By Seenu M. Hariprasad, M.D.

Author�s note: The following information contains a
discussion on a non-FDA approved use of nepafenac.

Ophthalmic NSAIDs have traditionally been used to effectively manage postoperative inflammation and to prevent intraoperative miosis during cataract surgery. Currently and increasingly, NSAIDs are effectively used to prevent and treat cystoid macular edema (CME) after cataract surgery. Many cataract surgery patients can benefit from their use before, during and after surgery. I am now using NSAIDs as a first-line defense with my patients where relevant, and it seems clear that NSAID prophylaxis is emerging as standard of care for cataract surgeons.

Case Study
On May 3, 2006, a 69-year-old African American woman presented with decreased vision in her right eye. She had a history of uncomplicated phacoemulsification cataract extraction and had IOL implantation in her right eye 10 months prior. She had failed topical prednisolone acetate 1% (Pred Forte, Allergan) and ketorolac tromethamine 0.4% (Acular LS, Allergan) therapy for  6 months. Her BCVA was 20/60 OD and 20/25 OS.
At presentation, foveal thickness OD was 715 �57 �m and the total macular volume OD was 10.36 mm2. In comparison, the foveal thickness OS was 205 �5 �m and the total macular volume OS was 7 mm2. (Figure 1)

Figure 1. At presentation, patient�s best-corrected visual acuity was 20/60 OD and foveal thickness was 715 �57 �m OD.

At this visit, the ketorolac 0.4% was discontinued, and nepafenac 0.1% (Nevanac, Alcon Laboratories, Inc.) t.i.d. was initiated. Twenty-eight days after switching from
ketorolac to nepafenac, the foveal thickness OD was 228 �12 �m and the total macular volume was 7.95 mm2, both significant decreases.

Six weeks after the patient�s initial presentation, her visual acuity was 20/30 OD and 20/25 OS. Foveal thickness OD was 227 �4 �m and total macular volume OD was 7.86 mm2. Foveal thickness OS was 215 �11 �m and total macular volume OS was 7.17 mm2. (Figure 2)

Figure 2. Six weeks after
initial presentation, visual acuity had improved to 20/30 OD and foveal thickness had decreased to 227�4 �m OD.

Discussion
Conventional NSAIDs, such as diclofenac and ketorolac, have been shown to be equally yet marginally effective in treating postop CME and postop inflammation. However, results like the one above have shown nepafenac to be more effective.

Nepafenac�s pro-drug mechanism has several advantages over conventional NSAIDs. Pro-drugs are the less active form of a drug that becomes active, or more active, after metabolic conversion within the vascular tissue. After nepafenac is instilled, it quickly penetrates the ocular tissues and is converted to amfenac, which is a potent NSAID. The pro-drug mechanism of action optimizes the concentration of nepafenac in increasing levels as the back of the eye is reached. Activation begins in the cornea, continues in the iris-ciliary body, and is at its highest in the retina/choroid. Since nepafenac�s structure increases penetration to target sites, it may also provide longer duration of action at these sites.
A study conducted by Ke and colleagues1 shows that nepafenac effectively penetrates the cornea and sclera and distributes intraocularly. Nepafenac quickly undergoes hydrolysis in the iris, ciliary body, retina and choroid. Additionally, nepafenac inhibits prostaglandin synthesis for more than 6 hours in the iris/ciliary body and for at least 4 hours in the retina/choroid.

Nepafenac also effectively reduces anterior and posterior segment inflammation. A study conducted by Gamache and colleagues2 found that the topical ocular administration nepafenac has the potential to suppress prostaglandin-mediated inflammation in anterior segment and retinal tissues. Investigators compared nepafenac and diclofenac in a rabbit model of ocular inflammation and found that, while nepafenac exhibited relatively less COX-1 inhibition, amfenac was a potent inhibitor of both COX-1 and COX-2 activity.
Additionally, ex vivo, a topical ocular dose of nepafenac 0.1% inhibited prostaglandin synthesis by 85% to 95% in the ciliary body for 6 hours and by 55% in the retina/choroid for 4 hours. In comparison, diclofenac 0.1% also suppressed iris/ciliary body prostaglandin synthesis, but only for 20 minutes, and a 75% recovery of prostaglandin synthesis occurred within 6 hours of  topical dosing. Additionally, diclofenac�s inhibition of prostaglandin synthesis in the retina/choroid was minimal.
The study also assessed nepafenac�s anti-inflammatory activity using a trauma-induced model of acute ocular inflammation. Eyes received a single topical ocular dose of nepafenac 0.1% or diclofenac 0.1%, and then a paracentesis was performed 45 minutes later to induce inflammation. Nepafenac 0.1% reduced protein accumulation by 61% and PGE2 synthesis by 98%, and significant anti-inflammatory activity was maintained from 15 minutes to 8 hours after dosing.
The use of nepafenac to treat macular edema from various other etiologies is being explored. The new-generation NSAIDs hold great promise in the treatment of CME; however, their precise role is yet to be determined. OM

Seenu M. Hariprasad, M.D., is an assistant professor and director of Clinical Research from the Vitreoretinal Service at the University of Chicago School of Medicine.

References
1. Ke T, 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.
2. 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.