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Comparing NSAIDs in aqueous humor

by Michael B. Raizman, M.D.

Michael B. Raizman, M.D. is an ophthalmologist, Ophthalmic Consultants of Boston, Boston, director, Cornea and Cataract Service, New England Eye Center, Boston, and associate professor of ophthalmology, Tufts University School of Medicine, Boston.

“... CME is estimated to occur in up to 12% of low-risk cataract cases, and the incidence of CME after routine phaco has been reported to be as high as 19%.”
Michael B. Raizman, M.D.

“The results [from a study addressing aqueous humor concentrations] found nepafenac initially has a very high concentration and then drops off after two to four hours.”
Michael B. Raizman, M.D.


Cystoid macular edema (CME) is one of the most frequent causes of visual decline following uncomplicated cataract surgery and can have an onset as late as four to six weeks post-op.1 The occurrence of clinical CME is greatly reduced after uncomplicated phacoemulsification operations, but the incidence of angiographic CME is still nearly equal to the incidence of the extracapsular technique.2 In 1% to 3% of cases, it is associated with a decrease in visual acuity (VA).3 In addition, CME is estimated to occur in up to 12% of low-risk cataract cases,4 and the incidence of CME after routine phaco has been reported to be as high as 19%.5
Optical coherence tomography (OCT) can be useful in identifying those with significant macular thickening, and in high-risk patients (such as those with diabetes), it can help us determine which of our patients are at risk of developing CME or a loss of vision.6,7
As technology has improved, the definitions of CME have changed. Clinical CME currently has been described as vessel leakage associated with a VA of 20/40 or worse, and today's definition of CME is more strict (20/25 or worse) because of higher patient expectations.8
Numerous studies have identified risk factors for CME, including preexisting ocular inflammation, epiretinal or vitreoretinal interface membrane problems, diabetic retinopathy, ocular vascular or cardiovascular disease, retinitis pigmentosa, iris trauma, and post-op anterior chamber inflammation.9
Once macular edema occurs, it can take many months to resolve. A number of studies shows that a proportion of patients will have permanent macular edema even if the edema is recognized early and treated aggressively.
Patients at higher risk of developing CME may benefit from treatment starting earlier than those in a lower-risk group, and the higher-risk patients should continue prophylaxis for an extended period after surgery.10
Miyake et al. offered a hypothesis on the mechanism of CME after cataract surgery. Prostaglandins produced by the anterior uveal tract enter the aqueous and vitreous and lead to a breakdown of the blood-aqueous barrier and the blood-retina barrier.11

Optimal therapy

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) appear to be effective in preventing post-surgical CME. They also have been shown to have a beneficial effect on visual function.1 Gaynes and Fiscella showed it may be necessary to achieve therapeutic concentrations of the NSAID in the posterior chamber to maximize the effect of the NSAID on the target tissue (the retina).12 Steroids alone have not been shown to be as effective in preventing or treating CME.4
O'Brien wrote about emerging guidelines for NSAID treatment regimens in cataract surgery and suggested at-risk patients receive NSAIDs one week pre-op and between four weeks to several months after surgery. For those not at risk, pre-op dosing should be between one to two days, and post-op treatment should be four weeks.13

Aqueous humor concentrations

A double-masked multicenter study looked at 75 patients randomized to receive nepafenac 0.1% (Nevanac, Alcon, Fort Worth, Texas), amfenac (a metabolite in nepafenac), ketorolac 0.4% (Acular LS, Allergan, Irvine, Calif.), or bromfenac 0.9% (Xibrom, ISTA Pharmaceuticals, Irvine, Calif.).14 The purpose of this study was to determine the aqueous humor concentration after one drop. All patients had been scheduled to undergo cataract sugery. Patients were administered one drop of the NSAID at 30, 60, 120, 180, or 240 minutes before surgery. Aqueous humor samples were collected at the time of paracentesis. The patients received no other nonsteroidals, but they did receive dilating drops prior to the surgery.
The results proved that nepafenac initially has a very high concentration and then drops off after two to four hours. Amfenac, the metabolite, peaks at about three hours.
Ketorolac has a slightly different time course; it rises rapidly over the first hour and then drops off. Bromfenac has a very low concentration throughout. Nepafenac had the highest area under the curve over this four-hour time course; ketorolac had the second highest area. Bromfenac had the lowest area under the curve in this time course.


1. Samiy N, Foster CS. The role of nonsteroidal anti-inflammatory drugs in ocular inflammation. Int Ophthalmol Clin. 1996;36:195-206.
2. Mentes J, Erakgun T, Afrashi F, Kerci G. Incidence of cystoid macular edema after uncomplicated phacoemulsification. Ophthalmologica. 2003;217:408-12.
3. Agostini HT, Hansen LL, Feltgen N. Treatment of pseudophakic cystoid macular edema. Ophthalmologe. 2007; 104:425-30.
4. McColgin AS, Raizman MB. Efficacy of topical Voltaren in reducing the incidence of post-operative cystoid macular edema. Invest Ophthalmol Vis Sci. 1999;40:S289.
5. Ursell PG, Spalton
DJ, Whitcup SM, Nussenblatt RB. Cystoid macular edema after phacoemulsification: relationship to blood-aqueous barrier damage and visual acuity.
J Cataract Refract Surg. 1999;25:1492-7. Comment in: 2000;26:474.
6. Kim SJ, Equi R, Bressler NM. Analysis of macular edema after cataract surgery in patients with diabetes using optical coherence tomography. Ophthalmology. 2007;114:881-9.
7. Torron-Fernandez-Blanco C, Ruiz-Moreno O, Ferrer-Novella E, Sanchez-Cano A, Honrubia-Lopez Fm. Pseudophakic cystoid macular edema. Assessment with optical coherence tomography. Arch Soc Esp Oftalmol. 2006;81:147-53.
8. 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;107:2034-8;
discussion 2039.
9. Gulkilik G, Kocabora S, Taskapili M, Engin G. Cystoid macular edema after phacoemulsification: risk factors and effect on visual acuity. Can J Ophthalmol. 2006;41:699-703.
10. Heier JS. Preventing post-cataract extraction CME: Early identification of patients at risk and prophylactic treatment may avert vision loss. Ophthalmology Management. 2004;
11. Miyake K, Shirato S, Oshika T, Eguchi K, et al. Comparison of diclofenac and fluorometholone in preventing cystoid macular edema after small incision cataract surgery: a multicentered prospective trial. Jpn J Ophthalmol. 2000;44:58-67.
12. Gaynes BI, Fiscella R. Topical nonsteroidal anti-inflammatory drugs for ophthalmic use: a safety review. Drug Saf. 2002;25:233-50.
13. O'Brien TP. Emerging guidelines for use of NSAID therapy to optimize cataract surgery patient care. Curr Med Res & Opin. 2005; 21:1131-7.
14. Walters TR, Raizman M, Ernest P, et al. A double-masked, randomized, single-dose, pharmacokinetic study of nepafenac, amfenac, ketorolac, and bromfenac in human aqueous humor following topical administration of Nevanac, Acular LS, or Xibrom. Invest Ophthalmol Vis Sci.

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