Diclofenac

"Diclo" redirects here. For the organic solvent sometimes called Di-clo, see Dichloromethane.

"Dichronic" redirects here. For common misspellings, see Diachronic (disambiguation).

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.^[6][10] 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.^[10][12][13] Improvements in pain last up to eight hours.^[10] It is also available as the fixed-dose combination diclofenac/misoprostol (Arthrotec) to help protect the stomach.^[14][15]

Diclofenac

Structure of diclofenac with ball and stick model
Clinical data
Pronunciation	/daɪˈkloʊfənæk/[1] or /dɪklɒˈfɛnæk/[2]
Trade names	Voltaren, others[1]
AHFS/Drugs.com	Monograph
MedlinePlus	a689002
License data	US DailyMed: Diclofenac
Pregnancy category	AU: C[3]
Routes of administration	Orally, rectal, intramuscular, intravenous, topical, ophthalmic
Drug class	Nonsteroidal anti-inflammatory agents
ATC code	D11AX18 (WHO) M01AB05 (WHO), M02AA15 (WHO), S01BC03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) / S3 / S2 CA: ℞-only[4] UK: POM (Prescription only) / P / GSL US: WARNING[5]Rx-only / OTC[6][7][8] In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding	More than 99%
Metabolism	Liver, oxidative, primarily by CYP2C9, also by CYP2C8, CYP3A4, as well as conjugative by glucuronidation (UGT2B7) and sulfation;[9] no active metabolites exist
Onset of action	Within 4 hours (gel), 30 min (non-gel)[10]
Elimination half-life	1.2–2 h (35% of the drug enters enterohepatic recirculation)
Excretion	35% bile, 65% urine[11]
Identifiers
IUPAC name [2-(2,6-Dichloroanilino)phenyl]acetic acid
CAS Number	15307-86-5 Y
PubChem CID	3033
IUPHAR/BPS	2714
DrugBank	DB00586 Y
ChemSpider	2925 Y
UNII	144O8QL0L1
KEGG	D07816 Y
ChEBI	CHEBI:47381 Y
ChEMBL	ChEMBL139 Y
PDB ligand	DIF (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID6022923
ECHA InfoCard	100.035.755
Chemical and physical data
Formula	C14H11Cl2NO2
Molar mass	296.15 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C(O)Cc1ccccc1Nc2c(Cl)cccc2Cl
InChI InChI=1S/C14H11Cl2NO2/c15-10-5-3-6-11(16)14(10)17-12-7-2-1-4-9(12)8-13(18)19/h1-7,17H,8H2,(H,18,19) Y Key:DCOPUUMXTXDBNB-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

Common side effects include abdominal pain, gastrointestinal bleeding, nausea, dizziness, headache, and swelling.^[10] Serious side effects may include heart disease, stroke, kidney problems, and stomach ulceration.^[15][10] Use is not recommended in the third trimester of pregnancy.^[10] It is likely safe during breastfeeding.^[15] Diclofenac is believed to work by decreasing the production of prostaglandins, like other drugs in this class.^[16]

In 2022, it was the 51st most commonly prescribed medication in the United States, with more than 12 million prescriptions.^[17][18] It is available as its acid or in two salts, as either diclofenac sodium or potassium.^[15]

Medical uses

Diclofenac is used to treat pain related to arthritis, dysmenorrhea, rheumatic diseases and other inflammatory disorders,^[10] kidney stones and gallstones. An additional indication is the treatment of acute migraines.^[7] 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.^[19]

Diclofenac is also available in topical forms and has been found to be useful for osteoarthritis but not other types of long-term musculoskeletal pain.^[20] Diclofenac may also help with actinic keratosis and with acute pain caused by minor strains, sprains and contusions.^[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 for traumatic corneal abrasion.^[23]

Diclofenac is often used to treat chronic pain associated with cancer, especially if inflammation is present.^[24]

• 
  Voltaren (diclofenac) 50 mg enteric coated tablets
• 
  Dyloject (diclofenac) 2 ml for IV and IM administration
• 
  Sintofarm (diclofenac) for suppository administration
• 
  150 gram tube diclofenac topical gel U.S. package generic

Contraindications

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.^[10][25][26]

Adverse effects

See also: Nonsteroidal anti-inflammatory drug § Adverse effects

Diclofenac consumption has been associated with significantly increased vascular and coronary risk in a study including coxib, diclofenac, ibuprofen and naproxen.^[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 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.^{[28][29][28][29]}

Heart

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 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.^[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". 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 will 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 or coxibs 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]

Diclofenac is similar in COX-2 selectivity to celecoxib.^{[34][contradictory]}

Gastrointestinal

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

Liver

• 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.^{[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]}

Kidney

• Nonsteroidal anti-inflammatory drugs "are associated with adverse renal [kidney] effects caused by the reduction in synthesis of renal prostaglandins"^[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

• 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]

Pharmacology

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. Diclofenac inhibits COX-1 and COX-2 with relative equipotency.^[38]

The main target in 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. It inhibits COX-2 approximately four times as much as COX-1. ^{[which is it, equipotent or 4 to 1?][39]}

The drug may be bacteriostatic via inhibiting bacterial DNA synthesis.^[40]

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.^[41] As in the rest of the body, it is thought to exert its effect in the brain through inhibition of COX-2.^[41] In addition, it may have effects inside the spinal cord.^[42]

Diclofenac may be a unique member of the nonsteroidal anti-inflammatory drugs in other aspects. Some evidence indicates it inhibits the lipoxygenase pathways,^[43][44] thus reducing 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.^[45]

Marked differences exist among nonsteroidal anti-inflammatory drugs in their selective inhibition of the two subtypes of cyclooxygenase, COX-1 and COX-2.^[46] 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, 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.^{[citation needed]}

Besides the COX-inhibition, a number of other molecular targets of diclofenac possibly contributing to its pain-relieving actions have recently been identified. These include:

• Blockage of voltage-dependent sodium channels (after activation of the channel, diclofenac inhibits its reactivation, also known as phase inhibition)^[47][48]
• Blockage of acid-sensing ion channels (ASICs)^[49]
• Positive allosteric modulation of KCNQ- and BK-potassium channels (diclofenac opens these channels, leading to hyperpolarization of the cell membrane)^[50][48]

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.^[51]

History

Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pfister in 1973.^[52][53] 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).^[54][55] It came into medical use in the United States in 1988.^[10] GlaxoSmithKline purchased the rights in 2015.^[52] It is available as a generic medication.^[10]

Society and culture

Formulations and brand names

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.^[56]

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.^[8]

In January 2015, diclofenac oral preparations were reclassified as prescription-only medicines in the UK. The topical preparations are available without prescription.^[57]

Ecological effects

Main article: Indian vulture crisis

Use of diclofenac for animals is controversial due to toxicity when eaten by scavenging birds that eat dead animals;^[58][59] the medication has been banned for veterinary use in several countries.^[60][61]

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^[62] and a 99.9% decline by 2008. The mechanism is presumed to be kidney failure;^[63] however, toxicity may be due to direct inhibition of uric acid secretion in vultures.^[64] Vultures eat the carcasses of livestock that have been administered veterinary diclofenac, and are poisoned by the accumulated chemical,^[65] 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.^[66] Meloxicam is a safer alternative to replace use of diclofenac.^[67] It is more expensive than diclofenac, but the cost is dropping^[when?] as more pharmaceutical companies are beginning to manufacture it.^{[citation needed]}

Steppe eagles have the same vulnerability to diclofenac as Old World vultures, and are therefore at a similar risk from its effects.^[68] Diclofenac has been shown also to harm freshwater fish species such as rainbow trout.^{[69][70][71][72]} 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.^[73]

"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 the main scavenger of wild and domestic ungulate carcasses. Associated with the rise in dog numbers is an increased risk of rabies"^[67] and casualties of almost 50,000 people.^[74] The Government of India cites this as one of the major consequences of a vulture species extinction.^[66] 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 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.^[75]

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.^[67]

Despite the vulture crisis, diclofenac remains available in other countries including many in Europe.^[76] 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 the number of deaths would be quite small.^[77][78] A paper published in 2021 identified the first authenticated death of a vulture from diclofenac in Spain, a cinereous vulture.^[59][79]

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.^[80] 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 the gills, kidneys and liver.^[81]

Veterinary use

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.^{[58][59][60][61]}

Diclofenac is approved as a veterinary medication in some countries^{[58][59][60][61]} 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.^[82] In South Asia in the 2000s, vulture populations were decimated after feeding on carcasses of livestock that had been treated with diclofenac.^[77]

References

1. "Diclofenac". Drugs.com. Archived from the original on 22 December 2018. Retrieved 22 December 2018.
2. O'Toole MT, ed. (2017). Mosby's Dictionary of Medicine, Nursing & Health Professions (10th ed.). Elsevier. p. 536. ISBN 978-0-323-22205-1.
3. "Diclofenac Use During Pregnancy". Drugs.com. 16 January 2000. Retrieved 18 February 2024.
4. "Product monograph brand safety updates". Health Canada. 6 June 2024. Retrieved 8 June 2024.
5. "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
6. "Voltaren Arthritis Pain- diclofenac sodium gel; Voltaren Arthritis Pain- diclofenac sodium kit". DailyMed. 13 March 2024. Retrieved 13 October 2024.
7. "Cambia- diclofenac potassium powder, for solution". DailyMed. 25 April 2024. Retrieved 13 October 2024.
8. "FDA Approves Three Drugs for Nonprescription Use Through Rx-to-OTC Switch Process". U.S. Food and Drug Administration (FDA). 14 February 2020. Retrieved 18 February 2024. This article incorporates text from this source, which is in the public domain.
9. Sayyad M (23 August 2018). "Diclofenac Oral Uses, Dosage, Side Effects And Composition". Medicine Reviews Agency. Archived from the original on 24 August 2018. Retrieved 18 February 2024.
10. "Diclofenac epolamine Monograph for Professionals". Drugs.com. Retrieved 18 February 2024.
11. Williams BS, Buvanendran A (1 January 2011). "Nonopioid analgesics: NSAIDs, COX-2 inhibitors, and acetaminophen". In Benzon HT, Raja SN, Liu SS, Fishman SM (eds.). Essentials of Pain Medicine (3 ed.). W.B. Saunders. pp. 130–139. doi:10.1016/b978-1-4377-2242-0.00026-2. ISBN 978-1-4377-2242-0. Archived from the original on 10 January 2023. Retrieved 10 January 2023.
12. 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. S2CID 74032271.
13. "Diclofenac Ophthalmic". medlineplus.gov. 15 July 2016. Retrieved 8 October 2024.
14. "Arthrotec- diclofenac sodium and misoprostol tablet, film coated". DailyMed. 16 August 2023. Retrieved 13 October 2024.
15. British national formulary : BNF 74 (74 ed.). British Medical Association. 2017. pp. 1033–1035. ISBN 978-0-85711-298-9.
16. Mosby's Drug Reference for Health Professions. Elsevier Health Sciences. 2017. p. 398. ISBN 978-0-323-56682-7.
17. "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
18. "Diclofenac Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
19. "Voltaren- diclofenac sodium solution". DailyMed. 1 October 2012. Retrieved 13 October 2024.
20. 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. PMID 17644321.
21. "Diclofenac (Topical Application Route) Description and Brand Names". MayoClinic.com. Mayo Clinic. Archived from the original on 23 November 2013.
22. "Naclof, oogdruppels 1 mg/ml" (PDF). Laboratoires THEA. Netherlands: Netherlands Medicines Authority MEB. Archived from the original (PDF) on 4 March 2016 – via Medicines Information Bank.
23. Wakai A, Lawrenson JG, Lawrenson AL, Wang Y, Brown MD, Quirke M, et al. (May 2017). "Topical non-steroidal anti-inflammatory drugs for analgesia in traumatic corneal abrasions". The Cochrane Database of Systematic Reviews. 2017 (5): CD009781. doi:10.1002/14651858.CD009781.pub2. PMC 6481688. PMID 28516471.
24. "WHO's cancer pain ladder for adults". World Health Organization (WHO). 27 November 2013. Archived from the original on 7 August 2003. Retrieved 26 April 2020.
25. "Diclofenac Sodium Topical Solution: PI". Drugs.com. 5 August 2024. Retrieved 13 October 2024.
26. "Diclofenac Sodium- diclofenac gel". DailyMed. 30 March 2018. Retrieved 13 October 2024.
27. Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Baron JA, et al. (August 2013). "Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials". Lancet. 382 (9894): 769–779. doi:10.1016/S0140-6736(13)60900-9. PMC 3778977. PMID 23726390.
28. "FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications". U.S. Food and Drug Administration (FDA) (Press release). 15 October 2020. Archived from the original on 16 October 2020. Retrieved 15 October 2020. This article incorporates text from this source, which is in the public domain.
29. "NSAIDs may cause rare kidney problems in unborn babies". U.S. Food and Drug Administration (FDA). 21 July 2017. Archived from the original on 17 October 2020. Retrieved 15 October 2020. This article incorporates text from this source, which is in the public domain.
30. Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C (June 2006). "Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials". BMJ. 332 (7553): 1302–1308. doi:10.1136/bmj.332.7553.1302. PMC 1473048. PMID 16740558.
31. "Press release: Diclofenac tablets now only available as a prescription medicine". Medicines and Healthcare products Regulatory Agency. 14 January 2015. Archived from the original on 22 January 2015. Retrieved 14 January 2015.
32. 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. PMID 16645966. S2CID 2082359.
33. Fosbøl EL, Folke F, Jacobsen S, Rasmussen JN, Sørensen R, Schramm TK, et al. (July 2010). "Cause-specific cardiovascular risk associated with nonsteroidal antiinflammatory drugs among healthy individuals". Circulation: Cardiovascular Quality and Outcomes. 3 (4): 395–405. doi:10.1161/CIRCOUTCOMES.109.861104. PMID 20530789.
34. 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. PMID 11496855.
35. "Voltaren Gel (diclofenac sodium topical gel) 1% – Hepatic Effects Labeling Changes". U.S. Food and Drug Administration (FDA). 4 December 2009. Archived from the original on 29 March 2015.
36. Brater DC (April 2002). "Renal effects of cyclooxygyenase-2-selective inhibitors". Journal of Pain and Symptom Management. 23 (4 Suppl): S15–20, discussion S21–23. doi:10.1016/S0885-3924(02)00370-6. PMID 11992745.
37. "Diclofenac Side Effects". Drugs.com. Archived from the original on 5 February 2013. Retrieved 21 January 2013.
38. Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR (December 1993). "Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase". Proceedings of the National Academy of Sciences of the United States of America. 90 (24): 11693–11697. Bibcode:1993PNAS...9011693M. doi:10.1073/pnas.90.24.11693. PMC 48050. PMID 8265610.
39. Alfaro RA, Davis DD (15 January 2024). "Diclofenac". National Library of Medicine (published 22 May 2023). PMID 32491802. Retrieved 15 January 2024.
40. 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. PMID 10773497.
41. Sandri A (August 2014). "Diclofenac: update on tolerableness and spinal anti-inflammatory action". Minerva Medica. 105 (4): 313–318. PMID 25078485. Archived from the original on 23 April 2023. Retrieved 23 April 2023.
42. Sandri A (June 2016). "Spinal antinflammatory action of Diclofenac". Minerva Medica. 107 (3): 167–172. PMID 27014880. Archived from the original on 23 April 2023. Retrieved 23 April 2023.
43. 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. PMID 20470236.
44. 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. PMID 3085488.
45. 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. PMID 3085490.
46. 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. PMID 9626023.
47. 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. PMID 16806078.
48. Gwanyanya 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. PMID 22943167.
49. Voilley N, de Weille J, Mamet J, Lazdunski M (October 2001). "Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors". The Journal of Neuroscience. 21 (20): 8026–8033. doi:10.1523/JNEUROSCI.21-20-08026.2001. PMC 6763876. PMID 11588175.
50. 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. PMID 11906715.
51. 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. PMID 6628528. S2CID 9803699.
52. Altman R, Bosch B, Brune K, Patrignani P, Young C (May 2015). "Advances in NSAID development: evolution of diclofenac products using pharmaceutical technology". Drugs. 75 (8): 859–877. doi:10.1007/s40265-015-0392-z. PMC 4445819. PMID 25963327.
53. Hasan MK, Akhter S, Fatema K, Hossain MR, Sultana T, Uzzaman M (January 2023). "Selective modification of diclofenac to reduce the adverse effects; A computer-aided drug design approach". Informatics in Medicine Unlocked. 36: 101159. doi:10.1016/j.imu.2023.101159. ISSN 2352-9148.
54. Fischer J (2006). Analogue-based drug discovery. Wiley-VCH. p. 517. ISBN 978-3-527-31257-3.
55. DE 1793592, Pfister R, Sallmann A, "Process for the production of new substituted phenylacetic acids", issued 26 January 1978, assigned to Ciba Geigy AG Archived 24 April 2023 at the Wayback Machine
56. Connelly D (28 April 2017). "A breakdown of the over-the-counter medicines market in Britain in 2016". The Pharmaceutical Journal. Archived from the original on 8 December 2021. Retrieved 23 April 2023.
57. "Oral diclofenac presentations with legal status 'P' – reclassified to POM". www.gov.uk. Archived from the original on 2 April 2015. Retrieved 31 March 2015.
58. Cuthbert RJ, Taggart MA, Prakash V, Chakraborty SS, Deori P, Galligan T, et al. (2014). "Avian scavengers and the threat from veterinary pharmaceuticals". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences. 369 (1656): 20130574. doi:10.1098/rstb.2013.0574. PMC 4213586. PMID 25405963.
59. Moreno-Opo R, Carapeto R, Casimiro R, Rubio C, Muñoz B, Moreno I, et al. (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. PMID 34271379.
60. European Medicines Agency, Committee for Medicinal Products for Veterinary Use, Opinion of the Committee pursuant to Article 30(3) of Regulation (EC) No 726/2004 on the risk to vultures and other necrophagous bird populations in the European Union in connection with the use of veterinary medicinal products containing the substance diclofenac (PDF), EMA/CVMP/761582/2014, archived (PDF) from the original on 7 July 2022, retrieved 16 April 2022
61. McKie R (11 April 2021). "Rare European vultures being poisoned by livestock drug". The Guardian. Archived from the original on 16 April 2022. Retrieved 16 April 2022. ...diclofenac has already been banned in India, Pakistan, Nepal and Bangladesh
62. Oaks JL, Gilbert M, Virani MZ, Watson RT, Meteyer CU, Rideout BA, et al. (February 2004). "Diclofenac residues as the cause of vulture population decline in Pakistan". Nature. 427 (6975): 630–633. Bibcode:2004Natur.427..630O. doi:10.1038/nature02317. PMID 14745453. S2CID 16146840.
63. Swan GE, Cuthbert R, Quevedo M, Green RE, Pain DJ, Bartels P, et al. (2006). "Toxicity of diclofenac to Gyps vultures". Biology Letters. 2 (2): 279–282. doi:10.1098/rsbl.2005.0425. PMC 1618889. PMID 17148382.
64. Naidoo V, Swan GE (2009). "Diclofenac toxicity in Gyps 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. PMID 18727958.
65. "Vet drug 'killing Asian vultures'". BBC News. 28 February 2004. Archived from the original on 3 December 2013. Retrieved 25 August 2010.
66. "Saving the Vultures from Extinction" (Press release). Press Information Bureau, Government of India. 16 May 2005. Archived from the original on 20 December 2005. Retrieved 12 May 2006.
67. Swan G, Naidoo V, Cuthbert R, Green RE, Pain DJ, Swarup D, et al. (2006). "Removing the threat of diclofenac to critically endangered Asian vultures". PLOS Biology. 4 (3): e66. doi:10.1371/journal.pbio.0040066. PMC 1351921. PMID 16435886.
68. Phadnis M (28 May 2014). "Eagles fall prey to vulture-killing chemical". Pune Mirror. Archived from the original on 29 May 2014. Retrieved 28 May 2014.
69. Schwaiger 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. PMID 15145224.
70. Triebskorn 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. PMID 15145225.
71. Schwaiger J, Triebskorn R (2005). "Subletale Wirkungen von Arzneimitteln bei aquatischen Organismen" [Sublethal effects of drugs in aquatic organisms] (PDF). Texte (in German). 29 (5): 217–226.
72. Triebskorn 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. PMID 17216161. S2CID 21170569.
73. Rattner BA, Whitehead MA, Gasper G, Meteyer CU, Link WA, Taggart MA, et al. (2008). "Apparent tolerance of turkey vultures (Cathartes aura) to the non-steroidal anti-inflammatory drug diclofenac". Environmental Toxicology and Chemistry. 27 (11): 2341–2345. Bibcode:2008EnvTC..27.2341R. doi:10.1897/08-123.1. PMID 18476752. S2CID 207267290. Archived from the original on 28 August 2021. Retrieved 15 July 2019.
74. Walker M (6 August 2008). "Rabies tragedy follows loss of India's vultures". New Scientist. Archived from the original on 23 April 2023. Retrieved 23 April 2023.
75. Choudhary S (29 August 2016). "'Decline in vulture population has given rise to diseases': Dr Vibhu Prakash". The Indian Express. Archived from the original on 15 December 2018. Retrieved 12 December 2018.
76. "E-010588/2015: answer given by Mr Andriukaitis on behalf of the Commission". European Parliament. Archived from the original on 13 May 2016. Retrieved 18 February 2024.
77. Becker R (2016). "Cattle drug threatens thousands of vultures". Nature. doi:10.1038/nature.2016.19839. S2CID 75173071.
78. "Vulture killing drug now available on EU market". International BirdLife. Archived from the original on 24 April 2014. Retrieved 18 February 2024.
79. "First evidence of a vulture killed by veterinary diclofenac in Spain – will the Spanish government and the EU act after this smoking gun?". Vulture Conservation Foundation. 7 April 2021. Archived from the original on 8 April 2021. Retrieved 8 April 2021.
80. Fernholm A (4 March 2010). "Val av smärtstillande påverkar miljön". LäkemedelsVärlden (in Swedish). Archived from the original on 15 August 2022. Retrieved 15 March 2023.
81. "Itämeren kalat häiriintyvät lääkeaineista – Teollisuudella paineita kehittää eettisempiä pillereitä". Yle Uutiset (in Finnish). 10 September 2014. Archived from the original on 15 March 2023. Retrieved 15 March 2023.
82. Hussain I, Khan MZ, Khan A, Javed I, Saleemi MK (2008). "Toxicological effects of diclofenac in four avian species". Avian Pathology. 37 (3): 315–321. doi:10.1080/03079450802056439. PMID 18568659. S2CID 12985124.

External links