NSAIDs for the treatment of postoperative inflammation

ByRoy S. Chuck, MD, PhD

Current uses for ophthalmic nonsteroidal anti-inflammatory drugs used during cataract surgery include preoperative application for the prevention of intraoperative miosis and reduction in postoperative cystoid macular edema (CME). NSAIDs are also used for the relief of postoperative pain, photophobia and ocular inflammation, which can be problematic for many patients following cataract surgery.

Currently available topical NSAIDs include diclofenac 0.1%, ketorolac 0.5%, ketorolac 0.4%, bromfenac 0.09%, and nepafenac 0.01% (Nevanac, Alcon). Specific indications vary among agents, with diclofenac, ketorolac 0.5%, bromfenac and nepafenac 0.01% being indicated for postoperative inflammation following cataract surgery and diclofenac and ketorolac 0.4% being indicated for ocular pain (Figure).

Figure: Review of Indications for Topical NSAIDs

The mechanism of action of NSAIDs allows for a range of ophthalmic uses.

(Figure courtesy of Roy S. Chuck, MD.)

Clinical studies have shown that efficacy rates among the topical ophthalmic NSAIDs are comparable. A comparative study showed diclofenac 0.1% and ketorolac 0.5% to be equally effective in the treatment of postoperative CME and inflammation in patients undergoing cataract surgery. Results from a separate study showed that ketorolac 0.5% and ketorolac 0.4% were equally effective in controlling postoperative inflammation when combined with prednisolone acetate 0.1%.

Both generic and branded diclofenac products have been associated with corneal melting problems. According to the Food and Drug Administration submission ketorolac 0.5% is associated with a 20% to 40% burning and stinging rate, although ketorolac 0.4% is associated with a reduced rate of burning and stinging. While one might predict a 5% to 20% incidence of ocular discomfort level with NSAIDs following cataract extraction, a recent double-masked, randomized, placebo-controlled phase 3 trial involving 527 patients reported rates of discomfort level and macular edema of 1.4% and 2%, respectively, with bromfenac. In this study, the incidence of macular edema was almost 2.5 times higher in the placebo group.

Clinical trials in Japan

Two Japanese clinical trials evaluated the dosing schedule of bromfenac for the treatment of inflammation following cataract surgery. One study compared the anti-inflammatory effects of twice-daily brom--fenac and diclofenac administered four times daily postsurgery. The results showed that after 14 days of treatment, significantly less flare occurred in bromfenac-treated patients compared with diclofenac-treated patients. A separate trial compared twice-daily bromfenac to three-times-a-day diclofenac and found significantly less anterior chamber cells and proteins in the first 3 days following surgery in the bromfenac patients, indicating a rapid and potent anti-inflammatory effect.

U.S. clinical trials

Before receiving approval in the United States, bromfenac 0.09% ophthalmic solution was investigated in a series of two parallel, double-masked, placebo-controlled phase 3 clinical trials. Of the 527 patients who underwent cataract surgery, 356 were randomized to receive twice-daily bromfenac and 171 were given placebo for 2 weeks. Unlike the Japanese trial, dosing was not permitted prior to or on the first day following the procedure. To be eligible for enrollment, patients had to have significant inflammation as defined by the Summed Ocular Inflammation Score (SOIS) for anterior chamber cells and flare that was greater than 3 (on a 5-point scale) at 12 to 36 hours following surgery. Treatment success was defined as the complete absence of ocular inflammation or an SOIS score of 0.

Pooled results from the trials were used to assess efficacy. The average baseline SOIS was 3.7, indicating a high degree of inflammation. Results showed that 64% of bromfenac-treated patients achieved SOIS scores of 0 compared with 43% of placebo-treated patients (P < .01). Patients in the bromfenac group also achieved significantly greater reductions in inflammation than did patients in the placebo group during the 14-day treatment period. Separate analyses of mean cell and flare scores showed a significant reduction in the bromfenac group compared with the placebo group at all time points throughout the 14-day treatment period.

A secondary end point in the phase 3 trials was a cell and flare score of 1 or lower before the end of the treatment period, which indicated a marked improvement of inflammation. Significantly more patients in the bromfenac group met this criterion compared with the placebo group (85.1% vs. 52.6%; P < .0001).

Clinician dosing review

Following cataract surgery, I typically prescribe a topical fourth-generation antibiotic three times a day for 1 week and topical prednisolone acetate twice daily for 2 weeks. I use ophthalmic bromfenac twice daily for 2 to 4 weeks in most patients, but extend treatment to 4 to 6 weeks for more complicated cases.

Studies demonstrate that bromfenac is effective as monotherapy. Therefore, I no longer prescribe topical steroids to patients who present as uncomplicated cases.

Conclusion

NSAIDs are an important part of postoperative management of pain and inflammation. The drugs in this class have a strong track record of safety and performance. The latest addition to this class, ophthalmic bromfenac, is a potent NSAID with a rapid onset of action and convenient twice-a-day dosing schedule. Although ophthalmic bromfenac gained FDA approval in the United States in March 2005, it has been marketed in Japan since 2000. Results from clinical trials in Japan and the United States demonstrate that bromfenac is safe and effective in reducing ocular inflammation following cataract surgery.

References

Flach AJ, Dolan BJ, Donahue ME, Faktorovich EG, Gonzalez GA. Comparative Effect of diclofenac 0.1% and ketorolac 0.5% on inflammation after cataract. Ophthalmology. 1998;105:1775-1779.
Bucci F, Evans, RE, Amico LM. Comparison of Ketorolac 0.4%, and Diclofenac 0.1% - Combined with Prednisolone 0.1% on Aqueous Flare Following Cataract Surgery. Presented at the annual meeting of the Association for Research in Vision and Ophthalmology; May 1, 2005; Fort Lauderdale, Fla.
Acular package insert.
Donnenfeld ED, Holland EJ, Stewart R. Topical Xibrom 0.1%, an investigational NSAID for post-cataract surgery inflammation, markedly decreases inflammation, markedly decreases inflammation. Presented at the annual meeting of the American Society of Cataract and Refractive Surgery, April 15-20, 2005; Washington D.C.
Congdon NG, Schein OD, von Kulajta P, Lubomski LH, Gilbert D, Katz J. Corneal complications associated with topical ophthalmic use of nonsteroidal antiinflammatory drugs. J Cataract Refract Surg. 2001;27:622-631.
Kawaguchi T, Kida T, Nemoto S, Gekka M, Tanabe T, Miyata K. Effect of bromfenac ophthalmic solution on ocular inflammation and corneal epithelial barrier function following cataract surgery. Folia Ophthalmol Jpn. 2003;54:276.
Ohara K, Ohkubo A, Miyamoto T, Miyakubo H, Nezu N. Prevention of miosis during cataract surgery by topical bromfenac sodium. Jpn J Clin Ophthalmol. 2004;58:1325.
PDR Drug information for Voltaren Ophthalmic Sterile Ophthalmic Solution. http://www.drugs.com/PDR/Voltaren_Ophthalmic_Sterile_Ophthalmic_Solution.html. Accessed January 26, 2006.
PDR Drug information for Acular Ophthalmic Solution. http://www.drugs.com/pdr/acular_ophthalmic_solution.html. Accessed January 26, 2006.
PDR Drug information for Acular LS Ophthalmic Solution. http://www.drugs.com/PDR/Acular_LS_Ophthalmic_Solution.html. Accessed January 26, 2006.
http://www.clinicaltrials.gov/ct/show/NCT00198445. Accessed January 26, 2006.

Discussion

David F. Chang, MD: FDA trials require a placebo control to demonstrate efficacy; however, data based on these trials are of limited value to clinicians faced with choosing between several different topical NSAIDs. Can the inflammation scores from one trial be compared with those of another, or are the trial protocols too different?

Roy S. Chuck, MD: The trials are too different. Head-to-head trials are necessary.

Chang: I agree. Interestingly, the phase 3 trials with bromfenac sodium 0.1% were unlike previous efficacy trials for NSAIDs in that the endpoint was the percentage of patients who had no inflammation after 2 weeks of treatment. The FDA raised the bar for these trials.

Deepinder K. Dhaliwal, M.D: Another important point to consider is that only patients with significant inflammation were entered into the study. Patients who had mild inflammation postoperatively were not included.

Chang: Regarding head-to-head trials, at least two Japanese studies directly compared diclofenac to bromfenac. Dr. Chuck, were the differences in efficacy statistically significant?

Chuck: Yes, however, the Japanese trials allowed preoperative dosing and the U.S. trials did not.

Chang: The issue of preoperative dosing is important. Do you dose preoperatively and, if so, when do you start dosing?

Chuck: I start dosing in the holding area for prevention of miosis and inflammation. I administer three doses every 5 or 10 minutes.

Monte S. Dirks, MD: I can speak to my partner’s experience with cataract surgery and my own experience with trabeculectomy. We administer a steroid and an NSAID 1 day prior to surgery. Postoperatively, we use an NSAID four-times daily. Twice-daily bromfenac is now used in most people with little postoperative inflammation. This approach is different than in the phase 3 studies, for which only one-half of the patients who consented qualified because of the relatively high ocular inflammation score of 3 that was required for entry. Many postoperative patients who did not qualify for these trials can easily be treated with bromfenac alone. This is what we are planning to do in our practice.

Following trabeculectomy, which generally results in greater inflammation than cataract surgery, I use both bromfenac and prednisolone acetate together. Usually, prednisolone is discontinued after 1 month; however, bromfenac is continued for several months following the procedure.

Barry A. Schechter, MD: I pre-dose with bromfenac only in patients who have a propensity for developing cystoid macular edema (i.e., patients with diabetes or patients with an epiretinal membrane). I usually begin bromfenac treatment 2 days before surgery. I have successfully switched exclusively to bromfenac.

Dhaliwal: High-risk patients receive an NSAID 4 to 7 days prior to surgery. All patients receive the NSAID every 15 minutes for 1 hour before surgery.

William B. Trattler, MD: Three days before surgery, I start my patients on an NSAID and a fourth-generation fluoroquinolone to eradicate bacteria in the ocular surface and reduce the risk of endophthalmitis. For high-risk patients, I start the NSAID 1 week before surgery.

Chang: The rationale for preoperative dosing is to block the synthesis of prostaglandins in ocular tissues prior to the inflammatory insult that triggers their release from cellular reservoirs. Also, dosing preoperatively helps to prevent intraoperative miosis and may also provide an analgesic benefit. Preoperative dosing therefore makes a lot of sense, and treatment for longer periods preoperatively may be needed in high-risk patients. How do you think preoperative dosing would have affected the FDA clinical trials?

Dhaliwal: If preoperative dosing was allowed in the trial, fewer patients would have had enough postoperative inflammation to qualify for the trials.

Chang: These placebo-controlled studies involving ophthalmic NSAIDs are interesting because many ophthalmologists have wondered if using anti-inflammatory drugs is needed; the cataract incision is so small and the surgery is so fast and atraumatic. In fact, these trials confirm that some patients do fine with no medication. However, those of us who have been involved in a randomized trial for an anti-inflammatory medication with a placebo control group have usually been impressed with how inflamed many eyes become following uncomplicated surgery when no medication is used. This was my experience with a trial for a sustained release steroid drug delivery system in which half of the patients were not treated prior to postoperative day 3.

Dhaliwal: Once an eye is inflamed, the inflammation is more difficult to control. The same is true of pain. The trials show bromfenac’s efficacy and power in controlling inflammation.

Dirks: Although it is important to consider what your colleagues are doing, it is also important to think about a patient’s comfort following surgery. Physicians are judged not only on the visual results, but on how a patient looks and feels postoperatively. We have found that with bromfenac patients are comfortable and have good vision the first day after surgery. If your patients are telling the rest of the community that the procedure was done in your facility, and that they were pain-free with excellent vision and great comfort the next day, then you may want to consider integrating the use of NSAIDs into your practice.

References

Flach AJ, Stegman RC, Graham J, Kruger LP. Prophylaxis of aphakic cystoid macular edema without corticosteroids. A paired-comparison, placebo-controlled double-masked study. Ophthalmology. 1990;97(10):1253-1258.