (nowNovartis).[56][57] It came into medical use in the United States in 1988.[8]GlaxoSmithKline purchased the rights in 2015.[54] It is available as ageneric medication.[8]
Diclofenac formulations are available worldwide under many different brand names.[1]
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.[58]
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 fornonprescription use.[7]
In January 2015, diclofenac oral preparations were reclassified as prescription-only medicines in the UK. The topical preparations are available without a prescription.[59]
This sectionis missing information about environmental buildup, wastewater; tryPMID27649472. Please expand the section to include this information. Further details may exist on thetalk page.(December 2022)
Use of diclofenac in animals has environmental effects: It is toxic to scavenging birds – these consume animal carcases in which the drug is present;[60][61] residues of the drug are found in marine and freshwater organisms, contaminated by agricultural runoff containing diclofenac.[62][63][64] The medication has been banned for veterinary use in several countries;[65][66] India restricted its use in 2006.[67][68]Meloxicam is an alternative to diclofenac, one which is safer for wildlife.[69][70]
Veterinary use in livestock resulted in a sharp decline in the vulture population in the Indian subcontinent – a 95% decline by 2003[71] 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.[72]
The mechanism of toxicity in vultures is presumed to bekidney failure;[73] however, toxicity may be due to direct inhibition of uric acid secretion in vultures.[74] Vultures eat the carcasses oflivestock that have been administered veterinary diclofenac, and are poisoned by the accumulated chemical,[75] 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.[76]
Despite the vulture crisis, diclofenac remains available in other countries including many in Europe.[79] 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.[80][81] A paper published in 2021 identified the first authenticated death of a vulture from diclofenac in Spain, acinereous vulture.[61][82]
Diclofenac is on the European Union's watch list because it pollutes theBaltic Sea. When the substance entersfresh water, it has an environmental impact and is considered more difficult to remove inwastewater treatment plants than, for example, ibuprofen.[83] Diclofenac has been shown also to harmfreshwater fish species such as rainbow trout.[62][63][84][64] 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.[85]
Diclofenac is used for livestock; such use was responsible for theIndian 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.[60][61][65][66]
Diclofenac is approved as a veterinary medication in some countries[60][61][65][66] for the treatment of pets as well as in livestock. In some species of birds, diclofenac causes accumulation ofuric acid crystals in internal organs—especially the liver and kidneys—resulting invisceral gout, as well as cellular damage andnecrosis.[86] In South Asia in the 2000s,vulture populations were decimated after feeding on carcasses of livestock that had been treated with diclofenac.[80]
^Chung CH (2017). "The use of Injectable Nonsteroidal Anti-Inflammatory Drugs in Local Accident & Emergency Practice".Hong Kong Journal of Emergency Medicine.9 (2):65–71.doi:10.1177/102490790200900201.S2CID74032271.
^Dutta NK, Mazumdar K, Dastidar SG, Park JH (2007). "Activity of diclofenac used alone and in combination with streptomycin against Mycobacterium tuberculosis in mice".International Journal of Antimicrobial Agents.30 (4):336–340.doi:10.1016/j.ijantimicag.2007.04.016.PMID17644321.
^Solomon DH, Avorn J, Stürmer T, Glynn RJ, Mogun H, Schneeweiss S (May 2006). "Cardiovascular outcomes in new users of coxibs and nonsteroidal antiinflammatory drugs: high-risk subgroups and time course of risk".Arthritis and Rheumatism.54 (5):1378–1389.doi:10.1002/art.21887.PMID16645966.S2CID2082359.
^FitzGerald GA, Patrono C (August 2001). "The coxibs, selective inhibitors of cyclooxygenase-2".The New England Journal of Medicine.345 (6):433–442.doi:10.1056/NEJM200108093450607.PMID11496855.
^Dastidar SG, Ganguly K, Chaudhuri K, Chakrabarty AN (April 2000). "The anti-bacterial action of diclofenac shown by inhibition of DNA synthesis".International Journal of Antimicrobial Agents.14 (3):249–251.doi:10.1016/S0924-8579(99)00159-4.PMID10773497.
^Gan TJ (July 2010). "Diclofenac: an update on its mechanism of action and safety profile".Current Medical Research and Opinion.26 (7):1715–1731.doi:10.1185/03007995.2010.486301.PMID20470236.
^Ku EC, Lee W, Kothari HV, Scholer DW (April 1986). "Effect of diclofenac sodium on the arachidonic acid cascade".The American Journal of Medicine.80 (4B):18–23.doi:10.1016/0002-9343(86)90074-4.PMID3085488.
^Scholer DW, Ku EC, Boettcher I, Schweizer A (April 1986). "Pharmacology of diclofenac sodium".The American Journal of Medicine.80 (4B):34–38.doi:10.1016/0002-9343(86)90077-x.PMID3085490.
^Cryer B, Feldman M (May 1998). "Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs".The American Journal of Medicine.104 (5):413–421.doi:10.1016/S0002-9343(98)00091-6.PMID9626023.
^Fei XW, Liu LY, Xu JG, Zhang ZH, Mei YA (August 2006). "The non-steroidal anti-inflammatory drug, diclofenac, inhibits Na(+) current in rat myoblasts".Biochemical and Biophysical Research Communications.346 (4):1275–1283.doi:10.1016/j.bbrc.2006.06.034.PMID16806078.
^abGwanyanya A, Macianskiene R, Mubagwa K (October 2012). "Insights into the effects of diclofenac and other non-steroidal anti-inflammatory agents on ion channels".The Journal of Pharmacy and Pharmacology.64 (10):1359–1375.doi:10.1111/j.2042-7158.2012.01479.x.PMID22943167.
^Ortiz MI, Torres-López JE, Castañeda-Hernández G, Rosas R, Vidal-Cantú GC, Granados-Soto V (March 2002). "Pharmacological evidence for the activation of K(+) channels by diclofenac".European Journal of Pharmacology.438 (1–2):85–91.doi:10.1016/S0014-2999(02)01288-8.PMID11906715.
^Fowler PD, Shadforth MF, Crook PR, John VA (1983). "Plasma and synovial fluid concentrations of diclofenac sodium and its major hydroxylated metabolites during long-term treatment of rheumatoid arthritis".European Journal of Clinical Pharmacology.25 (3):389–394.doi:10.1007/BF01037953.PMID6628528.S2CID9803699.
^Fischer J (2006).Analogue-based drug discovery. Wiley-VCH. p. 517.ISBN978-3-527-31257-3.
^DE 1793592, Pfister R, Sallmann A, "Process for the production of new substituted phenylacetic acids", issued 26 January 1978, assigned to Ciba Geigy AGArchived 24 April 2023 at theWayback Machine
^abcdMoreno-Opo R, Carapeto R, Casimiro R, Rubio C, Muñoz B, Moreno I, et al. (November 2021). "The veterinary use of diclofenac and vulture conservation in Spain: Updated evidence and socio-ecological implications".The Science of the Total Environment.796 148851.Bibcode:2021ScTEn.79648851M.doi:10.1016/j.scitotenv.2021.148851.PMID34271379.
^abSchwaiger J, Ferling H, Mallow U, Wintermayr H, Negele RD (2004). "Toxic effects of the non-steroidal anti-inflammatory drug diclofenac. Part I: histopathological alterations and bioaccumulation in rainbow trout".Aquatic Toxicology.68 (2):141–150.Bibcode:2004AqTox..68..141S.doi:10.1016/j.aquatox.2004.03.014.PMID15145224.
^abTriebskorn R, Casper H, Heyd A, Eikemper R, Köhler HR, Schwaiger J (2004). "Toxic effects of the non-steroidal anti-inflammatory drug diclofenac. Part II: cytological effects in liver, kidney, gills and intestine of rainbow trout (Oncorhynchus mykiss)".Aquatic Toxicology.68 (2):151–166.Bibcode:2004AqTox..68..151T.doi:10.1016/j.aquatox.2004.03.015.PMID15145225.
^abTriebskorn R, Casper H, Scheil V, Schwaiger J (2007). "Ultrastructural effects of pharmaceuticals (carbamazepine, clofibric acid, metoprolol, diclofenac) in rainbow trout (Oncorhynchus mykiss) and common carp (Cyprinus carpio)".Analytical and Bioanalytical Chemistry.387 (4):1405–1416.doi:10.1007/s00216-006-1033-x.PMID17216161.S2CID21170569.
^Naidoo V, Swan GE (2009). "Diclofenac toxicity inGyps vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction".Comparative Biochemistry and Physiology. Toxicology & Pharmacology.149 (3):269–274.doi:10.1016/j.cbpc.2008.07.014.hdl:2263/13907.PMID18727958.
^"Saving the Vultures from Extinction" (Press release). Press Information Bureau, Government of India. 16 May 2005.Archived from the original on 20 December 2005. Retrieved12 May 2006.
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