American Academy of Ophthalmology Web Site: www.aao.org
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March 2005

 
CORNEA

Demystifying NSAIDs
By Marianne Doran, Contributing Writer
 
 

As bromfenac (Xibrom), a new topical nonsteroidal anti-inflammatory drug, nears FDA approval, ophthalmologists are still sorting out topical NSAIDs’ indications and risk-benefit profiles.

“Many of these agents have great promise, but there is confusion about how to use them and which ones to use,” said Ivan R. Schwab, MD, professor of ophthalmology at the University of California, Davis. “The other issue is that we really don’t understand their potential risks at this point—witness Celebrex [celecoxib] and Vioxx [rofecoxib]—on the systemic level.”

In many respects, topical NSAIDs are still trying to carve out their niche in ophthalmology practice. Ketorolac (Acular), for example, is approved for ocular allergy but may not be the first choice for many physicians. And while the drugs’ anti-inflammatory properties are mild compared with those of steroids, much of the inflammation seen in the cornea is immune-mediated and therefore is not responsive to NSAIDs, noted Elisabeth J. Cohen, MD, director of Corneal Associates in Philadelphia.

Mitchell H. Friedlaender, MD, director of cornea and refractive surgery at the Scripps Clinic in La Jolla, Calif., said that early on he had questions about topical NSAIDs’ potential role in ophthalmology. “When they first came on the market, I thought, ‘These are just drugs in search of a use. They’re pretty safe, but where do you use them? If a patient has real inflammation, you’d just use steroids.’” He noted, however, that his opinion has changed as their usefulness has become apparent.

Myriad Applications

Cystoid macular edema. One of the more common and long-standing applications of topical NSAIDs is in the prevention and treatment of CME, especially in people with diabetes. Dr. Schwab said, “Voltaren [diclofenac] and Acular are quite good at preventing CME, and they are also good at rescue. With diabetics, I often will prescribe them before cataract surgery as a preventative.”

Intraoperative mydriasis. Another established use is intraoperative maintenance of mydriasis. Dr. Schwab says flurbiprofen (Ocufen) is a good agent for preventing miosis during cataract surgery.

Ocular allergies. Acular has antiallergy effects, but here NSAIDs compete with other, well-established ocular allergy medications. “I basically never use Acular for allergy because we have better medications available in the mast cell stabilizer agents,” Dr. Cohen said.

Uveitis. Corticosteroids are the mainstay of uveitis treatment, and the value of topical nonsteroidals is unproven in this setting. Nonetheless, some practitioners suggest that NSAIDs may play a supplemental role in controlling the inflammation.

Blepharitis. Because blepharitis typically involves mild inflammation, NSAIDs are being tried in this condition as well.

Steroid-induced IOP. NSAIDs appear to mitigate the increase in IOP caused by corticosteroids.

Pain Relief

Topical NSAIDs can provide pain relief for some conditions:

Corneal abrasion and recurrent erosions. “That’s probably because it numbs the cornea a little and then takes away the inflammation around the corneal nerves,” Dr. Schwab said. “It’s a good anti-inflammatory and a mild anesthetic. You can’t use it forever, but it does appear to be helpful.” He added that the drugs should be used with care in these conditions because the epithelium is especially vulnerable to toxicity.

After LASIK and PRK. Nonsteroidals also are being used for pain relief after LASIK and PRK. In addition, they seem to inhibit fibroblastic migration and change and are mild blockers of neovascularization. In theory, these characteristics mean that NSAIDs may be useful in modifying scarring in LASIK.

Dry eye. “Some people also are using these medications for dry eye,” Dr. Schwab added. “I don’t because dry eye is a chronic condition, and you don’t want to have people on these drugs chronically. But they can temporarily help” with the discomfort of dry eye.

Surgical procedures. Other pain-relief applications include their use in panretinal photocoagulation, strabismus surgery and cycloablation. Dr. Cohen added that she may use a topical NSAID as a single dose at the end of a surgical procedure such as a debridement for a recurrent erosion, but she does not prescribe them for pain.

Corneal Toxicity Concerns

In general, topical NSAIDs appear to be safe, Dr. Friedlaender said. Many people have some burning with the drops, but the burning usually isn’t severe enough for a patient to stop the medication. The lingering unknown is whether scattered reports about corneal toxicity are reason for concern.

“All of these drugs in drop form are epithelial-toxic,” Dr. Schwab said. “That’s no surprise because they damage the epithelium in the gut and elsewhere when used orally. That may have to do with inhibition of sensory stimulus, or they may have direct toxic effects on the plasma membrane or both.”

He continued, “As a result, you can get scattered punctate epithelial keratopathy or even an erosion where those PEKs unite. Even frank melts have been described.” Corneal melting has been related primarily to generic diclofenac, although cases also have been reported with the proprietary Voltaren, he added.

In a review of NSAID-associated adverse corneal events, researchers at the Wilmer Eye Institute found that most confirmed cases involved generic diclofenac. Cases associated with Voltaren or Acular were more likely to have involved ocular comorbidity or the administration of higher total doses. Patients who experienced severe adverse events were more likely to have had a history of diabetes, previous surgery in the affected eye or surgery other than for cataract.¹

Dr. Friedlaender noted that in general the corneal melts are mostly anecdotal reports, and it’s difficult to know how valid they are or whether it was the medication or the patient’s underlying condition that led to the problem.

Other Problems

Patients who need monitoring. “People who have ocular surface disease, such as dry eye or pemphigoid, are at increased risk of intolerance of these medicines, with the potential for significant ocular surface complications. They need to be monitored very closely,” said Dr. Cohen. She added that diabetics also need close monitoring because they frequently have decreased corneal sensation by the time they have diabetic macular edema.

Dr. Friedlaender added that patients with corneal defects or corneal abrasions and those who have undergone PRK are at high risk of adverse effects, as are people with epithelial lesions from herpes infection. “These people would require caution with almost any drops because a lot of the drops do have some toxicity. Because a drop is a combination of things—not just the active ingredient—it’s harder to sort things out and to know whether it was the drug or the benzalkonium chloride.”

Potential drug interactions. Topical NSAIDs can interact with drugs like ciprofloxacin (Ciloxan) and possibly with the other fluoroquinolones, Dr. Schwab said. “I wouldn’t use them together because there may be potential synergism to create epithelial toxicity.”

Delayed healing response. Finally, topical NSAIDs (and topical corticosteroids) have the potential to slow or delay healing, and healing problems are more likely if the two are used together. Dr. Friedlaender noted that there has been some debate about whether these medications interfere with the healing of corneal abrasions or with corneal healing after laser vision correction.

Looking Ahead

Dr. Schwab pointed out that topical NSAIDs can’t be lumped together and that there are subtle differences between drugs. That raises the question of whether the expected approval of Xibrom will add anything new.

“I haven’t had a chance to work with Xibrom much,” he said. “But it’s always worth comparing drugs because we don’t know which one will be best. You need to play with them—and get a feel for them clinically.”

He added that although there have been surprisingly few complaints with the available NSAIDs, he’s still concerned about the long-term unknowns. “I have no trouble being cautious with these medications. We thought Celebrex was the greatest thing going, and all of a sudden we’ve got troubles. These medications hold great promise, but let’s be concerned about the long-term potential for side effects. Our patients’ trust depends on it.”



1 Congdon, N. G. et al. J Cataract Refract Surg 2001;27(4):622–631.



Drs. Schwab and Cohen have no related financial interests. Dr. Friedlaender has been involved with clinical trials for all except Ista Pharmaceuticals.