Topical nonsteroidal anti-inflammatory drugs for ophthalmic use: a safety review

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used agents that despite chemically heterogeneity, share similar therapeutic properties and adverse effects. Topical ophthalmic NSAIDs are limited to the relatively water soluble phenylacetic and phenylalkanoic acids as well as indole derivatives, which are more suitable for ophthalmic use. Topical ophthalmic NSAIDs are commonly used in the treatment of post-operative inflammation following cataract extraction and various surgical refractive procedures. They are also used in the prevention and treatment of cystoid macular oedema and for the treatment of allergic conjunctivitis. Absorption of topical ophthalmic NSAIDs through the nasal mucosa results in systemic exposure and the occurrence of adverse systemic events, including exacerbation of bronchial asthma. Local irritant effects of topical ophthalmic NSAIDs include conjunctival hyperaemia, burning, stinging and corneal anaesthesia. A more serious complication involves the association of topical ophthalmic NSAIDs with indolent corneal ulceration and full-thickness corneal melts. Analysis of NSAID-associated corneal events implicates the now defunct generic dicolfenac product, diclofenac sodium ophthalmic solution as the agent primarily responsible. However, these events generated a renewed interest in the safety of ophthalmic NSAIDs and a scrutiny of the pharmacology regarding NSAID action in the eye. An elucidation of possible pharmacodynamic explanations of NSAID-induced corneal injury includes the role of epithelial hypoxia, which not only appears to aid in determining the metabolic destination of arachidonate, it may play a key role in orchestrating a novel inflammatory response unrelated to prostanoid formation. The use of NSAIDs under conditions of corneal hypoxia may therefore not only result in a disappointing therapeutic response, it may result in a paradoxical inflammatory exacerbation. Other potential mechanisms include the relationship between NSAIDs and corneal matrix metalloproteinase and direct toxicity due to cytotoxic excipients such as surfactants, solubilisers and preservatives found in topical NSAID ophthalmic preparations. In general, ophthalmic NSAIDs may be used safely with other ophthalmic pharmaceuticals; however, concurrent use of agents known to adversely effect the corneal epithelium, such as gentamicin, may lead to increased corneal penetration of the NSAID. The concurrent use of NSAIDs with topical corticosteorids in the face of significant pre-existing corneal inflammation has been identified as a risk factor in precipitating corneal erosions and melts and should be undertaken with caution. Until clinical evidence dictates otherwise, data supporting theories of potential pharmacodynamic mechanisms of NSAID injury do not alter the favorable benefit-risk ratio of ophthalmic NSAID use when employed in an appropriate and judicious manner.