Ocular and systemic adverse effects of topical non-steroidal anti-inflammatory drugs ‒ a narrative review with quantitative synthesis
DOI:
https://doi.org/10.15584/ejcem.2026.1.19Keywords:
adverse drug reactions, anti-inflammatory medications, ocular drug delivery, ocular pharmacokinetics, topical ophthalmic non-steroidal anti-inflammatory drugsAbstract
Introduction and aim. The impacts of topical ophthalmic non-steroidal anti-inflammatory drugs (NSAIDs) have been studied, with instances of an unprecedented quantitative assessment of adverse drug reaction prevalence among several NSAID classes. This study aimed to systematically observe and synthesize the relevant information on the pharmacodynamic mechanism of adverse drug reactions (ADR) corresponding to topical NSAID administration.
Material and methods. A preliminary search on PubMed Central, Google Scholar, and ScienceDirect databases yielded 83 articles.
Analysis of literature. Conditions such as corneal perforation, ulceration, infiltration, keratitis, melt, corneal issues involving epithelial defects, tissue loss, stromal thinning, and delayed wound healing accentuate a comprehensive range of consequences on corneal integrity and physiology. The topical NSAID group also conveys more diversified systemic adverse reactions involving dilated ventricle, tricuspid regurgitation, pulmonary insufficiency, closure of the ductus arteriosus, and prenatal ductal constriction, which constitute a concern for their impact on cardiac activity and developing embryos.
Conclusion. Burning sensation is reported to be the most commonly reported frequency after photophobia. Notably, preferential COX-2 inhibitors had a significantly greater prevalence of ADRs than both nonselective COX inhibitors (mean difference=1.05, p=0.023) and selective COX-2 inhibitors. Longitudinal studies with frequent follow-ups are essential to fully characterize the incidence, severity, and long-term effects of adverse consequences.
Downloads
References
Bettman JW. Seven hundred medicolegal cases in ophthalmology. Ophthalmology. 1990;97(10):1379-1384. doi:10.1016/s0161-6420(90)32406-5
Brick DC. Medication errors result in costly claims for ophthalmologists. Surv Ophthalmol. 1995;40(3):232-236. doi:10.1016/s0039-6257(95)80031-x
Fernandez E, Phillips E, Saeed HN. Ocular involvement in allergic drug reactions. Curr Opin Allergy Clin Immunol. 2023;23(5):397-408. doi:10.1097/ACI.0000000000000932
Dhingra D, Kaur S, Ram J. Illicit drugs: Effects on eye. Indian J Med Res. 2019;150(3):228-238. doi:10.4103/ijmr.IJMR_1210_17
Gaynes BI, Fiscella R. Topical nonsteroidal anti-inflammatory drugs for ophthalmic use: a safety review. Drug Saf. 2002;25(4):233-250. doi:10.2165/00002018-200225040-00002
World Health Organization (WHO). Safety of medicines: adverse drug reactions-key facts. https://www.who.int/docs/default-source/medicines/safety-of-medicines--adverse-drug-reactions-jun18.pdf?sfvrsn=4fcaf40_2. Accessed October 20, 2025.
Tandon VR, Mahajan V, Khajuria V, Gillani Z. Under-reporting of adverse drug reactions: a challenge for pharmacovigilance in India. Indian J Pharmacol. 2015;47(1):65-71. doi:10.4103/0253-7613.150344
Manu MS, Mehta K, Das M, et al. Ocular adverse events in drug sensitive TB patients on daily fixed dose combination anti-TB drugs: A record review study from Kerala, India. Indian J Tuberc. 2020;67(2):216-221. doi:10.1016/j.ijtb.2020.02.008
Qureshi O, Dua A. COX Inhibitors. In: StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK549795/. Published February 28, 2024. Accessed December 3, 2025.
Shanbhag SS, Sangwan VS, Singh A, et al. Clinical Aspects of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis With Severe Ocular Complications in India. Front Med (Lausanne). 2021;8:643955. doi:10.3389/fmed.2021.643955
Li J, Tripathi RC, Tripathi BJ. Drug-induced ocular disorders. Drug Saf. 2008;31(2):127-141. doi:10.2165/00002018-200831020-00003
Patel TK, Barvaliya MJ, Sharma D, Tripathi C. A systematic review of the drug-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Indian population. Indian J Dermatol Venereol Leprol. 2013;79(3):389-398. doi:10.4103/0378-6323.110749
Zimmerman D, Dang NH. Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN): Immunologic Reactions. Oncologic Critical Care. 2019;267-280. doi:10.1007/978-3-319-74588-6_195
Peponis V, Kyttaris VC, Chalkiadakis SE, Bonovas S, Sitaras NM. Ocular side effects of anti-rheumatic medications: what a rheumatologist should know. Lupus. 2010;19(6):675-682. doi:10.1177/0961203309360539
Rigas B, Huang W, Honkanen R. NSAID-induced corneal melt: Clinical importance, pathogenesis, and risk mitigation. Surv Ophthalmol. 2020;65(1):1-11. doi:10.1016/j.survophthal.2019.07.001
Haddaway NR, Page MJ, Pritchard CC, McGuinness LA. PRISMA2020: An R package and Shiny app for producing PRISMA 2020-compliant flow diagrams, with interactivity for optimised digital transparency and Open Synthesis. Campbell Syst Rev. 2022;18(2):e1230. doi:10.1002/cl2.1230
Kim SJ, Flach AJ, Jampol LM. Nonsteroidal anti-inflammatory drugs in ophthalmology. Surv Ophthalmol. 2010;55(2):108-133. doi:10.1016/j.survophthal.2009.07.005
Nichols J, Snyder RW. Topical nonsteroidal anti-inflammatory agents in ophthalmology. Curr Opin Ophthalmol. 1998;9(4):40-44. doi:10.1097/00055735-199808000-00007
Flach AJ. Corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs. Trans Am Ophthalmol Soc. 2001;99:205-212.
Lin JC, Rapuano CJ, Laibson PR, Eagle RC Jr, Cohen EJ. Corneal melting associated with use of topical nonsteroidal anti-inflammatory drugs after ocular surgery. Arch Ophthalmol. 2000;118(8):1129-1132.
Guidera AC, Luchs JI, Udell IJ. Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs. Ophthalmology. 2001;108(5):936-944. doi:10.1016/s0161-6420(00)00538-8
Isawi H, Dhaliwal DK. Corneal melting and perforation in Stevens Johnson syndrome following topical bromfenac use. J Cataract Refract Surg. 2007;33(9):1644-1646. doi:10.1016/j.jcrs.2007.04.041
Asai T, Nakagami T, Mochizuki M, Hata N, Tsuchiya T, Hotta Y. Three cases of corneal melting after instillation of a new nonsteroidal anti-inflammatory drug. Cornea. 2006;25(2):224-227. doi:10.1097/01.ico.0000177835.93130.d4
Jesus J, Almeida I, Soares R, Geraldes R, Chibante-Pedro J. Corneal perforation associated with the use of ketorolac tromethamine after cataract surgery. J EuCornea. 2020;6:1-3. doi:10.1016/j.xjec.2019.12.002
Murtagh P, Comer R, Fahy G. Corneal perforation in undiagnosed Sjögren's syndrome following topical NSAID and steroid drops post routine cataract extraction. BMJ Case Rep. 2018;2018:bcr2018225428. doi:10.1136/bcr-2018-225428
Congdon NG, Schein OD, von Kulajta P, Lubomski LH, Gilbert D, Katz J. Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs. J Cataract Refract Surg. 2001;27(4):622-631. doi:10.1016/s0886-3350(01)00801-x
Mikropoulos DG, Kymionis GD, Chatzea MS, et al. Acute Corneal Melting Induced by the Concomitant Use of a Non-steroidal Anti-inflammatory Agent with an Antiseptic Eye Drop. Ophthalmol Ther. 2024;13(2):645-649. doi:10.1007/s40123-023-00864-0
Sun R, Gimbel HV. Effects of topical ketorolac and diclofenac on normal corneal sensation. J Refract Surg. 1997;13(2):158-161. doi:10.3928/1081-597X-19970301-12
Donnenfeld ED, Donnenfeld A. Global experience with Xibrom (bromfenac ophthalmic solution) 0.09%: the first twice-daily ophthalmic nonsteroidal anti-inflammatory drug. Int Ophthalmol Clin. 2006;46(4):21-40. doi:10.1097/01.iio.0000212134.83513.11
Fossati G, Bartoli E, Montericcio A, et al. Neurotrophic Keratopathy after wide retinal endolaser and postoperative Ketorolac eye drops: A case series. Eur J Ophthalmol. 2024;34(3):NP18-NP21. doi:10.1177/11206721241228005
Aragona P, Stilo A, Ferreri F, Mobrici M. Effects of the topical treatment with NSAIDs on corneal sensitivity and ocular surface of Sjögren's syndrome patients. Eye (Lond). 2005;19(5):535-539. doi:10.1038/sj.eye.6701537
Aragona P, Tripodi G, Spinella R, Laganà E, Ferreri G. The effects of the topical administration of non-steroidal anti-inflammatory drugs on corneal epithelium and corneal sensitivity in normal subjects. Eye (Lond). 2000;14(Pt 2):206-210. doi:10.1038/eye.2000.55
Seitz B, Sorken K, LaBree LD, Garbus JJ, McDonnell PJ. Corneal sensitivity and burning sensation. Comparing topical ketorolac and diclofenac. Arch Ophthalmol. 1996;114(8):921-924. doi:10.1001/archopht.1996.01100140129002
Szerenyi K, Sorken K, Garbus JJ, Lee M, McDonnell PJ. Decrease in normal human corneal sensitivity with topical diclofenac sodium. Am J Ophthalmol. 1994;118(3):312-315. doi:10.1016/s0002-9394(14)72954-x
Acosta MC, Berenguer-Ruiz L, García-Gálvez A, et al. Changes in corneal sensitivity after topical NSAIDs. Invest Ophthalmol Vis Sci. 2005;46(1):282. doi:10.1167/iovs.04-0884
Shimazaki J, Saito H, Yang HY, Toda I, Fujishima H, Tsubota K. Persistent epithelial defect following penetrating keratoplasty: an adverse effect of diclofenac eyedrops. Cornea. 1995;14(6):623-627.
Hsu JK, Johnston WT, Read RW, et al. Histopathology of corneal melting associated with diclofenac use after refractive surgery. J Cataract Refract Surg. 2003;29(2):250-256. doi:10.1016/s0886-3350(02)01702-9
Tomas-Barberan S, Fagerholm P. Influence of topical treatment on epithelial wound healing and pain in the early postoperative period following photorefractive keratectomy. Acta Ophthalmol Scand. 1999;77(2):135-138. doi:10.1034/j.1600-0420.1999.770203.x
Assouline M, Renard G, Arne JL, et al. A prospective randomized trial of topical soluble 0.1% indomethacin versus 0.1% diclofenac versus placebo for the control of pain following excimer laser photorefractive keratectomy. Ophthalmic Surg Lasers. 1998;29(5):365-374.
Chen X, Gallar J, Belmonte C. Reduction by antiinflammatory drugs of the response of corneal sensory nerve fibers to chemical irritation. Invest Ophthalmol Vis Sci. 1997;38(10):1944-1953.
Rodríguez NA, Abarzuza R, Cristóbal JA, Sierra J, Mínguez E, Del Buey MA. Eyelid contact allergic eczema caused by topical ketorolac tromethamine 0.5%. Arch Soc Esp Oftalmol. 2006;81(4):213-216. doi:10.4321/s0365-66912006000400007
Rajpal RK, Ross B, Rajpal SD, Hoang K. Bromfenac ophthalmic solution for the treatment of postoperative ocular pain and inflammation: safety, efficacy, and patient adherence. Patient Prefer Adherence. 2014;8:925-931. doi:10.2147/PPA.S46667
Demarinis G, Tatti F, Taloni A, et al. Treatments for Ocular Diseases in Pregnancy and Breastfeeding: A Narrative Review. Pharmaceuticals (Basel). 2023;16(10):1433. doi:10.3390/ph16101433
Auer M, Brezinka C, Eller P, Luze K, Schweigmann U, Schwärzler P. Prenatal diagnosis of intrauterine premature closure of the ductus arteriosus following maternal diclofenac application. Ultrasound Obstet Gynecol. 2004;23(5):513-516. doi:10.1002/uog.1038
Sitenga GL, Ing EB, Van Dellen RG, Younge BR, Leavitt JA. Asthma caused by topical application of ketorolac. Ophthalmology. 1996;103(6):890-892. doi:10.1016/s0161-6420(96)30591-5
Sharir M. Exacerbation of asthma by topical diclofenac. Arch Ophthalmol. 1997;115(2):294-295. doi:10.1001/archopht.1997.01100150296037
Polachek J, Shvartzman P. Acute bronchial asthma associated with the administration of ophthalmic indomethacin. Isr J Med Sci. 1996;32(11):1107-1109.
Sheehan GJ, Kutzner MR, Chin WD. Acute asthma attack due to ophthalmic indomethacin. Ann Intern Med. 1989;111(4):337-338. doi:10.7326/0003-4819-111-4-337
Donnenfeld ED, Holland EJ, Stewart RH, et al. Bromfenac ophthalmic solution 0.09% for postoperative ocular pain and inflammation. Ophthalmology. 2007;114(9):1653-1662.e1.
Wright JM. The double-edged sword of COX-2 selective NSAIDs. CMAJ. 2002;167(10):1131-1137.
Agrahari V, Mandal A, Agrahari V, et al. A comprehensive insight on ocular pharmacokinetics. Drug Deliv Transl Res. 2016;6(6):735-754. doi:10.1007/s13346-016-0339-2
Ahmed S, Amin MM, Sayed S. Ocular Drug Delivery: a Comprehensive Review. AAPS PharmSciTech. 2023;24(2):66. doi:10.1208/s12249-023-02516-9
Jitendra SP, Banik A, Dixit S. Ocular drug delivery system: a new trend. PharmaSci Monit. 2011;2:1-25.
Worakul N, Robinson JR. Ocular pharmacokinetics/pharmacodynamics. Eur J Pharm Biopharm. 1997;44(1):71-83. doi:10.1016/S0939-6411(97)00064-7
Urtti A. Challenges and obstacles of ocular pharmacokinetics and drug delivery. Adv Drug Deliv Rev. 2006;58(11):1131-1135. doi:10.1016/j.addr.2006.07.027
Farkouh A, Frigo P, Czejka M. Systemic side effects of eye drops: a pharmacokinetic perspective. Clin Ophthalmol. 2016;10:2433-2441. doi:10.2147/OPTH.S118409
Marino M, Jamal Z, Zito PM. Pharmacodynamics. In: StatPearls. Treasure Island (FL): StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK507791/. Published January 29, 2023. Accessed December 3, 2025.
Park Y, Ellis D, Mueller B, Stankowska D, Yorio T. Principles of Ocular Pharmacology. Handb Exp Pharmacol. 2017;242:3-30. doi:10.1007/164_2016_25
Novack GD, Robin AL. Ocular Pharmacology. J Clin Pharmacol. 2024;64(9):1068-1082. doi:10.1002/jcph.2451
Gaudana R, Ananthula HK, Parenky A, Mitra AK. Ocular drug delivery. AAPS J. 2010;12(3):348-360. doi:10.1208/s12248-010-9183-3
Foster CS. The pathophysiology of ocular allergy: current thinking. Allergy. 1995;50(21):6-38. doi:10.1111/j.1398-9995.1995.tb04250.x
Solomon A, Pe'er J, Levi-Schaffer F. Advances in ocular allergy: basic mechanisms, clinical patterns and new therapies. Curr Opin Allergy Clin Immunol. 2001;1(5):477-482. doi:10.1097/01.all.0000011063.28808.cc
Baudouin C. Allergic reaction to topical eyedrops. Curr Opin Allergy Clin Immunol. 2005;5(5):459-463. doi:10.1097/01.all.0000183112.86181.9e
Russo A, Costagliola C, Delcassi L, et al. Topical nonsteroidal anti-inflammatory drugs for macular edema. Mediators Inflamm. 2013;2013:476525. doi:10.1155/2013/476525
Ahuja M, Dhake AS, Sharma SK, Majumdar DK. Topical ocular delivery of NSAIDs. AAPS J. 2008;10(2):229-241. doi:10.1208/s12248-008-9024-9.
Tripathy KD. Essentials of Medical Pharmacology. 8th ed. New Delhi: The Health Science Publisher; 2019.
Carreño E, Portero A, Galarreta DJ, Herreras JM. Update on twice-daily bromfenac sodium sesquihydrate to treat postoperative ocular inflammation following cataract extraction. Clin Ophthalmol. 2012;6:637-644. doi:10.2147/OPTH.S23381
Dwivedi AK, Gurjar V, Kumar S, Singh N. Molecular basis for nonspecificity of nonsteroidal anti-inflammatory drugs (NSAIDs). Drug Discov Today. 2015;20(7):863-873. doi:10.1016/j.drudis.2015.03.004
Heier J, Cheetham JK, Degryse R, et al. Ketorolac tromethamine 0.5% ophthalmic solution in the treatment of moderate to severe ocular inflammation after cataract surgery: a randomized, vehicle-controlled clinical trial. Am J Ophthalmol. 1999;127(3):253-259. doi:10.1016/s0002-9394(98)00413-9
Mahmoodi AN, Kim PY. Ketorolac. In: StatPearls. StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK545172/. Published 2022. Accessed Decembre 3, 2025.
Markham A, Faulds D. Ganciclovir. An update of its therapeutic use in cytomegalovirus infection. Drugs. 1994;48(3):455-484. doi:10.2165/00003495-199448030-00009
Gupta SK, Velpandian T, Mathur P, Sengupta S. Comparative analgesic activity of nimesulide and diclofenac by intramuscular route: correlation with pharmacokinetic profile of nimesulide. Pharmacology. 1998;56(3):137-143. doi:10.1159/000028191
Cohen B, Preuss CV. Collectible. In: StatPearls. StatPearls Publishing. https://www.ijbls.org/images/IJBLS_2_2023_Full_issue_with_bookmarks.pdf. Published 2024. Accessed Decembre 3, 2025.
Botting RM. Mechanism of action of acetaminophen: is there a cyclooxygenase 3?. Clin Infect Dis. 2000;31(5):S202-S210. doi:10.1086/317520
Gerrett D. Pharmacology. In: Clinical Skills in Treating the Foot. 2nd ed. Turner W, Merriman LM, ed. Churchill Livingstone: Elsevier; 2005:161-191.
de Ladoucette A. Management of perioperative pain after TKA. Orthop Traumatol Surg Res. 2023;109(1S):103443. doi:10.1016/j.otsr.2022.103443
Chawla J, Le Guern ME, Alquier C, Kalhorn TF, Levy RH. Effect of route of administration on the pharmacokinetic behavior of enantiomers of nefopam and desmethylnefopam. Ther Drug Monit. 2003;25(2):203-210. doi:10.1097/00007691-200304000-00010
Pillans PI, Woods DJ. Adverse reactions associated with nefopam. N Z Med J. 1995;108(1008):382-384.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2026 European Journal of Clinical and Experimental Medicine

This work is licensed under a Creative Commons Attribution 4.0 International License.
Our open access policy is in accordance with the Budapest Open Access Initiative (BOAI) definition: this means that articles have free availability on the public Internet, permitting any users to read, download, copy, distribute, print, search, or link to the full texts of these articles, crawl them for indexing, pass them as data to software, or use them for any other lawful purpose, without financial, legal, or technical barriers other than those inseparable from having access to the Internet itself.
All articles are published with free open access under the CC-BY Creative Commons attribution license (the current version is CC-BY, version 4.0). If you submit your paper for publication by the Eur J Clin Exp Med, you agree to have the CC-BY license applied to your work. Under this Open Access license, you, as the author, agree that anyone may download and read the paper for free. In addition, the article may be reused and quoted provided that the original published version is cited. This facilitates freedom in re-use and also ensures that Eur J Clin Exp Med content can be mined without barriers for the research needs.




