Nonsteroidal anti-inflammatory drugs (NSAIDs) play a vital role in the treatment of our patients. Thus, we must understand this drug categorys role, its off-label use and its adverse effects; and we must be aware of the exciting forthcoming additions to this medication grouping.

The Role of NSAIDs
NSAIDs diminish inflammation and mediate pain by inhibiting the activity of cyclooxygenase (COX) enzymes, which catalyze the conversion of arachidonic acid into pros-taglandins and thromboxanesboth powerful mediators of inflammation. However, arachidonic acid may also be acted upon by another enzymelipoxygenasewhich yields a different class of chemical mediators called leukotrienes. Leukotrienes increase microvascular permeability and mobilize/activate white blood cells. As a drug class, NSAIDs do not directly inhibit lipoxygenase. Therefore, they do not address the entire inflammatory cascade. However, at least one NSAIDVoltaren (diclofenac sodium 0.1%, Novartis Ophthalmics)appears capable of reducing the level of leukotriene formation in vitro by an indirect means.1 There is also evidence that NSAIDs have some degree of free radical scavenger activity that may be beneficial in cases of inflammation.2

Highly symptomatic mechanical keratopathy responds very well to topical NSAIDs.

NSAIDs Used Off-Label
Initially, NSAIDS were used for inhibiting intraocular miosis during cataract extraction. But, physicians soon realized that these drugs were effective in the postoperative management of inflammation and pain.   Many clinicians have found that NSAIDs are of benefit in a variety of off label clinical situations, such as the prevention and treatment of cystoid macular edema (CME) in post-operative cataract patients. A total of 9% of patients who undergo uncomplicated phacoemulsification still show angiographic evidence of CME.3 A small percentage of these patients may have visual symptoms, particularly if the surgery is prolonged or complicated. Many controlled clinical trials have shown that topical NSAIDs have a beneficial role in the prevention of CME.4-8 And, at least one study showed that topical NSAIDs may improve cases of chronic CME, even when initiated two years after cataract surgery.9 NSAIDs have also been reportedly beneficial in treating CME that can follow Nd:YAG laser capsulotomy.10
The most common use for NSAIDs is in the temporary management of ocular pain due to superficial corneal insult. Because NSAIDs inhibit prostaglandin synthesis, they help to rapidly and effectively break the pain cycle. So, we use these drugs to treat corneal abrasions, corneal foreign bodies, recurrent corneal erosions and chemical keratitis. Typically, we prescribe Acular LS (ketorolac tromethamine 0.4%, Allergan) every 4 hours as needed, over a 24 to 48 hour period. Used judiciously, NSAIDs can often take the place of oral analgesics in alleviating pain. When the inflammation is more severe or deeper in the eye (i.e. when a secondary uveitis is present following corneal insult), NSAIDs and topical steroids can be used concurrently without fear of detrimental interaction.

Adverse Effects
NSAIDs are not without the potential for adverse reactions, such as corneal melting.11 The problem of corneal melting first surfaced in August of 1999, after members of the American Society of Cataract and Refractive Surgery (ASCRS) responded to an internal survey about complications associated with NSAID use. The news sparked tremendous controversy, ultimately resulting in the withdrawal of generic diclofenac (Falcon Laboratories) from the U.S. market. Similar cases have been reported, implicating various drugs in this category.12-14 While you should certainly take this association into consideration whenever utilizing these agents, no one to date has accurately described the model by which NSAID-induced corneal melting occurs. Moreover, researchers have suggested that this phenomenon is likely a multi-factorial issue, which goes well beyond simple drug toxicity.12

NSAIDs in the Pipeline
In the very near future, you will likely have two new NSAIDs to prescribe: Xibrom (bromfenac sodium 0.09%, ISTA Pharmaceuticals) and Nevanac (nepa-fenac 0.1%, Alcon).

Xibrom received FDA approval in March for the treatment of postoperative inflammation in patients who have undergone cataract extraction. This drug is the first topical NSAID approved for twice-daily dosing (all other medications are indicated for q.i.d. administration). Bromfenac has been used in Japan since 2002 for managing post-surgical ocular inflammation.

Nevanac is currently under FDA review and may receive approval in late 2005. The drugs proposed indication is for the treatment of inflammation and pain following cataract surgery. Nevanac is different from other NSAIDs in that it is a pro-drug converted by enzymatic reaction into a more powerful cyclooxygenase inhibitor known as amfenac sodium shortly after penetrating the ocular tissues. Because of this mechanism, Alcon claims the drug delivers excellent anti-inflammatory efficacy to the cornea, iris/ciliary body and the retina. In addition, Nevanac is extremely bio-friendly, as it boasts a physiologic pH of 7.4 and a very low concentration of benzalkonium chloride (0.005%).

Topical NSAIDs hold an important place in our armamentarium, and the future of these drugs appears very promising. By understanding this drug categorys mechanism, adverse effects and versatility, you can feel confident in prescribing these drugs for a wide range of ocular conditions.

Drs. Kabat and Sowka are members of Alcons Speakers Alliance. They do not have a financial interest in any of the products mentioned.

1. Ku ED, Lee W, Kothari HV, Scholer DW. Effect of diclofenac sodium on the arachidonic acid cascade. Am J Med 1986; Apr 28;80(4B):18-23.
2. Flach AJ. Cyclo-oxygenase inhibitors in ophthalmology. Surv Ophthalmol 1992; Jan-Feb;36(4):259-84. Review.
3. Mentes J, Erakgun T, Afrashi F, Kerci G. Incidence of cystoid macular edema after uncomplicated phacoemulsification. Ophthalmologica. 2003 Nov-Dec;217(6):408-12.
4. Solomon LD. Efficacy of topical flurbiprofen and indomethacin in preventing pseudophakic cystoid macular edema. Flurbiprofen-CME Study Group I. J Cataract Refract Surg. 1995 Jan;21(1):73-81.
5. Efficacy of diclofenac eyedrops in preventing postoperative inflammation and long-term cystoid macular edema. Italian Diclofenac Study Group. J Cataract Refract Surg 1997; Oct;23(8):1183-9.
6. Miyake K, Masuda K, Shirato S, et al. Comparison of diclofenac and fluorometholone in preventing cystoid macular edema after small incision cataract surgery: a multicentered prospective trial. Jpn J Ophthalmol 2000; Jan-Feb;44(1):58-67.
7. Heier JS, Topping TM, Baumann W, et al. Ketorolac versus prednisolone versus combination therapy in the treatment of acute pseudophakic cystoid macular edema. Ophthalmology 2000; Nov;107(11):2034-8;discussion 2039.
8. Rho DS. Treatment of acute pseudophakic cystoid macular edema: Diclofenac versus ketorolac. J Cataract Refract Surg 2003; Dec;29(12):2378-84.
9. Weisz JM, Bressler NM, Bressler SB, Schachat AP.Related Articles, Links Ketorolac treatment of pseudophakic cystoid macular edema identified more than 24 months after cataract extraction. Ophthalmology. 1999 Sep;106(9):1656-9.
10. Lee MS, Lass JH. Rapid response of cystoid macular edema related to Nd:YAG laser capsulotomy to 0.5% ketorolac. Ophthalmic Surg Lasers Imaging 2004; Mar-Apr;35(2):162-4.
11. Lin JC, Rapuano CJ, Laibson PR, et al. Corneal melting associated with use of topical non-steroidal anti-inflammatory drugs after ocular surgery. Arch Ophthalmol 2000; Aug;118(8):1129-32.
12. Flach AJ. Corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs. Trans Am Ophthalmol Soc 2001; 99:205-10.
13. Hsu JKW, Reed R, McDonnell PJ, et al. Corneal melts associated with diclofenac after LASIK [poster no. 353]. Symposium on Cataract, IOL and Refractive Surgery. American Society of Cataract and Refractive Surgery (ASCRS); 2000 May 20-22; Boston (MA).
14. Mah FS, Dhaliwal D, Barad R. Do NSAIDs cause wound melting following uncomplicated, small incision, scleral tunnel phacoemulsification [poster no. 351]. Symposium on Cataract, IOL and Refractive Surgery. American Society of Cataract and Refractive Surgery (ASCRS ); 2000 May 20-22; Boston (MA).

Vol. No: 142:8Issue: 8/15/2005