Article Date: 9/1/2006

CONTINUING MEDICAL EDUCATION
Comparing NSAIDs
Experts share their views on the available agents.

Dr. Heier: I would like to know how everyone perceives the efficacy of the different nonsteroidal anti-inflammatory drugs.

Dr. Rho: I have studied diclofenac sodium 0.1% ophthalmic solution (Voltaren), ketorolac tromethamine 0.5% ophthalmic solution (Acular) and bromfenac ophthalmic solution 0.09% (Xibrom). According to data I published in 2003, ketorolac and diclofenac were equally efficacious in treating pseudophakic CME — in percentage of CME resolution and visual outcomes.1

The data for bromfenac show that it trends toward superiority over diclofenac and ketorolac with p-values of 0.28 and 0.25, respectively. Therefore, in my experience, these agents are equally efficacious in the treatment of acute pseudophakic CME. One advantage bromfenac offers over either ketorolac or diclofenac is b.i.d. dosing. As a result, I have noticed an improvement in patient compliance. Patients respond positively to instilling one drop twice a day versus three or four times a day.

IS SAFETY A CONCERN?

Dr. Heier: I wonder about the safety of these agents, especially in light of the reports of corneal melts in 1999 and 2000.

Dr. Orellana: Recent issues are possible delays in epithelial healing, corneal haze and vision loss associated with nepafenac ophthalmic suspension 0.1% (Nevanac) after refractive surgery. The studies completed in Japan and the United States on bromfenac ophthalmic solution 0.09% showed it is a safe drug, with no significant adverse effects.2 In addition, bromfenac has been prescribed to more than 7.8 million patients in both the U.S. and Japan with only a 0.0002% serious ocular adverse event rate.3 Some of the study findings were as follows:

1. The b.i.d. dosing of bromfenac ophthalmic solution 0.09% resulted in statistically significant visual improvement comparable to results achieved through q.i.d. dosing of diclofenac sodium and ketorolac tromethamine 0.5% ophthalmic solution. Researchers made this comparison based on randomized treatment of 64 patients during a 3-month period when all three agents were used to treat cystoid macular edema (CME) that was less than 1 year in duration.4

2. Preoperative instillation of bromfenac ophthalmic solution 0.09% resulted in a peak aqueous humor concentration 150 to 180 minutes after administration, at a mean concentration of 78.7 ng/mL.5 This data, derived from a study of 64 subjects, suggested bromfenac may remain at an effective concentration in the aqueous humor more than 12 hours and can be found in retinal tissue at 24 hours.6

3. Bromfenac ophthalmic solution 0.09% rapidly resolved ocular pain after cataract surgery, demonstrating better statistically significant effects than placebo. This success, based on a randomized study of 527 subjects, was achieved without pretreatment.7

ANTERIOR PERSPECTIVE

Dr. Heier: These are impressive early findings. Dr. Mah, as an anterior segment surgeon, how do you respond to these data?

Dr. Mah: As far as determining which agent is clinically superior, I am still waiting for more data. One important consideration is dosing implications. As Dr. Orellana mentioned, ketorolac tromethamine 0.5% ophthalmic solution and diclofenac sodium must be used q.i.d. Nepafenac ophthalmic suspension 0.1% requires t.i.d. dosing. Bromfenac ophthalmic solution 0.09% requires b.i.d. dosing. Many studies, particularly in the glaucoma literature where therapy is chronic, show that patient compliance increases when required dosing frequency decreases.8,9 Twice-a-day dosing is particularly helpful when you are treating a patient prophylactically.

Another measure, in vitro, is potency. Continuing studies will help determine whether potency makes a clinical difference in terms of managing inflammation and pain.

And what is the significance of penetration differences? If we're trying to treat prophylactically and also address a posterior segment disease or condition, penetrating the posterior segment makes sense. On the other hand, most of the important inflammation related to cataract surgery occurs in the anterior segment where we should target prostaglandin synthesis.

As Dr. Orellana stated earlier, one study found similar concentrations of bromfenac ophthalmic solution 0.09% when observed 24 hours after instillation in the aqueous humor, iris/ciliary body, choroid and, to a slightly lesser extent, the retina.6 This study, based on 14 to 18 randomly assigned rabbit eyes, suggests a favorable effect may be possible throughout the eye. The drug was also well tolerated. So penetration is an evolving issue. The data being presented are excellent and should help us further our decision-making.

The final factor for me, as an anterior segment specialist, is toxicity. In response to reports of corneal melts in 1999 and 2000, many anterior segment surgeons began avoiding NSAIDs. Reviewing the studies, such as the one focusing on photorefractive keratectomy and epithelial wound healing, will be very important as we look at differences in toxicity. Obviously, we want to choose the agent that is the least toxic.

Right now, we're compiling data for a study of the effects of 3 days of dosing with ketorolac tromethamine 0.5% ophthalmic solution and nepafenac ophthalmic suspension 0.1% in patients who have undergone uncomplicated cataract surgery. As the data from controlled trials accumulate, we will be in a better position to make the best decisions for our patients.

EXCITING NEW MEDICATIONS

Dr. Mah: The important point is that we have these exciting new medications. We have discussed the number of days we should use them preoperatively and learned there are studies showing 3 days may be optimal. But I don't think that's been definitively determined by existing studies. I think the optimum use of NSAIDs will be defined through prospective studies in the next several years. Optimal postoperative periods will also need to be determined. Should we stop at 2 weeks? Four weeks? Eight weeks? We really have no idea based on scientific data when to stop NSAIDs. If you ask 100 anterior segment specialists, you will probably get 100 different answers.

A lot of this will become clearer with time.

Looking into The Future

Jeffrey S. Heier, MD: As we move forward with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), what developments can we expect?

Seth Yoser, MD: We all appreciate and respect the fact that most of the research has been done in animals. But the reality is that we are treating patients who are in the best position to tell us what is working and what is not. We need to look at distinguishing factors.

For example, bromfenac ophthalmic solution 0.09% (Xibrom), with its impressive ability to penetrate, is present in the eye for more than 24 hours. It reminds me of the long-acting prostaglandin analogues that have been used so effectively to treat glaucoma. I think it is possible this medication will be approved for once-a-day dosing.

What's more, if we can get to the point where we can combine an NSAID with an antibiotic, we might create a postoperative standard of care for cataract surgery. Or if we can combine an NSAID with a corticosteroid, that could prove to be a powerful treatment as well.

Juan Orellana, MD: Determining the extent of penetration you can achieve when combining medications may become a key consideration. The study findings in the pipeline may alter how anterior segment surgeons treat patients prophylactically. A big issue always will be compliance. Patients prefer a b.i.d. versus a q.i.d. dosing schedule. If the patient is compliant with his or her medication, there is a better chance the medication in question will be helpful in preventing postoperative CME.

Dr. Heier: We will also need to separate hype from reality, as we usually need to do after the release of a new medication. In retinal care, we see a lot of cystoid macular edema patients. So many new agents and new treatments are coming out for several different diseases. It will be incumbent upon us to examine the data and recognize what is really a clinically significant benefit to our patients. Efficacy and safety should be the driving forces.

NSAIDs vs. Corticosteroids

Jeffrey S. Heier, MD: We know nonsteroidal anti-inflammatory drugs (NSAIDs) block cyclo-oxygenase, the enzyme that converts arachidonic acid to prostaglandins. By stopping prostaglandins, we avoid postoperative inflammation, miosis, lower pain thresholds and photophobia. What about corticosteroids?

David S. Rho, MD: The mechanism of action of corticosteroids is higher in the inflammatory cascade with inhibition of phospholipase-A2 blocking both the cyclo-oxygenase and the lipo-oxygenase pathways. The cyclo-oxygenase pathway is important in the inflammatory process because it creates prostaglandins as we have discussed. The lipo-oxygenase pathway is responsible for leukotriene synthesis.

Theoretically, inhibition of both pathways could achieve greater anti-inflammatory effects than inhibition of either cyclo- or lipo-
oxygenase singularly. However, corticosteroids have potential risks that do not exist for NSAIDs such as IOP increases and potiential activation of antecedent viral or fungal infections.

REFERENCES

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

2.   Kawaguchi T, Kida T, Nemoto S, et al. Effect of bromfenac ophthalmic solution on ocular inflammation and corneal epithelial barrier function following cataract surgery. Folia Jpn. 2003;54:276.

3.   Data on file: Safety. ISTA Pharmaceuticals.

4..   Rho DS, Soll SM, Markovitz BJ. Bromfenac 0.09% versus diclofenac sodium 0.1% versus ketorolac tromethamine 0.5% in the treatment of acute pseudophakic cystoid macular edema. Presented at The Association for Research in Vision and Ophthalmology; April 30-May 4, 2006; Fort Lauderdale, FL.

5.   Ogawa T, Miyake K, McNamara TR, et al. Pharmacokinetic profile of topically applied bromfenac sodium ophthalmic solution 0.1% in subjects undergoing cataract surgery. Presented at The Association for Research in Vision and Ophthalmology; April 30-May 4, 2006; Fort Lauderdale, FL.

6.   McNamara T, Baklayan GA, Deshmukh HM, et al. Concentrations of radioactivity in ocular tissues following a single topical ocular dose of c-Bromfenac ophthalmic solution (Xibrom). Presented at The Association for Research in Vision and Ophthalmology; April 30-May 4, 2006; Fort Lauderdale, FL..

7.   Seward MS, Cooke DL, Grillone LR, et al. Topical Xibrom 0.09%, significantly reduced ocular pain following cataract surgery. Presented at The Association for Research in Vision and Ophthalmology; April 30-May 4, 2006; Fort Lauderdale, FL.

8.   Goni FJ. Brimomidine/Timolol Fixed Combination Study Group. 12-week study comparing the fixed combination of brimonidine and timolol with concomitant use of the individual components in patients with glaucoma and ocular hypertension. Eur J Ophthalmol. 2005;15:581-590.

9.   Stewart WC, Konstas AG, Pfeiffer N. Patient and ophthalmologist attitudes concerning compliance and dosing in glaucoma treatment. J Ocul Pharmacol Ther. 2004;20:461-469.

Great Expectations

Please select the single best answer and indicate your choice on the Evaluation Form on the next page.

1. How does Francis S. Mah, MD, use NSAIDs for cataract surgery?

a. Prevent cystoid macular edema
b. Control inflammation
c. Prevent miosis during surgery
d. All of the above

2. According to studies by Flach, Gaynes and others, the incidence of CME increased in 1999 and 2000 when many anterior segment surgeons stopped using NSAIDs because of reports of corneal melts.

a. True
b. False

3. Seth Yoser, MD, recommends aggressive treatment with NSAIDs before and after cataract surgery for patients who have which of the following characteristics?

a. History of wet age-related macular degeneration
b. Poorly controlled keratoconus
c. Dry eye
d. Diabetes without complete resolution of macular edema, following a laser treatment or triamcinolone acetonide (Kenalog) injection

4. According to Dr. Yoser, patients with a history of viral keratitis, poorly controlled uveitis or inflammation in the fellow eye will benefit from preoperative dosing of an NSAID how many days before surgery?

a. 1, 2 or 3
b. 4 or 5
c. 6 or 7
d. 8 

5. According to Dr. Mah, patients who are not at risk for complications following cataract surgery and who are following a normal postoperative course can continue with an NSAID for 2 to 3 weeks?

a. True
b. False  

6. According to panel members, you can use an NSAID for better patient outcomes after which type of surgery?

a. Selective laser trabeculoplasty
b. Retinal laser treatments
c. Vitrectomies
d. All of the above

7. NSAIDs effectively block which enzyme that converts arachidonic acid to prostaglandins?

a. Phospholipase A2
b. Lipo-oxygenase
c. Cyclo-oxygenase
d. Hydrolase

8. Which complication can result from using an intraocular corticosteroid to treat CME?

a. Endophthalmitis
b. Secondary cataract development
c. IOP spikes
d. All of the above

9. According to Juan Orellana, MD, which of the following risk factors is a contraindication for intravitreal steroid injections?

a. History of dry AMD
b. History of glaucoma
c. History of blepharitis
d. History of papillary conjunctivitis

10. Typically, what is the visual acuity of the 30% to 40% of Dr. Heier's patients who don't respond to vitrectomy surgery for CME?

a. 20/40
b. 20/60
c. 20/100
d. 20/200 or worse

11. If a patient is experiencing less-than-optimal, postoperative vision, which routine test can you perform to help identify CME?

a. Optical coherence tomography
b. Amsler grid
c. Contrast sensitivity
d. All of the above

12. According to Dr. Orellana, usually you will see CME in children only if they've undergone extracapsular extractions with anterior vitrectomies.

a. True
b. False  

13. According to a study by Michael B. Raizman, MD, what was the incidence of postoperative CME among patients who did not receive post-extraction NSAID therapy?

a. 5%
b. 12%
c. 20%
d. 40%

14. When edema becomes persistent, what complication could occur that may lead to photoreceptor damage and progressive fibrosis?

a. Retinal thinning
b. Choroidal neovascularization
c. Retinal vein occlusion
d. Retinal tearing

15. Which diagnostic test is critical in differentiating between the different causes of CME?

a. Ocular coherence tomography
b. Fluorescein angiography
c. Amsler grid
d. Contrast sensitivity  

16. A telltale sign of pseudophakic CME is angiographic disc hyperfluorescence.

a. True
b. False  

17. What signs or symptoms should alert you that perhaps something other than CME is present?

a. Macular leakage
b. Occlusions
c. Posterior uveitis
d. All of the above  

18. According to data published by David Rho, MD, ketorolac tromethamine 0.5% ophthalmic solution (Acular) and diclofenac sodium 0.1% ophthalmic solution (Voltaren) were equally efficacious in treating pseudophakic CME.

a. True
b. False

19. According to McNamara and colleagues, data derived from a study of 64 subjects suggested bromfenac ophthalmic solution 0.09% (Xibrom) remained in the aqueous humor more than 12 hours and in retinal tissue for what duration?

a. 12 hours
b. 24 hours
c. 36 hours
d. 72 hours

20. In Dr. Orellana's experience, which dosing schedule for administering NSAIDs is most favorable for patient compliance?

a. Once a day
b. Twice a day
c. Three times a day
d. Four times a day



Retinal Physician, Issue: September 2006