Are You Getting the Most from NSAIDs?
New products and varied applications are energizing this category.
BY JERRY HELZNER, SENIOR EDITOR

Though all ophthalmologists are familiar with the use of topical nonsteroidal anti-inflammatory drugs (NSAIDs) to control inflammation stemming from a number of common eye conditions, and to treat the pain and inflammation following ocular surgery, not all ophthalmologists appreciate the versatility of these NSAIDs. This article will address some of the ways that topical NSAIDs can be used for a variety of conditions and situations. Also noted in this article is how growth in sales of topical ophthalmic NSAIDs is expected to accelerate as newer, more potent formulations become available.

Interest in topical ophthalmic NSAIDs recently received a boost when the Food and Drug Administration (FDA) approved Xibrom (bromfenac ophthalmic solution 0.09%, ISTA Pharmaceuticals) the first twice-a-day ophthalmic NSAID to be approved in the United States. ISTA believes that Xibrom represents an advance in ophthalmic care because of the drug's potency, it's early onset of action and because twice-daily instillation is likely to improve patient compliance. Xibrom has been used extensively in Japan since 2002, and ISTA reports that the drug has an excellent safety profile.

Also expected to energize the NSAID category is Nevanac (nepafenac ophthalmic suspension 0.1%, Alcon), a formulation that the company says is the first ophthalmic NSAID to be activated in the ocular tissue. Alcon says this mechanism of action allows greater concentrations of the drug to reach the back of the eye. In studies, Nevanac has shown efficacy in the treatment of inflammation and has also proved effective against retinal edema.

Alcon filed a New Drug Application for Nevanac in the first quarter of this year. The drug has been given priority review status and is expected to be approved by the end of 2005.

New additions to the category will join such well-known topical NSAIDs as Acular LS (ketorolac tromethamine ophthalmic solution 0.4%, Allergan) and Voltaren (diclofenac sodium 0.1%, Novartis) in a U.S. ophthalmic anti-inflammatory market consisting of NSAIDs, steroids and other related products with overall sales now estimated at about $250 million a year. According to data on retail prescriptions gathered by Verispan, ophthalmic NSAIDs alone generated almost $100 million in sales in 2004. That was a 15% increase over the prior year. Ophthalmologists generate 62% of all the ophthalmic NSAID prescriptions, and the Acular franchise accounts for 74% of all prescriptions written.

"The NSAIDs market has been growing through wider use of these products in cataract and refractive surgery," says Tim McNamara, Pharm.D, director of Medical Affairs for ISTA Pharmaceuticals. "The market should continue to grow as more potent NSAIDs can replace steroids in some situations. The advantage of NSAIDs over steroids is that steroids can cause significant increases in IOP and also increase the risk of infection while NSAIDs don't present those risks."

NSAIDs with Restasis

One of the more interesting uses of NSAIDs is offered by Barry A. Schechter, M.D., director of the Department of Corneal and External Disease, Rand Eye Institute, Pompano Beach, Fla. Dr. Schechter reports that he began to use the dry eye treatment Restasis (cyclosporine ophthalmic emulsion 0.05, Allergan) for most of his dry eye patients soon after Restasis received FDA approval.

"My success rate with the medication is approximately 85% to 90%, but during the first several weeks of using Restasis, some patients remained symptomatic. For those 10% to 15% of patients who remained symptomatic, I cautiously added Acular LS twice a day, 10 minutes prior to the instillation of Restasis, and monitored these initial patients closely. Almost all of them experienced a significant reduction in their dry eye symptoms."

After treating 400 patients with Acular LS b.i.d. and Restasis b.i.d., Dr. Schechter has observed no adverse events. He generally discontinues the Acular LS at or before 6 weeks of use.

"I have avoided NSAIDs in cases in which Restasis would be unlikely to succeed, such as radiation-induced dryness or limbal stem cell deficiency," Dr. Schechter notes. "I also avoid using NSAIDs in cases where corneal thinning is present and/or perforation might occur."

Dr. Schechter also prescribes concurrent Acular LS and Restasis for patients who complain about stinging upon instillation of Restasis.

"The Acular LS reduces the stinging and helps patients stay compliant until their ocular surface improves," he says.

To test his theories about the benefits of concurrent Acular LS and Restasis, Dr. Schechter initiated a single-center, randomized, 6-week open-label clinical trial involving 23 patients. Some of the patients received Acular LS and Restasis, while other received Restasis alone. Study visits were at baseline, after 2 weeks, and after 6 weeks.

Outcome measures included evaluation of corneal staining, ocular comfort, OSDI and Schirmer scores, and tear break-up time.

After 6 weeks of therapy, Dr. Schechter found that the concomitant use of Acular LS and Restasis provided increased ocular comfort compared to Restasis monotherapy.

On a scale of 1 to 4, the mean ocular comfort score of the patients on both Acular LS and Restasis improved 2.1 points, compared with an improvement of 1.3 points for patients on monotherapy. The study also revealed more significant reductions in corneal staining for the group given both drugs.

"My finding is that using the combination of Acular LS and Restasis in the first few weeks of Restasis therapy may provide a viable method of increasing patient compliance and reducing discomfort," concludes Dr. Schechter.

Chilling Reduces Stinging

Just as Dr. Schechter uses Acular LS to reduce stinging in some patients being introduced to Restasis, John Sheppard, M.D., of Virginia Eye Consultants in Norfolk, Va., uses chilled NSAIDs to reduce stinging in some patients who require multiple medications on a daily basis. For example, for a uveitis patient with dry eye, Dr. Sheppard might prescribe an NSAID, followed in 5 minutes (to avoid washout) by Muro 128, followed in 5 more minutes by homatropine. He notes that Muro 128 stings because of its hypertonicity, and homatropine stings due to a low-formulation pH. Application of the topical NSAID makes the subsequent drops sting less.

He also will chill NSAIDs when treating ocular allergies. He says the chilled NSAID augments vasoconstriction. He cautions that freezing of the NSAID must be avoided so that the medication does not crystallize.

NSAIDs with Surface Ablation

Marguerite McDonald, M.D., F.A.C.S., clinical professor of ophthalmology at the Tulane School of Medicine, New Orleans, has returned to performing only surface ablations in her refractive practice. Recognizing that successful pain management is a key to patients' satisfaction with surface procedures, Dr. McDonald has created a multi-faceted pain management regimen that includes the use of topical ophthalmic NSAIDs.

This regimen includes the following elements:

► vitamin C: 500 mg orally for 1 week before and 1 week after surgery

► Alphagan P: one drop 30 minutes before surgery

► use of chilled BSS throughout surgery

► prednisone tablets: 80 mg given exactly 30 minutes before the laser ablation, followed by 5 more days of oral steroids: 80 mg, 40 mg, 20 mg, 10 mg and 5 mg (previous LASIK patients also get 2 extra days of 80 mg, which serves as a pre-loading dose to prevent DLK).

► Zantac: 150 mg b.i.d. during the time the patient is on oral prednisone

► topical ketorolac: q.i.d. for 3 days post-op

► "comfort drops" (1/20th of 1% tetracaine): every hour while the patient is awake for the first 3 days postoperative, as needed for discomfort

► prednisolone acetate drops: q.i.d. for 1 week postop

► fluoroquinolone antibiotic eye drop: q.i.d. for 1 week postop

► Softlens 66 bandage contact lens: kept on the eye for 6 days postop

► unpreserved artificial tears: every 2 hours postop

► Tylenol Extra Strength: one tab every 4 to 6 hours for pain

► cold packs for 10 minutes after surgery, while the patient is lying flat.

In a study she conducted, Dr. McDonald asked 44 refractive patients who had alcohol-free LASEK to evaluate their pain levels on a scale of 0 to 10, with 0 representing absolutely no pain and 10 representing the worst pain in the patient's life. For this study, she replaced the NSAID she had been using, Voltaren, with Acular LS in 22 patients and found that the Acular LS patients reported an average pain level of 2.0 at 1-day postop. That compared with an average pain level of 3.1 for the 22 patients using the same regimen with Voltaren .

"I found that the improvement in pain reduction with ketorplac was most pronounced at 1-day postop," says Dr. McDonald. "At days 2 and 3, the difference in pain reduction between the two NSAIDs was not as significant."

Dr. McDonald has yet to do a formal pain management study on epi-LASIK patients, but believes they also may be more comfortable with topical NSAIDs in their regimen.

NSAIDS with Corneal Abrasions

Five separate studies have been conducted in recent years in which topical ophthalmic NSAIDs were evaluated for their effectiveness in reducing pain and promoting healing in corneal abrasions. These studies were summarized and reviewed in the June 2003 issue of the Journal of Family Practice.

Overall, the studies demonstrate that NSAIDs are helpful in reducing pain and promoting healing, but some of the researchers point to another advantage in using NSAIDs for patients such as police officers, truck drivers and military personnel who need to return to work quickly and whose jobs require a high level of alertness. Use of NSAIDs avoids the drowsiness and lethargy associated with the narcotic painkillers that affect the central nervous system and that are typically given to patients with corneal abrasions.

Some ophthalmologists may be reluctant to use NSAIDs for corneal abrasions because of an incident that occurred in 2000 when seven cases of corneal melting were initially linked to the use of a generic diclofenac NSAID.

However, a study conducted in 2001 by Allan J. Flach, M.D., cites other factors specific to the individuals who experienced these corneal melts. Dr. Flach concludes that "coexistant factors, other than a simple drug toxicity are implicated, if not causative, in NSAID-associated corneal melting."

Dr. Flach and other researchers note that clinical studies involving hundreds of patients have demonstrated the safety of topically applied brand-name NSAIDs.

Though corneal melting is rare, ophthalmologists may want to consider therapies other than NSAIDs for patients with severe dry eye, pre-existing neurotrophic disease, persistent epithelial defects, or a highly compromised ocular surface. Patients with any of these conditions treated with NSAIDs should be closely monitored.

NSAIDs in Cataract Surgery

Finally, Ralph Chu, M.D., of the Chu Vision Institute in Edina, Minn., offers his approach to using NSAIDs with cataract surgery patients.

Dr. Chu has several uses for topical ophthalmic NSAIDS in the perioperative management of cataract patients. The top three reasons he cites for using nonsteroidals are their importance in the prevention of postop cystoid macular edema, for management of postop inflammation, and in preventing miosis during cataract surgery.

His preferred treatment regimen of topical NSAIDs is q.i.d. for 3 days preop and then q.i.d. for 2 weeks postop, tapered down to b.i.d for 2 weeks for a total of 4 weeks of treatment postop. Preoperatively, the NSAID is used only in conjunction with a fourth generation fluoroquinolone. Dr. Chu believes that this loads the tissues with the appropriate concentration levels of the NSAID, which has been shown in multiple studies to prevent intraoperative miosis.

"Eric Donnenfeld, M.D., and his group have recently done a study showing that not only does the NSAID prevent intraoperative miosis during cataract surgery, but it also increases the ease and smoothness at which the procedure proceeds," says Dr. Chu. "This decreases intraoperative time and improves operative efficiency for all surgeons. We use nonsteroidals in all of our cataract patients because we feel this minimizes the development of clinically significant CME with loss of best-corrected vision."

For patients who are at risk for development of post-operative CME, such as patients with diabetes, Dr. Chu says that he would consider using the NSAID at a higher concentration for a longer period of time, depending on the individual situation.

The Versatile NSAID

Given the variety of ideas for using NSAIDs presented in this article, it is clear that topical ophthalmic NSAIDs should have a place in the ophthalmologist's arsenal of anti-inflammatory and pain-combating drugs. As Dr. John Sheppard concludes:

"With new NSAIDs becoming available, practitioners now have more viable choices for post-cataract inflammation, as well as ancillary uses including allergy, refractive surgery pain and viral keratitis-associated pain."