View source for Chemistry:Diclofenac

{{Short description|Nonsteroidal anti-inflammatory drug}}
{{Infobox drug
| Verifiedfields     = changed
| Watchedfields      = changed
| verifiedrevid      = 443636249
| image              = Diclofenac.svg
| width              = 250
| alt                = 
| image2             = Diclofenac-from-xtal-3D-bs-17.png
| width2             = 250
| alt2               = 

<!--Clinical data-->
| tradename          = Cataflam, Voltaren, Zipsor, 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=15 February 2020 | archive-date=29 July 2020 | archive-url=https://web.archive.org/web/20200729232727/https://www.drugs.com/pregnancy/diclofenac.html | url-status=live }}</ref>
| routes_of_administration = [[Medicine:Oral administration|By mouth]], [[Medicine:Rectal administration|rectal]], intramuscular, intravenous, [[Medicine:Topical medication|topical]]
| ATC_prefix         = D11
| ATC_suffix         = AX18
| ATC_supplemental   = {{ATC|M01|AB05}}, {{ATC|M02|AA15}}, {{ATC|S01|BC03}}

| legal_AU           = S4
| legal_AU_comment   = /&nbsp;S3&nbsp;/&nbsp;S2
| legal_UK           = POM
| legal_UK_comment   = /&nbsp;P&nbsp;/&nbsp;GSL
| legal_US           = Rx-only
| legal_US_comment   = /&nbsp;OTC<ref name="FDA switch">{{cite web | title=FDA Approves Three Drugs for Nonprescription Use Through Rx-to-OTC Switch Process | website=U.S. [[Organization:Food and Drug Administration|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 | url-status=live | access-date=14 February 2020}} {{PD-notice}}</ref>
| legal_status       = Rx-only

<!--Pharmacokinetic data-->
| protein_bound      = More than 99%
| metabolism         = Liver, oxidative, primarily by [[Biology:CYP2C9|CYP2C9]], also by [[Biology:CYP2C8|CYP2C8]], [[Biology:CYP3A4|CYP3A4]], as well as conjugative by [[Chemistry:Glucuronidation|glucuronidation]] ([[Biology:UGT2B7|UGT2B7]]) and [[Biology:Sulfation|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 = Sayyad M |date=23 August 2018|access-date=24 August 2018|archive-url=https://web.archive.org/web/20180824135214/https://www.medicinereviews.ooo/2018/08/diclofenac-oral-uses-dosage-side.html|archive-date=24 August 2018|url-status=dead}}</ref> no active metabolites exist
| onset              = Within 4 hours (gel),<ref>{{cite web |title=How Long Does It Take for Voltaren Gel to Work? |url=https://www.youdrugstore.com/health/voltaren-gel-usage.html |website=YouDrugstore |access-date=1 June 2020 |language=en-CA |archive-date=30 July 2020 |archive-url=https://web.archive.org/web/20200730041151/https://www.youdrugstore.com/health/voltaren-gel-usage.html |url-status=live }}</ref> 30 min (non-gel)<ref name="AHFS2018" />
| elimination_half-life = 1.2–2 [[Hour|h]] (35% of the drug enters enterohepatic recirculation)
| excretion          = 35% [[Biology:Bile|bile]], 65% [[Biology:Urine|urine]]<ref>{{cite book |vauthors=Williams BS, Buvanendran A |chapter=Chapter 17 - 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=Third |pages=130–139 |veditors=Benzon HT, Raja SN, Liu SS, Fishman SM |publisher=W.B. Saunders |language=en |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>

<!--Identifiers-->
| CAS_number_Ref     = {{cascite|correct|??}}
| CAS_number         = 15307-86-5
| PubChem            = 3033
| IUPHAR_ligand      = 2714
| DrugBank_Ref       = {{drugbankcite|changed|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
| PDB_ligand         = DIF

<!--Chemical data-->
| IUPAC_name         = [2-(2,6-Dichloroanilino)phenyl]acetic acid <!-- the locant '2' for acetic acid is not cited, see P-14.3.4.3 Nomenclature of Organic Chemistry – IUPAC Recommendations and Preferred Names 2013 (Blue Book) -->
| 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)
| StdInChIKey_Ref    = {{stdinchicite|correct|chemspider}}
| StdInChIKey        = DCOPUUMXTXDBNB-UHFFFAOYSA-N
}} 

<!-- Definition and medical uses -->

'''Diclofenac''' (pronounced {{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 |editor-last1=O'Toole |editor-first1= Marie T. |page=536 |edition=tenth |date=2017 |publisher=[[Company:Elsevier|Elsevier]] |isbn=978-0-323-22205-1}}</ref>), sold under the brand name '''Voltaren''', among others, is a [[Chemistry:Nonsteroidal anti-inflammatory drug|nonsteroidal anti-inflammatory drug]] (NSAID) used to treat pain and inflammatory diseases such as [[Medicine:Gout|gout]].<ref name=AHFS2018/> It is taken by mouth or rectally in a suppository, used by injection, or applied to the skin.<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 |date=11 December 2017 |volume=9 |issue=2 |pages=65–71 |doi=10.1177/102490790200900201 |s2cid=74032271}}</ref> Improvements in pain last for as much as eight hours.<ref name=AHFS2018>{{cite web |title=Diclofenac epolamine Monograph for Professionals |url=https://www.drugs.com/monograph/diclofenac-epolamine.html |website=Drugs.com |publisher=AHFS |access-date=22 December 2018 |archive-date=18 September 2020 |archive-url=https://web.archive.org/web/20200918212837/https://www.drugs.com/monograph/diclofenac-epolamine.html |url-status=live }}</ref> It is also available in combination with [[Chemistry:Misoprostol|misoprostol]] in an effort to decrease stomach problems.<ref name=BNF74/>

<!-- Side effects and mechanism -->
Common side effects include [[Medicine:Abdominal pain|abdominal pain]], [[Medicine:Gastrointestinal bleeding|gastrointestinal bleeding]], nausea, dizziness, headache, and swelling.<ref name=AHFS2018/> Serious side effects may include heart disease, [[Medicine:Stroke|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 [[Social:Breastfeeding|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 |date=2017 |publisher=Elsevier Health Sciences |isbn=978-0-323-56682-7 |page=398 |url=https://books.google.com/books?id=KOM2DwAAQBAJ&pg=PA398}}</ref>

<!-- History and culture -->
Diclofenac was patented in 1965 by J.R. Geigy AG;<ref>{{cite book | vauthors = Fischer J |title=Analogue-based drug discovery |date=2006 |publisher=Wiley-VCH |isbn=978-3-527-31257-3 |page=517}}</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>{{Verify source|date=November 2022|reason=I followed the source "Analogue-based drug discovery" to find the patent DE1793592, but there's no mention of diclofenac or something similar to 2-[(2,6-dichlorophenyl)amino]benzeneacetic acid in 1965. My (chemical) German isn't great, so I might have missed something.}} it came into medical use in the United States in 1988.<ref name=AHFS2018/> It is available as a generic medication.<ref name=AHFS2018/> In 2021, it was the 61st most commonly prescribed medication in the United States, with more than 11{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Diclofenac – Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Diclofenac | access-date = 14 January 2024 }}</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 |date=2017 |publisher=British Medical Association |isbn=978-0-85711-298-9 |pages=1033–1035 |edition=74}}</ref> It is also widely 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.<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 | pages = 20130574 | date = November 2014 | pmid = 25405963 | pmc = 4213586 | doi = 10.1098/rstb.2013.0574 }}</ref><ref name="ste 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 |language=en |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>

== Medical uses ==
Diclofenac is used to treat [[Medicine:Pain|pain]], inflammatory disorders, and [[Medicine:Dysmenorrhea|dysmenorrhea]].<ref name=AHFS>{{cite web|title=Diclofenac Epolamine|url=https://www.drugs.com/monograph/diclofenac-epolamine.html|work=The American Society of Health-System Pharmacists|access-date=3 April 2011|archive-date=18 September 2020|archive-url=https://web.archive.org/web/20200918212837/https://www.drugs.com/monograph/diclofenac-epolamine.html|url-status=live}}</ref>

=== Pain ===
Inflammatory disorders may include [[Medicine:Arthritis|arthritis]], [[Medicine:Rheumatoid arthritis|rheumatoid arthritis]], [[Medicine:Polymyositis|polymyositis]], [[Medicine:Dermatomyositis|dermatomyositis]], [[Medicine:Osteoarthritis|osteoarthritis]], dental pain, [[Medicine:Temporomandibular joint|temporomandibular joint]] (TMJ) pain, spondylarthritis, [[Medicine:Ankylosing spondylitis|ankylosing spondylitis]], [[Medicine:Gout|gout]] attacks,<ref name="BPC">{{cite web |title=Rufenal|publisher=Birzeit Pharmaceutical Company |url= http://www.bpc.ps/products/prod_desc/72.html |url-status=dead |archive-url= https://web.archive.org/web/20110526184251/http://www.bpc.ps/products/prod_desc/72.html |archive-date=26 May 2011}}</ref> and [[Medicine:Pain management|pain management]] in cases of kidney stones and [[Medicine:Gallstone|gallstone]]s. An additional indication is the treatment of acute migraines.<ref>{{cite web|url= http://www.cambiarx.com/|title= Patient Site – Cambia (diclofenac potassium) for oral solution|website= cambiarx.com|publisher= |date= |accessdate= |archive-date= 16 August 2011|archive-url= https://web.archive.org/web/20110816014707/http://www.cambiarx.com/|url-status= live}}</ref> Diclofenac is used commonly to treat mild to moderate postoperative or post-traumatic pain, in particular when inflammation is also present.<ref name= BPC/> It is also effective against  [[Medicine:Endometriosis|endometriosis]].

Diclofenac is also available in topical forms and has been found to be useful for [[Medicine:Osteoarthritis|osteoarthritis]] but not other types of long-term musculoskeletal pain.<ref>{{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 | date = October 2007 | pmid = 17644321 | doi = 10.1016/j.ijantimicag.2007.04.016 }}</ref>

It may also help with actinic keratosis and with acute pain caused by minor strains, sprains and contusions (bruises).<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=  |accessdate=  |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,<ref>{{cite web | title = Naclof, oogdruppels 1 mg/ml | url = http://db.cbg-meb.nl/IB-teksten/h12800.pdf | work = Laboratoires THEA | via = Medicines Information Bank | archive-url = https://web.archive.org/web/20160304033446/http://db.cbg-meb.nl/IB-teksten/h12800.pdf | archive-date=4 March 2016 | publisher = Netherlands Medicines Authority MEB | location = Netherlands }}</ref> eye drops are sold to treat acute and chronic nonbacterial inflammation of the anterior part of the eyes (such as postoperative states). The eye drops have also been used to manage pain for [[Medicine:Corneal abrasion|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 | pages = CD009781 | date = May 2017 | pmid = 28516471 | pmc = 6481688 | doi = 10.1002/14651858.CD009781.pub2 }}</ref>

Diclofenac is often used to treat chronic [[Medicine:Cancer pain|pain associated with cancer]], especially if inflammation is present.<ref>{{cite web | title=WHO's cancer pain ladder for adults | website=[[Organization:World Health Organization|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/ | url-status=dead | archive-date=7 August 2003 | access-date=26 April 2020}}</ref> Use of diclofenac gel should not exceed {{cvt|32|g|mg}} in a day.<ref>{{cite journal | vauthors = Haroutiunian S, Drennan DA, Lipman AG | title = Topical NSAID therapy for musculoskeletal pain | journal = Pain Medicine | volume = 11 | issue = 4 | pages = 535–549 | date = April 2010 | pmid = 20210866 | doi = 10.1111/j.1526-4637.2010.00809.x | doi-access = free }}</ref>

<gallery>
File:Voltaren tablets.jpg|Voltaren (diclofenac) 50&nbsp;mg [[Chemistry:Enteric coating|enteric coated]] tablets
File:Arthrotec50.JPG|Arthrotec (diclofenac and [[Chemistry:Misoprostol|misoprostol]]) 50&nbsp;mg tablets
File:Diclofenac sodium IV 75mg.jpg|Dyloject (diclofenac) 2 ml for [[Chemistry:Intravenous therapy|IV]] and [[Biology:Intramuscular injection|IM]] administration
File:Diclofenac sodium 100mg.jpg|Sintofarm (diclofenac) for [[Chemistry:Suppository|suppository]] administration
File:Diclofenac Topical Gel.jpg|150 gram tube diclofenac [[Medicine:Topical gels|topical gel]] U.S. package generic
</gallery>

== Contraindications ==
* Hypersensitivity to diclofenac
* History of allergic reactions (bronchospasm, [[Medicine:Shock (circulatory)|shock]], [[Medicine:Rhinitis|rhinitis]], urticaria) to other NSAIDs, such as [[Chemistry:Aspirin|aspirin]]
* [[Medicine:Pregnancy#Third trimester|Third-trimester pregnancy]]
* Active stomach and/or duodenal ulceration or [[Medicine:Gastrointestinal bleeding|gastrointestinal bleeding]]
* [[Medicine:Inflammatory bowel disease|Inflammatory bowel disease]] such as [[Medicine:Crohn's disease|Crohn's disease]] or [[Medicine:Ulcerative colitis|ulcerative colitis]]
* Severe congestive heart failure ([[Organization:New York Heart Association Functional Classification|NYHA]] III/IV)
* Pain management in the setting of coronary artery bypass graft (CABG) surgery
* Severe liver insufficiency (Child-Pugh Class C)
* Severe [[Medicine:Chronic kidney disease|chronic kidney disease]] (creatinine clearance <30 ml/min)
* Caution in patients with pre-existing hepatic porphyria, as diclofenac may trigger attacks
* Caution in patients with severe, active bleeding such as cerebral hemorrhage
* NSAIDs in general should be avoided during [[Medicine:Dengue fever|dengue fever]], as it induces (often severe) capillary leakage and subsequent heart failure.
* Caution in patients with fluid retention or heart failure
* Can lead to onset of new hypertension or worsening of pre-existing hypertension
* Can cause serious skin adverse events such as exfoliative dermatitis, [[Medicine:Stevens–Johnson syndrome|Stevens–Johnson syndrome]] (SJS), and [[Medicine:Toxic epidermal necrolysis|toxic epidermal necrolysis]] (TEN), which can be fatal<ref name = "Drugs.com_Diclofenac">{{cite web | url = https://www.drugs.com/pro/diclofenac-potassium.html | title = Diclofenac Potassium | website = Drugs.com | access-date = 15 November 2015 | archive-date = 4 October 2017 | archive-url = https://web.archive.org/web/20171004060307/https://www.drugs.com/pro/diclofenac-potassium.html | url-status = live }}</ref>

== Adverse effects ==

Diclofenac consumption has been associated with significantly increased vascular and coronary risk in a study including coxib, diclofenac, [[Chemistry:Ibuprofen|ibuprofen]] and [[Chemistry:Naproxen|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 (MACE) 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 was increased significantly by diclofenac.<ref name="BhalaEmbersonEtAl" />

In October 2020, the U.S. [[Organization:Food and Drug Administration|Food and Drug Administration]] (FDA) required the [[Medicine:Drug labelling|drug label]] to be updated for all nonsteroidal anti-inflammatory medications to describe the risk of kidney problems in unborn babies that result in low amniotic fluid.<ref name="FDA PR 20201015" /><ref name="FDA safety 20201015" /> They recommend avoiding NSAIDs in pregnant women at 20 weeks or later in pregnancy.<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. [[Organization:Food and Drug Administration|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 | url-status=live }} {{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 | 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 | url-status=live }} {{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 [[Biology:COX-2 inhibitor|COX-2 inhibitor]] [[Chemistry:Rofecoxib|rofecoxib]] in 2004, attention has focused on all the other members of the NSAIDs 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 [[Chemistry:Aspirin|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. In Britain the [[Organization:Medicines and Healthcare products Regulatory Agency|Medicines and Healthcare products Regulatory Agency]] (MHRA) said in June 2013 that the drug should not be used by people with serious underlying heart conditions{{snd}}people who had had heart failure, heart disease or a stroke were advised to stop using it completely.<ref>{{cite news |url=https://www.bbc.co.uk/news/health-23109314 |title=Heart risk warning over painkiller |date=29 June 2013 |work=BBC News |access-date=21 June 2018 |archive-date=20 September 2018 |archive-url=https://web.archive.org/web/20180920110812/https://www.bbc.co.uk/news/health-23109314 |url-status=live }}</ref> As of 15 January 2015, the MHRA announced that diclofenac will 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 subsequent large study of 74,838 Danish users of NSAIDs 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 NSAIDs 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|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 [[Biology:Celecoxib|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 ===
* Gastrointestinal complaints are most often noted. The development of ulceration and/or bleeding requires immediate termination of treatment with diclofenac. Most patients receive a gastro-protective drug as prophylaxis during long-term treatment ([[Chemistry:Misoprostol|misoprostol]], [[Chemistry:Ranitidine|ranitidine]] 150&nbsp;mg at bedtime or [[Chemistry:Omeprazole|omeprazole]] 20&nbsp;mg at bedtime).

=== Liver ===
* Liver damage occurs infrequently, and is usually reversible. [[Medicine:Hepatitis|Hepatitis]] may occur rarely without any warning symptoms and may be fatal. Patients with [[Medicine:Osteoarthritis|osteoarthritis]] more often develop symptomatic liver disease than patients with rheumatoid arthritis. Liver function should be monitored regularly during long-term treatment. If used for the short-term treatment of pain or fever, diclofenac has not been found more hepatotoxic than other NSAIDs.{{medical citation needed|date=April 2020}}
* {{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= [[Organization:Food and Drug Administration|Food and Drug Administration]] |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 |url-status= dead|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. [[Medicine:Postmarketing surveillance|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|date=April 2020}}
* Physicians should measure transaminases periodically in patients receiving long-term therapy with diclofenac. Based on clinical trial data and postmarketing experiences, transaminases should be monitored within 4 to 8 week after initiating treatment with diclofenac.{{medical citation needed|date=April 2020}}

=== Kidney ===
* NSAIDs "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 | pages = S15–20; discussion 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... Consequently, the same precautions regarding renal risk that are followed for nonselective NSAIDs should be used when selective COX-2 inhibitors are administered."<ref name="Brater2002" /> However, diclofenac appears to have a different mechanism of renal toxicity.{{Citation needed|date=October 2018}}
* Studies in Spain showed diclofenac caused acute kidney failure in vultures when they ate the carcasses of animals that had recently been treated with it. Drug-sensitive species and individual humans are initially assumed to lack genes expressing specific drug detoxification enzymes.<ref name = "Becker_2006">{{cite journal | vauthors = Becker R |title=Cattle drug threatens thousands of vultures |journal=Nature |date=29 April 2016 |doi=10.1038/nature.2016.19839 |s2cid=75173071 }}</ref>

=== 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>

== Mechanism of action ==
As with most NSAIDs, the primary [[Chemistry:Mechanism of action|mechanism]] responsible for its [[Chemistry:Anti-inflammatory|anti-inflammatory]], [[Chemistry:Antipyretic|antipyretic]] and [[Biology:Analgesic|analgesic]] action is thought to be inhibition of prostaglandin synthesis through [[Biology:Cyclooxygenase|COX]]-inhibition. Diclofenac inhibits [[Biology:PTGS1|COX-1]] and COX-2 with relative equipotency.<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 | doi-access = free | bibcode = 1993PNAS...9011693M }}</ref>

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.<ref>{{cite web |date=15 January 2024 |editor-last=Alfaro |editor-first=Robert |editor2-last=Davis |editor2-first=Donald |title=Diclofenac |url=https://www.ncbi.nlm.nih.gov/books/NBK557879/ |access-date=15 January 2024 |website=National Library of Medicine |publication-date=22 May 2023}}</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 NSAIDs that are able to enter the brain by crossing the [[Biology:Blood–brain barrier|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 NSAIDs in other aspects. Some evidence indicates it inhibits the [[Biology:Lipoxygenase|lipoxygenase]] pathways,{{Citation needed|date=March 2009}} thus reducing formation of [[Biology:Leukotriene|leukotriene]]s (also pro-inflammatory [[Chemistry:Autacoid|autacoid]]s). It also may inhibit [[Biology:Phospholipase A2|phospholipase A2]], which may be relevant to its mechanism of action. These additional actions may explain its high potency – it is the most potent NSAID on a broad basis.<ref name="pmid3085490">{{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 NSAIDs in their selective inhibition of the two subtypes of cyclooxygenase, [[Biology:PTGS1|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 NSAIDs. In practice, use of some [[Biology:COX-2 inhibitor|COX-2 inhibitor]]s with their [[Medicine:Adverse drug reaction|adverse effects]] has led to massive numbers of lawsuits alleging wrongful death by heart attack, yet other significantly COX-selective NSAIDs, such as diclofenac, have been well tolerated by most of the population.{{Citation needed|date=May 2010}}

Besides the [[Biology:Cyclooxygenase|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 [[Biology:Sodium channel|sodium channel]]s (after activation of the channel, diclofenac inhibits its reactivation, also known as phase inhibition){{Citation needed|date=March 2009}}
* Blockage of acid-sensing [[Biology:Ion channel|ion channel]]s (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-[[Biology:Potassium channel|potassium channel]]s (diclofenac opens these channels, leading to hyperpolarization of the cell membrane){{Citation needed|date=March 2009}}

The duration of action (i.e., duration of pain relief) of a single dose is longer (6 to 8&nbsp;[[Hour|h]]) than the drug’s 1.2–2&nbsp;h half-life. This could be partly because it persists for over 11 hours in [[Biology:Synovial fluid|synovial fluid]]s.<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>

== Society and culture ==
=== History ===
In the United States, 1% diclofenac gel was approved by the FDA in 2007. It was approved as a prescription drug and was indicated for the relief of the pain of osteoarthritis of joints responsive to topical treatment; in particular, it was prescribed for the joints in the hands, knees and feet.<ref name="FDA switch" /> It has not been shown to work for strains, sprains, bruises or sports injuries.<ref name="FDA switch" /> It was intended for the temporary relief of joint pain due to the most common type of arthritis, osteoarthritis.<ref name="FDA switch" /> In February 2020, the gel became an over-the-counter drug, and the FDA granted the approval of the nonprescription product to [[Company:GlaxoSmithKline|GlaxoSmithKline plc]].<ref name="FDA switch" />

=== Formulations and brand names ===
{{anchor|trade names}}

The name "diclofenac" derives from its chemical name: 2-(2,6-'''dichlo'''ranilino) '''phen'''yl'''ac'''etic acid. Diclofenac was first synthesized by Alfred Sallmann and Rudolf Pfister and introduced as Voltaren by Ciba-Geigy (now [[Company:Novartis|Novartis]]) in 1973. [[Company:GlaxoSmithKline|GlaxoSmithKline]] purchased the rights in 2015.<ref name=Alt2015>{{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>

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>{{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 January 2015, diclofenac oral preparations were reclassified as prescription-only medicines in the UK. The topical preparations are available without 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>

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>

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

Use of diclofenac for animals is controversial due to toxicity when eaten by scavenging birds that eat dead animals;<ref name="vulture1"/><ref name="ste 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 | pages = 148851 | date = November 2021 | pmid = 34271379 | doi = 10.1016/j.scitotenv.2021.148851 | bibcode = 2021ScTEn.796n8851M }}</ref> the medication has been banned for veterinary use in several countries.<!--Is a medical cite really necessary? This is surely a legal claim, albeit in  a medical article. Possibly this EMA will suffice... {{medcn|date=February 2020}}--><ref name="vulture2"/><ref name="vulture3"/>

Use of diclofenac in animals has been reported to have led to a sharp decline in the [[Biology:Old World vulture|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. The mechanism is presumed to be renal 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 | date = June 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 | date = April 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=http://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> [[Chemistry:Meloxicam|Meloxicam]] is a safer alternative to replace use of diclofenac.<ref name="Swan2006">{{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 | pages = e66 | date = March 2006 | pmid = 16435886 | pmc = 1351921 | doi = 10.1371/journal.pbio.0040066 | doi-access = free }}</ref> It is more expensive than diclofenac, but the cost is dropping{{when|date=February 2020}} as more pharmaceutical companies are beginning to manufacture it.{{citation needed|date=February 2020}}

Steppe eagles have the same vulnerability to diclofenac as vultures and may also fall victim to it.<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> Diclofenac has been shown also to harm freshwater fish species such as rainbow trout.<ref>{{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 | date = June 2004 | pmid = 15145224 | doi = 10.1016/j.aquatox.2004.03.014 | bibcode = 2004AqTox..68..141S }}</ref><ref>{{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 | date = June 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 |date=2005 |pages=217–226 |url=https://www.umweltbundesamt.de/sites/default/files/medien/publikation/long/2976.pdf |access-date=23 April 2023 |archive-date=23 April 2023 |archive-url=https://web.archive.org/web/20230423164934/https://www.umweltbundesamt.de/sites/default/files/medien/publikation/long/2976.pdf |url-status=live }}</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 | date = February 2007 | pmid = 17216161 | doi = 10.1007/s00216-006-1033-x | s2cid = 21170569 }}</ref> In contrast, [[Biology:New World vulture|New World vulture]]s, such as the [[Biology:Turkey vulture|turkey vulture]], can tolerate at least 100 times the level of diclofenac that is lethal to ''[[Biology:Gyps|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 | date = November 2008 | pmid = 18476752 | doi = 10.1897/08-123.1 | 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 }}</ref>

"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 [[Biology:Dog|dog]]s (''Canis familiaris'') have increased sharply from the disappearance of ''[[Biology:Gyps|Gyps]]'' vultures as the main scavenger of wild and domestic [[Biology:Ungulate|ungulate]] carcasses. Associated with the rise in dog numbers is an increased risk of [[Medicine:Rabies|rabies]]"<ref name="Swan2006"/> and casualties of almost 50,000 people.<ref>{{cite news |vauthors=Walker M |title=Rabies tragedy follows loss of India's vultures |url=https://www.newscientist.com/article/mg19926684-400-rabies-tragedy-follows-loss-of-indias-vultures/ |work=New Scientist |date=6 August 2008 |access-date=23 April 2023 |archive-date=23 April 2023 |archive-url=https://web.archive.org/web/20230423164017/https://www.newscientist.com/article/mg19926684-400-rabies-tragedy-follows-loss-of-indias-vultures/ |url-status=live }}</ref> The Government of India cites this as one of the major consequences of a vulture species extinction.<ref name="PIB2005"/> 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 young survive. Even if the government ban is fully implemented, it will take several 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 loss of vultures has had a social impact on the Indian [[Religion:Zoroastrianism|Zoroastrian]] Parsi community, who traditionally use vultures to dispose of human corpses in [[Religion:Tower of Silence|Towers of Silence]], but are now compelled to seek alternative methods of disposal.<ref name="Swan2006"/>

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=2 May 2016 |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 medicine agency presented simulations suggesting that the number of deaths would be quite small.<ref name = "Becker_2006" /><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=24 April 2014 |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 |url-status=dead }}</ref> A paper published in 2021 identified the first authenticated death of a vulture from diclofenac in Spain, a Cinereous Vulture.<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/|url-status=dead}}</ref><ref name="ste 2021"/>

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.<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> 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.<ref>{{cite web |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 |website=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 }}</ref>

== Veterinary uses ==
Diclofenac is approved as a veterinary medication. It is used in the treatment of companion animals and livestock. In sheep, pigs, cattle and goats, it is used in the management of several bacterial diseases, including diarrhoea, enteritis, dysentery, foot rot and septicaemia.<ref>{{cite web | title=Diclofenac Sodium Injection: Product Information | url=https://www.advacarepharma.com/en/amp/veterinary/diclofenac-sodium-injection | author=<!--Not stated--> | date=2018 | publisher=AdvaCare Pharma USA | access-date=3 August 2022 | archive-date=25 April 2023 | archive-url=https://web.archive.org/web/20230425230341/https://www.advacarepharma.com/en/amp/veterinary/diclofenac-sodium-injection | url-status=live }}</ref> In some bird species, diclofenac causes accumulation of [[Chemistry:Uric acid|uric acid]] crystals in organs, especially kidneys, triggering acute renal necrosis and visceral gout.<ref>{{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 | date = June 2008 | pmid = 18568659 | doi = 10.1080/03079450802056439 | s2cid = 12985124 | doi-access = free }}</ref> Vultures, among other carrion-eating birds, are known to scavenge deceased livestock. In South Asia in the 2000s, vulture populations were decimated after feeding on carcasses of livestock that had been treated with diclofenac.<ref name = "Becker_2006" />

== References ==
{{Reflist}}

== External links ==

{{Other dermatological preparations}}
{{Anti-inflammatory and antirheumatic products}}
{{Topical products for joint and muscular pain}}
{{Analgesics}}

[[Category:Acetic acids]]
[[Category:Anilines]]
[[Category:Chloroarenes]]
[[Category:Dermatoxins]]
[[Category:Haleon]]
[[Category:Hepatotoxins]]
[[Category:Nephrotoxins]]
[[Category:Nonsteroidal anti-inflammatory drugs]]
[[Category:Wikipedia medicine articles ready to translate]]

{{Sourceattribution|Diclofenac}}