Corneal melting linked to use of topical NSAIDs

ByTerry Kim, MD

Terry Kim, MD [photo]
Terry Kim, MD

A number of reported complications are associated with nonsteroidal anti-inflammatory drugs, although they are fairly uncommon.

A number of reported complications are associated with nonsteroidal anti-inflammatory drugs, although they are fairly uncommon. Complications include superficial punctate keratitis, stromal infiltrates, persistent epithelial defects and the more severe complication of corneal melting.

Corneal melting and NSAIDs

Numerous observations of corneal melting after routine anterior segment procedures and surgeries were first noted in a 1999 American Society of Cataract and Refractive Surgery survey.¹ The melting was linked to the generic formulation of diclofenac made by Falcon Pharmaceuticals, which was subsequently recalled from the market. It was hypothesized that the vitamin E solubilizer, tocophersolan, which has been shown to inhibit epithelial cell proliferation and induce apoptosis in cells, in the generic formulation induced corneal melting.²

Other reports of corneal melting have occurred with the brand diclofenac, Voltaren (diclofenac sodium, Novartis), as well as with Acular (ketorolac tromethamine 0.5%, Allergan),^1-4 raising the concern that other factors may contribute to corneal melting (Figure).

Matrix metalloproteinases and NSAID-related corneal melting

Matrix metalloproteinases (MMPs) are a family of proteases or collagenolytic enzymes that have multiple functions that include degradation of the extracellular matrix components, such as collagen, lamina and proteoglycans. MMPs are also involved in cell-cell and cell-matrix communication. In normal tissues, MMPs are rarely detected. MMP expression is typically seen in human tissues during rapid matrix turnover, such as tissues undergoing metastatic tumor invasion or wound healing. MMP expression has been found in corneal tissue during the wound-healing process as well.

In the eye, MMPs are involved in many physiologic and pathophysiologic conditions such as age-related macular degeneration, diabetic retinopathy, IOP regulation and glaucoma. Specifically in the cornea, MMPs have been detected in bacterial, chemical and thermal corneal ulcerations. MMP expression has also been reported in corneas following PRK, and it is thought to play a role in the pathophysiology of keratoconus.

What role can these MMPs play in NSAID-related corneal melts? Corneal melting occurs when an imbalance exists between extracellular matrix deposition and degradation. MMP expression that occurs normally in wound healing may become unregulated with NSAID use, creating an imbalance and subsequently corneal melting.

Based on a number of studies,^5,6 a link between MMPs and corneal melts has been shown. As research continues, MMPs are being found to play a greater role in the eye. However, the exact role of each MMP is still unknown.

Figure

Reports of corneal melting have occurred with Voltaren (diclofenac sodium, Novartis) and Acular (ketorolac tromethamine 0.5%, Allergan) in addition to the generic diclofenac formulation (Falcon Pharmaceuticals).

(Figure courtesy of Terry Kim, MD.)

Clinical factors to consider in using NSAIDs

It has been shown that topical NSAIDs decrease normal corneal sensation,^7,8 hence their efficacy in decreasing postoperative pain following PRK or other surface ablation procedures. Topical NSAIDs can affect normal corneal epithelial healing,^9,10 but this is a topic of controversy; other studies have shown that topical NSAIDs may not have as adverse an effect on wound healing as topical corticosteroids.^11,12

As has been demonstrated, potential problems with NSAID use exist, but can be limited if used properly. Long-term use of NSAIDs and dosing more frequently than four times daily should be avoided, and patients should be carefully evaluated for risk factors linked to corneal melting. Patients who have the following characteristics should be observed carefully during NSAID use: severe dry eye; recurrent epithelial keratopathy or persistent epithelial defect; active bacterial keratitis or neurotrophic situations from previous herpes simplex or zoster keratitis; severe ocular surface disease, such as ocular cicatricial pemphigoid or chemical burn; potential long-term use of concurrent topical steroids; and systemic disorders such as diabetes and rheumatoid arthritis. Compliance with regard to medication dosing and follow-up is important to ensure that normal wound healing occurs and corneal melting is avoided. In the setting of a corneal melt, infection should always be ruled out.

Conclusion

Complications associated with NSAID use are uncommon and typically benign.

While corneal melting represents a rare but severe complication potentially related to NSAIDs, the mechanism is unclear and probably involves multiple factors. MMPs serve as a starting point in defining these mechanisms, but more study is needed to elucidate their role in corneal melting. In the meantime, by adhering to established guidelines, eye care practitioners can use NSAIDs safely and benefit greatly from their use in CME prevention and treatment, postoperative inflammation management, postoperative pain reduction and other ocular conditions.

References

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;118:1129-1132.

Hargrave SL, Jung JC, Fini ME, Gelender H, Cather C, Guidera A, Udell I, Fisher S, Jester JV, Bowman RW, McCulley JP, Cavanagh HD. Possible role of vitamin E solubilizer in topical diclofenac on matrix metalloproteinase expression in corneal melting: an analysis of postoperative keratolysis. Ophthalmology. 2002;109(2):343-350.

Guidera AC, Luchs JI, Udell IJ. Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs. Ophthalmology. 2001;108(5):936-944.

Flach AJ. Corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs. Trans Am Ophthalmol Soc. 2001;99:205-10; discussion 210-212.

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.

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.

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.

Sun R, Gimbel HV. Effects of topical ketorolac and diclofenac on normal corneal sensation. J Refract Surg. 1997;13(2):158-161.

Hersh PS, Rice BA, Baer JC, Wells PA, Lynch SE, McGuigan LJ, Foster CS. Topical nonsteroidal agents and corneal wound healing. Arch Ophthalmol. 1990;108(4):577-583.

Assouline M, Renard G, Arne JL, David T, Lasmolles C, Malecaze F, Pouliquen YJ. 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.

Srinivasan BD, Kulkarni PS. The effect of steroidal and nonsteroidal anti-inflammatory agents on corneal re-epithelialization. Invest Ophthalmol Vis Sci. 1981;80:758-822.

Srinivasan BD. Corneal re-epithelialization and anti-inflammatory agents. Trans Am Ophthalmol Soc. 1982;80:758-822.

Discussion

Adverse events with NSAIDs

Donnenfeld: There are no data in the United States on any long-term toxicity issues with Xibrom (bromfenac sodium, Ista), although it has been available in Japan for many years and has been shown to be a well-tolerated drug in that country’s literature.⁵ There appear to be minimal short-term side effects associated with bromfenac based on the FDA clinical trials.⁶ What adverse events have been associated with other NSAIDS?

Kim: The most well-known adverse event associated with topical NSAIDs, corneal melting, occurred with the generic form of diclofenac.⁷ Subsequently, the same issue has been recently seen in case reports with Acular (ketorolac tromethamine 0.5%, Allergan) and Voltaren (diclofenac sodium, Novartis).^8-10 These uncommon cases were not reported until after a few years of NSAID use. While the incidence of corneal melts is more widespread with generic formulations, these studies show that the branded NSAIDs are not immune to the complication. However, it is important to note that this complication is rare and may be associated with other variables.

Donnenfeld: In the studies performed that look at toxicity with NSAIDs, the affected patients almost always had some type of ocular surface disease. Do you believe that NSAIDs should be used routinely after cataract surgery in patients who have ocular surface disease, or should they be reserved for special cases?

Kim: I agree that the exact mechanism of NSAID-related corneal toxicity is unclear and that factors such as ocular surface disease can contribute to the problem. However, NSAIDs can be used safely and effectively in these patients after cataract surgery as long as practical guidelines are followed. The degree or severity of ocular surface pathology should be assessed, and if the decision is made to institute therapy, these patients should be followed closely. Patients with predisposing conditions such as severe keratoconjunctivitis sicca, persistent epithelial defects, neurotrophic keratopathy, ocular cicatricial pemphigoid and certain systemic disorders like rheumatoid arthritis are at higher risk for corneal complications and should be identified prior to NSAID therapy.

Otherwise, I strongly advocate the use of NSAIDs routinely after cataract surgery to protect against CME. I typically start NSAID therapy the day before surgery, continuing for 1 month. For those who are at a higher risk for developing CME after cataract surgery, such as patients with diabetic retinopathy, central retinal vein occlusion or branch retinal vein occlusion, uveitis or a previous history of CME, I start NSAID therapy 1 week prior to surgery and continue dosing for 2 months to 3 months. However, the use of NSAIDs after cataract surgery should not be reserved only for these patients at a higher risk for developing CME.

Katsev: When the reports of corneal melting with generic diclofenac first became public, I was routinely using NSAIDs for my cataract surgeries. As soon as I discontinued using NSAIDs, my CME rate rose dramatically. A high volume cataract practice can expect an additional five to six cases of CME when the clinician is not using NSAIDs. Not only does this flood a practice with dissatisfied patients, but it also places additional time demands on the clinical staff. As soon as it was clear that the corneal melts were due mostly to generic diclofenac only, I went back using ketorolac routinely and my rate of CME subsided. I have never had a case of corneal melting in my practice, before or since the initial reports.

Donnenfeld: In our practice, we typically see 100,000 patients per year and we have had no cases of corneal melting from NSAIDs. This zero incidence underscores the importance of using nonsteroidals in a careful and controlled manner for patients who have ocular surface disease.

Perry: Evidence suggests that the preoperative use of NSAIDs for patients with ocular surface disease, such as keratoconjunctivitis sicca, rheumatoid arthritis and Sjögren’s disease, will lessen the inflammation that these patients experience.^11,12

Chang: I generally will not use an NSAID postoperatively in eyes at higher risk for corneal melting. This includes eyes with concurrent pterygium removal, large epithelial defects or neurotrophic corneas. In addition, I try to avoid NSAIDs if there is severe dry eye or keratoconjunctivitus sicca.

However, there are occasions when I see unexpected corneal epithelial toxicity associated with postoperative use of topical NSAIDs. It will be interesting to see if twice-daily dosing reduces this type of problem.