For the past few years, surgeons have had a number of topical NSAID options, including Acular, Acular PF, and Acular LS (ketorolac tromethamine, Allergan), Ocufen (flurbiprofen sodium, Allergan), and Voltaren (diclofenac sodium, Novartis). In the past year, the choices of topical NSAIDs have expanded with approval by the Food and Drug Administration of Xibrom (bromfenac ophthalmic solution, Ista Pharmaceuticals) and Nevanac (nepafenac, Alcon) for use with cataract surgery.
With all of these choices, it is important for practitioners to understand when and how to use topical NSAIDs, so that patients obtain the maximum benefits with the fewest number of postoperative issues. Our understanding of this class of medications has increased with the publication of many peer-reviewed papers, which has allowed surgeons to use topical NSAIDs to make a positive impact on patient care. For example, patients undergoing cataract surgery who have been pretreated with topical NSAIDs have a larger pupil size during surgery as compared to controls. This has allowed for safer and more efficient cataract procedures and has helped reduce postoperative pain and inflammation. Topical NSAIDs also help reduce the risk of postoperative cystoid macular edema.
Cataract Surgery
With this data in mind, one would think that all surgeons would automatically recommend pre- and postoperative topical NSAIDs with every cataract surgery. Interestingly, there is controversy among ophthalmologists as to the optimal pre- and postoperative anti-inflammatory medications with routine cataract surgery. In fact, there are three different points of view on this matter: Some believe topical steroids alone are the best option; others believe topical NSAIDs are the best option; and still others believe in the combination of topical NSAIDs and steroids.
Before delving into this controversy, it may be helpful to further evaluate the medical literature to help determine which regimen provides optimal visual results.
Significant data support the fact that the use of topical NSAIDs pre- and post-surgery provides the many benefits outlined above, including mitigation of macular swelling and prevention of CME. While adverse events have been associated with the use of topical NSAIDs following cataract surgery in the past, the current formulations on the market appear very safe when used appropriately.
In one of the first studies to document the beneficial effects of topical NSAIDs with cataract surgery, the investigators found that patients using topical steroids had a 12 percent incidence of developing postoperative CME, while patients randomized to Voltaren preoperatively and postoperatively avoided the development of CME.1
One of the challenges with patients after cataract surgery is that, even when patients have good postoperative visual acuity as measured on a Snellen chart, subtle or mild CME may be present. In a recent study, Calvin Roberts, MD, found that even when a patient shows no change in Snellen visual acuity, there may be low levels of post-cataract CME and decreased contrast sensitivity.2 In this unpublished study, presented at the 2005 American Society of Cataract and Refractive Surgery meeting, Dr. Roberts tested 200 patients who underwent routine phacoemulsification and were randomized to one of two regimens: a topical antibiotic, topical steroids, and a topical NSAID (Acular LS) or a topical antibiotic and topical steroids, but not a topical NSAID. Evaluation of patients' macular thickness was determined pre- and post-surgery with optical coherence tomography (OCT). Contrast sensitivity was measured one-month postoperatively. The results showed that patients who did not use prophylactic ketorolac had macular swelling and decreased contrast sensitivity. In short, this study demonstrated that the use of topical NSAID drops can reduce CME and improve contrast sensitivity in routine phacoemulsification.
Another study targeted at evaluating CME and NSAIDs found that diclofenac sodium 0.1% solution and ketorolac tromethamine 0.5% topical ophthalmic solution are effective in reducing the severity and duration of CME after cataract surgery and posterior chamber IOL implantation.3 This prospective, randomized study included 34 patients with clinical CME after routine phacoemulsification cataract extraction with posterior chamber IOL implantation. Eyes with CME were treated with one drop four times daily of either diclofenac sodium 0.1% solution or ketorolac tromethamine 0.5% solution. Both drugs provided a significant reduction in CME and significant improvement in visual acuity.
Besides prevention of CME, another important role of topical NSAIDs is enlargement of pupil size during cataract surgery. A study conducted at a teaching hospital in India found that topical ketorolac was more effective at inhibiting miosis than topical diclofenac during extracapsular cataract extraction and IOL implantation.4 Additionally, ketorolac provided a more stable mydriatic effect throughout surgery.
More recently, the importance of pupil dilation in surgical efficiency was specifically evaluated by Eric Donnenfeld, MD, and colleagues.5 In this study, also presented at the 2005 ASCRS meeting, the clinical benefit, relative efficacy and dose response curve of preoperative Acular LS (ketorolac 0.04%) as a surgical tool in cataract surgery was examined. In the study, 100 patients were randomized to four groups to receive preoperative Acular LS for three days, one day, one hour, or placebo in a double-masked fashion prior to phacoemulsification. The maintenance of pupil size, phacoemulsification time and energy, operative time, corneal clarity, postoperative inflammation, and intraoperative and postoperative discomfort were significantly improved with three days of NSAID prophylaxis versus one day of prophylaxis, which in turn was significantly better than instilling the NSAID one hour in advance or using placebo. In addition, there was a trend toward improved pachymetry on postoperative day one and endothelial cell counts at three months in the three-day pre-treatment group relative to placebo. In short, the preoperative use of Acular LS 0.05% for three days significantly improved surgical efficacy and operative outcomes relative to pre-treatment for one day, one hour, or placebo.
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| This 60-year-old male underwent phacoemulsification cataract surgery and intraocular lens insertion. His best-corrected visual acuity dropped to 20/40 following his development of cystoid macular edema. He also has an epiretinal membrane. He was started on a topical NSAID, and over three months, the CME improved and the BCVA improved to 20/20 (see next page). |
One big question is whether a combination of topical NSAIDs with topical steroids is better for CME than topical NSAIDs alone. One study suggests that topical NSAIDs and corticosteroids have the potential for synergistic activity in treating CME. The researchers found that NSAID treatment alone or combination therapy may be more effective than using a steroid alone.6 This randomized, double-masked, prospective trial included 28 patients who underwent cataract extraction and developed CME 21 to 90 days after surgery. Patients were randomized to receive ketorolac, prednisolone or ketorolac and prednisolone combination therapy four times daily. Patients who were treated with combination therapy were more likely to recover two or more lines of visual acuity than patients in the other two groups. Additionally, patients treated with combination therapy or ketorolac monotherapy responded more quickly than patients who received prednisolone monotherapy.
During the past 12 months, I have had the opportunity to use Acular LS, Nevanac and Xibrom for my cataract surgery patients. I am a strong believer that the combination of topical NSAIDs and topical steroids works synergistically to help provide optimal outcomes for my cataract surgery patients, especially those undergoing surgery with a multifocal IOL, where crispness of vision is critical to patient satisfaction. To date, my experience has been very positive with all three medications when used with cataract surgery. I do expect that, in the future, we will have comparative studies of these medications to determine which provides the best results.
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| The same patient described on p. 57, three months after initiating NSAID treatment. Despite the epiretinal membrane the patient"s functional vision returned to 20/20. |
Refractive Surgery
Just as with cataract surgery, NSAIDs play an important role in refractive surgery. With surface ablation procedures, NSAIDs have been shown to be safe and effective for reducing pain and discomfort. A 2001 study found that ketorolac 0.4% ophthalmic solution is safe and effective in reducing ocular pain when used four times daily for up to four days after PRK.7 This multicenter, randomized, double-masked, vehicle-controlled study included 313 patients who underwent unilateral PRK. Postoperatively, 156 patients were treated with one drop of ketorolac tromethamine 0.4% ophthalmic solution four times daily for up to four days, while 157 patients were given vehicle.
Patients in the ketorolac group experienced significantly less pain intensity. In fact, during the first 12 hours after surgery, 50 percent fewer patients in the ketorolac group than in the vehicle group had severe to intolerable pain, and the median time to no pain was 30 hours in the ketorolac group compared to 54 hours in the vehicle group. Throughout the study, patients in the ketorolac group reported significantly greater pain relief than those who received vehicle, and they used significantly less escape medication than vehicle patients for 48 hours after surgery. Additionally, patients in the ketorolac group experienced fewer treatment-related adverse events compared with vehicle patients.
Due to the favorable results when used to control pain with surface ablation, the FDA approved Acular LS for the "reduction of ocular pain and burning/stinging following PRK." Because the other NSAIDs also effectively decrease pain and discomfort, many surgeons are using Xibrom and Nevanac off-label with surface ablation for the reduction of pain. To date, the overall experience with Xibrom when used with surface ablation has been favorable. However, my personal experience with Nevanac for surface ablation has been mixed. Anecdotal, unpublished early reports suggest that Nevanac has worked very well for some patients in this setting.8,9 Other surgeons have reported that they have experienced delays in epithelial healing followed by corneal haze and vision loss.10
Early analysis of the differences between the group of doctors who experienced issues with Nevanac compared to those who had none suggests that delays in epithelial healing can occur when Nevanac is placed on the bare corneal surface, prior to bandage contact lens placement.10 Additionally, some surgeons are recommending that Nevanac should be used for only the first 48 to 72 hours after surface ablation surgery. Further studies are under way to better understand which parameters will make Nevanac safer when used with surface ablation.
Surgeons are fortunate to have a wide choice of topical NSAIDs to assist in improving patient outcomes with both cataract and refractive surgery. With more patients opting for multifocal implants and with higher patient expectations after both cataract and refractive surgery, the ability of topical NSAIDs to prevent macular swelling, reduce postoperative discomfort, and improve quality of vision are critical attributes of this class of medications.
Dr. Trattler is in private practice at the Center for Excellence in Eye Care in Miami. Contact him at (305) 598-2020 or wtrattler@earthlink.net. He has been a speaker for and has received funding for research from Allergan and Alcon, and has consulted for and received research funding from Ista.
1. McColgin AZ, Raizman MB. Efficacy of topical Voltaren in reducing the incidence of post operative cystoid macular edema. Invest Ophthmol Vis Sci. 1999; 40 S289.
2. Roberts CW. NSAID to decrease postoperative macular edema. Presented at the 2005 ASCRS meeting in Washington, D.C.
3. Rho DS. Treatment of acute pseudophakic cystoid macular edema: diclofenac versus ketorolac. Journal of Cataract and Refractive Surgery 2003;29:2378-2384.
4. Srinivasan R, Madhavaranga MS. Topical ketorolac tromethamine 0.5% versus diclofenac sodium 0.1% to inhibit miosis during cataract surgery. J Cat and Refr Surg 2002;28:517-520.
5. Donnenfeld ED. Dose-response curve of a topical NSAID as a surgical tool before cataract surgery. Presented at the 2005 ASCRS meeting in Washington, D.C.
6. 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;107:2034-2039.
7. Solomon KD, Cheetham JK, DeGryse R, et al. Topical ketorolac tromethamine 0.5% ophthalmic solution in ocular inflammation after cataract surgery. Ophthalmology 2001;108:331-337.
8. Lindstrom, R. New Strategies with Ophthalmic Therapeutics for Surgeons. Presented at Royal Hawaiian Eye 2006, Maui, HI, January 2006.
9. Durrie, D. Wavefront-guided Retreatment of Previously Treated Eyes. Both presented at Royal Hawaiian Eye 2006, Maui, HI, January 2006.
10. Trattler, W. PRK and LASEK to Enhance Previous LASIK. Presented at Royal Hawaiian Eye 2006, Maui, HI, January 2006.
