Risk:benefit ratio guides off-label NSAID use

February 1, 2008

Topical nonsteroidal anti-inflammatory drugs often are administered for off-label purposes to patients who are undergoing cataract surgery, but surgeons should consider the cost, the risks, and the evidence available to support such use.

Key Points

"The only approved indications for topical NSAIDs in cataract surgery are to treat postoperative pain or inflammation, and all of the agents appear to be safe and effective for these intended uses. However, NSAIDs are also being widely used off-label to potentiate mydriasis as well as to prevent or treat cystoid macular edema [CME]," said Dr. Stark, professor of ophthalmology, Wilmer Eye Institute, Johns Hopkins University, Baltimore.

"With an average wholesale cost of about $79 per bottle, a retail cost of up to $130 per bottle, and considering that approximately 2.5 million cataract operations are performed annually, topical NSAID use can add $250 million to the cost of cataract surgery," he added. "In addition to the cost factor, surgeons also need take into account the potential risks of long-term NSAID treatment, which include rare corneal melts."

Reviewing the literature relating to off-label NSAID use in cataract surgery, Dr. Stark noted that a few studies have shown that topical NSAIDs increase pupil size and decrease constriction. In one study Dr. Stark performed, pupil size remained 10% larger during surgery in eyes treated with a topical NSAID 1 hour prior to surgery compared with the untreated controls. In a more recent trial, Eric Donnenfeld, MD, reported less pupil constriction in patients treated with ketorolac tromethamine (Acular, Allergan) 3 days preoperatively compared with groups treated 1 day or 1 hour before surgery.

Some data show that topical NSAID treatment reduces the rate of angiographically proven CME, Dr. Stark observed. For example, in a study from Kraff et al., the addition of a topical NSAID to a topical corticosteroid was associated with an approximate halving of the rate of fluorescein-positive, angiographically proven CME compared with corticosteroid treatment alone, 9.6% versus 18.5%, at 2.5 to 5 months. Another study by Yavas et al. also showed that patients treated with a topical corticosteroid plus a topical NSAID pre-and postoperatively had less fluorescein-positive CME than did patients treated with NSAID or corticosteroid monotherapy postoperatively (0% versus 15% and 32%, respectively). Dr. Donnenfeld also reported that pre-and postoperative topical NSAID use reduced the rate of postoperative CME, although the difference compared with the control group was not statistically significant.

"However, Kraff et al. found no benefit of NSAID treatment for improving visual acuity outcome, and the rate of CME in the corticosteroid monotherapy group in the study by Yavas et al. was questionably high," Dr. Stark said.

Benefit for persistent CME

Studies are available that show a benefit of topical NSAID treatment in eyes with persistent CME, as measured by improvement in lines of vision. For example, Heier reported a greater gain in vision after 1 to 3 months in patients treated with the combination of ketorolac plus prednisolone compared with ketorolac or prednisolone alone, 3.8 lines versus 1.9 versus 1.1, respectively. Additionally, in a study of patients with CME present for 2 years, Weisz et al. reported that topical ketorolac resulted in an average visual acuity gain of 3.2 lines after 3 months. The study by Heier, however, had no long-term follow-up after NSAID discontinuation, and in the latter study, the CME recurred in all eyes within 3 months of stopping ketorolac, Dr. Stark noted.

Describing his own protocol for off-label NSAID use in cataract surgery, Dr. Stark told attendees that he uses topical NSAIDs preoperatively to help maintain pupil dilation, administering four doses beginning 1 hour prior to surgery when starting the dilating drops. In eyes predisposed to CME, however, NSAID treatment is initiated 1 to 3 days preoperatively and continued for 2 to 3 weeks after surgery.

Clinical findings that are considered indications for CME prophylaxis treatment include the presence of diabetes mellitus, epiretinal membrane, macular degeneration, retinitis pigmentosa, uveitis, complicated surgery, need for iris retraction, presence of CME in the fellow eye, and use of tamsulosin HCl (Flomax, Boehringer Ingelheim).