Diseases Retinal of Treatment the in (NSAIDs) Drugs Inflammatory-Anti chapNonsteroidal• 29

between the bromfenac and placebo groups demonstrated in these phase III clinical trials.

CONTRAINDICATIONS, COMPLICATIONS, AND TOXICITY

While NSAIDs used in ophthalmology possess a quite heterogeneous chemical constitution, these agents share similar therapeutic properties and adverse effects. Topical NSAIDs reduce the systemic absorption of the medication and thereby diminish the potential for systemic sideeffects such as renal dysfunction or gastric ulcer. Nevertheless, absorption of topical ophthalmic NSAIDs in the nasal mucosa promotes systemic exposure and the occurrence of adverse systemic events, for instance exacerbation of bronchial asthma. Local consequences of topical ophthalmic NSAIDs include conjunctival hyperemia, burning, stinging, and corneal anesthesia.19,20 A more serious complication with topical ophthalmic NSAIDs is indolent corneal ulceration and fullthickness corneal melts.

The analysis of NSAID-associated corneal events suggests that diclofenac sodium ophthalmic solution may be the primary most frequent agent. An elucidation of possible pharmacodynamic explanations of NSAID-induced corneal injury refers to the initiation of severe epithelial hypoxia. Moreover, the use of NSAIDs under conditions of corneal hypoxia may therefore cause worsening of the therapeutic response, but it may also induce a paradoxical inflammatory exacerbation.19,20 Other potential mechanisms include the relationship between NSAIDs and corneal matrix metalloproteinase and direct toxicity due to cytotoxic excipients such as surfactants, solubilizers, and preservatives found in topical NSAID ophthalmic preparations. The concurrent use of NSAIDs with topical corticosteroids in the face of significant preexisting corneal inflammation has been identified as a risk factor in precipitating corneal erosions and melts. Until clinical evidence dictates otherwise, care should be taken to prevent NSAID toxicity after ophthalmic NSAID use.

SUMMARY AND KEY POINTS

NSAIDs act primarily as COX inhibitors and thus reduce the formation of endogenous PGs. Several NSAIDs have been commercially available for many years: diclofenac, flurbiprofen, indomethacin, ketorolac, and suprofen. Despite their controversial history, topical NSAIDs offer various advantages after intraocular and refractive surgery. For intraocular surgery NSAIDs can promote the prevention of intraoperative miosis, reduction of ocular pain, decrease of postoperative inflammation, and prevention of CME. Indeed, topical NSAIDs have been proven to be efficacious as prophylactic treatment to reduce the incidence of angiographic aphakic and pseudophakic CME. In refractive surgery, some NSAIDs provide an analgesic effect and again diminish postoperative discomfort. However, a number of past generations of NSAIDs have been associated with problems that varied from corneal stinging to corneal melt, and their use has subsequently declined.

Newer-generation NSAIDs have arisen in recent years for the treatment of ocular pain and inflammation. Nepafenac ophthalmic suspension 0.1% is a new topical NSAID prodrug that has been approved by the FDA for the treatment of pain and inflammation after cataract surgery. Preliminary data suggest nepafenac may also provide unique efficacy in the posterior segment, since its corneal permeability characteristics are superior to those of other NSAIDs. The FDA recently approved Xibrom as a topical twice-daily NSAID solution for the treatment of ocular inflammation following cataract surgery. The company asserts that Xibrom is one of the most selective and potent COX-2

inhibitors known. The distinct clinical difference between the two newgeneration NSAIDs, nepafenac and bromfenac, in treating retinal diseases including ME has yet to be determined. Several retinal, choroidal, and vitreous diseases may be the target for future nepafenac studies, either as monotherapy or as concomitant treatments.

ACKNOWLEDGMENTS

We are grateful to Fundação de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) and to Pan-American Association of Ophthalmology (PAAO)/Pan-American Ophthalmological Foundation (PAOF) for their support.

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