NSAIDs & Steroids Form Dynamic Duo

Cataract surgeons increasingly partner the two to head off cystoid macular edema and improve results.

BY RENÉ LUTHE, SENIOR ASSOCIATE EDITOR

Once shunned for their association with corneal melts, NSAIDs have redeemed themselves in recent years, proving invaluable to a growing number of cataract surgeons. According to these surgeons, two medications are definitely better than one in preventing one of a cataract surgeon's worst nightmares — cystoid macular edema — as well as helping to meet the increasing demands for better visual results.

A Bumpy Start

NSAIDs were infamously linked to corneal melts in the late 1990s, as well as ulceration and even perforation. Further investigation showed, however, that the problems were linked to a generic form of diclofenac. Surgeons agree that branded forms of NSAIDs are safe.

"As long as you don't overdose, you follow the FDA guidelines of dosing and choose your patients correctly, I think that, by and large, NSAIDs are relatively safe medications," says Francis S. Mah, MD, co-medical director of the Charles T. Campbell Ophthalmic Microbiology Laboratory at the University of Pittsburgh. Patients at high risk for inflammation include those with diabetes — a growing demographic in the United States — as well as those with severe dry eye, those with rheumatoid arthritis, patients who have had CME in their other eye and those with a prior history of uveitis or epiretinal membrane.

"All nonsteroidals have some anaesthetic effect on the cornea," cautions John R. Wittpenn, Jr., MD, associate clinical professor of ophthalmology at Stony Brook Medical Center in New York. "It's a secondary effect of the medication itself. And whenever you're dealing with an anesthetic effect in an ocular surface that's already compromised, you have to be very careful."

And while Dr. Wittpenn will start patients with ocularsurface disease on NSAIDs at the time of cataract surgery, he says he watches this group more closely.

New Drugs, New Demands

The high visual standards fostered by the advent of premium IOLs have also helped to make many surgeons regard NSAIDs as an indispensable ally.

"Premiums come with very high expectations, so the cataract patients are really more like the LASIK patients, expecting a lot," explains Terrence O'Brien, MD of Miami's Bascom Palmer Eye Institute. "We have to try to be sure we get the best outcomes."

Applying NSAIDs preoperatively allows the surgeon to use the drug as a tool to prepare the eye for surgery. Their use helps to maintain the dilation of the pupil intraoperatively and to stabilize the blood-ocular barrier.

"This way, the trauma — even minimal trauma from normal surgery — will not trigger a chain of inflammatory events that could lead to postoperative complications such as inflammation or elevated intraocular pressure, or probably the most feared would be cystoid macular edema," Dr. O'Brien says.

The Case for "NSAIDs Plus"

What helped persuade the cataract surgeons who now use NSAIDs in conjunction with steroids to use the drug class after the corneal-melt scare of the late 1990s was the growing body of research indicating their efficacy in reducing rates of CME vs. steroids alone, as well as their ability to control postoperative discomfort. Dr. Wittpenn reports that he has been combining steroids with ketorolac for approximately 10 years now.

"What convinced me that it was worth doing was a study by Mike Raizman in 1999.¹ He demonstrated, using diclofenac in a small group of patients, the rate of CME among those who had steroids only as measured by OCT was, I think, 12%, while the group that got nonsteroidal diclofenac plus steroid was 0%. It was that study that made me think it made some sense to do this on everybody instead of just some of the patients."

It also made Dr. Wittpenn want to experiment further to test NSAIDs' value in the treatment of CME. He used ketorolac in his 2008 study, to see whether it would behave similarly to how diclofenac had in Dr. Raizman's investigation.² It did, he reports, with a group of 268 ketorolac/ steroid patients showing significantly less definite or probable CME than the 278-patient steroid-only group. Additionally, fewer patients in the ketorolac/steroid group showed retinal thickening of more than 10 μm, as compared with the steroid-only group.

Several other recent studies show the greater efficacy of NSAIDs combined with steroids for preventing CME vs. steroids alone, according to Edward J. Holland, MD, professor of ophthalmology at the University of Cincinnati and director of cornea service at Cincinnati Eye Institute. He points to research done by Wolf et al., Lane et al. and Nardi, et al.^3-5

In the June issue of Ophthalmology Management's sister publication, Retinal Physician, Keith A. Warren, MD, reported that "the currently available NSAIDs are effective in both prophylaxis and treatment of CME" and that, for treatment of CME, "combination therapy may in fact offer the best treatment, particularly for recalcitrant CME."⁶

Dr. Holland believes that, while nonsteroidals may be very effective in treating CME, surgeons would be much wiser to be proactive and begin administering them to patients before surgery. For him, it is a classic case of the old adage: "An ounce of prevention is worth a pound of cure."

"There are two camps here, and there shouldn't be," Dr. Holland says. "Some surgeons say, 'I strongly believe NSAIDs are important and I use NSAIDs in all my cataract surgeries.' Then there's the camp that says, 'I don't think they're valuable, it's an extra medication for my patient and I'll use them only if CME occurs.'"

A critical message for surgeons, however, Dr. Holland points out, is that while CME can be treated and then improved in the majority of patients, those patients who recover vision, even to 20/20, will not have the same quality of vision they did before the CME.

"Even in a patient who gets all his vision back, you'll not have retinal performance as you would if you had prevented CME," says Dr. Holland. "Prevention of CME is superior to treatment of CME."

Moreover, Steve A. Arshinoff, MD, of the University of Toronto points out that CME occurs asymptomatically in a significant number of patients, so administering NSAIDs both peri- and postoperatively helps surgeons avoid the problem of previously undiagnosed CME. Dr. Arshinoff says that a not insignificant proportion of patients who do not receive topical NSAIDs demonstrate a delay in achieving optimal acuity. With OCT, transient macular thickening is often seen.

"This is mild subclinical, but not entirely asymptomatic CME," Dr. Arshinoff explains. "It's not surprising that, if part of the eye gets inflamed postoperatively, the whole eye gets inflamed. It's almost childish of us to think that we go in and cut up someone's eye and they won't get any inflammatory response. If we give them medications to prevent that, healing is more rapid."

Like Dr. Holland, Dr. Arshinoff believes that it is better to prevent inflammation than treat it after the fact.

Cystoid macular edema, imaged by widefield angiography.

"An eye is different from a hand," Dr. Arshinoff says. "If you cut your hand, a little scar heals and goes away, but that doesn't affect function in the long term. If you cut your eye and you get a little bit of inflammation, that inflammation can cause degeneration of retinal photoreceptors and some permanent loss of function. By using steroids and NSAIDs together in the postop period, we hope to prevent most cases of CME, or any other inflammation. We like to see the eyes crystal-clear on day one postop and then we give them enough medication to prevent them from getting inflammation afterwards."

Their Working Relationship

While steroids work further "upstream" in the inflammatory cascade, they tend to be less specific in their antiinflammatory effect and may cause serious side effects, such as spikes in IOP or potential infection, Dr. O'Brien points out. However, Dr. Wittpenn notes that steroids also provide additional advantages to the surgeon — namely, a swifter reduction of the sort of cellular response and the ciliarybody discomfort that patients can get with photophobia.

And while steroids block prostaglandins and leukotrienes, Dr. Wittpenn warns that they are not an absolute block. "Things get past them. The way to think of it is that when they bind or they interfere with the cascade, it's a reversible binding. It's a competitive binding. It's there, but it goes on and off, and it can be inundated by more inflammation," Dr. Wittpenn explains.

Nonsteroidals work "downstream," inhibiting the production of prostaglandins by inhibiting the cyclo-oxygenase (COX) enzyme in its two isoforms, COX-1 and COX-2. COX-2 is induced by surgical trauma, Dr. Warren points out.

"The newer non-steroidals have an increased affinity for the enzyme receptor, and therefore they may have a greater potency in inhibiting the cyclo-oxygenase pathway," Dr. O'Brien explains. "So any arachidonic acid metabolites that are spilling into this pathway will be more effectively blocked from ultimately releasing proinflammatory mediators into the eye."

"The nonsteroidals block sort of irreversibly to the enzyme," says Dr. Wittpenn. "Once they've taken that enzyme out of commission, it's done. It's not going to produce any prostaglandins. And so that's why NSAIDs are effective on the prostaglandin side, but they have no effect on the leukotrienes or any other aspect of inflammation. They are strictly a prostaglandin blocker."

Although NSAIDs may not have some of the antiinflammatory benefits of steroids, Dr. O'Brien says that they do offer other protective effects, particularly stabilization of the blood-ocular barrier and CME prevention.

"By using steroids and NSAIDs together, we get a complementary action that really shuts down inflammation at several points on the pathway of inflammation," says Dr. O'Brien.

Dosing Issues

Dr. Arshinoff gives all his cataract patients an NSAID, a steroid and an antibiotic six times a day for the first three days postop and then four times a day until all the bottles are finished. The high dosing during the first days postop is his effort to account for likely noncompliance. A study in Sweden involving eyedrops in bottles with computer chips to record compliance found that, "in almost in every case, for drops given for any indication, the patient takes the drops about half as often as prescribed." Dr. Arshinoff says. "I'm pretty sure that all the drops we give are effective taken three times a day. So I tell them to take them six times a day. If they do, it's fine; it causes no harm and may yield more rapid healing. When they decrease to three times a day, or four, they are very happy; it's a much easier schedule. I tell them to take the drops until all the bottles are empty, because if you give them a date endpoint, they cut short if they feel okay. But if you tell them to take every single drop in the bottle, they hopefully will."

Dr. Mah uses NSAIDs on every patient starting an hour before surgery, as he does his antibiotics. "I'll continue it for typically 3 or 4 weeks. In higher-risk patients, such as patients with diabetes, I'll start it sooner."

He prescribes the steroids as well, in case the patient is among the 5% to 10% of cataract surgery patients who have a more severe inflammatory response.

"I don't want to have to go behind the eightball and start treating the severe inflammation that could result," Dr. Mah explains. "The cost of the steroid is relatively inexpensive and I can quickly taper them off."

His schedule is t.i.d. for one week, then b.i.d. for the second week, and once a day for the third week.

"More Research Is Needed"

Despite the growing embrace of an NSAID-steroid combination for cataract surgery patients, some point out that crucial questions have yet to be resolved. Most significant, to Dr. Wittpenn, is whether all NSAIDs are equally effective.

"The new nonsteroidals will say, 'We're a nonsteroidal. Therefore, we do all the good things nonsteroidals do. But we're different. In one case, we�re a prodrug, and that's better. But don't worry, we still do all the good things.' Another says, 'We're COX-2–specific. But we still do all the good things, and we're comfortable,'" Dr. Wittpenn says. "You really need to look at what the underlying chemical is — what's the prostaglandin?

"People would not assume that all antibiotics behave the same. They would not assume that all glaucoma medications behave the same. But they�re willing to assume that all nonsteroidals will give the same good qualities. I think we want to be a little careful and watch the data."

Dr. Mah is more optimistic. "I think there's some suspicion in some people's minds that industry is driving this, but I think NSAIDs are a necessary part of the medication profile that I use in surgery because of all the benefits: they decrease pain, they decrease inflammation, and the most important thing is the prophylaxis of CME." OM

References

1. McColgin AZ, Raizman MB. Efficacy of topical Voltaren in reducing the incidence of postoperative cystoid macular edema. Invest Ophthalmol Vis Sci. 1999; 40:S289.
2. Wittpenn JR, Silverstein S, Heier J, Kenyon KR, Hunkeler JD, Earl M; Acular LS for Cystoid Macular Edema (ACME) Study Group. A randomized, masked comparison of topical ketorolac 0.4% plus steroid vs steroid alone in low-risk cataract surgery patients. Am J Ophthalmol. 2008 Oct;146:554-560.
3. Wolf EJ, Braunstein A, Shih C, Braunstein RE. Incidence of visually significant pseudophakic macular edema after uneventful phacoemulsification in patients treated with nepafenac. J Cataract Refract Surg. 2007 Sep;33: 1546-1549.
4. Lane SS, Modi SS, Lehmann RP, Holland EJ. Nepafenac ophthalmic suspension 0.1% for the prevention and treatment of ocular inflammation associated with cataract surgery. J Cataract Refract Surg. 2007 Jan;33:53-58.
5. Nardi M, Lobo C, Bereczki A, et al. Analgesic and anti-inflammatory effectiveness of nepafenac 0.1% for cataract surgery. Clinical Ophthalmology. 2007:1:1-7.
6. Warren KA. Current Concepts in the Etiology and Treatment of Pseudophakic Cystoid Macular Edema. Retinal Physician. 2009;6:22-27.