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The following reader/author exchange refers to the article an NSAID prior to surgery to supplement anesthesia, provide titled “NSAIDs and Delayed Healing” by William Trattler, MD, analgesia, and minimize pain postoperatively. A suggestion and Juan Carlos Abad, MD. The article appeared in our March for surgeons using NSAIDs postoperatively is for them to make certain the flap has fully adhered and the junction isdry for at least 1 minute. The speculum would be carefully removed and the patient instructed to blink before instilla- A recent study by Trattler and Abad1 includes a clinical tion of the NSAID. The NSAID will most likely not have to be observation suggesting delays in corneal epithelial wound used for more than 1 to 2 days postoperatively at dosing fre- healing in four of seven eyes undergoing Epi-LASIK with Nevanac (Alcon Laboratories, Inc., Fort Worth TX) use. The I congratulate the investigators on their astute clinical differences in time to epithelial healing were not statistically observations and their diligence in alerting refractive sur- significant in the study involving Epi-LASIK wherein the geons to the potential concerns with topical NSAID use in epithelial flap was discarded (P=.073). The seven eyes are not surface ablation procedures. Pharmacovigilance is important enough to make definitive conclusions but may be enough with the use of any new agent in unique clinical and surgical for us to carefully examine the protocol in an attempt to de- circumstances. We should not ignore the past concerns5 but termine if there were other factors that could lead to the rather learn and adapt usage to reap the pharmacologic observed results. In the surgical protocol, there were indeed factors that would seem to be outside the standard for Problems with ophthalmic NSAIDs can most often be advanced surface ablation. According to this protocol, traced to improper dosing rather than the active ingredient patients were prescribed topical cyclosporine A for 1 to 3 in the formulation. It is important for the surgeon to follow a weeks prior to surgery and were fitted with punctal plugs.
proper regimen of dosing in order to maximize the analgesic Preoperative punctal plugs and topical cyclosporine A, and anti-inflammatory benefits of ophthalmic NSAIDs.
although potentially helpful in select subpopulations, are notuniversally recognized as standard practice for all patients.
These pretreatments were uniformly applied regardless of a definitive clinical diagnosis of dry eye and stratification ofseverity. The epithelial defect created as part of the Epi-LASIK 1. Trattler W, Abad JC. NSAIDs and delayed healing. Cataract & Refractive Surgery Today.
2006;6:3:112-116. surface ablation was 10mm, larger than the 7.5 to 8.0mm 2. O’Brien TP. Emerging guidelines for use of NSAID therapy to optimize cataract surgery patient care.
typically associated with standard surface PRK. It appears Curr Med Res Opin. 2005;21:1131-1137.
3. Mian SI, Gupta A, Pineda R 2nd. Corneal ulceration and perforation with ketorolac tromethamine that the patients in this smal case series were maintained on (Acular) use after PRK. Cornea. 2006;25:232-233.
the NSAID past postoperative day 5 if their eyes had not 4. O’Brien TP, Li QJ, Sauerberger F, Reviglio V, et al. The role of matrix metalloproteinases in ulcerativekeratolysis associated with perioperative diclofenac use. Ophthalmology. 2001;108:656-659.
5. Congdon NG, Schein OD, von Kulajta P, et al. Corneal complications associated with topical oph- Proper dosing regimens of topical NSAIDs should be eval- thalmic use of nonsteroidal anti-inflammatory drugs. J Cataract Refract Surg. 2001;27:622-631.
uated for patients undergoing both cataract surgery andrefractive surgery. A recent peer-reviewed article shows that, in patients undergoing cataract surgery, the duration of topi- We appreciate your review of our article in which we cal dosing should be continued for at least 4 weeks postop- reported on our separate but similar experiences with delays eratively in order to optimally prevent cystoid macular in epithelial healing and the development of early corneal edema.2 In refractive surgery, it is important that we limit the haze associated with the off-label use of Nevanac (Alcon dosing in a compromised cornea where epithelial integrity is Laboratories, Inc., Fort Worth, TX) for pain control with sur- breached; this includes refractive procedures such as PRK and Epi-LASIK.3 Ophthalmic NSAIDs should be dosed at a In response to your letter, we want to point out a few very frequency of two to three times per day for a short duration important omissions as well as to make a few comments.
of 2 to 3 days postoperatively, and then the treatment Our article discussed two separate studies. should be discontinued. Ophthalmic NSAIDs should also be Dr. Abad compared 10 bilateral PRK cases (20 eyes) in avoided postoperatively in patients with severe dry eye or in which a single drop of Nevanac was used at the end of sur- those with connective tissue and autoimmune diseases as gery with 10 bilateral PRK control cases (20 eyes) in which no each of these groups are more prone to develop punctate NSAIDs were used. He found a significant difference in the epitheliopathy and even possible ulcerative keratolysis.4 mean time to re-epithelialization—9.0 days for eyes treated Using an ophthalmic NSAID in LASIK poses two choices with Nevanac versus 4.7 days for the control eyes (P<.001).
to the surgeon. One option is to dose one or two drops of He also found a statistically significant difference in the JUNE 2006 I CATARACT & REFRACTIVE SURGERY TODAY I 13
degree of corneal haze at 1 month: 1.3 in the Nevanac-treated eyes versus 0.2in the control eyes (P<.001).
Dr. Trattler reported on four of seven cases of delayed healing in which Nevanac was used. Seven out of seven contralateral eyes that receivedketorolac in a similar manner to Nevanac did not experience delays inhealing. We both noted that eyes that experienced delays in epithelial healing also experienced early corneal haze. The vast majority of these eyes experienced aloss of BCVA. Your comments on the preoperative use of cyclosporine, the placement of punctal plugs, and the size of the epithelial defect are true of the seven casesreported by Dr. Trattler. However, Dr. Abad did not use cyclosporine in his 10bilateral PRK cases, and they did not receive plugs. The average size of theepithelial defects in Dr. Abad’s patients was ≤ 8mm. Despite these differences,Dr. Abad’s patients still experienced severe healing delays and corneal haze.
We therefore disagree with your suggestion that cyclosporine, punctal plugs,or the size of the epithelial defect played any “additive” role in the delays ofepithelial healing seen in eyes treated with Nevanac.
The extended use of Nevanac was not an issue with Dr. Abad’s 10 bilateral PRK cases, because his patients only received Nevanac on the stromal bed atthe time of surgery. His patients did not use NSAIDs during the postoperativeperiod. Just the single application of Nevanac resulted in delayed epithelialhealing and corneal haze.
We disagree with your statement that with surface ablation NSAIDs should be dosed b.i.d. or t.i.d. for a short duration of 2 to 3 days. A study bySolomon et al,1 is particularly demonstrative of the safety of using ketorolac0.4% more extensively than you recommend. In this study, Dr. Solomonplaced ketorolac 0.4% on the stromal bed following PRK, and then used thedrug q.i.d. for 4 days. Dr. Solomon found that ketorolac 0.4% significantlyreduced pain compared to placebo, yet it did not cause a statistically signifi-cant delay in epithelial healing. The results from this study were the basis forthe FDA’s approval of ketorolac 0.4%, specifically for the reduction of painwith PRK.
We think it is critical to point out that there are differences in formulations of available topical NSAIDs. Nevanac is a prodrug and is in a suspended for-mulation, while all of the other available ophthalmic NSAIDs are active andare a solution. Formulation issues, not frequency of dosing, were the reasonthat generic diclofenac led to corneal melts with cataract surgery. Similarly,our experience with Nevanac clearly suggests that this medication behavesdifferently than the other available ophthalmic NSAIDS when used on thestromal bed prior to bandage contact lens placement following surfaceablation. As mentioned in our article, we continue to urge surgeons to avoid apply- ing Nevanac to the stromal surface prior to placing a bandage contact lensafter surface ablation. ■ WILLIAM TRATTLER, MDJUAN CARLOS ABAD, MDMiami, Florida 1. Solomon KD, Donnenfeld ED, Raizman M, et al, for the Ketorolac Reformulation Study Groups 1 and 2. Safety and efficacy of ketorolac tromethamine 0.4% ophthalmic solution in post-photorefractive keratectomy patients. J Cataract Refract Surg. 2004;30:1653-1660.
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Source: http://www.bmcpromotion.com/crstdb/PDFfiles/0606-Letter-1153148991.pdf