Therapeutic Insights
NSAIDs in Practice

Coordinated by Bobby Christensen, O.D., F.A.A.O.

A guide to alternative uses for these agents.

By Scot Morris, O.D., F.A.A.O., Leawood, Kans.

Topical pain management is still the primary focus for the use of non-steroidal anti-inflammatory drugs (NSAIDs), but we can use them for many other applications. We can use these agents as anti-inflammatories or as adjuncts to other medical therapies to increase efficacy and patient compliance. This article will look at these alternative uses for NSAIDs in optometric practices.

Available drugs

The two ophthalmic topical NSAIDs generally available to clinicians today are approved for the management of post-op inflammation after cataract extraction when used q.i.d. 24 hours after cataract surgery and continuing through the first 2 weeks of the post-op period. Both preparations are sterile isotonic aqueous solutions fairly equivalent in penetration of the ocular surface and in their effect on the cyclo-oxygenase pathway. They are:

• Ketorolac tromethamine 0.5% (Acular and Acular PF). This NSAID is also approved to provide temporary relief of itching associated with seasonal allergic conjunctivitis when used q.i.d. Ketorolac is preserved with benzylkonium chloride but also comes in a non-preserved version (Acular PF).
• Diclofenac sodium 0.1% (Voltaren). Approved for the temporary relief of pain and photophobia in corneal or refractive surgery patients, diclofenac is preserved with ascorbic acid.

Mechanism

Use NSAIDs to manage pain in a recurrent corneal erosion like the one above.

The primary mechanism of action with NSAIDs is through the inhibition of the enzyme cyclo-oxygenase I (COX-1). This enzyme is essential in the production of many components of the inflammatory cascade including prostaglandin (PGE2), prostacyclin (PGI2) and thromboxane (TXA2). Specifically, PGI2 and TXA2 have proven their importance in the regulation of blood flow.

Inhibition of the inflammatory cascade may help to decrease localized vasodilation and vascular permeability. This not only limits localized edema, but also exposure of the area to various inflammatory components found in the bloodstream. NSAIDs may also have some effect on cyclo-oxygenase II (COX-2) components by decreasing cellular sensitivity to histamine and bradykinins.

NSAIDs also act to inhibit prothrombin synthesis, which may lead to prolonged bleeding and clotting time. Unlike steroids, NSAIDs have no effect on the lipo-oxygenase pathway and so no effect on the leukotrienes, which are responsible for chemotaxis and white blood cell migration.

"Non-approved" uses

"Non-approved" clinical uses for NSAIDs include managing pain and inflammation on the ocular surface. The following section will discuss other "non-approved," yet common, applications for topical and oral NSAIDs.

	NSAIDs are useful in treating inflammation associated with allergies

• Analgesic applications. The effect NSAIDs have on pain is most likely an elevation of peripheral nerve threshold above symptomatic awareness. The following are some analgesic applications for NSAIDs.
  • Use topical NSAIDs as an analgesic to prevent chronic pain for patients who have psuedo-phakic bullous keratopathy (PBK). Use them judiciously, however, because of the likelihood of overuse and the risk of developing corneal toxicity as well as superficial ocular infection and infiltrate formation.
  • In fact, in managing ocular surface abrasion and recurrent corneal erosion (RCE), it has become a standard practice to use a therapeutic bandage contact lens, cycloplegia, lubricants and topical antibiotics to provide prophylaxis and to use topical NSAIDs to provide effective analgesia.
    Though topical NSAIDs may slightly reduce the overall epithelial healing rate, effectively managing ocular surface pain is crucial to the patient's recovery during the epithelial healing process. As with any epithelial defect, it's critical that you follow these patients daily until the epithelium has healed completely. You may then taper the NSAIDs as needed to provide sufficient comfort.
  • In instances where the patient has had a foreign body on the ocular surface, use topical NSAIDs to manage the pain and to control localized surface inflammation from the trauma.
  • You may use NSAIDs in severe flare-ups of vernal or atopic conjunctivitis to manage ocular discomfort and inflammation while initiating the use of a mast cell stabilizer.
    Use topical NSAIDs as well in instances where patients are non-responsive to topical antihist-amines or mast cell stabilizers and short-term steroid use is contraindicated. Both of the topical NSAIDs have been effective in treating hyperemia, edema and itching associated with an allergic reaction of the ocular surface.
  • Similarly, you may use topical NSAIDs to manage symp-toms associated with giant papillary conjunctivitis (GPC).
  • One of the primary uses of topical NSAIDs in optometric practices is to manage postoperative pain and inflammation after corneal surgery, and specifically, refractive procedures. It's common in most refractive practices to administer one of these agents to patients in the immediate postoperative period to manage discomfort associated with ocular surface disruption that occurs during flap adherence.
    In many practices, optometrists pretreat patients prior to surgery to control chemotaxis. Many studies show that pretreatment or immediate postoperative treatment is significantly better than long-term treatment. Use these agents judiciously and discontinue use after the epithelial cells have covered the flap gutter.
  • You may want to use topical NSAIDs in patients who have a low pain threshold during initial rigid gas permeable (RGP) contact lens wear. Again, use these agents as a short-term analgesic during this adaptation period because of the potential for infection, epithelial shedding and defects with chronic use.
  • For pain associated with infectious bacterial keratitis, use topical non-steroidal agents to provide analgesia, increase compliance and decrease the overall inflammatory response when used in conjunction with topical antibiotics.
    Use special care when treating viral keratitis because prolonged use of topical NSAIDs may exacerbate epithelial herpes simplex keratitis (HSK).
  • Many studies suggest that treatment of epidemic keratoconjunctivitis (EKC) with topical NSAIDs may be a safer alternative than topical steroids for the treatment of the subepithelial infiltrates as well as the ocular discomfort associated with EKC.
• Anti-inflammatory applications. In addition to pain management, you may also use NSAIDs to effectively control mild ocular inflammation.
  • Use topical NSAIDs either primarily or as an adjunct therapy with topical or oral steroids in cases of anterior uveitis and episcleritis. These agents may also be used to "melt" fibrin deposits of the optic of an IOL or to melt an inflammatory membrane after a uveitic attack.
  • Many surgeons, before surgery on a second eye with a history of cystoid macular edema (CME), epiretinal membrane (ERM) or uveitis, may choose to pretreat the patient with one of the topical NSAIDs and continue post-op well after topical steroids are discontinued to prevent or reduce CME.
  • For patients who are steroid responders, topical NSAIDs may provide significant anti-inflammatory action for conditions such as CME, uveitis and various ocular surface disorders without the secondary increase in intraocular pressure (IOP).
  • Recent reports highlight the successful treatment of refractive surgery overcorrection when one of the topical NSAIDs is used in conjunction with a steeply fit and tightly adherent contact lens to induce regression on LASIK and PRK patients. The NSAID may lead to epithelial proliferation and thickening of anterior stroma. The contact lens then induces hypoxia and increases mechanical stress. This process has been termed contact lens assisted, pharmacologically induced kerato-steepening (CLPIKS).

Adverse effects

Adverse effects are possible with topical non-steroidals. In controlled clinical studies, the most frequent adverse events reported are transient stinging and burning on instillation in app-roximately 40% of patients. It's recommended that when you educate the patient about his medication and condition, you also remember to mention the possibility of these adverse effects.

In all development studies conducted, other adverse events occurring less than 5% of the time included ocular irritation, allergic reactions, superficial ocular infections and superficial keratitis, dry eye, corneal infiltrates and blurred vision.

Many of the complaints of irritation and superficial keratitis may be caused by the effects of the preservative, if used frequently. If the epithelium is compromised, consider preservative-free preparations.

It's also been well documented that these drugs will decrease epithelial healing time, though to less of a degree than topical steroids. Since chemotaxis isn't prevented, use caution with NSAIDs in large open epithelial breaks because white blood cells will migrate into the area and potentially accumulate and create a dense infiltrate.

Also use topical NSAIDs with caution in patients with known bleeding tendencies or with patients who are concomitantly taking anti-coagulants because of the risk of sub-conjunctival hemorrhage or hyphema -- especially those patients who are undergoing ocular surgery. Generic diclofenac was shown to cause corneal melt and has since been voluntarily recalled.

Treat early and appropriately

Use NSAIDs to melt corneal infiltrates

Topical NSAIDs have various uses in managing pain and ocular surface inflammation when used alone or adjunctively with other agents. Remember, it's always easier to prevent pain and inflammation than to try to play catch-up.

Treat early, aggressively and synergistically with systemic and other topical agents, such as steroids, but use caution in prolonged treatment. The overall best theory is to use sound clinical judgment and know what therapy is appropriate and what's not. 

Dr. Morris has no direct financial interest in the products mentioned in this article. He is a member of the Discover Vision Centers refractive surgery team and the American Optometric Association.