This article is more than 5 years old. Information may no longer be current.

Preventing cystoid macular edema with NSAIDs

ByJohn R. Wittpenn Jr., MD, FAAO

Add topic to email alerts

Receive an email when new articles are posted on

Please provide your email address to receive an email when new articles are posted on .

Subscribe

Added to email alerts

You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

You've successfully added to your alerts. You will receive an email when new content is published.

Click Here to Manage Email Alerts

Back to Healio

We were unable to process your request. Please try again later. If you continue to have this issue please contact customerservice@slackinc.com.

Back to Healio

Success in ophthalmic surgery has resulted in greater patient expectations. Patients expect excellent visual acuity immediately with no reduction in visual function and without complications such as cystoid macular edema (CME).

Small incision surgery, combined with premium IOLs, including multifocal lenses, allows ophthalmologists to provide patients with excellent distance and near vision. Multifocality, however, requires maximum contrast sensitivity; as the macula receives less light from the respective focal points, the total light must be divided in order to achieve distance focus and near focus simultaneously. Consequently, any loss of contrast sensitivity significantly affects visual function and patient satisfaction.

Changing definition of CME

As a result of these higher standards, the definition of CME has changed over the past several years. In the days of extracapsular surgery, CME was defined as a reduction in visual acuity to 20/40 or less due to macular leakage. In 2006, any reduction in visual function, including loss of contrast sensitivity, even if visual acuity is maintained, that results from a thickening of the macula is considered CME. The risk for CME increases in certain patients, including those with diabetes, vascular occlusion, uveitis, pre-existing CME in the nonsurgical eye, previous ocular surgery in the surgical eye and macular pucker. But whether the more encompassing definition of CME makes it a concern in patients without high-risk factors is yet to be determined.

Changes in the macula following cataract surgery

In 2004, Conceição L. Lobo, MD, PhD, reported on a series of 32 patients, not considered high risk for CME, who agreed to undergo fluorescein angiography and optical coherence tomography (OCT) following uneventful cataract surgery.¹ All patients were treated postoperatively with antibiotic and steroid drops only. At 1 week postoperatively, all eyes but one showed some degree of fluorescein leakage. When measured by OCT at 6 weeks postoperatively, 41% of the eyes showed macular thickening, although best-corrected visual acuity for every patient was 20/25 or better (measured by Snellen visual acuity test). Researchers concluded that Snellen visual acuity is not a sensitive indicator of changes that might occur in the macula. ¹ Michael B. Raizman, MD, conducted a study with similar results, although the macular thickening noted in patients treated with steroids alone was reflected in visual acuity tests.²

In a study involving 200 patients, Calvin Roberts, MD, and colleagues compared the use of steroids plus a nonsteroidal anti-inflammatory drug to the use of steroids alone following cataract surgery (Table 1), measuring visual acuity, macular edema and contrast sensitivity.³

OCT showed significantly less macular thickening in the group of patients receiving both steroids and NSAIDs when compared to those receiving steroids alone, but there was no correlation with visual acuity, as visual acuity measurements for both groups were nearly identical (Table 2).³ Patients who received steroids and NSAIDs, however, had statistically significant better contrast sensitivity than patients who received steroids alone.

Researchers subsequently concluded that macular edema decreases the quality of vision postoperatively by affecting contrast sensitivity. The use of pre- and postoperative NSAIDs decreases the amount of postoperative macular thickening, improving the overall quality of vision in patients. In addition, Snellen visual acuity measurements are not an effective means of measuring macular changes, as changes in contrast sensitivity will not be detected.³ Currently, larger studies on NSAIDs and their effect on the macula are being conducted.

Choosing an NSAID

A number of NSAIDs are available, which complicates an ophthalmologist’s choice for patient treatment. Ketorolac 0.5% (Acular, Allergan, Inc.) has received U.S. Food and Drug Administration approval for a multitude of indications including allergy, ocular inflammation following cataract surgery and ocular pain following incisional refractive surgery. Ketorolac 0.4% (Acular LS, Allergan, Inc.), a change in the formulation of Acular, has received approval for the control of ocular pain, burning and stinging following laser refractive surgery. Despite the change in formulation from ketorolac 0.5% to ketorolac 0.4%, studies have shown that ketorolac 0.4% remains clinically effective in suppressing inflammation and pain (Figure 1).^4-6

Although ketorolac has a long history with a safe profile, it is dangerous to assume such efficacy and safety is applicable to all NSAIDs, particularly in the long-term. Safety issues involving significant corneal melting have been associated with generic diclofenac,^7-9 which went undiscovered until the drug had been available for nearly a year and a quarter million prescriptions had already been written.

Bromfenac 0.9% (Xibrom, Ista Pharmaceuticals) was recently approved by the FDA for the treatment of ocular inflammation following cataract surgery. In two phase 3 trials, bromfenac dosed twice daily was more efficacious than vehicle in the treatment of inflammation following cataract surgery.¹⁰ However, according to data submitted to the FDA, 2% of the patients receiving bromfenac had CME (defined as the presence of macular cysts noted with direct ophthalmoscopy) at 15 days post-treatment.¹⁰

Nepafenac 0.1% (Nevanac, Alcon Laboratories, Inc.) has been approved by the FDA for treatment of inflammation following cataract surgery, proving to be efficacious at three-times-daily dosing compared to vehicle.¹¹

Outcomes of nepafenac’s, bromfenac’s and ketorolac’s phase 3 clinical trials cannot be compared because the protocols for each study were different. To qualify for the ketorolac trial, patients had to demonstrate clinically significant inflammation on day 1 post-surgery. In the nepafenac trial, patients were enrolled regardless of the amount of postoperative inflammation; in the bromfenac trial, patients had to demonstrate a summed ocular inflammation score of 3 or greater to enroll.

Furthermore, all patients enrolled in the nepafenac trial were treated with the NSAID preoperatively as well as postoperatively; no patient in the ketorolac trial or the bromfenac trial received preoperative treatment.

Nepafenac as a prodrug

The active ingredient of nepafenac is amfenac.Nepafenac, as a prodrug, delivers this particular active ingredient into the intraocular environment with statistically significant better penetration than diclofenac (Figure 2).¹² However, the question remains: How much nepafenac is being converted into active amfenac inside the eye? In a recent study conducted by Frank A. Bucci Jr., MD, data showed that ketorolac penetrated into the anterior chamber in levels greater than both nepafenac and amfenac combined.¹³ Data also showed greater suppression of prostaglandin E2 by ketorolac 0.4% than by nepafenac 0.1%.¹³

Conclusion

Prevention of inflammation and CME must meet the challenge of rising patient expectations. Data have shown that pre- and postoperative NSAIDs decrease macular thickening and reduce the risk for CME, and a number of NSAIDs are available. Ketorolac 0.4% has a long history of being safe and efficacious.^14-16 However, NSAIDs such as bromfenac and nepafenac have recently received FDA approval, although no true comparison among the agents exists. Further research including comparative studies must be conducted to enable ophthalmologists to make educated, informed decisions when choosing among these agents.

References

1. Lobo CL, Faria PM, Soares MA, et al. Macular alterations after small-incision cataract surgery. J Cataract Refract Surg. 2004;30(4):752-760.
2. Raizman M. Presented at the annual meeting of the American Academy of Ophthalmology; October 24-27, 1999; Orlando, Fla.
3. Nelson PL, Roberts C. Comparative analysis of prednisolone acetate suspensions. Program/poster 1750/B519, presented at the annual meeting of the Association for Research in Vision in Ophthalmology; May 2, 2005: Fort Lauderdale, Fla.
4. Sandoval HP, Fernandez de Castro LE, Vroman DT, Solomon KD. Comparison of 0.4% ketorolac tromethamine ophthalmic solution vs. 0.5% ketorolac tromethamine ophthalmic solution to prevent inflammation after phacoemulsification and intraocular lens implantation: a prospective, randomized, double-masked, clinical trial. Program/poster 796/B770, presented at the annual meeting of the Association for Research in Vision and Ophthalmology; May 1, 2005; Fort Lauderdale, Fla.
5. Bucci FA, Evans RE, Amico LM. Comparison of ketorolac 0.5%, ketorolac 0.4%, and diclofenac 0.1% combined with prednisolone 0.1% on aqueous flare following cataract surgery. Program/poster 789/B763, presented at the annual meeting of the Association for Research in Vision and Ophthalmology; May 1, 2005; Fort Lauderdale, Fla.
6. Bucci FA, Evans RE, Amico LM. Efficacy of ketorolac 0.5% versus ketorolac 0.4 following cataract surgery. Program/poster 790/B764, presented at the annual meeting of the Association for Research in Vision and Ophthalmology; May 1, 2005; Fort Lauderdale, Fla.
7. Flach AJ. Corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs. Trans Am Ophthalmol Soc. 2001;99:205-210; discussion 210-212.
8. 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.
9. Gaynes BI, Fiscella R. Topical nonsteroidal anti-inflammatory drugs for ophthalmic use: A safety review. Drug Saf. 2002;25(4):233-250.
10. Xibrom [package insert]. Irvine, Calif.; Ista Pharmaceuticals; 2005.
11. Nevanac [package insert]. Fort Wort, Texas: Alcon Laboratories, Inc.; 2005.
12. Ke TL, Graff G, Spellman JM, Yanni JM. Nepafenac, a unique nonsteroidal prodrug with potention utility in the treatment of trauma-induced ocular inflammation: II. In vitro bioactivation and permeation of external ocular barriers. Inflammation. 2000;24(4):371-384.
13. Amico LM, Bucci FA Jr., Waterbury D. Aqueous PGE2 inhibition of ketorolac 0.4% vs. nepafenac 0.1% in patients undergoing phacoemulsification. Program/poster 2602/B761, presented at the annual meeting of the Association for Research in Vision and Ophthalmology; May 2, 2005; Fort Lauderdale, Fla.
14. Congdon NG, Schein OD, von Kulajta P, et al. Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs. J Cataract Refract Surg. 2001;27(4):622-631.
15. Price MO, Price FW. Efficacy of topical ketorolac tromethamine 0.4% for control of pain or discomfort associated with cataract surgery. Curr Med Res Opin. 2004;20(12):2015-2019.
16. Donnenfeld ED, Perry H, Wittpenn J, et al. Efficacy of pre-surgical ketorolac tromethamine 0.4% to improve phacoemulsification clinical outcomes: A pharmacokinetic response curve. J Cataract Refract Surg. In press.