Rx Perspective
Using NSAIDs to Full Potential
Expert guidance on maximizing utility, safety and efficacy.
COORDINATED BY PAUL N. SCHACKNOW, M.D., PH.D.

Nonsteroidal anti-inflammatory drugs are extremely versatile. Oral NSAIDS are highly effective in the treatment of rheumatoid arthritis and osteoarthritis, as well as post-traumatic inflammatory pain syndromes. In ophthalmology, global indications include analgesia, mydriasis, and inflammation. Oral and topical NSAIDs are used to control the ocular pain and inflammation associated with a variety of conditions. (See "A Key Tool in Our Armamentarium,")

We have several NSAIDs in topical form specifically for the eye at our disposal:

• diclofenac (Voltaren, Novartis Ophthalmics)
• ketorolac (Acular, Allergan Pharmaceuticals), which is also available in preservative-free single-dose units
• flurbiprofen (Ocufen, Allergan Pharmaceuticals) and suprofen (Profenal, Alcon) are approved for intraoperative miosis
• Akorn Inc. is awaiting FDA approval for piroxicam for topical ophthalmic use.

Some important points about using NSAIDS as safely and effectively as possible:

NSAIDs work well as preventive medication. Because inflammatory precursors must be processed by enzymatic cascades leading to mediator substances including prostaglandins, interruption and downregulation of this process before an anticipated inflammatory insult is extremely useful to the clinician. Therefore, pretreatment with a topical NSAID prior to elective eye surgery can reduce the overall extent of postoperative inflammation and the total amount of postoperative anti-inflammatory medications required.

Also, low-dose NSAID drops can play an important role in preventing the recurrence of scleritis, uveitis, or cystoid macular edema. I find that a drop a day, or even a drop a week, can prevent recurrences of these conditions, or at least limit the frequency, duration and severity of recurrences in predisposed individuals. NSAID drops are ideal for maintenance therapy because of their remarkable safety profile, particularly when compared with most topical steroids.

NSAID drops sting less when chilled. Medications that sting because of formulation requirements or low equilibrium pH become more comfortable if chilled prior to application. Chilling is also effective when NSAIDS are being used as a treatment for allergy because it augments vasoconstriction. Inadvertent freezing should be avoided due to crystallization of the medication.

Furthermore, a topical NSAID will make subsequent drops sting less, which is strategically important for squeamish patients who require multiple medications every day. For example, a uveitis patient who has dry eye can start his regimen in the morning with his NSAID, followed in 5 minutes (to avoid washout) by Muro 128, followed in 5 more minutes by homatropine. Muro 128 stings due to its hypertonicity, and homatropine stings due to a low formulation pH.

NSAID drops work instantaneously as analgesics. Pre-treatment with a drop of topical NSAID makes suture or foreign-body removal much easier on the patient and the doctor. This effect is additive to topical anesthetics such as proparacaine.

A clean bottle of NSAID should be available in every exam and treatment room. Limbal foreign body or rust-ring removal is greatly facilitated by a topical NSAID followed by a 30-second pledget soaked in 4% xylocaine applied directly to the lesion. This approach is particularly useful in the classic vagal, blue-collar male.

NSAID pledgets are useful adjuncts to topical anesthesia. A drop of NSAID applied to a sterile cotton tip applicator impregnated with 4% lidocaine provides a potent local anesthetic when applied to the superior or inferior conjunctival cul de sac prior to local injections. This technique is useful for sub-Tenon, sub-conjunctival, and palpebral injections.

Similarly, a difficult topical cataract patient may respond very nicely to a 3 x 5 mm pledget of Murocel drape impregnated with preservative-free tetracaine and a drop of NSAID, especially if conjunctival manipulation for global positioning or injection is required.

The potential toxic effects of NSAIDs must be taken into account. Topical NSAIDs create a relative neurotrophic keratitis, with inhibition of ocular surface neurotransmitter production. This is of no short-term consequence for the vast majority of patients. However, patients with severe dry eye, pre-existing neurotrophic disease, persistent epithelial defects, or a highly compromised ocular surface are at risk for corneal melting. Melting is exceedingly rare, but it's highly publicized and worrisome.

By no means do these conditions preclude NSAID use. Nevertheless, other therapies should be considered for any patient with severe or advanced conditions. If topical NSAIDS are prescribed to any dry, neurotrophic or surface-disease patient, meticulous observation is warranted. Patients with these conditions can also be treated and given topical NSAIDS once the conditions are controlled.

The systemic effects of NSAIDs must be taken into account. Oral NSAIDs create gastric irritation by inhibiting mucosal homeostasis mechanisms. An increased risk of peptic ulcer disease has been documented with oral NSAID use. This risk is markedly reduced by the use of COX2 agents. (For more on COX2 agents see, "Newer Oral NSAIDS Target COX2".) Oral NSAIDs are also nephrotoxic, and prolonged use should be avoided unless careful monitoring of renal functions is practical. Care should be taken when prescribing oral NSAIDs to patients with renal disease, renal allografts, or elevated creatinine and blood urea nitrogen (BUN).

In addition, a predisposition to bleeding results from platelet aggregation inhibition. This effect lasts for the life of a platelet, which is about 2 weeks; therefore, oral NSAIDs should be discontinued 2 weeks before elective eye surgeries where bleeding would be a risk. Many plastic surgeons find that the selective COX2 inhibitors, rofecoxib (Vioxx) and celecoxib (Celebrex), are indeed associated with increased intra- and postoperative bleeding, although not as severe as with nonselective NSAIDS. COX2 agents can be administered during the postoperative period without added risk of hemorrhage.

A Key Tool in Our Armamentarium

In ophthalmology, the global indications for topical NSAIDS include analgesia, mydriasis, and inflammation. Oral NSAIDS are widely used for scleritis, episcleritis, uveitis, cystoid macular edema, post-herpetic neuralgia, migraine, and sinusitis. Topical ophthalmic NSAIDs are useful for pain control in refractive surgery, corneal resurfacing, foreign body removal, suture removal, forced ductions, postoperative adjustable suture manipulation, periocular injections, pterygium surgery, punctal occlusion, impression cytology, and cataract surgery. Topical ophthalmic NSAIDs also provide potent anti-inflammatory control for uveitis, scleritis, episcleritis, cystoid macular edema, allergic conjunctivitis, blepharitis, ocular trauma, viral keratitis, bacterial keratitis, and conditions following many surgeries, including cataract, refractive, pterygium, vitrectomy, corneal allograft, trabeculectomy, and glaucoma seton implantation. They're useful for maintenance of pupillary mydriasis during cataract surgery. And, even given within 1 hour of surgery, they don't significantly inhibit post-op pupillary constriction (when it's desired) by agents such as acetylcholine (Miochol).

Dr. Sheppard is clinical director of the Tommy Lee Center for Ocular Pharmacology, Ophthalmology Residency Program Director, and Professor of Ophthalmology, Microbiology, and Immunology at Eastern Virginia Medical School in Norfolk. You can contact him at docshep@hotmail.com .