The Increasing Use of New Generation NSAIDs in the Treatment of Cystoid Macular Edema

SEENU M. HARIPRASAD, MD

Cystoid macular edema (CME) can be a serious consequence of numerous ocular procedures and conditions, including cataract surgery, ocular inflammatory diseases, retinal vascular diseases, and tractional disorders.¹ Although subclinical angiographic or optical coherence tomography-defined CME has no associated vision loss and typically spontaneously resolves, it can develop into clinical CME, which involves a decrease in visual acuity (VA) that can be permanent if not appropriately treated. Because inflammation is a known risk factor for the development of CME,² anti-inflammatory corticosteroids are commonly used to treat this condition, either through topical, subconjunctival/sub-Tenon's, or intravitreal administration. While steroid regimens have been shown to effectively treat CME,^3-6 they are occasionally associated with serious side effects, including elevated intraocular pressure (IOP) and posterior subcapsular cataract.⁷ Because of this, less toxic but equally effective alternatives to corticosteroids are desirable.

EVIDENCE OF NSAIDS' EFFICIACY

In recent years, both the prevention and treatment of CME has been increasingly managed with nonsteroidal anti-inflammatory drugs (NSAIDs). In fact, the most common off-label use of NSAIDs is for the prevention of CME after cataract surgery. Side effects of topical NSAIDs are most commonly ocular and include burning, stinging, and conjunctival hyperemia. NSAIDs, specifically indomethacin, first demonstrated efficacy for the prevention of pseudophakic CME in 1977,⁸ but it was not until much later that ketorolac 0.5% (Acular, Allergan) and diclofenac 0.1% (Voltaren, Novartis) proved effective in the treatment of this condition.^9,10

In 2005, 2 new-generation topical NSAIDs were approved by the Food and Drug Administration: nepafenac 0.1% (Nevanac, Alcon) and bromfenac 0.09% (Xibrom, Ista). Bromfenac is a conventional NSAID similar to diclofenac but with a less frequent dosing regimen; nepafenac is unique in that it is a prodrug that is metabolized into a more active NSAID metabolite, amfenac, by intraocular hydrolases.^11,12 While no randomized trials have yet been conducted to test the ability of either new-generation NSAID agent to treat CME, numerous reports suggest that these agents also have activity against this condition. At the 40th scientific meeting of the Retina Society, which was held in Boston in September 2007, 4 different abstracts described below were presented (3 nepafenac and 1 bromfenac), providing evidence of NSAID activity for the treatment of CME.^13-16

Warren and Fox¹³ conducted a prospective study of the use of nepafenac 0.1% as an alternative to steroids in steroid IOP responders with CME. Of the 15 patients enrolled, 11 developed CME following uncomplicated cataract surgery and 4 had CME associated with vitreoretinal disorders. After 12 weeks of nepafenac treatment, 12 of the 15 patients showed an improvement in VA of at least 2 Snellen lines and 14 of 15 had a reduction in retinal thickness (mean = 206.9 μm). No patients experienced an elevation in IOP with nepafenac use. These results suggest that nepafenac monotherapy is a promising alternative to topical steroids for the treatment of both acute and chronic CME.

Akduman and colleagues¹⁴ described 9 consecutive patients with chronic pseudophakic CME who were treated with nepafenac 0.1%. These patients had been previously treated unsuccessfully with the NSAIDs ketorolac and flurbiprofen (Ansaid, Pfizer), as well as the steroid prednisolone acetate. Eight of the 9 patients were treated with nepafenac alone; the other patient received concomitant prednisolone acetate 1%. After a mean follow-up of 4 months, the average improvement in VA was approximately 1 Snellen line and the mean reduction in central retinal thickness was 22.4%. This case series illustrates the utility of nepafenac for the treatment of chronic CME that is recalcitrant to other topical medications.

I presented 9 cases of acute pseudophakic, chronic pseudophakic, and recalcitrant uveitic CME treated with nepafenac 0.1%.¹⁵ One of the 2 patients with acute CME was treated with nepafenac alone; the other received concurrent prednisolone acetate. Both experienced an improvement in retinal thickness (mean = 191 μm). One also demonstrated a 2.5-line improvement in VA. The other patient showed no change in VA, but this was due to preexisting geographic atrophy of the retinal pigment epithelium from dry age-related macular degeneration (AMD). Three of the 4 cases of chronic pseudophakic CME and all 3 recalcitrant uveitic CME cases had been unsuccessfully treated with ketorolac plus prednisolone acetate; the other pseudophakic patient had received no prior therapy for CME. After treatment with nepafenac 0.1%, retinal thickness in the chronic pseudophakic CME group decreased by a mean of 331 μm and VA improved by an average of 3.6 lines. The recalcitrant uveitic CME group had a mean retinal thickness decrease of 351 μm and an improvement in VA of 5.0 lines. Results from this retrospective study suggest that nepafenac has activity against several types of CME.

One study reported on 17 cases of CME with varying underlying etiologies (retinal vein occlusion, diabetic retinopathy, macular epiretinal membrane, and AMD) that were treated with bromfenac 0.09% for 6 to 28 weeks.¹⁶ Thirteen patients responded to treatment with a decrease in retinal thickness and/or cystic spaces, indicating that bromfenac may have activity against CME secondary to retinal vascular diseases and tractional disorders.

NOT ALL NSAIDS THE SAME

The above studies suggest that the new-generation NSAIDs can effectively treat several types of CME. Nepafenac may be particularly well-suited to manage and prevent CME for multiple reasons. First, the conversion of nepafenac into amfenac is performed by intraocular hydrolases, which are at their highest concentrations in the retina/choroid,¹⁷ effectively targeting the drug to the site of inflammation. Furthermore, nepafenac 0.1% has been shown to have greater ocular bioavailability than either ketorolac 0.4% or bromfenac 0.09%.¹⁸ Finally, nepafenac's prodrug structure may produce an even more favorable safety profile than other NSAIDs because conversion of the drug into its more active metabolite does not occur in the cornea, reducing the chance of corneal complications. The distinct clinical difference between the 2 new-generation NSAIDS, nepafenac and bromfenac, in treating macular edema has yet to be determined. In certain situations, it may be advantageous to consider treatment with a newgeneration NSAID for patients with recalcitrant CME prior to considering intravitreal triamcinolone acetonide (Kenalog, Bristol-Myers Squibb) or bevacizumab (Avastin, Genentech) injection, both of which carry a higher risk of complications. RP

Editor's note: The opinions expressed are that of the author and are based on a series of case reports. No controlled clinical studies have been performed to support the conclusions made in this article.

REFERENCES

1. Tranos PG, Wickremasinghe SS, Stangos NT, Topouzis F, Tsinopoulos I, Pavesio CE. Macular edema. Surv Ophthalmol. 2004;49:470-490.
2. Gulkilik G, Kocabora S, Taskapili M, Engin G. Cystoid macular edema after phacoemulsification: risk factors and effect on visual acuity. Can J Ophthalmol. 2006;4:699-703.
3. Heier JS, Topping TM, Baumann W, Dirks MS, Chern S. Ketorolac versus prednisolone versus combination therapy in the treatment of acute pseudophakic cystoid macular edema. Ophthalmology. 2000;107:2034-2038;discussion 2039.
4. Massin P, Audren F, Haouchine B, et al. Intravitreal triamcinolone acetonide for diabetic diffuse macular edema: preliminary results of a prospective controlled trial. Ophthalmology. 2004;111:218-224; discussion 224-225.
5. Sutter FK, Simpson JM, Gillies MC. Intravitreal triamcinolone for diabetic macular edema that persists after laser treatment: three-month efficacy and safety results of a prospective, randomized, double-masked, placebo-controlled clinical trial. Ophthalmology. 2004;111:2044-2049.
6. Gillies MC, Sutter FK, Simpson JM, Larsson J, Ali H, Zhu M. Intravitreal triamcinolone for refractory diabetic macular edema: two-year results of a doublemasked, placebo-controlled, randomized clinical trial. Ophthalmology. 2006;113:1533-1538.
7. Sivaprasad S, McCluskey P, Lightman S. Intravitreal steroids in the management of macular oedema. Acta Ophthalmol Scand. 2006;84:722-733.
8. Miyake K. Prevention of cystoid macular edema after lens extraction by topical indomethacin (I). A preliminary report. Graefes Arch Klin Exp Ophthalmol. 1977;203:81-88.
9. Flach AJ, Dolan BJ, Irvine AR. Effectiveness of ketorolac tromethamine 0.5% ophthalmic solution for chronic aphakic and pseudophakic cystoid macular edema. Am J Ophthalmol. 1987;103:479-486.
10. McColgin AZ, Raizman MB. Efficacy of topical Voltaren in reducing the incidence of postoperative cystoid macular edema. Invest Ophthalmol Vis Sci. 1999;40(Suppl):289.
11. Colin J. The role of NSAIDs in the management of postoperative ophthalmic inflammation. Drugs. 2007;67:1291-1308.
12. Gamache DA, Graff G, Brady MT, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: I. Assessment of anti-inflammatory efficacy. Inflammation. 2000;24:357-370.
13. Warren K, Fox JE. NSAID as an alternate treatment modality for CME in the steroid-responsive patient. Poster F-1 presented at: Annual Meeting of the Retina Society; September 27-30; Boston.
14. Akduman L, Clever JA, Feman S. Nepafenac used for the treatment of chronic pseudophakic cystoid macular edema. Poster F-2 presented at: Annual Meeting of the Retina Society; September 27-30; Boston.
15. Hariprasad S, Mieler WF. Treatment of acute pseudophakic, chronic pseudophakic, and recalcitrant uveitic cystoid macular edema with nepafenac 0.1% (Nevanac^®). Poster F-4 presented at: Annual Meeting of the Retina Society; September 27-30; Boston.
16. Gross JG. Xibrom (bromfenac) reduces cystoid macular edema associated with vein occlusions, macular epiretinal membrane, diabetic retinopathy and agerelated macular degeneration. Poster F-3 presented at: Annual Meeting of the Retina Society; September 27-30; Boston.
17. Ke TL, Graff G, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: II. In vitro bioactivation and permeation of external ocular barriers. Inflammation. 2000;24:371-384.
18. Walters T, Raizman M, Ernest P, Gayton J, Lehmann R. In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac. J Cataract Refract Surg. 2007;33:1539-1545.