Surgical applications for NSAIDs

ByWilliam B. Trattler, MD

Surgical applications of nonsteroidal anti-inflammatory drugs are becoming more important in cataract and refractive surgery. As topical NSAIDs are incorporated in presurgical and postsurgical medication regimens, it is important to understand how they improve patient outcomes as well as the optimal dosing regimens. Studies on cataract surgery examining the timing of topical NSAIDs show that better results occur when patients start the medications a few days before surgery. Studies on surface ablation have shown that topical NSAIDs help reduce postoperative discomfort. Studies have also shown that it is important to study new topical NSAIDs to determine how they affect postoperative healing when they are used off-label. Because patients have high expectations with cataract and refractive surgery, optimizing the use of topical NSAIDs in surgery can maximize patient outcomes.

Studies on cataract surgery demonstrate that better results are seen when patients start the medications before surgery.
— William B. Trattler, MD

NSAIDs improve visual outcomes

Eric D. Donnenfeld, MD, and colleagues showed that pre-dosing with topical NSAIDs is effective in maintaining a larger intraoperative pupil size, shortening surgery times, improving ultrasound times, reducing intraoperative and postoperative discomfort and improving visual outcomes (Figure).¹ The study included 100 patients undergoing cataract surgery. Patients pretreated with topical ketorolac tromethamine 0.4% 3 days, 1 day or 1 hour before surgery were evaluated and compared to patients who received placebo. Results showed that the pupil size of patients who received placebo constricted throughout surgery. Pupils constricted less in patients who received ketorolac tromethamine 0.4% 1 day and 1 hour before the procedure. Only patients pretreated 3 days before surgery maintained their pupil size throughout the entire surgical case. Furthermore, preoperative dosing decreased patient discomfort during and after surgery. Patients pretreated with topical NSAIDs 1 day and 3 days before surgery had less discomfort during and after cataract surgery than patients not pretreated with topical NSAIDs.¹

The study also illustrated the beneficial effects of topical NSAIDs on postoperative visual acuity. At postoperative day 1, patients pretreated with NSAIDs 1 day or 3 days before cataract surgery had better uncorrected visual acuity and better best corrected visual acuity than patients receiving NSAIDs immediately preoperatively or patients receiving placebo. These findings of improved vision were also seen at the 2-week visit. Although the difference between the groups narrowed at the 3-month postoperative period, it is important to understand that with high patient expectations, providing a more rapid return of visual functioning is critical to the success of surgery.

NSAIDs and refractive surgery

Because expectations of rapid visual recovery with refractive surgery are high, selecting postoperative medications that do not delay epithelial healing is critical in surface ablation. Kerry D. Solomon, MD, and colleagues examined the speed of healing in a study of 313 patients undergoing PRK, in which ketorolac tromethamine 0.4% was compared to placebo. In this study, ketorolac tromethamine 0.4% was placed directly on the stromal bed before the bandage contact lens and provided a reduction in postoperative pain without causing a delay in epithelial healing.²

NSAID pretreatment improved visual outcomes

Figure. Administering NSAIDs before cataract surgery improves visual outcomes.¹

Figure courtesy of Eric D. Donnenfeld, MD.

In a more recent study, I examined pain control in a double-masked contralateral eye study comparing ketorolac tromethamine 0.4% to nepafenac suspension 0.1% following flapless Epi-LASIK.³ Of note, ketorolac tromethamine 0.4% is approved by the Food and Drug Administration for pain reduction with PRK, whereas nepafenac suspension is a pro-drug that is off-label when used for pain reduction following PRK. Both topical NSAIDs were placed directly on the stromal bed before contact lens placement. Although 30 patients were scheduled to be enrolled, the study was halted after seven patients, because four of the seven eyes treated with nepafenac suspension experienced a significant delay in epithelial healing. The average time for epithelial closure was 2.2 days longer with nepafenac suspension compared to ketorolac tromethamine 0.4%. Six of seven eyes treated with nepafenac suspension experienced early corneal haze, and three eyes had loss of BCVA at the 1-month visit. With extensive use of topical steroids and cyclosporine eye drops, eyes treated with nepafenac suspension had a reduction of haze by postoperative month 3. Rolando Toyos, MD, enrolled five patients using a similar protocol and his patients did not experience delays in epithelial healing. Dr. Toyos and I are working to determine which differences in our methods may explain our different findings.

In a separate study, my colleagues and I evaluated pain and speed of epithelial healing comparing ketorolac tromethamine 0.4% and nepafenac suspension 0.1% in a PRK model.⁴ The study was scheduled to include 40 patients, with 20 patients receiving the topical NSAID directly on the stromal bed and 20 patients receiving the topical NSAID only after the bandage contact lens was placed. As in the Epi-LASIK study, delays in epithelial healing occurred when nepafenac suspension was placed directly on the stromal bed. For this reason, this arm of the study was ended after five patients. Although the study is ongoing, when nepafenac suspension is placed after the bandage contact lens, many patients experienced delays in epithelial healing. The results of 68 cases of delays in healing with nepafenac suspension have been accepted as a poster for the 2006 annual meeting of the American Academy of Ophthalmology.⁴

At the Center for Excellence in Eye Care in Miami, Fla, ophthalmologists conducted a study in which bromfenac sodium was shown to control pain.⁵ Delays in healing or early haze did not occur. Bromfenac sodium was used off-label for pain control in more than 100 eyes. Formal studies are under way to evaluate the safety and efficacy of bromfenac sodium with surface ablation.

Reduced dosing and compliance

The use of topical NSAIDs is important for achieving optimal postsurgical outcomes. Dosing before cataract and refractive surgery improves visual outcomes, stabilizes pupil size and decreases pain and surgical times. A study showed that patients who took medications dosed once or twice a day were more compliant than patients who took medications dosed more frequently.⁶ Reduction in the dosing frequency may help improve compliance following cataract and refractive surgery. Studies looking at compliance with NSAIDs dosed twice a day vs. NSAIDs dosed four times a day with the other postoperative medications must be performed.

Topical NSAIDs can play a valuable role in improving outcomes with cataract and refractive surgery. Pre-treatment with NSAIDs 3 days before cataract surgery maximizes the positive effects of these medications. Topical NSAIDs have also been shown to provide pain control with a high degree of safety with surface ablation. As more surgeons incorporate topical NSAIDs into their cataract and refractive presurgical and postsurgical regimens, ophthalmologists will continue to see the positive impact of this class of medications on surgical outcomes.

References

Donnenfeld ED, Perry H, Wittpen J, Solomon R, Chou T, Snyder R. The dose response curve of a topical NSAID as a surgical tool prior to cataract surgery. Paper presented at: Annual Meeting of the American Society of Cataract and Refractive Surgeons; 2005; Washington, DC.

Solomon KD, Donnenfeld ED, Raizman M, et al. Safety and efficacy of ketorolac tromethamine 0.4% ophthalmic solution in post-photorefractive keratectomy patients. J Cataract Refract Surg. 2004;30:1653-1660.

McDonald MB, Trattler W. Double-masked comparison of ketorolac tromethamine 0.4% versus nepafenac sodium 0.1% for postoperative healing rates and pain control in eyes undergoing surface ablation. Poster presented at: Annual Meeting of the Association for Research in Vision and Ophthalmology; May 2006; Fort Lauderdale, Fla.

Trattler W, Stulting RD, Speaker M, et al. Delayed epithelial healing with nepafenac ophthalmic solution. Poster accepted: Annual Meeting of the American Academy of Ophthalmology; November 2006; Las Vegas, Nev.

Trattler W. Update on surface ablation. Paper presented at: Annual Meeting of the Florida Society of Ophthalmology; December 11, 2005; Boca Raton, Fla.

Ikeda H, Sato M, Tsukamoto H, et al. Evaluation and multivariate statistical analysis of factors influencing patient adherence to ophthalmic solutions. [In Japanese.] Yakugaku Zasshi. 2001;121:799-806.

Discussion

Eric D. Donnenfeld, MD: Dr. Mah, please address the differences between bromfenac sodium and nepafenac suspension and explain why bromfenac sodium is a solution and nepafenac is a suspension.

Francis S. Mah, MD: Bromfenac sodium is a solution similar to the other NSAIDs, whereas nepafenac is a suspension of a gel-like formulation that potentially increases contact time. Small particles of the drug are present within the gel. Placing the NSAID underneath the contact instead of on top may result in a higher concentration of the NSAID. The gel prevents nepafenac suspension from becoming absorbed by the tissues and from escaping from beneath the contact lens. Thus, contact time is increased, which can cause complications.

Donnenfeld: This issue is similar to ciprofloxacin crystallization occurring on epithelial defects with nepafenac suspension. Because crystallization of the suspension probably occurs on the ocular surface, in my opinion it is best to be cautious when placing nepafenac suspension on the ocular surface. More information from controlled studies is needed before ophthalmologists can evaluate nepafenac suspension in surface ablation. Dr. Toyos, what is your recommendation for how long an NSAID should be used after surface ablation?

Rolando Toyos, MD: Nepafenac suspension should be used the day of surgery. Nepafenac suspension is a prodrug, which makes it different from the other NSAIDs. Because nepafenac remains in suspension on its own, the suspension may not be causing the complication. Perhaps the prodrug formulation causes the complication, especially because no other NSAID is a prodrug. When I participated in Dr. Trattler’s study of surface ablation, differences between ketorolac tromethamine 0.4% and nepafenac suspension were not found. Epi-LASIK is a multifactorial surgery in terms of how quickly patients heal. I have had no complications using bromfenac sodium, nepafenac suspension or ketorolac tromethamine 0.4% with Epi-LASIK patients in terms of wound healing, especially when one eye is compared to the other. No differences exist between the eyes. I find the difference in Epi-LASIK in terms of wound healing and handling the flap afterwards. With more experience, I have noticed that patients are healing better. The day of surgery, a drop of the NSAID is used after contact lens placement, in contrast to the use of NSAIDs in Dr. Trattler’s study. Although bromfenac sodium is not placed on the corneal bed, one drop of an NSAID is used immediately after surgery and for 4 days afterward according to recommended dosage. Bromfenac sodium would be used twice a day. Compliance becomes important when a patient is using many drops. Using a drop twice a day instead of three times a day or four times a day is more likely to improve patient compliance.

Y. Ralph Chu, MD: The Food and Drug Administration studies on PRK and multiple studies with NSAIDs have shown that ophthalmologists should minimize the duration of NSAID use. Patients should not use an NSAID if they do not feel considerable discomfort, and they should not use it for more than 3 days.

Donnenfeld: I agree with Dr. Chu. I give patients an NSAID for at least the first day because the second day is often the most uncomfortable. But, in assessing patients postoperatively, it is a clinician’s responsibility to address the healing pattern of the surface ablation. If delayed healing occurs in a patient following surface ablation, then the NSAID should be discontinued because safety is an issue. Nonsteroidals are safe pharmaceuticals when used correctly. Risks occur when NSAIDs are overused for long periods of time and when healing is not assessed. NSAIDs are the most important medication I use following PRK to maintain patient comfort.

Toyos: I use NSAIDs in some patients who are overcorrected after surface ablation, after the epithelium is healed. If a patient is -4 D before surgery and is 1 D after surgery has been performed and the epithelium has healed, I use NSAIDs to treat the hyperopia.