Healio
Healio
ByEric D. Donnenfeld, MD
September 01, 2005
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Versatility of NSAIDs enhanced by twice-daily dosing regimen

ByEric D. Donnenfeld, MD

Eric D. Donnenfeld, MD [photo]
Eric D. Donnenfeld, MD

The ideal NSAID would have decreased dosing requirements for increased convenience and patient compliance, improved tolerability and rapid onset of response.

Nonsteroidal anti-inflammatory drugs are versatile pharmacologic agents. Available NSAIDs include bromfenac sodium 0.1%, diclofenac sodium, ketorolac tromethamine 0.5%, ketorolac tromethamine 0.4% and flurbiprofen sodium.

NSAIDs are attractive agents in ophthalmology because of the variety of indications for use and the diverse effects that these agents have in the eye. The primary mechanism of action for NSAIDs is to inhibit prostaglandin synthesis and intraoperative miosis in the cyclooxygenase (COX)-1 and COX-2 pathways. NSAIDs not only reduce postoperative inflammation and pain but also minimize itching from allergic conjunctivitis.

NSAIDs are important in prophylaxis for and in the treatment of cystoid macular edema (CME) following cataract surgery and are also effective for treating postoperative uveitis. Although steroids can help reduce postoperative inflammation, preoperative loading will not have any effect, whereas loading the eye with NSAIDs preoperatively is a helpful strategy to reduce the incidence of postoperative CME and uveitis.

Side effects associated with NSAIDs include burning and stinging (up to a 40% incidence with ketorolac 0.5% in the Food and Drug Administration trials1) and corneal melting, particularly found with generic diclofenac and, in some cases, the branded diclofenac.2 To address the burning and stinging issues associated with ketorolac tromethamine 0.5%, Allergan introduced a reformulation at a reduced concentration, 0.4%.

Although flurbiprofen is an NSAID that has few to no side effects, it works at a lower concentration level, which results in the lowest rate of efficacy of all the available NSAIDs.3-5

Corticosteroids are also used in ophthalmic surgery. The most commonly used steroids include loteprednol, prednisolone acetate and dexamethasone. Like NSAIDs, steroids are used for the prevention of postoperative inflammation, reduction of postoperative pain and the treatment of uveitis. While effective, steroids have several adverse effects that must be noted. Steroids work by inhibiting the entire network of anti-inflammatory pathways and, thus, inhibit wound healing.6,7 Steroids can increase the risk of viral infection and can also worsen fungal, amoebic and bacterial infections,8 whereas NSAIDs actually have an antiviral effect in some cases.9 Additionally, steroids have been shown to cause cataracts in some patients.10-12

Profile of the ideal NSAID

Today’s cataract surgeon has the advantage of improved surgical techniques, smaller incision sizes and foldable IOLs. These technological advances translate to improved clinical outcomes for patients. As a result, patients expect more from their surgery, including reduced pain during and after the procedure and fast postoperative visual rehabilitation. The use of NSAIDs has also contributed to increased patient expectations by significantly decreasing pain, increasing patient comfort and reducing the incidence of side effects.

The ideal NSAID would have decreased dosing requirements for increased convenience and patient compliance, improved tolerability and rapid onset of response.

In March 2005, bromfenac 0.1% was approved by the Food and Drug Administration for the treatment of ocular inflammation following cataract surgery. The advantages to bromfenac include higher potency, which allows twice-a-day dosing compared to four-times-daily dosing with other available NSAIDs.

Figure 1
Figure [chart]

Figure 1. In phase 3 of its U.S. clinical trials, patients taking bromfenac cleared inflammation at statistically significant rates in the first two weeks of treatment, reaching a summed ocular inflammation score (anterior chamber cell and flare) of 0.

(Figure courtesy of Eric D. Donnenfeld, MD.)

Japanese studies

The first studies on topical bromfenac for ophthalmic use were performed in Japan. In 1995, a study was performed on the effect of bromfenac on ocular inflammation. The study found that bromfenac inhibited prostaglandin synthesis from the rabbit ciliary body by 50% and that bromfenac was 3.8 times more potent than indomethacin and 10.9 times more potent than pranoprofen.13

In a double-masked trial, the anti-inflammatory effect of bromfenac sodium ophthalmic solution 0.1% instilled twice a day was compared to that of pranoprofen 0.1% instilled four times daily to treat anterior uveitis following cataract surgery. The only adverse drug reaction in the bromfenac group was bulbar conjunctiva injection in one eye (0.9%), but in this case it was not accompanied by any remarkable changes in IOP or laboratory test values.14

Another study compared twice-a-day bromfenac to four-times-daily panoprofen and found that the efficacy of the two drugs was similar at these dosing schedules, indicating that bromfenac is more potent than pranoprofen.15

Figure 2
Figure [chart]

Figure 2. Adverse events occurred less frequently in patients treated with bromfenac than in those on placebo.

(Figure courtesy of Ophthalmic Consultants of Long Island.)

U.S. clinical trials

Phase 3 of the U.S. clinical trials included the pooled results of two trials comprising 527 patients who had undergone cataract surgery and who scored 3 on the ocular inflammation scale. The double-masked study evaluated how well twice-daily bromfenac treated postoperative inflammation and reduced eye pain and photophobia after surgery. The primary endpoint of the study was an ocular inflammation score of 0. Patients were also tested for liver function to confirm that bromfenac, although not a systemic drug, does not cause liver-related complications that have been associated with systemic NSAIDs. Secondary endpoints of the trial included time to resolution of ocular inflammation and ocular pain; mean change in ocular inflammation score; proportion of patients with summed ocular inflammation of 1 or less; percentage of improvement of anterior chamber cell and flare scores; and percentage of patients with adverse ocular events, for example, photophobia or CME.

In the analysis of efficacy for the primary endpoint of total clearance of ocular inflammation, 64% of the 356 patients taking bromfenac achieved ocular inflammation scores of 0, compared to 43% of 171 patients on placebo (P< .01). The reduction of inflammation by bromfenac throughout the study demonstrates statistical significance throughout all time points vs. placebo (Figure 1). There was also significant pain reduction for patients taking bromfenac. Pain was resolved in 1.9 days with bromfenac compared to 5.9 days with placebo.

In regard to adverse effects, liver function tests were normal for both groups and other side effects, including iritis, pain, burning and stinging, conjunctival hyperemia and photophobia, were lower in the group taking bromfenac than in those on placebo (Figure 2).

Conclusion

The studies that have been performed on bromfenac show that this agent is safe, tolerable and effective. The twice-daily dosing of bromfenac is a significant advantage over the other available NSAIDs, and the drug’s total clearance of inflammation can greatly enhance patients’ experience with ophthalmic surgery.

References
  1. Acular [package insert]. Irvine, Calif.: Allergan, Inc.; 2002.
  2. Flach AJ. Corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs. Trans Am Ophthalmol Soc. 2001;99:205-210;discussion:210-212.
  3. Fry LL. Efficacy of diclofenac sodium solution in reducing discomfort after cataract surgery. J Cataract Refract Surg. 1995;21(2):187-190.
  4. Solomon KD, Turkalj JW, Whiteside SB, Stewart JA, Apple DJ. Topical 0.5% ketorolac vs. 0.03% flurbiprofen for inhibition of miosis during cataract surgery. Arch Ophthalmol. 1997;115(9):1119-1122.
  5. Accosta MC, Berenguer-Ruiz L, Garcia-Galvez A, Perea-Tortosa D, Gallar J, Belmonte C. Changes in the mechanical, chemical, and thermal sensitivity of the cornea after topical application of nonsteroidal anti-inflammatory drugs. Invest Ophthalmol Vis Sci. 2005;46(1):282-286.
  6. Luo JC, Shin VY, Liu ES, et al. Non-ulcerogenic dose of dexamethosone delays gastric ulcer healing in rats. J Pharmacol Exp Ther. 2003;307(2):692-698.
  7. Chung JH, Kang YG, Kim HJ. Effect of 0.1% dexamethosone on epithelial healing in experimental corneal alkali wounds: Morphological changes during the repair process. Graefes Arch Clin Exp Ophthalmol. 1998;236(7):537-545.
  8. Renfro L, Snow JS. Ocular effects of topical and systemic steroids. Dermatol Clin. 1992;10(3):505-512.
  9. Romanowski EG, Gordon YJ. Effectos of diclofenac or ketorolac on the inhibitory activity of cidofovir in the Ad5/NZW rabbit model. Invest Ophthalmol Vis Sci. 2001;42(1):158-62.
  10. Carnahan MC, Goldstein DA. Ocular complications of topical, periocular, and systemic corticosteroids. Curr Opin Ophthalmol. 2000;11(6):468-483.
  11. Rathi VM, Krishnamachary M, Gupta S. Cataract formation after penetrating keratoplasty. J Cataract Refract Surgery. 1997;23(4):562-564.
  12. Fisher DA. Adverse effects of topical corticosteroid use. West J Med. 1995;162(2):123-126.
  13. Ogawa T, Sakaue T, Terai T, Fukiage C. Effects of bromfenac sodium, nonsteroidal anti-inflammatory drug, on acute ocular inflammation. Nippon Ganka Gakkai Zasshi. 1995;99(4):406-411.
  14. Masuda K, et al. Effect of bromfenac sodium (AHR-10282B) on postoperative inflammation: A double masked trial. Folia Ophthalmologica Japonica. 1997.
  15. Shimizu H, et al. Clinical effect of bromfenac sodium ophthalmic solution of inflammation following intraocular lens implantation: Optimal frequency of instillation. Atarashii Ganka. 1997.

Discussion

Dosing regimens with NSAIDs

Donnenfeld: Dr. Chang, how do the available NSAIDs differ in dosing?

Chang: The dosing for all of the ophthalmic NSAIDs has been four times daily, until the arrival of Xibrom (bromfenac sodium ophthalmic solution, Ista Pharmaceuticals), which is approved for twice-daily dosing. A twice-daily regimen is an advantage for patients in terms of convenience and compliance.

By using bromfenac, an ophthalmologist cuts the total drops administered by one half, allowing the achievement of therapeutic goals with less drug. Less frequent dosing could lower the risk of side effects such as corneal epithelial toxicity.

Kim: In the clinical trials, a statistically significant difference was noted in the percentage of patients who took bromfenac (approximately 60%) vs. placebo (approximately 27%) in reaching the targeted inflammatory endpoint at 15 days post cataract surgery with twice-daily dosing. If an ophthalmologist can decrease dosing and duration of treatment with any medication, this is an advantage to the patient.

Donnenfeld: Dr. Kim, does the use of an NSAID twice a day reduce the incidence of side effects more effectively than four times-daily dosing?

Kim: Dosing has not been specifically addressed in any of the human studies on adverse effects such as corneal melting. However, data from animal studies show that frequent dosing of NSAIDs, particularly diclofenac, may induce apoptosis.8 Generally speaking, it seems logical that decreasing the frequency of NSAID dosing would minimize the potential for toxicity and other potential side effects like corneal melting. For this reason, I recommend that topical NSAID dosing not exceed four times-daily frequency with available formulations like Acular LS (ketorolac tromethamine 0.4%, Allergan) or Voltaren (diclofenac sodium, Novartis).

Perry: Several large studies have been performed with various medications, mostly for glaucoma, that compare four times-daily dosing vs. two times-daily dosing. Reduced frequency of dosing has consistently been found to have a positive effect on patient compliance.19

Donnenfeld: When I trained 20 years ago, most of the glaucoma drops were dosed four times daily and compliance was a significant issue. Currently, no glaucoma medications are dosed more than twice daily and, as compliance has improved, so have clinical outcomes. I expect the same will hold true for the NSAIDs.

Dr. Perry, what is your dosing regimen for NSAIDs in routine cataract surgery?

Perry: Routinely at my practice, we use ketorolac tromethamine 0.4% on our patients 3 days preoperatively in conjunction with an antibiotic four times daily. We dose NSAIDs on the day of surgery along with dilating drops. Postoperatively, I have patients continue NSAIDs for at least 2 to 4 weeks, with the exception of patients with diabetes or chronic uveitis. I have these patients continue taking NSAIDs for up to 3 months postoperatively, and sometimes longer, depending on the clinical situation. Patients who have pre-existing CME will most likely continue taking NSAIDs indefinitely.

Katsev: I have my patients begin taking ketorolac tromethamine 0.5% four times daily, 2 to 3 days preoperatively. On the day of surgery, I either administer a dilating drop or have the patient instill the drop at home and add an NSAID to maintain pupillary dilation during surgery.

Donnenfeld: We also use NSAIDs prior to surgery to improve clinical outcomes. NSAIDs are important preoperatively because they inhibit prostaglandin synthesis and reduce the release of formed prostaglandins at the time of surgery.

References
  1. Raizman M. Macular Edema After Cataract Surgery. Presented at the Royal Hawaiian Eye Meeting; Jan. 24-29, 1999; Waikoloa, Hawaii.
  2. Perry HD, Kanellopulos AJ, Donnenfeld ED. Decrease in normal human corneal sensitivity with topical ketorolac tromethamine 0.5%. Invest Ophthalmol Vis Sci. 1995;36:4, 979.
  3. Acular [package insert]. Irvine, Calif.: Allergan, Inc.; 2002.
  4. Voltaren [package insert]. Duluth, Ga.: Novartis Ophthalmics; 2002.
  5. Data on file at Ista Pharmaceuticals.
  6. Donnenfeld ED, Holland EJ, Stewart. Topical Xibrom 0.1%, an investigational NSAID for post-cataract surgery 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.
  7. Lin JC, Rapuano CJ, Laibson PR, Eagle RC Jr, Cohen EJ. Corneal melting associated with use of topical nonsteroidal anti-inflammatory drugs after ocular surgery. Arch Ophthalmol. 2000;118:1129-1132.7.
  8. Hargrave SL, Jung JC, Fini ME, Gelender H, Cather C, Guidera A, Udell I, Fisher S, Jester JV, Bowman RW, McCulley JP, Cavanagh HD. Possible role of vitamin E solubilizer in topical diclofenac on matrix metalloproteinase expression in corneal melting: an analysis of postoperative keratolysis. Ophthalmology. 2002;109(2):343-350.
  9. Guidera AC, Luchs JI, Udell IJ. Keratitis, ulceration, and perforation associated with topical nonsteroidal anti-inflammatory drugs. Ophthalmology. 2001;108(5):936-944.
  10. Flach AJ. Corneal melts associated with topically applied nonsteroidal anti-inflammatory drugs. Trans Am Ophthalmol Soc. 2001;99:205-10; discussion 210-212.
  11. Schalnus R. Topical nonsteroidal anti-inflammatory therapy in ophthalmology. Ophthalmologica. 2003;217(2):89-98.
  12. Caronia RM, Perry HD, Donnenfeld ED. Antiinflammatory effect of preoperative ketorolac in phacoemulsification. J Cataract Refract Surg. 2002;28(10):1880-1881.
  13. Srinivasan R, Madhavaranga. Topical ketorolac tromethamine 0.5% versus diclofenac sodium 0.1% to inhibit miosis during cataract surgery. J Cataract Refract Surg. 2003;29(3):423.
  14. Papa V, Russo S, Russo P, Di Bella A, Santocono M, Milazzo G, Naproxen Study Group. Topical naproxen sodium for inhibition of miosis during cataract surgery. Prospective, randomized clinical trials. Eye. 2002;16:292-296.
  15. Donnenfeld ED, Perry HD, Solomon R. The dose-response curve of ketorolac tromethamine. Presented at the annual meeting of the American Society of Cataract and Refractive Surgery; April 15-20, 2005; Washington, D.C.
  16. Dionne RA, Haynes D, Brahim JS, Rowan JS, Guivarch PH. Analgesic effect of sustained-release flurbiprofen administered at the site of tissue injury in the oral surgery model. J Clin Pharmacol. 2004;44(12):1418-1424.
  17. Solomon KD, Vroman DT, Barker D, Gehlken J. Comparison of ketorolac tromethamine 0.5% and rimexolone 1% to control inflammation after cataract extraction. Prospective randomized double-masked study. J Cataract Refract Surg. 2001;27(8):1232-1237.
  18. Brown RM, Roberts CW. Preoperative and postoperative use of nonsteroidal anti-inflammatory drugs in cataract surgery. Insight. 1996;21(1):13-16.
  19. Patel SC, Spaeth GL. Compliance in patients prescribed eyedrops for glaucoma. Ophthalmic Surg. 1995;26(3):233-236.