NSAIDs Dosing Regimens
A review of the steps doctors can take to improve patient compliance.
STEVE PASCUCCI, M.D.

Ophthalmologists have seen considerable advances in surgical corrections for a variety of vision compromising and vision threatening conditions over the past decade. Indeed, we have witnessed remarkable progress in corneal surgical procedures, such as excimer laser vision correction, conductive keratoplasty and lens-based procedures like phakic IOL placement for extreme myopia and refractive lens exchange, which offer solutions for presbyopic patients and cataract removal. As surgical sophistication has evolved, so have the expectations of our patients in our ability to deliver a pleasant, painless, safe and visually successful experience. Undoubtedly, this begins with proper patient selection and counseling, moves through a properly completed surgical procedure and concludes with the selection of the appropriate pharmacologic agents during the postoperative period.

Practice patterns in America have evolved to where the vast majority of practitioners are using forth-generation fluoroquinolones, such as gatifloxacin (Zymar, Allergan, Inc.) and moxifloxacin (Vigamox, Alcon Laboratories, Inc.), following ophthalmic surgery. Topical steroids are also commonly employed by over 90% of surgeons, but these agents do not offer any relief of discomfort for patients both intraoperatively or postoperatively. Therefore, it has become increasingly imperative that NSAIDs become a component of a standard pharmacologic regimen following corneal refractive and anterior segment-based procedures. Topical NSAIDs are becoming increasingly popular following anterior segment surgery, particularly for cataracts. Indeed, over 60% of surgeons commonly use NSAIDs to leverage the synergy between the steroidal and nonsteroidal medications at reducing postoperative inflammation.

The work of Jeffrey Heier, M.D., Calvin Roberts, M.D., and Eric Donnenfeld, M.D., has clearly demonstrated the benefit to patients from NSAID use. Most recently, at the 2005 American Society of Cataract and Refractive Surgery, Dr. Donnenfeld presented the results of a prospective randomized study that demonstrated a number of significant effects, which occurred in patients using NSAIDS with cataract surgery. He demonstrated reduced surgical times, greater pupil dilation, less corneal edema and no cystoid macular edema in the population of patients who received ketorolac tromethamine 0.4% (Acular LS, Allergan, Inc.) 3 days prior to surgery in comparison to all other groups, which comprised various other dosing regimes of 1 day prior to surgery, 1 hour prior to surgery and no preoperative use at all.

Toxicity Concern with Newer NSAIDs

NSAIDs have previously served a useful purpose for ophthalmologists, but likewise they have caused significant toxicity problems. Most notable has been the associated reports of corneal ulceration/melts with generic diclofenac, which required the removal of this agent from the market. Indeed, our enthusiasm for these agents has been tempered by this experience, and we have become acutely sensitive to potential risks of newer agents until we have evaluated their performance in the market. Bromfenac sodium ophthalmic sodium (Xibrom, ISTA Pharmaceuticals) and nepafenac ophthalmic suspension (Nevanac, Alcon Laboratories, Inc.) are two such new agents receiving attention. Both have received FDA approval just this year. Each offer reduced dosing in comparison to the more tested and most commonly prescribed NSAID, ketorolac 0.4%. Caution must be raised when evaluating these newer agents, as a paucity of information currently exists regarding the toxicity of these medications when used topically and specifically when used at dosages higher than recommended. A report by K. Kashiwagi, M.D., noted an incidence of corneal abrasions and erosions of up to 5% in patients using bromfenac at a dosing schedule of q.i.d. Presently, there are no published reports of toxicity related to nepafenac when used improperly of which I am aware.

It seems that an FDA approval does not offer an unconditional guarantee to practitioners and patients alike that any given pharamocologic agent is totally without concerns for safety. Additionally, one has to take into consideration that a subset of patients will use these agents improperly so it behooves the ophthalmologist to remain vigilant for potential toxicity issues with these medicines.

Indeed, one must be on the look out for signs of both under dosing and over dosing in patients who are receiving NSAIDs. Signs of a suboptimal dosing schedule may be greater than anticipated degrees of inflammation, lack of response to therapy or suboptimal vision. One can ask probing questions that may indicate whether a patient is compliant by requesting that they elaborate all of their eye drops that are being used and their respective doses. Another useful measure would be to request that the patient bring in their eye medications and assess how much remains in the bottles relative to the prescribed dose and the date the bottle was started. If a greater than the prescribed dosing schedule is suspected, then classic topical toxicity signs are usually present.

Steps to Ensure Proper Compliance

In order to ensure proper compliance with prescribed regimens, steps must be taken by practices for patient benefit. This may be something as simple and low-tech as clearly printed instructions that are given to the patient at the conclusion of their procedure to methods more sophisticated, such as computer-generated instruction videos for patients. I favor the former as it offers an inexpensive and personal way to help insure patient compliance. Additionally, it gives patients an item they can bring home and reference. I have also found that, when possible, it helps to place an actual picture of the prescribed drops on the instruction sheets. This provides an additional measure of safety in terms of greater patient compliance and drop administration accuracy. Personally, I like the simplicity of dosing for all topical medications prescribed at the same time rather than using different drops at different schedules. With my patients, I believe that reduced dosing does not necessarily offer simplicity or convenience for patients. However, reduced dosing may lead to confusion and improper medicine administration. It is challenging enough for them to remember to take their medications at all, much less to take their steroid and anti-infective q.i.d and their NSAID t.i.d or even b.i.d.

Ophthalmology is certainly embarking upon an exciting time in its history. We all have an opportunity to participate and offer tremendous satisfaction to our patients, as well as life enhancement. We must recognize the considerable burden that will be placed upon us in terms of expectations by our patients, as well as ourselves. To meet those expectations, we must bring to bear all the factors we can to ensure successful outcomes for our patients. I would advance that NSAIDs will play a key role in securing such outcomes. If we are not currently using these agents as part of our standard regimens, we must begin. It would be wise of us to consider the potential for toxicity from the newer agents until they prove themselves in the market and in clinical use.

Steve Pascucci, M.D., is in private practice in Bonitas, Fla. Dr. Pascucci has no financial interest in the information contained in this article. He can be reached at stevepascucci@aol.