Pr Eric E. GabisonCornea and ocular surface · Paris
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Home › NSAIDs & corneal healing › Clinical practice and references
Course contents ▾
  1. The two-hit model
  2. The 1998-1999 US outbreak
  3. The landmark series
  4. The signal by molecule
  5. Surgical contexts
  6. Incidence: the methodological void
  7. The 1999-2002 reasoning
  8. Compared formulations
  9. The facts that refute the hypothesis
  10. The topographic argument
  11. TPGS: a vehicle, not a toxin
  12. COX-1 and COX-2 in the cornea
  13. PGE2 is not the driver
  14. 12-HHT and the BLT2 receptor
  15. Lipid signals of repair
  16. Aspirin, non-acetylating NSAIDs and coxibs
  17. MMP, TIMP and the epithelial-stromal interface
  18. EMMPRIN/CD147, the control point
  19. Induced corneal hypoaesthesia
  20. Ranked mechanisms
  21. At-risk patients
  22. Before prescribing
  23. During treatment
  24. Facing suspected keratolysis
  25. References
Chapter 5 of 5

Clinical practice and references

This final chapter translates the preceding chapters into practical conduct. The guiding principle is simple: the state of the epithelium is the only truly discriminating risk factor, and pain is not a reliable warning signal since the causative agent is itself analgesic.

Before prescribing

  • Examine the epithelium at the slit lamp, with fluorescein, before initiation. This is the only truly discriminating risk factor.
  • Actively look for: dry eye and Sjögren's syndrome (including undiagnosed — a Schirmer test and BUT cost little), rheumatoid arthritis and connective tissue disease, diabetes and its control, past herpes or shingles, neurotrophic keratopathy, GVHD, keratoconus and pachymetry, rosacea, contact lens wear, repeated or closely spaced ocular surgery.
  • List co-prescriptions: topical corticosteroid, aminoglycoside, antiseptic, anaesthetic, BAK-preserved drops, bandage contact lens.
Do not prescribe at all in ocular GVHD

This is the only situation in which the literature supports proscription rather than a warning: 23.6% ulceration or perforation in a cohort of 140 patients, with explicit over-representation following NSAIDs, for a benefit never demonstrated[Bourdin 2025]. The risk persists late — median latency of 39 months after transplantation.

Avoid — neurotrophic keratopathy, established melt, severe dry eye (a relative or even absolute contraindication according to Rigas[Rigas 2020]), associated pterygium, large epithelial defect, corneal graft.

During treatment

  • Do not exceed 4 instillations per day or the strictly necessary duration. Cumulative dose is a documented risk factor.
  • No open-ended or repeatable prescription without review. Two of the most severe published cases resulted from treatment prescribed for one week and continued for six, or continued for seven months without documented indication.
  • After uncomplicated cataract surgery: 4 to 6 weeks. Extension to 12 weeks in patients at high risk of CMO must be assumed as an explicit trade-off, since it concerns precisely the population at risk of melt and no quality trial supports it.
  • Prefer preservative-free formulations, without this precaution dispensing with surveillance: Guidera's patient 14 perforated bilaterally in 4 days under preservative-free ketorolac.
  • See the patient again, and give written instructions to consult in case of redness, reduced vision or new discomfort. Do not rely on pain as a warning signal.
The diagnostic trap

NSAID-related melt is pauci-symptomatic and pauci-inflammatory, because the causative agent is analgesic and hypoaesthetising. Asai describes melts of 60 to 80% depth with "discrete" hyperaemia and infiltration. The mean diagnostic delay in the literature (≈ 44 days, range 3 to 450 days) reflects this latency. Slit-lamp examination is the only screening tool.

Facing suspected keratolysis

  1. Immediate withdrawal of the NSAID — and of all non-essential topical agents, preservatives included.
  2. Rule out infection: scrapings, cultures, stains. All published series have negative cultures, but that is precisely why the step is mandatory.
  3. Systemic disease workup: rheumatoid factor, antinuclear antibodies, anti-Ro/anti-La, ANCA — Sjögren's or rheumatoid arthritis was diagnosed after perforation in several reports, and it changes subsequent management.
  4. Restrain proteolysis: systemic tetracyclines (non-specific MMP inhibition), preservative-free lubrication, autologous serum, bandage contact lens or conjunctival flap depending on context.
  5. Anticipate a tectonic procedure — cyanoacrylate glue, amniotic membrane graft, lamellar or penetrating keratoplasty. One published case progressed from ulcer to full perforation within twelve hours.
Regulatory framework

No learned society and no SmPC establishes any ocular condition as an absolute contraindication. The regulatory framework rests entirely on warnings and surveillance — that is, responsibility rests with the prescriber. The only formal contraindications in the French SmPC for diclofenac eye drops are hypersensitivity and a history of allergy, urticaria, acute rhinitis or asthma triggered by diclofenac.

References

Clinical series and case reports

  1. Guidera AC, Luchs JI, Udell IJ. Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs. Ophthalmology 2001;108(5):936-944. PMID 11320025.
  2. Flach AJ. Corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs. Trans Am Ophthalmol Soc 2001;99:205-212. PMID 11797308.
  3. 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. PMID 11311634.
  4. 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. PMID 10922213. (5 cases: 2 on Voltaren, 3 on generic.)
  5. Hargrave SL, Jung JC, Fini ME, et al. Possible role of the vitamin E solubilizer in topical diclofenac on matrix metalloproteinase expression in corneal melting. Ophthalmology 2002;109(2):343-350. PMID 11825822.
  6. Gabison EE, Chastang P, Menashi S, Mourah S, Doan S, Oster M, Mauviel A, Hoang-Xuan T. Late corneal perforation after photorefractive keratectomy associated with topical diclofenac: involvement of matrix metalloproteinases. Ophthalmology 2003;110(8):1626-1631. PMID 12917183.
  7. O'Brien TP, Li QJ, Sauerburger F, Reviglio VE, Rana T, Ashraf MF. The role of matrix metalloproteinases in ulcerative keratolysis associated with perioperative diclofenac use. Ophthalmology 2001;108(4):656-659. PMID 11297478.
  8. Rigas B, Huang W, Honkanen R. NSAID-induced corneal melt: clinical importance, pathogenesis, and risk mitigation. Surv Ophthalmol 2020;65(1):1-11. PMID 31306671.
  9. 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. PMID 16371788.
  10. Feiz V, Oberg TJ, Kurz CJ, Mamalis N, Moshirfar M. Nepafenac-associated bilateral corneal melt after photorefractive keratectomy. Cornea 2009;28(8):948-950. PMID 19654513.
  11. Mohamed-Noriega K, Butrón-Valdez K, Vazquez-Galvan J, et al. Corneal melting after collagen cross-linking for keratoconus in a thin cornea of a diabetic patient treated with topical nepafenac. Case Rep Ophthalmol 2016;7(1):119-124. PMID 27293413.
  12. Cabourne E, Lau N, Flanagan D, Nott J, Bloom J, Angunawela R. Severe corneal melting after cataract surgery in patients prescribed topical postoperative NSAIDs and dexamethasone/neomycin combination therapy. J Cataract Refract Surg 2020;46(1):138-142. PMID 32050243.
  13. Mortemousque B, Suchocki D, Velou S, Leger F, Colin J. Sodium diclofenac eye drops and corneal perforations: two case reports [in French]. J Fr Ophtalmol 2002;25(5), April 2002.
  14. Zanini M, Savini G, Barboni P. Corneal melting associated with topical diclofenac use after laser-assisted subepithelial keratectomy. J Cataract Refract Surg 2006;32(9):1570-1572. PMID 16931276.
  15. Johnson CC. Central corneal melting associated with reformulated generic diclofenac. Ophthalmol Eye Dis 2011;3. PMCID PMC3661476.
  16. 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.
  17. Moramarco A, di Geronimo N, Gardini L, Grendele A, Fontana L. Management of corneal melting after collagen cross-linking for keratoconus. BMC Ophthalmol 2024;24(1):131.
  18. Harada K, Mohamed YH, Uematsu M, et al. Three cases of acute sterile corneal melt after cataract surgery. Am J Ophthalmol Case Rep 2018;13:62-65. PMID 30582074.

Mechanisms and lipid biology

  1. Iwamoto S, Koga T, Ohba M, et al. Non-steroidal anti-inflammatory drug delays corneal wound healing by reducing production of 12-hydroxyheptadecatrienoic acid, a ligand for leukotriene B4 receptor 2. Sci Rep 2017;7:13267.
  2. Liclican EL, Nguyen V, Sullivan AB, Gronert K. Selective activation of the prostaglandin E2 circuit in chronic injury-induced pathologic angiogenesis. Invest Ophthalmol Vis Sci 2010;51(12):6311-6320.
  3. Schlötzer-Schrehardt U, Zenkel M, Nüsing RM. Expression and localization of FP and EP prostanoid receptor subtypes in human ocular tissues. Invest Ophthalmol Vis Sci 2002;43(5):1475-1487.
  4. Gronert K. Lipoxins in the eye and their role in wound healing. Prostaglandins Leukot Essent Fatty Acids 2005;73(3-4):221-229. PMID 15979295.
  5. Riley GP, Harrall RL, Watson PG, Cawston TE, Hazleman BL. Collagenase (MMP-1) and TIMP-1 in destructive corneal disease associated with rheumatoid arthritis. Eye (Lond) 1995;9(Pt 6):703-718.
  6. Gabison EE, Mourah S, Steinfels E, Yan L, Hoang-Xuan T, Watsky MA, De Wever B, Calvo F, Mauviel A, Menashi S. Differential expression of extracellular matrix metalloproteinase inducer (CD147) in normal and ulcerated corneas: role in epithelio-stromal interactions and matrix metalloproteinase induction. Am J Pathol 2005;166(1):209-219. PMID 15632013.
  7. Huet E, Vallée B, Szul D, Verrecchia F, Mourah S, Jester JV, Hoang-Xuan T, Menashi S, Gabison EE. EMMPRIN/CD147 promotes myofibroblast differentiation by inducing α-smooth muscle actin expression and collagen gel contraction. FASEB J 2008;22(4):1144-1154. PMID 17965264.
  8. Gabison EE, Huet E, Baudouin C, Menashi S. Direct epithelial-stromal interaction in corneal wound healing: role of EMMPRIN/CD147 in MMPs induction and beyond. Prog Retin Eye Res 2009;28(1):19-33. PMID 19056510.
  9. Huet E, Vallée B, Delbé J, Mourah S, Prulière-Escabasse V, Tremouilleres M, Kadomatsu K, Doan S, Baudouin C, Menashi S, Gabison EE. EMMPRIN modulates epithelial barrier function through a MMP-mediated occludin cleavage: implications in dry eye disease. Am J Pathol 2011;179(3):1278-1286.
  10. Reviglio VE, Rana TS, Li QJ, Ashraf FM, Daly MK, O'Brien TP. Effects of topical nonsteroidal antiinflammatory drugs on the expression of matrix metalloproteinases in the cornea. J Cataract Refract Surg 2003;29(5):989-997. PMID 12781288.
  11. Bron AJ, de Paiva CS, Chauhan SK, et al. TFOS DEWS II pathophysiology report. Ocul Surf 2017;15(3):438-510. PMID 28736335.

Corneal sensitivity, at-risk groups and regulatory sources

  1. 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 2000;14(Pt 2):206-210.
  2. 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 2005;19(5):535-539.
  3. Singer DD, Kennedy JM, Wittpenn JR. Topical NSAIDs effect on corneal sensitivity. Cornea 2015;34(5):541-543. PMID 25826326.
  4. Bourdin A, Gournay V, Doan S, Prata PH, Kaphan E, Michonneau D, Socié G, Peffault de Latour R, Gabison EE. Severe corneal manifestations of graft-versus-host disease: experience of a tertiary referral center. Ocul Surf 2025;36:19-24. PMID 39709126.
  5. Saad S, Abdelmassih Y, Saad R, Guindolet D, El Khoury S, Doan S, Cochereau I, Gabison EE. Neurotrophic keratitis: frequency, etiologies, clinical management and outcomes. Ocul Surf 2020;18(2):231-236. PMID 31759182.
  6. Medsafe New Zealand. Ocular nonsteroidal anti-inflammatory drugs (NSAIDs) and corneal melting. Prescriber Update 2023;44(2):32-33.
  7. Hoffman RS, Braga-Mele R, Donaldson K, et al. (ASCRS Cataract Clinical Committee). Cataract surgery and nonsteroidal antiinflammatory drugs. J Cataract Refract Surg 2016;42(9):1368-1379.
  8. Wingert AM, Liu SH, Lin JC, Sridhar J. Non-steroidal anti-inflammatory agents for treating cystoid macular edema following cataract surgery. Cochrane Database Syst Rev 2022;12:CD004239.
  9. Summaries of Product Characteristics (SmPC) — ANSM and EMA: Voltarenophta, Voltarenophtabak, Indocollyre, Acular, Nevanac, Yellox, Ocufen.

Several cited works come from the author's own group — Gabison 2003 (late perforation under diclofenac), Gabison 2005 and 2009 and Huet 2008 and 2011 (the EMMPRIN/CD147 axis), Saad 2020 (neurotrophic keratitis) and Bourdin 2025 (ocular GVHD) — and are shown in bold in the reference list. Course for educational and professional purposes. This narrative review substitutes neither for the Summary of Product Characteristics nor for the prescriber's clinical judgement.