Using NSAIDs in Eye Care
You've used these drugs for years, but have you used them in these instances?
By Robert B. DiMartino, O.D., M.S., Lafeyette, Calif.

We use non-steroidal anti-inflammatory drugs (NSAIDs) widely in oral form to manage pain and to control inflammation and fever. This category of drugs is also available for topical ophthalmic use, and with the appropriate patient and disease condition, it's a valuable treatment modality.

As a group, NSAIDs are relatively safe and effective. With few cautions and side effects, we can simply consider these agents as "aspirin for the eye," which share a common mechanism of action regardless of how we administer them. In fact, because they're in the same family of drugs as aspirin and ibuprofen, the same cautions and contra-indications apply.

Cautions in common

Patients on anticoagulant therapy or who have bleeding disorders can have increased clotting times with oral or topical NSAID use. Anyone who's allergic to aspirin or to other oral NSAIDs shouldn't use these topical agents. Finally, a history of nasal polyps and bronchial asthma are a contraindication for topical or oral NSAID use.

Even with these limitations, NSAIDs are an important group of drugs for the topical control of eye pain and itch. Fortunately, scientists have a good under-standing of the mechanism by which NSAIDs work.

Behind the scenes

Certain naturally occurring chemical substances within the body modulate the sensations of pain and itch. These substances are called prostaglandins and are created as part of a biochemical reaction referred to as the arachidonic acid pathway.

A number of sources produce arachidonic acid, which is synthesized by enzymes into eico-senoids. The enzymes that metabolize arachidonic acid are cyclo-oxygenase and lipoxygenase. The cyclo-oxygenase enzyme pathway converts arachi-
donic acid into prostaglandins. The lipoxygenase enzyme pathway converts arachidonic acid into leukotrienes.

The synthesis of arachidonic acid into the eicosenoids is a competitive reaction. If one of the enzyme pathways is blocked, then all of the available arachidonic acid is converted by the remaining functional pathway into its respective eicosenoid.

NSAIDs inhibit the cyclo-oxygenase pathway and prevent the formation of prostaglandins. Because prostaglandins potentiate sensory neural response, inhibiting their formation reduces the sensation of pain.

NSAIDs and asthma

By preventing the formation of prostaglandins through the inhibition of the cyclo-oxygenase pathway, lipoxygnease metabolizes all of the available arachidonic acid into leukotrienes.

While the role of leukotrienes isn't completely understood, increased levels of these substances have been found in asthmatics during a respiratory event. Serious respiratory crisis has occurred in a patient who has asthma and nasal polyps that were treated with an NSAID.

For this reason, we must consider NSAID use risky for these susceptible individuals and as a contraindication in asthmatics who have nasal polyps. This is true regardless of the route of administration because both topical and oral NSAIDs can precipitate this reaction.

In the beginning

NSAIDs have a place in primary care optometric practice for a number of conditions. The early topical NSAIDs were approved for the treatment of intraoperative miosis. Surgeons noted that pupillary constriction would occur during cataract procedures even though they'd used mydriatic agents. This led to the discovery that prostaglandins develop from surgical trauma. NSAIDs were used to prevent the formation of prostaglandins and resultant intraoperative miosis. The first of these agents were flurbiprofen (Ocufen) and suprofen (Profenal).

Finding a place today

Newer drugs in this group, diclofenac (Voltaren) and ketorolac tromethamine (Acular), have much broader indications, such as the control of postoperative inflammation following cataract surgery and the treatment of seasonal allergic conjunctivitis.

Controlling inflammation. Diclofenac is approved for the treatment of inflammation following argon laser trabeculo-plasty. It's indicated for the control of pain following radial keratotomy or excimer laser procedures as well.

Treating allergy symptoms. The main complaint of seasonal allergic conjunctivitis (SAC) patients is itching. The administration of an NSAID results in a decrease in prostaglandin synthesis by inhibiting the cyclo-oxygenase pathway. This reduces the sensation of itch. When treating this condition, I've found diclofenac or ketorolac of moderate usefulness. Patients can use these agents q.i.d. OU.

NSAIDs don't prevent the degranulation of mast cells from antigenic exposure during an allergic episode. Therefore, it might be prudent to prescribe both an NSAID and a mast cell stabilizing drug concomitantly. This combination therapy will reduce the acute symptoms of itch and the mast cell stabilizer will prevent further allergic episodes.

An NSAID for extended therapy. Keterolac is also approved for the treatment of cystoid macular edema (CME). Research suggests that treatment of CME with NSAIDs requires long-term therapy, often in excess of 1 month, before you can expect any detectable improvement in visual acuity. Fortunate-ly, keterolac is usually well tolerated in extended therapy.

Using NSAIDs off label

Over the years we've discovered many uses for NSAIDs -- both approved and off label. We've already reviewed the approved uses for NSAIDs, so here's a brief rundown of typical situations in which we turn to the off-label use of NSAIDs to help us help our patients.

Relieving pain. All clinicians can relate to the intense pain that patients suffer when they have a corneal abrasion. We also understand the complete, but short-term relief of these symptoms that accompany topical anesthesia. But what can we do for our patients when the anesthesia wears off?

We can place the patient on oral analgesics such as Tylenol #3, but what if you're reticent or not licensed to use oral pain relief agents? Topical NSAIDs play an important role in relieving pain from corneal trauma. I use either keterolac or diclofenac four to five times each day for corneal anesthesia. This approach is equally effective with corneal abrasion patients who've been treated with a pressure patch or a therapeutic contact lens.

I usually start NSAID therapy in the office immediately after instilling an anesthetic and confirming the diagnosis by physical examination. I'll often instill two drops of an NSAID separated by 5 minutes. At the conclusion of the initial office visit, I'll write a prescription for keterolac or diclofenac for the patient to use for 3 to 5 days, although the time interval can vary.

• Using NSAIDs to relieve pain caused by corneal abrasions does carry with it a couple of risks. This indication isn't an FDA-approved use of a topical NSAID and as a result, you have a greater exposure for liability should complications arise.
• Secondly, some reports in the literature suggest delayed epithelial wound healing with some topical NSAIDs. Although I haven't observed a delay in expected epithelial abrasion healing when treating patients with NSAIDs for pain relief, I'd easily trade a 24-hour longer healing time for patient comfort.
• Another concern about the use of NSAIDs for corneal abrasion or other approved indications, is the associated sting upon instillation. In the case of the corneal abrasion patient, I instill the NSAID following topical corneal anesthesia to minimize discomfort.

It's my experience that patients who have a resolving corneal abrasion will often discontinue a topical NSAID when the sting from the drops exceeds the discomfort from their trauma. You can use this transition clinically to identify a juncture in the patient's healing response.

Overall, I've found that patients tolerate NSAIDs well and that they're effective in the topical control of pain from corneal abrasions.

Treating EKC. Another off-label use of topical NSAIDs is in treating epidemic keratoconjuntivitis (EKC). Some clinicians suggest that you use cortico-steroids as a first line treatment for this condition. A more conservative approach is to use corticosteroids only when visual acuity is reduced from corneal infiltrates and you estimate the risk of scarring as great.

Because patients who have EKC are so uncomfortable and there's little therapy other than time, some clinicians use NSAIDs to relieve the pain and discomfort. I've used this yet unapproved therapy with limited success.

Controlling inflammation. A third off-label use of NSAIDs is for the control of intraocular inflammation from surgical trauma or other causes. NSAIDs such as keterolac and diclofenac have been shown to decrease postoperative inflammation although corticosteroids remain the clinical mainstay in treating inflammation.

I've used NSAIDs to treat anterior uveitis without significant clinical success and feel their role is limited for this diagnosis.

A mainstay of practice

NSAIDs have a limited but well-defined role in primary eye care. We can use them safely in most patients to treat eye pain from corneal abrasions and to relieve itching from seasonal allergic conjunctivitis. There's always the possibility of finding yet another use for this group of drugs, so keep an eye out.

Dr. DiMartino is an assistant professor of Clinical Optometry at the University of California, Berkeley School of Optometry and is in group practice in Lafayette, Calif. He is also a fellow in the American Academy of Optometry.

Dr. Christensen has a partnership practice in Midwest City, Okla. He's a diplomate in the Cornea and Contact Lens Section of the American Academy of Optometry. He's also a member of National Academies of Practice.