With the regular use of femtosecond lasers for cataract surgery on the horizon, expectations for outcomes have soared. Ultimately, it is up to the surgeon to do whatever he feels is necessary to increase the likelihood of a successful, sequelae-free surgery through the medicines he prescribes. With the trend toward off-label use of nonsteroidal anti-inflammatory drugs for the prevention of cystoid macular edema after cataract surgery, it’s crucial to keep up-to-date on the supporting studies. Here’s a look at key NSAID data.

CME and Off-label Use of NSAIDs
CME is generally characterized by the collection of fluid in the macula and most often associated with inflammation following cataract surgery and secondary to a breakdown of the blood-retinal barrier.¹ It’s is the main source of visual deterioration following uncomplicated cataract surgery.^1,2 The precise cause of CME is unclear. A recently conducted review of 139,759 Medicare cataract surgeries suggested that the overall incidence of CME is 1. 95 percent.³ Although physicians may take prophylactic measures, the potential for CME is still an ongoing struggle despite its relatively low incidence.

NSAIDs are cyclo-oxygenase inhibitors that work by preventing the synthesis of prostaglandins, metabolic products of arachidonic acid, which are potent mediators of inflammation. Thus, topically applied ophthalmic NSAIDs are often used in the management of postop ocular inflammation in the belief that they will hamper potential complications and prevent CME.⁴ The appeal of using NSAIDs in the treatment of ocular inflammation revolves around avoiding the recurrent complications associated with corticosteroids, and NSAIDs’ beneficial effects include stabilizing intraocular pressure, inducing analgesia and reducing the risk of secondary infections. Still, it’s important to distinguish between the approved label use and the off-label use of NSAIDs for CME. As indicated by their labels, NSAIDs were approved to treat inflammation, and in some cases, received a second indication for pain after cataract surgery. This was based on the treatment of iritis. It was the hope that despite the anatomically different locations of iritis and CME, NSAIDs could suppress inflammation.⁵

The relatively low incidence rate of CME makes it a difficult indication for a drug to garner, so it’s common for physicians to use drugs off-label to treat it. Presently, there is no Food and Drug Administration-approved therapy for the treatment of CME, but there are six topically administered ophthalmic NSAIDs with approval for the treatment of postop inflammation in patients who have undergone cataract extraction: Voltaren (diclofenac 0.1%); Acular (ketorolac 0.5%); Xibrom (bromfenac 0.09%); Nevanac (nepafenac 0.1%); Acuvail (ketorolac 0. 45%) and Bromday (bromfenac 0.09%) (See Figure 1). These drugs are routinely used to decrease inflammation that may cause CME.

In addition to the approved uses, it’s become the standard of care to use these preparations both pre- and postop to try to avoid and possibly treat CME.⁶ Currently, it seems that prevention is the most viable therapeutic option. For example, one study comparing an NSAID (nepafenac 0.1%) with a placebo dosed q.d., b.i.d. or t.i.d. preop, the day of surgery and postop, demonstrated a significant reduction in the percentage of treatment failures with the NSAID compared to the placebo (p.0.0020). Nepafenac treatment also increased the proportion of patients with resolved ocular inflammation.⁷

Off-label Treatment
Since it's become customary to prescribe NSAIDs off-label for CME, it should also be routine for practitioners to be conscious of outcomes, including those of various dosing regimens (Some of them appear in Figure 2) . CME often resolves spontaneously, and medical treatment is actually successful in about 90 percent of cases where it's required,8 which makes persistent cases of CME worrisome. While frequently asymptomatic, CME can cause blurred or decreased central vision and retinal inflammation or swelling. Though vision loss from CME is usually temporary, it can be permanent in some cases.

Some risk factors for CME include pre-existing ocular inflammation, epiretinal or vitreoretinal interface membrane problems, and diabetic retinopathy.¹ For patients without risk factors, preoperative dosing of NSAIDs for one to two days is recommended and postop dosing of a drop q. i.d. for an average of three to four weeks is typical. For patients exhibiting any risk factors, treatment should be initiated earlier and extended longer, and any patients with increased risk factors should receive preop and postop dosing for several months.¹

Clinical Experience
Clinical experience gives prescribing physicians the most current and updated information regarding the pharmacokinetics, efficacy and safety of a drug.

While the perfect study would lookat the actual incidence of CME ratherthan a surrogate, studies often use surrogates such as retinal thickness as endpoints for CME. One study found that adding perioperative topical ketorolac tromethamine 0.4% to prednisolone acetate 1%, as opposed to prednisolone alone, can provide measurable benefits in patients without known risk factors for CME. The addition of ketorolac 0.4% beginning three days before surgery and extending roughly four weeks postoperatively significantly reduced the incidence of CME, defined by biomicroscopy and optical coherence tomography analysis as “definite,” “probable” or “possible,” and associated with retinal thickness. No patients in the ketorolac and steroid group had clinically apparent CME, in contrast to five patients in the steroid group alone (p=0.032). Furthermore, based on OCT, no patients in the ketorolac and steroid group had definite or probable CME, compared with six steroid patients (2.4 percent; p=0.018).¹⁰ Although this study assesses the effects of extended perioperative ketorolac with steroids as CME prophylaxis for uncomplicated cataract surgery, it can be argued that the primary endpoint of studies evaluating CME should be visual function.¹¹

Ocular instillation of topical NSAIDs delivers ocular tissue and aqueous humor levels of the drugs adequate to impede prostaglandin synthesis,⁴ which is crucial in order to create therapeutic anti-inflammatory effects in the target areas. One study examined the aqueous humor concentrations and cyclo-oxygenase inhibitory activities of a drop of nepafenac 0.1%, ketorolac 0.4% or bromfenac 0. 09% 30, 60, 120, 180 or 240 minutes before cataract surgery. Nepafenac had the shortest time to peak concentration and the greatest peak aqueous humor concentration compared to the other drugs (C[max]). Ketorolac showed the most potent COX-1 inhibition,and nepafenac showed significantly greater ocular bioavailability.¹²

The peak incidence of CME after surgery varies between four and six weeks,¹ though in some cases its onset may be delayed for months. Even so, studies have shown the promising effects of NSAIDs in the treatment of established, chronic CME. In one study, known steroid responders with CME were treated with nepafenac 0. 1% and experienced significant improvement in visual acuity and retinal thickness at four and 12 weeks post-treatment compared with baseline (p<0.0001), possibly due to the penetration ability of nepafenac.^1,13,14 Another study concluded that diclofenac sodium 0.1% was as effective as topical ketorolac tromethamine 0. 5% solution in reducing the severity and duration of clinical CME after uneventful cataract surgery.¹⁵ After observing for improvement in CME and visual acuity, within 26 weeks diclofenac eliminated CME in 14 Patients (78 percent) and ketorolac eliminated it in 12 patients (75 percent) (p=0.86, CI 95%). It’s important to note, however, that studies conducted without a placebo make it difficult to tell the true effect beyond the natural healing response of the eye.

Another study looked at patients with pseudophakic CME diagnosed more than two years after cataract surgery and the effectiveness of ketorolac tromethamine 0.5% dosed q.i.d. for at least three months and continued until the CME resolved.¹⁶ Best corrected visual acuities measured on retroilluminated Bailey-Lovie charts and contact lens biomicroscopy were performed at each visit, and fluorescein angiography was performed at the initial visit, the first three-month follow-up visit and as clinically indicated thereafter. Although some patients did experience a recurrence of CME and a reduction in visual acuity, four out of five of these patients responded favorably when restarted with ketorolac. While this study shows an effectiveness of ketorolac on established CME, it also suggests that persistent use might be required.

The surgeon’s experience will determine the best treatment. When patients present with extensive inflammation after surgery, we may find that they’re better treated with a potent topical steroid dosed eight times a day to target the inflammation, and may see results sooner, in some cases as soon as two weeks. Newer, potent steroids allow clinicians to treat this way.

Conventional observations from cataract surgeons and a review of the literature^1,6 suggest that the length of use for ophthalmic NSAIDs as monotherapy or combination therapy in conjunction with corticosteroids varies based on risk factors for CME. One study examined the use of topical NSAIDs (diclofenac 0.1%, ketorolac 0. 4%, nepafenac 0.1%, bromfenac 0. 09%) or placebo with intravitreal steroids and antiangiogenesis treatment for chronic pseudophakic CME. The results concluded that NSAID therapy assisted the improvements produced by steroids and antivascular endothelial growth factor therapy. Nepafenac- and bromfenac-treated eyes compared with placebo showed reduced retinal thickness at 12 and 16 weeks (nepafenac, p=0.0048, brom fenac, p=0.0113). Nepafenac produced a sustained improvement in visual acuity at weeks 12 and 16.¹⁷ This regimen shows potential for patients unresponsive to less-invasive therapies.

Reading the Literature
Prescribing off-label dosing is a must in the ophthalmic world, but constant, continuing self-education must accompany it. Also, it’s essential that patients complete the entire course of treatment, even if symptoms seem to have resolved. In the end, prescribing physicians must be aware of all peer-reviewed literature pertaining to CME and NSAIDs. While offlabel use is still caveat emptor, there are dedicated ophthalmologists at both the FDA and at drug companies working together toward the approval of indications, and to ensure that drugs pass rigorous scientific and regulatory requirements.

 

Dr. Abelson, an associate clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at Schepens Eye Research Institute, consults in ophthalmic pharmaceuticals. Ms. Lafond is a medical writer at Ora in Andover.

 

^{1. O'Brien TP. Emerging guidelines for use of NSAID therapy to optimize cataract surgery patient care. Curr Med Res Opin 2005;21:7:1131-1137.}

^{2. Flach AJ. The incidence, pathogenesis and treatment of cystoid macular edema following cataract surgery. Trans Am Ophthalmol Soc 1998;96:557.}

^{3. Schmier JK, Halpern MT, Covert DW, Matthews GP. Evaluation of costs for cystoid macular edema among patients after cataract surgery. Retina 2007;27:5:621-628.}  

^{4. Flach AJ. Topical nonsteroidal antiinflammatory drugs in ophthalmology. Int Ophthalmol Clin 2002;42:1:1-11.}

^{5. Hsu JK, Johnston WT, Read RW, et al. Histopathology of corneal melting associated with diclofenac use after refractive surgery. J Cataract Refract Surg 2003;29:2:250-256.}

^{6. Colin J. The role of NSAIDs in the management of postoperative ophthalmic inflammation. Drugs 2007;67:9:1291-1308.}

^{7. Maxwell WA, Reiser HJ, Stewart RH, et al. Nepafenac dosing frequency for ocular pain and inflammation associated with cataract surgery. J Ocul Pharmacol Ther 2008;24:6:593-599.}

^{8. Wolfensberger TJ, Herbort CP. Treatment of cystoid macular edema with non-steroidal anti-inflammatory drugs and corticosteroids. Doc Ophthalmol 1999;97:3-4:381-386.}

^{9. Lane SS, Modi SS, Lehmann RP, et al. Nepafenac ophthalmic suspension 0.1% for the prevention and treatment of ocular inflammation associated with cataract surgery. J Cataract Refract Surg 2007;33:1:53-58.}

^{10. Wittpenn JR, Silverstein S, Heier J, et al. A randomized, masked comparison of topical ketorolac 0.4% plus steroid vs. steroid alone in low-risk cataract surgery patients. Am J Ophthalmol 2008;146:4:554-560.}

^{11. Kim A, Stark WJ. Are topical NSAIDs needed for routine cataract surgery? Am J Ophthalmol 2008;146:4:483-485.}

^{12. Walters T, Raizman M, Ernest P, et al. In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac. J Cataract Refract Surg. 2007;33:9:1539-1545.}

^{13. Warren KA, Fox JE. Topical nepafenac as an alternate treatment for cystoid macular edema in steroid responsive patients. Retina 2008;28:10:1427-1434.}

^{14. Lindstrom R, Kim T. An examination of data and expert opinion on the clinical utility of nepafenac. Curr Med Res Opin 2006;22:2:397-404.}

^{15. Rho DS. Treatment of acute pseudophakic cystoid macular edema: Diclofenac versus ketorolac. J Cataract Refract Surg 2003;29:12:2378-2384.}

^{16. Weisz JM, Bressler NM, Bressler SB, Schachat AP. Ketorolac treatment of pseudophakic cystoid macular edema identified more than 24 months after cataract extraction. Ophthalmology 1999;106:9:1656-1659.}

^{17. Warren KA, Bahrani H, Fox JE. NSAIDs in combination therapy for the treatment of chronic pseudophakic cystoid macular edema. Retina 2010;30:2:260-266.}

^{18. Solomon KD, Cheetham JK, DeGryse R, Brint SF, Rosenthal A. Topical ketorolac tromethamine 0.5% ophthalmic solution in ocular inflammation after cataract surgery. Ophthalmology 2001;108:2:331-337.}

^{19. Flach AJ, Dolan BJ, Donahue ME, et al. Comparative effects of ketorolac 0.5% or diclofenac 0.1% ophthalmic solutions on inflammation after cataract surgery. Ophthalmology 1998;105:9:1775.}

^{20. Heier JS, Awh CC, Busbee BG, et al. Vitreous nonsteroidal antiinflammatory drug concentrations and prostaglandin E2 levels in vitrectomy patients treated with ketorolac 0.4%, bromfenac 0.09%, and nepafenac 0.1%. Retina 2009;29:9:1310-1313.}

^{21. Bucci FA, Jr., Waterbury LD, Amico LM. Prostaglandin E2 inhibition and aqueous concentration of ketorolac 0.4% (Acular LS) and nepafenac 0.1% (Nevanac) in patients undergoing phacoemulsification. Am J Ophthalmol 2007;144:1:146-147.}

^{22. Hariprasad SM, Callanan D, Gainey S,et al. Cystoid and diabetic macular edema treated with nepafenac 0.1%. J Ocul Pharmacol Ther 2007;23:6:585-590.}

^{23. Bucci FA, Jr., Waterbury LD. Aqueous prostaglandin E(2) of cataract patients at trough ketorolac and bromfenac levels after 2 days dosing. Adv Ther 2009;26:6:645-650.}

^{24. Roberts CW. Pretreatment with topical diclofenac sodium to decrease postoperative inflammation. Ophthalmology 1996;103:4:636-639.}