Diclofenac

{{Short description|Nonsteroidal anti-inflammatory drug}} {{Redirect|Diclo|the organic solvent sometimes called Di-clo|Dichloromethane}} {{Redirect|Dichronic|common misspellings|Diachronic (disambiguation)}} {{Use dmy dates|date=January 2026}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | Verifiedfields = changed | Watchedfields = changed | verifiedrevid = 443636249 | image = Diclofenac.svg | image_class = skin-invert-image | width = 250 | alt = | caption = Structure of diclofenac with ball and stick model | image2 = Diclofenac-from-xtal-3D-bs-17.png | image_class2 = bg-transparent | width2 = 250 | alt2 =  | pronounce = {{IPAc-en|d|aɪ|'|k|l|oʊ|f|ə|n|æ|k}}<ref name=tn /> or {{IPAc-en|d|ɪ|k|l|ɒ|'|f|ɛ|n|æ|k}}<ref>{{cite book|title=Mosby's Dictionary of Medicine, Nursing & Health Professions| veditors = O'Toole MT |page=536 |edition=10th |year=2017 |publisher=Elsevier|location=|isbn=978-0-323-22205-1}}</ref> | tradename = Voltaren, others<ref name=tn/> | Drugs.com = {{drugs.com|monograph|diclofenac-epolamine}} | MedlinePlus = a689002 | DailyMedID = Diclofenac | pregnancy_AU = C | pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web|title=Diclofenac Use During Pregnancy|website=Drugs.com|date=16 January 2000|url=https://www.drugs.com/pregnancy/diclofenac.html|access-date=18 February 2024}}</ref> | routes_of_administration = Oral, rectal, intramuscular, intravenous, topical, ophthalmic | class = Nonsteroidal anti-inflammatory drug (NSAID) | ATC_prefix = D11 | ATC_suffix = AX18 | ATC_supplemental = {{ATC|M01|AB05}}, {{ATC|M02|AA15}}, {{ATC|S01|BC03}}

| legal_AU = S4 | legal_AU_comment = / S3 / S2 | legal_BR =  | legal_BR_comment = | legal_CA = Rx-only | legal_CA_comment = <ref>{{cite web | title=Product monograph brand safety updates | website=Health Canada | date=6 June 2024 | url=https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/drug-product-database/label-safety-assessment-update/product-monograph-brand-safety-updates.html | access-date=8 June 2024}}</ref> | legal_DE =  | legal_DE_comment = | legal_NZ =  | legal_NZ_comment = | legal_UK = POM | legal_UK_comment = / P / GSL | legal_US = Rx-only | legal_US_comment = / OTC<ref name="Voltaren FDA label">{{cite web | title=Voltaren Arthritis Pain- diclofenac sodium gel; Voltaren Arthritis Pain- diclofenac sodium kit | website=DailyMed | date=13 March 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=30a94282-0892-442a-aa10-6525cbd4fe88 | access-date=13 October 2024}}</ref><ref name="Cambia FDA label">{{cite web | title=Cambia- diclofenac potassium powder, for solution | website=DailyMed | date=25 April 2024 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d249ced1-4ca0-4f57-adcb-23440f58f659 | access-date=13 October 2024}}</ref><ref name=FDAswitch>{{cite web|title=FDA Approves Three Drugs for Nonprescription Use Through Rx-to-OTC Switch Process|website=U.S. Food and Drug Administration (FDA) |date=14 February 2020|url=http://www.fda.gov/news-events/press-announcements/fda-approves-three-drugs-nonprescription-use-through-rx-otc-switch-process|archive-url=https://web.archive.org/web/20200215012930/https://www.fda.gov/news-events/press-announcements/fda-approves-three-drugs-nonprescription-use-through-rx-otc-switch-process|archive-date=15 February 2020|access-date=18 February 2024}} {{PD-notice}}</ref> | legal_EU = | legal_EU_comment = | legal_UN =  | legal_UN_comment = | legal_status = SE: Rx-only / OTC{{efn |It's Rx-only in pill form, it's OTC as a gel.}} <br /> In general: Prescription only

| bioavailability = | protein_bound = More than 99% | metabolism = Liver, oxidative, primarily by CYP2C9, also by CYP2C8, CYP3A4, as well as conjugative by glucuronidation (UGT2B7) and sulfation;<ref>{{cite web|url=http://www.medicinereviews.ooo/2018/08/diclofenac-oral-uses-dosage-side.html|title=Diclofenac Oral Uses, Dosage, Side Effects And Composition|publisher=Medicine Reviews Agency | vauthors = Sayyed M|date=23 August 2018|access-date=18 February 2024|archive-date=24 August 2018|archive-url=https://web.archive.org/web/20180824135214/https://www.medicinereviews.ooo/2018/08/diclofenac-oral-uses-dosage-side.html}}</ref> no active metabolites exist | metabolites = | onset = Within 4 hours (gel), 30 min (non-gel)<ref name=AHFS2018/> | elimination_half-life = 1.2–2 h (35% of the drug enters enterohepatic recirculation) | duration_of_action = | excretion = 35% bile, 65% urine<ref>{{cite book|vauthors=Williams BS, Buvanendran A|chapter=Nonopioid analgesics: NSAIDs, COX-2 inhibitors, and acetaminophen|date=1 January 2011|chapter-url=https://www.sciencedirect.com/science/article/pii/B9781437722420000262|title=Essentials of Pain Medicine|edition=3|pages=130–139|veditors=Benzon HT, Raja SN, Liu SS, Fishman SM|publisher=W.B. Saunders|doi=10.1016/b978-1-4377-2242-0.00026-2|isbn=978-1-4377-2242-0|access-date=10 January 2023|archive-date=10 January 2023|archive-url=https://web.archive.org/web/20230110202200/https://www.sciencedirect.com/science/article/pii/B9781437722420000262|url-status=live}}</ref>

| CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 15307-86-5 | PubChem = 3033 | IUPHAR_ligand = 2714 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00586 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 2925 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 144O8QL0L1 | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D07816 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 47381 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 139 | NIAID_ChemDB = | PDB_ligand = DIF | synonyms =  | IUPAC_name = [2-(2,6-Dichloroanilino)phenyl]acetic acid  | C = 14 | H = 11 | Cl = 2 | N = 1 | O = 2 | SMILES = O=C(O)Cc1ccccc1Nc2c(Cl)cccc2Cl | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 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) | StdInChI_comment = | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = DCOPUUMXTXDBNB-UHFFFAOYSA-N | density = | density_notes = | melting_point = | melting_high = | melting_notes = | boiling_point = | boiling_notes = | solubility = | sol_units = | specific_rotation = }}

'''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>{{cite web|title=Diclofenac epolamine Monograph for Professionals|website=Drugs.com |url=https://www.drugs.com/monograph/diclofenac-epolamine.html|access-date=18 February 2024}}</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>{{cite journal | vauthors = Chung CH | title = The use of Injectable Nonsteroidal Anti-Inflammatory Drugs in Local Accident & Emergency Practice | journal = Hong Kong Journal of Emergency Medicine | volume = 9 | issue = 2 | pages = 65–71 | year = 2017 | doi = 10.1177/102490790200900201 | s2cid = 74032271 }}</ref><ref>{{Cite web |date=2016-07-15 |title=Diclofenac Ophthalmic |url=https://medlineplus.gov/druginfo/meds/a606003.html |access-date=2024-10-08 |website=medlineplus.gov}}</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>{{cite web | title=Arthrotec- diclofenac sodium and misoprostol tablet, film coated | website=DailyMed | date=16 August 2023 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=600fe842-45d9-4d68-9ef2-456dbbebaa11 | access-date=13 October 2024}}</ref><ref name=BNF74/><ref>{{cite journal |vauthors=Tai FW, McAlindon ME |title=Non-steroidal anti-inflammatory drugs and the gastrointestinal tract |journal=Clinical Medicine |volume=21 |issue=2 |pages=131–134 |date=March 2021 |pmid=33762373 |pmc=8002800 |doi=10.7861/clinmed.2021-0039 }}</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>{{cite book|title=Mosby's Drug Reference for Health Professions|year=2017|publisher=Elsevier Health Sciences|location=|isbn=978-0-323-56682-7|page=398|url=https://books.google.com/books?id=KOM2DwAAQBAJ&pg=PA398}}</ref><ref>https://www.tga.gov.au/sites/default/files/medicines-review-safety-diclofenac.pdf</ref>

In 2023, it was the 73rd most commonly prescribed medication in the United States, with more than 9{{nbsp}}million prescriptions.<ref name="Top300Drugs">{{cite web | title=Top 300 of 2023 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=12 August 2025 | archive-date=12 August 2025 | archive-url=https://web.archive.org/web/20250812130026/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Diclofenac Drug Usage Statistics, United States, 2014 - 2023 | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Diclofenac | access-date = 18 August 2025 }}</ref> It is available as its acid or in two salts, as either diclofenac sodium or potassium.<ref name=BNF74>{{cite book|title=British national formulary: BNF 74|year=2017|publisher=British Medical Association|isbn=978-0-85711-298-9|pages=1033–1035|edition=74}}</ref>

==Medical uses== 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>{{cite web | title=Voltaren- diclofenac sodium solution | website=DailyMed | date=1 October 2012 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=65037222-146c-493d-aa1c-e6df89bf5b8d | access-date=13 October 2024}}</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>{{cite journal|vauthors=Dutta NK, Mazumdar K, Dastidar SG, Park JH|title=Activity of diclofenac used alone and in combination with streptomycin against Mycobacterium tuberculosis in mice|journal=International Journal of Antimicrobial Agents|volume=30|issue=4|pages=336–340|year=2007|pmid=17644321|doi=10.1016/j.ijantimicag.2007.04.016}}</ref> Diclofenac may also help with actinic keratosis and with acute pain caused by minor strains, sprains and contusions.<ref>{{cite web |url= http://www.mayoclinic.com/health/drug-information/DR600545 |title= Diclofenac (Topical Application Route) Description and Brand Names |website= MayoClinic.com |publisher= Mayo Clinic |date= |archive-date= 23 November 2013 |archive-url= https://web.archive.org/web/20131123224442/http://www.mayoclinic.com/health/drug-information/DR600545 |url-status= live }}</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>{{cite web |title=Naclof, oogdruppels 1 mg/ml |url=http://db.cbg-meb.nl/IB-teksten/h12800.pdf |archive-url=https://web.archive.org/web/20160304033446/http://db.cbg-meb.nl/IB-teksten/h12800.pdf |archive-date=4 March 2016 |work=Laboratoires THEA |publisher=Netherlands Medicines Authority MEB |via=Medicines Information Bank |location=Netherlands}}</ref> The eye drops have also been used to manage pain for traumatic corneal abrasion.<ref name="Wakai">{{cite journal | vauthors = Wakai A, Lawrenson JG, Lawrenson AL, Wang Y, Brown MD, Quirke M, Ghandour O, McCormick R, Walsh CD, Amayem A, Lang E, Harrison N | title = Topical non-steroidal anti-inflammatory drugs for analgesia in traumatic corneal abrasions | journal = The Cochrane Database of Systematic Reviews | volume = 2017 | issue = 5 | article-number = CD009781 | date = May 2017 | pmid = 28516471 | pmc = 6481688 | doi = 10.1002/14651858.CD009781.pub2 }}</ref>

Diclofenac is often used to treat chronic pain associated with cancer, especially if inflammation is present.<ref>{{cite web | title=WHO's cancer pain ladder for adults | website=World Health Organization (WHO) | date=27 November 2013 | url= https://www.who.int/cancer/palliative/painladder/en/ | archive-url= https://web.archive.org/web/20030807014332/http://www.who.int/cancer/palliative/painladder/en/ | archive-date=7 August 2003 | access-date=26 April 2020}}</ref>

<gallery> File:Voltaren tablets.jpg|Voltaren (diclofenac) 50 mg enteric coated tablets File:Diclofenac sodium IV 75mg.jpg|Dyloject (diclofenac) 2 ml for IV and IM administration File:Diclofenac sodium 100mg.jpg|Sintofarm (diclofenac) for suppository administration File:Diclofenac Topical Gel.jpg|150 gram tube diclofenac topical gel U.S. package generic </gallery>

==Contraindications== 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>{{cite web | title=Diclofenac Sodium Topical Solution: PI | website=Drugs.com | date=5 August 2024 | url=https://www.drugs.com/pro/diclofenac-sodium-topical-solution.html | access-date=13 October 2024}}</ref><ref>{{cite web | title=Diclofenac Sodium- diclofenac gel | website=DailyMed | date=30 March 2018 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=f64b68a5-d6d2-4e92-87e7-90af04c1f9db | access-date=13 October 2024}}</ref>

==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 COX-2 inhibitors, diclofenac, ibuprofen and naproxen.<ref name="BhalaEmbersonEtAl">{{cite journal | vauthors = Bhala N, Emberson J, Merhi A, Abramson S, Arber N, Baron JA, Bombardier C, Cannon C, Farkouh ME, FitzGerald GA, Goss P, Halls H, Hawk E, Hawkey C, Hennekens C, Hochberg M, Holland LE, Kearney PM, Laine L, Lanas A, Lance P, Laupacis A, Oates J, Patrono C, Schnitzer TJ, Solomon S, Tugwell P, Wilson K, Wittes J, Baigent C | title = Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: meta-analyses of individual participant data from randomised trials | journal = Lancet | volume = 382 | issue = 9894 | pages = 769–779 | date = August 2013 | pmid = 23726390 | pmc = 3778977 | doi = 10.1016/S0140-6736(13)60900-9 }}</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 prescribing 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.<ref name="FDA PR 20201015">{{cite press release | title=FDA Warns that Using a Type of Pain and Fever Medication in Second Half of Pregnancy Could Lead to Complications | website=U.S. Food and Drug Administration (FDA) | date=15 October 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-warns-using-type-pain-and-fever-medication-second-half-pregnancy-could-lead-complications | access-date=15 October 2020 | archive-date=16 October 2020 | archive-url=https://web.archive.org/web/20201016180003/https://www.fda.gov/news-events/press-announcements/fda-warns-using-type-pain-and-fever-medication-second-half-pregnancy-could-lead-complications }} {{PD-notice}}</ref><ref name="FDA safety 20201015">{{cite web | title=NSAIDs may cause rare kidney problems in unborn babies | website=U.S. Food and Drug Administration (FDA) | date=21 July 2017 | url=https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic | access-date=15 October 2020 | archive-date=17 October 2020 | archive-url=https://web.archive.org/web/20201017014419/https://www.fda.gov/drugs/drug-safety-and-availability/fda-recommends-avoiding-use-nsaids-pregnancy-20-weeks-or-later-because-they-can-result-low-amniotic }} {{PD-notice}}</ref>

===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.<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">{{cite journal | vauthors = Kearney PM, Baigent C, Godwin J, Halls H, Emberson JR, Patrono C | title = Do selective cyclo-oxygenase-2 inhibitors and traditional non-steroidal anti-inflammatory drugs increase the risk of atherothrombosis? Meta-analysis of randomised trials | journal = BMJ | volume = 332 | issue = 7553 | pages = 1302–1308 | date = June 2006 | pmid = 16740558 | pmc = 1473048 | doi = 10.1136/bmj.332.7553.1302 }}</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>{{cite web |url=http://www.mhra.gov.uk/NewsCentre/Pressreleases/CON500341 |title=Press release: Diclofenac tablets now only available as a prescription medicine |date=14 January 2015 |access-date=14 January 2015 |website=Medicines and Healthcare products Regulatory Agency |archive-date=22 January 2015 |archive-url=https://web.archive.org/web/20150122224346/http://www.mhra.gov.uk/NewsCentre/Pressreleases/CON500341 |url-status=live }}</ref>

A 2006 large observational study of 74,838 US users of nonsteroidal anti-inflammatory drugs or coxibs found no additional cardiovascular risk from diclofenac use.<ref name="ArthritisRheum2006-Solomon">{{cite journal | vauthors = Solomon DH, Avorn J, Stürmer T, Glynn RJ, Mogun H, Schneeweiss S | title = Cardiovascular outcomes in new users of coxibs and nonsteroidal antiinflammatory drugs: high-risk subgroups and time course of risk | journal = Arthritis and Rheumatism | volume = 54 | issue = 5 | pages = 1378–1389 | date = May 2006 | pmid = 16645966 | doi = 10.1002/art.21887 | s2cid = 2082359 | doi-access = }}</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">{{cite journal | vauthors = Fosbøl EL, Folke F, Jacobsen S, Rasmussen JN, Sørensen R, Schramm TK, Andersen SS, Rasmussen S, Poulsen HE, Køber L, Torp-Pedersen C, Gislason GH | title = Cause-specific cardiovascular risk associated with nonsteroidal antiinflammatory drugs among healthy individuals | journal = Circulation: Cardiovascular Quality and Outcomes | volume = 3 | issue = 4 | pages = 395–405 | date = July 2010 | pmid = 20530789 | doi = 10.1161/CIRCOUTCOMES.109.861104 | doi-access = free }}</ref>

Diclofenac is similar in COX-2 selectivity to celecoxib.<ref name="pmid11496855">{{cite journal | vauthors = FitzGerald GA, Patrono C | title = The coxibs, selective inhibitors of cyclooxygenase-2 | journal = The New England Journal of Medicine | volume = 345 | issue = 6 | pages = 433–442 | date = August 2001 | pmid = 11496855 | doi = 10.1056/NEJM200108093450607 }}</ref>{{Contradictory inline|reason=This contradicts the later (also substantiated) statement that diclofenac and naproxen have relatively equipotent COX inhibition. Diclofenac is not usually categorised as COX-2-selective, but this source would seem to suggest that it is.|date=November 2022|section=Mechanism of action}}

===Gastrointestinal=== {{unreferenced section|date=October 2024}} * 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.<ref>{{Citation |title=Diclofenac |date=2012 |work=LiverTox: Clinical and Research Information on Drug-Induced Liver Injury |url=http://www.ncbi.nlm.nih.gov/books/NBK547953/ |access-date=2025-12-22 |place=Bethesda (MD) |publisher=National Institute of Diabetes and Digestive and Kidney Diseases |pmid=31643286}}</ref> * {{As of|December 2009}}, 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>{{cite web |title= Voltaren Gel (diclofenac sodium topical gel) 1% – Hepatic Effects Labeling Changes|website=U.S. Food and Drug Administration (FDA) |url= https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm193047.htm |archive-url= https://web.archive.org/web/20150329100526/https://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm193047.htm |date= 4 December 2009|archive-date= 29 March 2015}}</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.<ref>{{Cite journal |last=Bessone |first=Fernando |date=2010 |title=Non-steroidal anti-inflammatory drugs: What is the actual risk of liver damage? |journal=World Journal of Gastroenterology |language=en |volume=16 |issue=45 |pages=5651 |doi=10.3748/wjg.v16.i45.5651 |doi-access=free |issn=1007-9327 |pmc=2997980 |pmid=21128314}}</ref>

===Kidney=== * Nonsteroidal anti-inflammatory drugs "are associated with adverse renal [kidney] effects caused by the reduction in synthesis of renal prostaglandins"<ref name="Brater2002">{{cite journal | vauthors = Brater DC | title = Renal effects of cyclooxygyenase-2-selective inhibitors | journal = Journal of Pain and Symptom Management | volume = 23 | issue = 4 Suppl | at = pp. S15–20; discussion pp. S21–23 | date = April 2002 | pmid = 11992745 | doi = 10.1016/S0885-3924(02)00370-6 | doi-access = free }}</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 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.<ref>{{cite web |url=https://www.drugs.com/sfx/diclofenac-side-effects.html |title=Diclofenac Side Effects |work=Drugs.com |access-date=21 January 2013 |archive-date=5 February 2013 |archive-url=https://web.archive.org/web/20130205085428/http://www.drugs.com/sfx/diclofenac-side-effects.html |url-status=live }}</ref>

==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.

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>{{cite journal | title = Diclofenac | date = 15 January 2024 | pmid = 32491802 | url = https://www.ncbi.nlm.nih.gov/books/NBK557879/ | website = National Library of Medicine | access-date = 15 January 2024 | publication-date = 22 May 2023 | vauthors = Alfaro RA, Davis DD }}</ref><ref>{{cite journal | vauthors = Patrono C, Patrignani P, García Rodríguez LA | title = Cyclooxygenase-selective inhibition of prostanoid formation: transducing biochemical selectivity into clinical read-outs | journal = The Journal of Clinical Investigation | volume = 108 | issue = 1 | pages = 7–13 | date = July 2001 | pmid = 11435450 | doi = 10.1172/JCI13418 | pmc = 209347 }}</ref><ref>{{cite journal | vauthors = Warner TD, Giuliano F, Vojnovic I, Bukasa A, Mitchell JA, Vane JR | title = Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: a full in vitro analysis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 96 | issue = 13 | pages = 7563–7568 | date = June 1999 | pmid = 10377455 | pmc = 22126 | doi = 10.1073/pnas.96.13.7563 | doi-access = free | bibcode = 1999PNAS...96.7563W }}</ref><ref>{{cite journal | vauthors = Mitchell JA, Akarasereenont P, Thiemermann C, Flower RJ, Vane JR | title = Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 90 | issue = 24 | pages = 11693–11697 | date = December 1993 | pmid = 8265610 | pmc = 48050 | doi = 10.1073/pnas.90.24.11693 | bibcode = 1993PNAS...9011693M | doi-access = free }}</ref>

The drug may be bacteriostatic via inhibiting bacterial DNA synthesis.<ref name="Dutta2000">{{cite journal | vauthors = Dastidar SG, Ganguly K, Chaudhuri K, Chakrabarty AN | title = The anti-bacterial action of diclofenac shown by inhibition of DNA synthesis | journal = International Journal of Antimicrobial Agents | volume = 14 | issue = 3 | pages = 249–251 | date = April 2000 | pmid = 10773497 | doi = 10.1016/S0924-8579(99)00159-4 }}</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">{{cite journal | vauthors = Sandri A | title = Diclofenac: update on tolerableness and spinal anti-inflammatory action | journal = Minerva Medica | volume = 105 | issue = 4 | pages = 313–318 | date = August 2014 | pmid = 25078485 | url = https://www.minervamedica.it/en/journals/minerva-medica/article.php?cod=R10Y2014N04A0313 | access-date = 23 April 2023 | archive-date = 23 April 2023 | archive-url = https://web.archive.org/web/20230423165313/https://www.minervamedica.it/en/journals/minerva-medica/article.php?cod=R10Y2014N04A0313 | url-status = live }}</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>{{cite journal | vauthors = Sandri A | title = Spinal antinflammatory action of Diclofenac | journal = Minerva Medica | volume = 107 | issue = 3 | pages = 167–172 | date = June 2016 | pmid = 27014880 | url = https://www.minervamedica.it/en/journals/minerva-medica/article.php?cod=R10Y2016N03A0167 | access-date = 23 April 2023 | archive-date = 23 April 2023 | archive-url = https://web.archive.org/web/20230423165313/https://www.minervamedica.it/en/journals/minerva-medica/article.php?cod=R10Y2016N03A0167 | url-status = live }}</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>{{cite journal | vauthors = Gan TJ | title = Diclofenac: an update on its mechanism of action and safety profile | journal = Current Medical Research and Opinion | volume = 26 | issue = 7 | pages = 1715–1731 | date = July 2010 | pmid = 20470236 | doi = 10.1185/03007995.2010.486301 }}</ref><ref>{{cite journal | vauthors = Ku EC, Lee W, Kothari HV, Scholer DW | title = Effect of diclofenac sodium on the arachidonic acid cascade | journal = The American Journal of Medicine | volume = 80 | issue = 4B | pages = 18–23 | date = April 1986 | pmid = 3085488 | doi = 10.1016/0002-9343(86)90074-4 }}</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 {{Ndash}}it is the most potent NSAID on a broad basis.<ref name="pmid3085490">{{cite journal | vauthors = Scholer DW, Ku EC, Boettcher I, Schweizer A | title = Pharmacology of diclofenac sodium | journal = The American Journal of Medicine | volume = 80 | issue = 4B | pages = 34–38 | date = April 1986 | pmid = 3085490 | doi = 10.1016/0002-9343(86)90077-x }}</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">{{cite journal | vauthors = Cryer B, Feldman M | title = Cyclooxygenase-1 and cyclooxygenase-2 selectivity of widely used nonsteroidal anti-inflammatory drugs | journal = The American Journal of Medicine | volume = 104 | issue = 5 | pages = 413–421 | date = May 1998 | pmid = 9626023 | doi = 10.1016/S0002-9343(98)00091-6 }}</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. However, the cardiovascular adverse effects of some COX-2 inhibitors has led to 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|date=May 2010}}

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-dependent sodium channels (after activation of the channel, diclofenac inhibits its reactivation, also known as phase inhibition)<ref>{{cite journal | vauthors = Fei XW, Liu LY, Xu JG, Zhang ZH, Mei YA | title = The non-steroidal anti-inflammatory drug, diclofenac, inhibits Na(+) current in rat myoblasts | journal = Biochemical and Biophysical Research Communications | volume = 346 | issue = 4 | pages = 1275–1283 | date = August 2006 | pmid = 16806078 | doi = 10.1016/j.bbrc.2006.06.034 }}</ref><ref name=":0">{{cite journal | vauthors = Gwanyanya A, Macianskiene R, Mubagwa K | title = Insights into the effects of diclofenac and other non-steroidal anti-inflammatory agents on ion channels | journal = The Journal of Pharmacy and Pharmacology | volume = 64 | issue = 10 | pages = 1359–1375 | date = October 2012 | pmid = 22943167 | doi = 10.1111/j.2042-7158.2012.01479.x }}</ref> * Blockage of acid-sensing ion channels (ASICs)<ref>{{cite journal | vauthors = Voilley N, de Weille J, Mamet J, Lazdunski M | title = Nonsteroid anti-inflammatory drugs inhibit both the activity and the inflammation-induced expression of acid-sensing ion channels in nociceptors | journal = The Journal of Neuroscience | volume = 21 | issue = 20 | pages = 8026–8033 | date = October 2001 | pmid = 11588175 | pmc = 6763876 | doi = 10.1523/JNEUROSCI.21-20-08026.2001 }}</ref> * Positive allosteric modulation of KCNQ- and BK-potassium channels (diclofenac opens these channels, leading to hyperpolarization of the cell membrane)<ref>{{cite journal | vauthors = Ortiz MI, Torres-López JE, Castañeda-Hernández G, Rosas R, Vidal-Cantú GC, Granados-Soto V | title = Pharmacological evidence for the activation of K(+) channels by diclofenac | journal = European Journal of Pharmacology | volume = 438 | issue = 1–2 | pages = 85–91 | date = March 2002 | pmid = 11906715 | doi = 10.1016/S0014-2999(02)01288-8 }}</ref><ref name=":0" />

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 in synovial fluids.<ref name="pmid6628528">{{cite journal | vauthors = Fowler PD, Shadforth MF, Crook PR, John VA | title = Plasma and synovial fluid concentrations of diclofenac sodium and its major hydroxylated metabolites during long-term treatment of rheumatoid arthritis | journal = European Journal of Clinical Pharmacology | volume = 25 | issue = 3 | pages = 389–394 | year = 1983 | pmid = 6628528 | doi = 10.1007/BF01037953 | s2cid = 9803699 }}</ref>

==History== Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pfister in 1973.<ref name=":1">{{cite journal | vauthors = Altman R, Bosch B, Brune K, Patrignani P, Young C | title = Advances in NSAID development: evolution of diclofenac products using pharmaceutical technology | journal = Drugs | volume = 75 | issue = 8 | pages = 859–877 | date = May 2015 | pmid = 25963327 | pmc = 4445819 | doi = 10.1007/s40265-015-0392-z }}</ref><ref>{{Cite journal | vauthors = Hasan MK, Akhter S, Fatema K, Hossain MR, Sultana T, Uzzaman M |date= January 2023 |title=Selective modification of diclofenac to reduce the adverse effects; A computer-aided drug design approach |journal=Informatics in Medicine Unlocked |volume=36 |article-number=101159 |doi=10.1016/j.imu.2023.101159 |issn=2352-9148|doi-access=free }}</ref> 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).<ref name=Fischer2006>{{cite book| vauthors = Fischer J |title=Analogue-based drug discovery|page=517|year=2006|publisher=Wiley-VCH|location=|isbn=978-3-527-31257-3}}</ref><ref>{{cite patent|country=DE|number=1793592|url=https://patents.google.com/patent/DE1793592A1/en?oq=DE1793592|inventor=Pfister R, Sallmann A|title=Process for the production of new substituted phenylacetic acids|assign1=Ciba Geigy AG|gdate=26 January 1978}} {{Webarchive|url=https://web.archive.org/web/20230424053935/https://patents.google.com/patent/DE1793592A1/en?oq=DE1793592|date=24 April 2023}}</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 names== Diclofenac formulations are available worldwide under many different brand names.<ref name=tn>{{cite web|title=Diclofenac|url=https://www.drugs.com/international/diclofenac.html|website=Drugs.com|access-date=22 December 2018|archive-date=22 December 2018|archive-url=https://web.archive.org/web/20181222173313/https://www.drugs.com/international/diclofenac.html|url-status=live}}</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>{{cite news|vauthors=Connelly D|title=A breakdown of the over-the-counter medicines market in Britain in 2016|url=https://pharmaceutical-journal.com/article/infographics/a-breakdown-of-the-over-the-counter-medicines-market-in-britain-in-2016|work=The Pharmaceutical Journal|date=28 April 2017|access-date=23 April 2023|archive-date=8 December 2021|archive-url=https://web.archive.org/web/20211208124752/https://pharmaceutical-journal.com/article/infographics/a-breakdown-of-the-over-the-counter-medicines-market-in-britain-in-2016|url-status=live}}</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>{{cite web|url=https://www.gov.uk/drug-device-alerts/drug-alert-oral-diclofenac-presentations-with-legal-status-p-reclassified-to-pom|title=Oral diclofenac presentations with legal status 'P' – reclassified to POM|website=www.gov.uk|access-date=31 March 2015|archive-date=2 April 2015|archive-url=https://web.archive.org/web/20150402164113/https://www.gov.uk/drug-device-alerts/drug-alert-oral-diclofenac-presentations-with-legal-status-p-reclassified-to-pom|url-status=live}}</ref>

=={{anchor|Ecological problems}}Ecological effects== {{missing information|section|environmental buildup, wastewater; try {{PMID|27649472}}|date=December 2022}} {{Main|Indian vulture crisis}}

Diclofenac in animals has environmental effects. It is toxic, for example, to scavenging birds.<ref name="vulture1" /><ref name="Moreno-Opo_2021">{{cite journal | vauthors = Moreno-Opo R, Carapeto R, Casimiro R, Rubio C, Muñoz B, Moreno I, Aymerich M | title = The veterinary use of diclofenac and vulture conservation in Spain: Updated evidence and socio-ecological implications | journal = The Science of the Total Environment | volume = 796 | article-number = 148851 | date = Nov 2021 | pmid = 34271379 | doi = 10.1016/j.scitotenv.2021.148851 | bibcode = 2021ScTEn.79648851M }}</ref> Too, residues of the drug are found in marine and freshwater organisms, contaminated by agricultural runoff containing diclofenac.{{r|Schwaiger|Triebskorn| pmid17216161}} The medication has been banned for veterinary use in several countries;<ref name="vulture2" /><ref name="vulture3" /> India restricted its use in 2006.<ref>{{cite magazine | vauthors = Burfield I, Bowden C | title = South Asian vultures and diclofenac | date = 28 September 2022 | url = https://www.cambridge.org/core/blog/2022/09/28/south-asian-vultures-and-diclofenac/ | department = Life Sciences | magazine = Cambridge Core Blog }}</ref><ref>{{cite news | vauthors = Ayyar K | title = Born to be wild: India's first captive-bred endangered vultures set free | date = 19 August 2021 | url = https://www.theguardian.com/environment/2021/aug/19/india-critically-endangered-vultures-wild-release-aoe | work = The Guardian }}</ref> Meloxicam is an alternative which is safer for wildlife.<ref name="Swan_2006">{{cite journal | vauthors = Swan G, Naidoo V, Cuthbert R, Green RE, Pain DJ, Swarup D, Prakash V, Taggart M, Bekker L, Das D, Diekmann J, Diekmann M, Killian E, Meharg A, Patra RC, Saini M, Wolter K | title = Removing the threat of diclofenac to critically endangered Asian vultures | journal = PLOS Biology | volume = 4 | issue = 3 | article-number = e66 | date = Mar 2006 | pmid = 16435886 | pmc = 1351921 | doi = 10.1371/journal.pbio.0040066 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Adawaren EO, Mukandiwa L, Chipangura J, Wolter K, Naidoo V | title = Percentage of faecal excretion of meloxicam in the Cape vultures (''Gyps corprotheres'') | journal = Comparative Biochemistry and Physiology. Toxicology & Pharmacology | volume = 215 | pages = 41–46 | date = January 2019 | pmid = 30336288 | doi = 10.1016/j.cbpc.2018.10.001 | url = https://www.sciencedirect.com/science/article/abs/pii/S1532045618301935 | hdl = 2263/67172 | hdl-access = free | url-access = subscription }}</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">{{cite journal | vauthors = Oaks JL, Gilbert M, Virani MZ, Watson RT, Meteyer CU, Rideout BA, Shivaprasad HL, Ahmed S, Chaudhry MJ, Arshad M, Mahmood S, Ali A, Khan AA | title = Diclofenac residues as the cause of vulture population decline in Pakistan | journal = Nature | volume = 427 | issue = 6975 | pages = 630–633 | date = February 2004 | pmid = 14745453 | doi = 10.1038/nature02317 | s2cid = 16146840 | bibcode = 2004Natur.427..630O }}</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">{{cite news |title='Decline in vulture population has given rise to diseases': Dr. Vibhu Prakash|url=https://indianexpress.com/article/lifestyle/health/decline-in-vulture-population-has-given-rise-to-diseases-dr-vibhu-prakash-3001298/|date=29 August 2016|access-date=12 December 2018|work=The Indian Express|vauthors=Choudhary S|archive-date=15 December 2018|archive-url=https://web.archive.org/web/20181215222409/https://indianexpress.com/article/lifestyle/health/decline-in-vulture-population-has-given-rise-to-diseases-dr-vibhu-prakash-3001298/|url-status=live}}</ref>

The mechanism of toxicity in vultures is presumed to be kidney failure;<ref>{{cite journal | vauthors = Swan GE, Cuthbert R, Quevedo M, Green RE, Pain DJ, Bartels P, Cunningham AA, Duncan N, Meharg AA, Oaks JL, Parry-Jones J, Shultz S, Taggart MA, Verdoorn G, Wolter K | title = Toxicity of diclofenac to Gyps vultures | journal = Biology Letters | volume = 2 | issue = 2 | pages = 279–282|year=2006 | pmid = 17148382 | pmc = 1618889 | doi = 10.1098/rsbl.2005.0425 }}</ref> however, toxicity may be due to direct inhibition of uric acid secretion in vultures.<ref name="pmid18727958">{{cite journal|vauthors=Naidoo V, Swan GE|title = Diclofenac toxicity in ''Gyps'' vulture is associated with decreased uric acid excretion and not renal portal vasoconstriction | journal = Comparative Biochemistry and Physiology. Toxicology & Pharmacology|volume=149|issue=3|pages=269–274|year=2009|pmid=18727958|doi=10.1016/j.cbpc.2008.07.014|hdl-access=free|hdl=2263/13907}}</ref> Vultures eat the carcasses of livestock that have been administered veterinary diclofenac, and are poisoned by the accumulated chemical,<ref name="BBC3">{{cite news|title=Vet drug 'killing Asian vultures'|work=BBC News|date=28 February 2004|url= https://news.bbc.co.uk/2/hi/science/nature/3437583.stm |access-date=25 August 2010|archive-date=3 December 2013|archive-url=https://web.archive.org/web/20131203033409/http://news.bbc.co.uk/2/hi/science/nature/3437583.stm |url-status=live}}</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">{{cite press release | publisher=Press Information Bureau, Government of India | date=16 May 2005 | url=http://pib.nic.in/release/release.asp?relid=9303 | title=Saving the Vultures from Extinction | access-date=12 May 2006 | archive-date=20 December 2005 | archive-url=https://web.archive.org/web/20051220213802/http://pib.nic.in/release/release.asp?relid=9303 | url-status=live }}</ref>

Steppe eagles have the same vulnerability to diclofenac as Old World vultures and are therefore at similar risk from its effects.<ref>{{cite news|title=Eagles fall prey to vulture-killing chemical|vauthors=Phadnis M |work=Pune Mirror|date=28 May 2014|url=http://www.punemirror.in/pune/others/Eagles-fall-prey-to-vulture-killing-chemical/articleshow/35639257.cms|access-date=28 May 2014|archive-date=29 May 2014|archive-url=https://web.archive.org/web/20140529124248/http://www.punemirror.in/pune/others/Eagles-fall-prey-to-vulture-killing-chemical/articleshow/35639257.cms|url-status=live}}</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>{{cite journal | vauthors = Rattner BA, Whitehead MA, Gasper G, Meteyer CU, Link WA, Taggart MA, Meharg AA, Pattee OH, Pain DJ | title = Apparent tolerance of turkey vultures (Cathartes aura) to the non-steroidal anti-inflammatory drug diclofenac | journal = Environmental Toxicology and Chemistry | volume = 27 | issue = 11 | pages = 2341–2345|year=2008 | pmid = 18476752 | doi = 10.1897/08-123.1 | bibcode = 2008EnvTC..27.2341R | s2cid = 207267290 | url = http://digitalcommons.unl.edu/cgi/viewcontent.cgi?article=1977&context=usgsstaffpub | access-date = 15 July 2019 | archive-date = 28 August 2021 | archive-url = https://web.archive.org/web/20210828062139/https://digitalcommons.unl.edu/cgi/viewcontent.cgi?referer=&httpsredir=1&article=1977&context=usgsstaffpub | url-status = live | url-access = subscription }}</ref>

Despite the vulture crisis, diclofenac remains available in other countries including many in Europe.<ref name="European Parliament">{{cite web|title=E-010588/2015: answer given by Mr Andriukaitis on behalf of the Commission|url=http://www.europarl.europa.eu/sides/getAllAnswers.do?reference=E-2015-010588&language=EN|website=European Parliament|access-date=18 February 2024|archive-date=13 May 2016|archive-url=https://web.archive.org/web/20160513232457/http://www.europarl.europa.eu/sides/getAllAnswers.do?reference=E-2015-010588&language=EN|url-status=live}}</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>{{cite web |url=http://www.birdlife.org/europe-and-central-asia/news/vulture-killing-drug-now-available-eu-market |title=Vulture killing drug now available on EU market|work=International BirdLife|access-date=18 February 2024|archive-date=24 April 2014|archive-url=https://web.archive.org/web/20140424125532/http://www.birdlife.org/europe-and-central-asia/news/vulture-killing-drug-now-available-eu-market}}</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>{{cite web |url= https://www.4vultures.org/first-evidence-of-a-vulture-killed-by-veterinary-diclofenac-in-spain|title=First evidence of a vulture killed by veterinary diclofenac in Spain – will the Spanish government and the EU act after this smoking gun?| work = Vulture Conservation Foundation |date=7 April 2021|access-date=8 April 2021|archive-date=8 April 2021|archive-url= https://web.archive.org/web/20210408082619/https://www.4vultures.org/first-evidence-of-a-vulture-killed-by-veterinary-diclofenac-in-spain/}}</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>{{cite web |vauthors=Fernholm A |date=4 March 2010 |title=Val av smärtstillande påverkar miljön |url=https://www.lakemedelsvarlden.se/val-av-smartstillande-paverkar-miljon/ |access-date=15 March 2023 |website=LäkemedelsVärlden |language=sv-SE |archive-date=15 August 2022 |archive-url=https://web.archive.org/web/20220815220610/https://www.lakemedelsvarlden.se/val-av-smartstillande-paverkar-miljon/ |url-status=live }}</ref> Diclofenac has been shown also to harm freshwater fish species such as rainbow trout.<ref name="Schwaiger">{{cite journal|vauthors=Schwaiger J, Ferling H, Mallow U, Wintermayr H, Negele RD|title = Toxic effects of the non-steroidal anti-inflammatory drug diclofenac. Part I: histopathological alterations and bioaccumulation in rainbow trout|journal=Aquatic Toxicology |volume=68 |issue=2 |pages= 141–150 |year=2004 |pmid=15145224 |doi=10.1016/j.aquatox.2004.03.014|bibcode = 2004AqTox..68..141S }}</ref><ref name="Triebskorn">{{cite journal |vauthors=Triebskorn R, Casper H, Heyd A, Eikemper R, Köhler HR, Schwaiger J | title = 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'') |journal=Aquatic Toxicology |volume=68 |issue=2 |pages = 151–166 |year=2004 |pmid=15145225 |doi=10.1016/j.aquatox.2004.03.015| bibcode = 2004AqTox..68..151T}}</ref><ref>{{cite journal|vauthors=Schwaiger J, Triebskorn R|title=Subletale Wirkungen von Arzneimitteln bei aquatischen Organismen|trans-title=Sublethal effects of drugs in aquatic organisms |language=de |journal=Texte |volume=29 |issue=5 |year=2005 |pages=217–226 |url= https://www.umweltbundesamt.de/sites/default/files/medien/publikation/long/2976.pdf}}</ref><ref name="pmid17216161">{{cite journal | vauthors = Triebskorn R, Casper H, Scheil V, Schwaiger J | title = Ultrastructural effects of pharmaceuticals (carbamazepine, clofibric acid, metoprolol, diclofenac) in rainbow trout (''Oncorhynchus mykiss'') and common carp (''Cyprinus carpio'') | journal = Analytical and Bioanalytical Chemistry | volume = 387 | issue = 4 | pages = 1405–1416|year=2007 | pmid = 17216161 | doi = 10.1007/s00216-006-1033-x | s2cid = 21170569 }}</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>{{cite news |date=10 September 2014 |title=Itämeren kalat häiriintyvät lääkeaineista – Teollisuudella paineita kehittää eettisempiä pillereitä |url=https://yle.fi/a/3-7455669 |access-date=15 March 2023 |work=Yle Uutiset |language=fi |archive-date=15 March 2023 |archive-url=https://web.archive.org/web/20230315175230/https://yle.fi/a/3-7455669 |url-status=live |trans-title=Fish in the Baltic Sea are disturbed by pharmaceuticals – Industry under pressure to develop more ethical medicines}}</ref>

==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. In many countries, agricultural use is now forbidden.<ref name=vulture1>{{cite journal | vauthors = Cuthbert RJ, Taggart MA, Prakash V, Chakraborty SS, Deori P, Galligan T, Kulkarni M, Ranade S, Saini M, Sharma AK, Shringarpure R, Green RE | title = Avian scavengers and the threat from veterinary pharmaceuticals | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 369 | issue = 1656 | article-number = 20130574 | date = November 2014 | pmid = 25405963 | pmc = 4213586 | doi = 10.1098/rstb.2013.0574 }}</ref><ref name="Moreno-Opo_2021" /><ref name=vulture2>{{citation|author1=((European Medicines Agency))|author2=((Committee for Medicinal Products for Veterinary Use))|title=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|url=https://www.ema.europa.eu/en/documents/other/opinion-committee-medicinal-products-veterinary-use-pursuant-article-303-regulation-ec-no-726/2004-risk-vultures-other-necrophagous-bird-populations-european-union-conne_en.pdf|id=EMA/CVMP/761582/2014|access-date=16 April 2022|archive-date=7 July 2022|archive-url=https://web.archive.org/web/20220707033019/https://www.ema.europa.eu/en/documents/other/opinion-committee-medicinal-products-veterinary-use-pursuant-article-303-regulation-ec-no-726/2004-risk-vultures-other-necrophagous-bird-populations-european-union-conne_en.pdf|url-status=live}}</ref><ref name=vulture3>{{cite news|vauthors=McKie R|title=Rare European vultures being poisoned by livestock drug|url=https://www.theguardian.com/environment/2021/apr/11/rare-european-vultures-being-poisoned-by-livestock-drug|access-date=16 April 2022 |work=The Guardian|date=11 April 2021|quote=...diclofenac has already been banned in India, Pakistan, Nepal and Bangladesh|archive-date=16 April 2022|archive-url=https://web.archive.org/web/20220416025605/https://www.theguardian.com/environment/2021/apr/11/rare-european-vultures-being-poisoned-by-livestock-drug|url-status=live}}</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>{{cite journal|vauthors=Hussain I, Khan MZ, Khan A, Javed I, Saleemi MK|title=Toxicological effects of diclofenac in four avian species|journal=Avian Pathology|volume=37|issue=3|pages=315–321|year=2008|pmid=18568659|doi=10.1080/03079450802056439|s2cid=12985124|doi-access=free}}</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>{{cite journal|vauthors=Becker R|title=Cattle drug threatens thousands of vultures|journal=Nature|year=2016|doi=10.1038/nature.2016.19839|s2cid=75173071 }}</ref>

== Notes == {{notelist}}

==References== {{Reflist}}

==External links== {{Commons category}}

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