The safety and efficacy of long-term topical NSAID therapy in patients with dry eye has long been a subject researchers have studied, with varying results.
"If you want to start controversy, just mention that you're going to use long-term NSAIDs," said Dr. Toyos, medical director and founder of Toyos Clinic, Memphis, TN. "We've had long-term legal battles tied to the long-term use of oral NSAIDs. We've also had this in ophthalmology with corneal melts with the use of NSAIDs."
NSAIDs act to block cyclooxygenase, which then prevents prostaglandins from causing inflammation in the eye, Dr. Toyos said.
"We've been using them in cataract surgery to decrease pain and inflammation," he added. "These agents have also been shown to reduce cystoid macular edema."
So, why use an NSAID in patients with dry eye? NSAIDs not only decrease inflammation, they also have a mild anesthetic effect.
"If you look at all the different groups and workshops that have gotten together to try to give a definition to dry eye, they've all included an inflammatory component," Dr. Toyos said. "Increased inflammatory mediators are also seen in the tear film of patients with dry eye.
"It would be great if we could use an anti-inflammatory [agent] like a steroid, but we cannot use these long term because of the side-effect profile," he added.
One of the first studies to document problems with topical nonsteroidal agents came from J.P. Gills in 1994, who reported that diclofenac ophthalmic solution was associated with medication keratitis.1 Other researchers then began to report that the use of NSAIDs in cataract surgeries had the potential to cause corneal melts.
A review of only 11 patients done by Flach is most likely the basis for the negative association between long-term NSAID use and corneal melts, Dr. Toyos noted.2 These researchers assumed that 2 of the 11 patients they studied had dry eye because they had punctal plugs. Seven of the 11 were treated with generic diclofenac, and the others received diclofenac (Voltaren). The range of corneal melts lasted from 6 days to 17 months. The conclusion of this study was that the cause of the corneal melts was multifactorial, and the author never said that the dry eye was what was causing the corneal melts.
Other studies drew the conclusion that the generic NSAIDs were the problem, continued Dr. Toyos.
Several mechanisms of action behind long-term NSAID use and corneal melts have since been proposed. According to Hargrave and colleagues, the vitamin E solubilizer in generic inhibited epithelial cell proliferation and induced apoptosis.3 According to O'Brien et al., the NSAIDs activated matrix metalloproteinases, which then degraded the collagen in these corneas.4 According to Abelson and Lilyestrom, NSAIDs caused a decrease in leukotrienes that enhanced the leukocyte chemotaxis that helps heal defective wounds.5