Nonsteroidal Anti-inflammatory Drugs for Age-Related Macular Degeneration
Nonsteroidal anti-inflammatory drugs (NSAIDs) are used extensively in ophthalmology for pain and photophobia after photorefractive surgery and to reduce inflammation and cystoid macular edema following cataract surgery. In recent years, the U.S. Food and Drug Administration has approved new topical NSAIDs and previously approved NSAIDs have been reformulated. These changes may allow for greater drug penetration into the retina and therapeutic inhibition of retinal prostaglandins.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are one of the most commonly prescribed classes of medications and are employed for their analgesic, antipyretic, and anti-inflammatory properties. A growing body of scientific evidence indicates that inflammation contributes to the pathogenesis of age-related macular degeneration (AMD)1-3 and prostaglandins (PGs) are an important class of inflammatory mediators that are biosynthesized from arachidonic acid by the cyclooxygenase (COX) enzyme.4 NSAIDs are potent inhibitors of COX enzyme and thereby the synthesis of all downstream PGs. Within the eye, PGs increase vascular dilation, disrupt the blood-ocular barrier, and facilitate leukocyte migration.4 Consequently, their inhibition may have favorable effects on both intraocular inflammation and macular edema.5 There is increasing evidence that PGs play a role in the pathogenesis of AMD and, in recent years, there have been more studies examining the therapeutic application of NSAIDs for this condition.
Nonsteroidal Anti-Inflammatory Drugs
NSAIDs are a class of medications that lack a steroid nucleus and inhibit COX enzyme. COX enzyme catalyzes the production of five classes of PGs: PGE2, PGD2, PGF2α, PGI2, and Thromboxane A2. Two main isoforms of COX, COX-1 and COX-2, exist. COX-1 contributes to normal physiological processes while COX-2 is mainly upregulated during inflammatory responses. There are several topical NSAIDs that are commercially available for ophthalmic use, including ketorolac, diclofenac, nepafenac, bromfenac, and flurbiprofen. Ketorolac is reported to be the most potent inhibitor of COX-1, while bromfenac and amfenac are the most potent inhibitors of COX-2.4,5 The relative importance of COX-1 versus COX-2 inhibition in ocular disease, however, remains unclear.
Age-Related Macular Degeneration
AMD is the leading cause of blindness in the United States; it is estimated that AMD will affect nearly 8 million Americans by 2020.6 Choroidal neovascularization (CNV) is the most common cause of severe vision loss in patients with neovascular AMD.6-8 It is now firmly established that vascular endothelial growth factor (VEGF) is a principle mediator of CNV, but while VEGF inhibitors have been an important advance in treating neovascular AMD, they do not slow down the underlying disease process. Moreover, VEGF is essential for normal homeostasis of retinal cells and its chronic inhibition may, therefore, be undesirable.9 For example, chronic VEGF inhibition may potentially promote geographic atrophy.10 Consequently, it is clear that strictly inhibiting VEGF neither addresses the multifactorial pathogenesis of CNV nor the underlying cause of VEGF upregulation. An accumulating body of scientific evidence indicates that inflammation plays a central role in CNV.1-3 An improved understanding of inflammatory mediators involved in VEGF induction may provide an opportunity to develop preventative strategies.
In this regard, COX-2 can be detected in human choroidal neovascular membranes11 and considerable scientific evidence indicates that COX is a promoter of angiogenesis.12-14 Patients who regularly take NSAIDs have a 40-50% reduction in mortality from colorectal cancer and a distinguishing feature of colorectal tumors is high expression of COX.14 Pharmacologic inhibition of COX appears to reduce VEGF expression in cultured human retinal pigment epithelium cells and suppresses VEGF in both trauma- and ischemia-induced models of retinal angiogenesis.15-17 Furthermore, animal studies have consistently shown that pharmacologic inhibition of COX reduces CNV.18-21 Finally, mice with genetic deletion of COX-2 have significantly less CNV in response to laser rupture of Bruch's membrane due to decreased retinal VEGF.21
Emerging clinical evidence also supports a potential therapeutic role of NSAIDs for AMD. A prospectively followed cohort of patients with rheumatoid arthritis had a low prevalence of AMD,22 and it was hypothesized that long-term anti-inflammatory treatment may have been responsible. In support of this, two recent prospective, randomized, controlled clinical studies reported favorable effects of topical bromfenac with respect to retinal thickness and reduced number of anti-VEGF treatments.23,24 Flaxel and colleagues investigated combination treatment with topical bromfenac 0.09% for exudative AMD.23 Patients received monthly intravitreal ranibizumab (IVR) for four months, followed by as needed treatment and were randomized to either combination treatment with IVR and bromfenac or IVR monotherapy. There was no observed difference with regards to vision or number of injections between groups, but there was a significantly greater reduction in central macular thickness (CMT) in the combination group (-82 microns) when compared to eyes treated with IVR monotherapy (-43 microns). In an independent study by Gomi and colleagues,24 combination treatment with bromfenac 0.1% and IVR for exudative AMD significantly reduced the number of anti-VEGF injections needed compared to IVR monotherapy. Moreover, there was a trend of greater reduction of CMT in the combination group that almost reached the level of statistical significance (P = 0.06).
It is well established that inflammation plays a pathogenic role in AMD, and anti-inflammatory based therapies have great promise for delaying disease progression. Emerging clinical evidence indicates a potential therapeutic role for NSAIDs in AMD but more compelling clinical data is needed before routine application can be recommended.
Supported by an unrestricted grant from Research to Prevent Blindness to the Vanderbilt University School of Medicine Department of Ophthalmology and Visual Sciences.
Conflicts of Interest: None
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About our author(s):
Stephen J. Kim, MD
Vanderbilt Eye Institute
Vanderbilt University Medical Center