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Short-term effects of flurbiprofen and diclofenac on refractive outcome and corneal haze after photorefractive keratectomy
Short-term effects of Hurbiprofen and diclofenac on refractive outcome and corneal haze after photorefractive keratectomy Seung-Hee Baek, MD, Sang Yul Choi, MD, Jin-Ho Chang, MD, Won Ryang Wee, MD, Jin-Hak Lee, MD ABSTRACT Purpose: To evaluate the short-term effects of topical nonsteroidal anti-inflammatory drugs (NSAIOs) on refractive outcome and corneal haze after excimer laser photorefractive keratectomy (PRK) according to the degree of myopia and to compare the results with those of topical steroids. Setting: Seoul National University Hospital, Seoul, Korea. Methods: Patients were divided into two groups: low to moderate myopia (-6.00 diopters [OJ or less) and high myopia (greater than 6.00 0). Then, each patient was randomly assigned to one of three drug subgroups for initial management (4 months post-PRK): corticosteroids (fluorometholone 0.1 %); flurbiprofen sodium 0.03% (Ocufen®); diclofenac sodium 0.1 % (Oecrol®). Follow-up was 6 months. Results: In eyes with low to moderate myopia, the steroid and diclofenac subgroups had significantly different refractions 2 and 4 months postoperatively but no difference at 6 months; subjective haze grading was consistently lower in the steroid subgroup than in the NSAIO subgroups (flurbiprofen, diclofenac) after 2 months. In eyes with high myopia, the steroid subgroup had significantly less myopic regression after 3 weeks and lower subjective haze after 2 months than the NSAIO subgroups. The steroid subgroup had severe myopic regression or corneal haze less frequently than the NSAIO subgroups. Conclusion: Topical NSAIOs were less effective than topical steroids in reducing myopic regression and haze after PRK, especially in highly myopic eyes. J Cataract Refract Surg 1997; 23:1317-1323
E
xcimer laser photorefractive keratectomy (PRK) for myopia involves surface photoablation of the anterior central corneal stroma to change its radius of curvature. It has been accepted as safe and effective for the correction of low to moderate myopia. However, Reprint requests to Jin-Hak Lee, MD, Department of Ophthalmology, Seoul National University College of Medicine, #28 Yeongun-dong, Chongro-ku, Seoul 110-744, Korea.
undercorrection, mainly resulting from refractive regression, and corneal haze, which can produce glare and a loss of best corrected visual acuity (BCVA), have been reported as major complications that seem more problematic in eyes with high myopia. 1 These phenomena are the result of corneal wound healing after PRK. Thus, there has been considerable interest in pharmacologic modification of the healing process? Corticosteroids,l-6 nonsteroidal anti-inflam-
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EFFECTS OF FLURBIPROFEN AND DICLOFENAC AFTER PRK
matory drugs (NSAIDs),7-1O plasmin inhibitors,lI antimetabolites,12 and cytokines 13 have been used after excimer laser PRK in animal experiments and clinical trials. Topical NSAIDs can reduce severe pain after PRK.7,10 However, the effect of the various pharmacologic agents on regression and corneal haze remains controversial. Photo refractive keratectomy for high myopia is thought to induce more regression and haze. 6 Thus, those with high myopia may benefit from topical pharmacologic agent therapy. We conducted this study to assess the effects of topical NSAIDs and compared the results with those of topical steroids used after excimer laser PRK for myopia.
Patients and Methods This prospective study was designed to compare the effects of three topical agents on refraction and haze according to the degree of myopia treated. An institutional review board approved the project, and prospective patients were sent background information. Eighty-five eyes of 51 patients had PRK to correct myopia. Mean myopia of the 16 men and 35 women was 6.01 diopters (D) (range 2.13 to 9.90 D spherical equivalent [SE]). Patients with extremely high myopia (10.00 D or more) were excluded; therefore, emmetropia was the aim in every case. All patients had visual acuities correctable to 20/30 or better with spectacles. Refractive astigmatism did not exceed 2.00 D. Patients younger than 18 years or with abnormal corneas or a history of ophthalmic disease or surgery were excluded. Mean patient age was 27.5 years (range 19 to 42 years). Patients were divided into two groups according to the preoperative SE: low to moderate myopia (6.00 D or less) and high myopia (greater than 6.00 D). The low to moderate myopia group comprised 44 eyes of 29 patients (7 men, 22 women) with a mean myopia of 4.34 D (range 2.13 to 6.00 D SE). The high myopia group comprised 41 eyes of 26 patients (11 men, 15 women) with a mean myopia of7.81 D (range 6.25 to 9.75 D SE). The patients were then randomly assigned to one of three subgroups based on topical agent regimen: steroid (fluorometholone 0.1 %) (n = 43); flurbiprofen sodium 0.03% (Ocufen®) (n = 20); diclofenac sodium 0.1 % (Decrol®) (n = 22). Tables 1 and 2 show the preoperative status in each group. 1318
Preoperatively, all patients had a complete ophthalmic examination including slitlamp biomicroscopy, Goldmann applanation tonometry, subjective refraction and visual acuity, cycloplegic refraction, corneal pachymetry, and computerized corneal topography.
Surgical Procedure An OmniMed excimer laser (Summit Technology) with a wavelength of 193 nm, fixed pulse repetition rate of 10 Hz, and radiant exposure of 180 mJ/cm2 at the corneal plane was used. Patients received topical pilocarpine 2% before surgery three times at 5 minute intervals. After topical anesthesia was obtained with proparacaine hydrochloride 0.5%, the central corneal epithelium was removed mechanically. A fixed ablation Table 1. Preoperative status of the low to moderate myopia group (6.00 D or less). Group Steroid (n = 20)
Flurbiprofen (n = 9)
Age Mean SD
27.5 6.0
25.6 8.9
Sex Male Female
5
2
15
7
Characteristic
Spherical equivalent (D) Mean SD
-4.33
-4.04
1.03
1.41
Diclofenac (n = 15) P-value 26.2
0.18
3.4 4 11
0.97
-4.55 0.89
0.65
Table 2. Preoperative status of the high myopia group (greater than 6.00 D).
Group Steroid (n = 23)
Flurbiprofen (n = 11)
Age Mean SD
27.8 6.1
26.4 4.1
33.3
Sex Male Female
7 16
9 2
1 6
Spherical equivalent (D) Mean SD
-7.80 1.11
Characteristic
-7.69 1.06
*Statistically significant; chi-square test
J CATARACT REFRACT SURG-VOL 23, NOVEMBER 1997
Diclofenac (n = 7) P-value 0.11
7.0
-8.05 1.02
0.005*
0.24
EFFECTS OF FLURBIPROFEN AND DICLOFENAC AFTER PRK
rate (0.25 J.lm per pulse) and a 5.0 mm ablation zone diameter were used. The number of pulses was computed by the laser's ablation algorithm. A single-zone treatment was done in every case. Postoperatively, topical homatropine 2% and ofloxacin ointment were instilled and a pressure patch was applied once a day until the epithelium healed completely. Oral analgesics and antibiotics were given for 3 days. Postoperative examinations were done 1 day after PRK and then daily until complete epithelial healing and then at 1 and 3 weeks and 2, 4, and 6 months. Manifest refraction and slitlamp examination were done at each visit from postoperative week 1. Subepithelial haze was graded clinically on a scale of a to +4.14 Intraocular pressure (lOP) was measured at 1 week and 3 months.
Postoperative Topical Agent Regimen Patients in the steroid subgroup had the following postoperative regimen: fluorometholone 0.1 % four times a day for 1 month; three times a day for 1 month; twice a day for 1 month; once a day for 1 month; discontinued. Patients in the two NSAID subgroups (flurbiprofen and diclofenac) received one drop of their assigned drug every 15 minutes four times preoperatively and one drop postoperatively before patching and then began the same postoperative tapering schedule as in the steroid group.
Statistical Analysis The data were not normally distributed, and the sample sizes were quite small. Thus, Kruskal-Wallis tests were used to compare age, preoperative refraction, postoperative refractive changes, and haze gradings. Chi-square tests were used to compare sex distribution and percentages of severe myopic regression or haze in each group. A P-value of less than 0.05 was considered statistically significant. When the postoperative refractive changes and haze gradings showed a statistically significant difference between the three subgroups by the Kruskal-Wallis test, the Wilcoxon rank-sum test was used to compare two of the three subgroups, yielding three combinations of two subgroups for the original three subgroups. Because an a-error could affect these combinations, a Wilcoxon rank-sum test was done only when the original groups showed a significant difference by the Kruskal-Wallis test. Thus, a P-value less than 0.05 was considered to indicate a possible trend of the changes in each subgroup.
Results Refractive Outcome Mean postoperative manifest refractions (SE) over time in the low to moderate and high groups are shown in Figures 1 and 2. In the low to moderate myopia group, the mean SE in the three subgroups was statistically significantly different at 2 and 4 months (P = .01
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Figure 1. (Baek) Mean refraction (SE) after PRK in the low to
Figure 2. (Baek) Mean refraction (SE) after PRK in the high
moderate myopia group (6.00 D or less). Extended bars represent standard error. Differences were considered statistically significant at P < .05; P < .05 is compared with similar marks (_a__. = steroid group; ... 0-.. = flurbiprofen group; ---/:x-- = diclofenac group).
myopia group (greater than 6.00 D). Extended bars represent standard error. Differences were considered statistically significant at P < .05; P < .05 is compared with similar marks (_a__. = steroid group; .. ·0··· = flurbiprofen group; ---6--- = diclofenac group).
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EFFECfS OF FLURBIPROFEN AND DICLOFENAC AFTER PRK
.*p < 0.05
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Figure 3. (Baek) Mean subjective corneal haze grading after PRK in the low to moderate myopia group (6.00 D or less). Extended bars represent standard error. Differences were considered statistically significant at P < .05; P < .05 is compared with similar marks (___ = steroid group; ···0·· = flurbiprofen group; ---l::,.--- = diclofenac group).
and .047, respectively); there was no difference at 6 months (Figure 1). At 2 and 4 months, the mean SE in the steroid subgroup was significantly different from that in the didofenac subgroup (P = .007 and .015, respectively). The differences in results in the flurbiprofen and didofenac subgroups were not significant at any time. Two eyes (22.2%) in the flurbiprofen subgroup and five (33.3%) in the didofenac subgroup had severe myopic regression (greater than 2.00 D), whereas one eye (5.0%) in the steroid subgroup did. In the high myopia group, the mean SE of the three subgroups was significantly different after 3 weeks (P < .006; Figure 2). The flurbiprofen and didofenac subgroups showed no significant difference at any point. Three eyes (13.0%) in the steroid subgroup, seven (63.6%) in the flurbiprofen subgroup, and five (71.4%) in the didofenac subgroup showed severe myopic regression (greater than 2.00 D). The percentage of eyes with severe myopic regression in each subgroup was statistically significantly different (P < .002). The steroid subgroup showed severe myopic regression less frequently than the NSAID subgroups.
Subjective Haze The time course for the development of anterior stromal haze, as subjectively assessed at the slitlamp, is shown in Figures 3 and 4. In the low to moderate myopia (Figure 3) and high myopia (Figure 4) groups, 1320
4
5
Time (month)
Figure 4. (Baek) Mean subjective corneal haze grading after PRK in the high myopia group (greater than 6.00 D). Extended bars represent standard error. Differences were considered statistically significant at P < .05; P < .05 is compared with similar marks (___ = steroid group; .. ·0'" = flurbiprofen group; ---l::,.--= diclofenac group).
the difference in haze gradings between the three subgroups was statistically significant. In both groups, the haze gradings in the steroid subgroup were consistently lower than in the NSAID subgroups after 2 months (P < .004). The difference between the two NSAID subgroups was not significant at any point. In the low to moderate myopia group, no eye had severe corneal haze (greater than grade 2) with a two or more line decrease in BCVA. In the high myopia group, two eyes (8.7%) in the steroid subgroup, seven (63.6%) in the flurbiprofen subgroup, and six (85.7%) in the didofenac subgroup had haze greater than grade 2 with a two line or more decrease in BCVA. The steroid subgroup developed severe corneal haze less frequently than the NSAID subgroups.
Complications There were two cases of complications associated with the treatment drug. The first was a 24-year-old man who had increased lOP 2 weeks after steroid instillation. The steroids were stopped immediately, and lOP was normal at the next visit. The second was a 42-year-old woman in the didofenac subgroup, high myopia group, who had myopic regression after 2 months. Two months after steroid instillation, a dendrite-like lesion appeared on her cornea. The steroids were stopped and trifluorothymidine eyedrops prescribed. The lesion had resolved by the next visit.
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EFFECTS OF FLURBIPROFEN AND DICLOFENAC AFTER PRK
Discussion Regression and corneal haze are the results of corneal wound healing after excimer laser PRK. Corneal wound healing passes through a series of welldefined stages: epithelial hyperplasia with epithelial wound healing, stromal regeneration, and wound remodeling (R.E Steinert, MD, "Phase III Two-Year Results of the Summit Technology Laser," presented at the Symposium on Cataract, 10L and Refractive Surgery, San Diego, California, USA, April 1995). Because aggressive wound-healing responses may produce unwanted effects, much effort has been focused on reducing these responses. Nonsteroidal anti-inflammatory drugs inhibit the formation of inflammatory mediators at a later step in the arachidonic acid pathway and have fewer widespread cellular effects than corticosteroids.1 5 They also retard fibroblast growth and proliferation. 16.17 Fluorometholone belongs to the class of corticosteroids that induce production of lipomodulin,18 a glycoprotein that functions as a specific phospholipase ~ inhibitor. This decreases arachidonic acid and, consequently, reduces lipoxygenase and cyclo-oxygenase metabolites. Flurbiprofen sodium, a propionic acid derivative, and diclofenac sodium, a phenylacetyl acid derivative, have well-defined abilities to disrupt the function of cyclo-oxygenase and hence the production of prostaglandins.1 5 Diclofenac sodium can reduce the availability of intracellular arachidonic acid by enhancing its uptake into triglyceride pools and thus influences the production of lipoxygenase as well as cyclooxygenase products. Hersh et al. 19 studied the effects on corneal wound healing of two NSAIDs, flurbiprofen sodium 0.03% and diclofenac sodium 0.1 %, and a topical corticosteroid, prednisolone sodium phosphate 1%. They found that all three decreased early epithelialization of corneal scrape wounds; however, they had no apparent effect on healing of the corneal stroma. Phillips et al. 8 showed that topical application of diclofenac after PRK caused a significant decrease in prostaglandin E2 levels but a significant increase in polymorphonuclear leukocytes in the anterior stroma. In contrast, fluorometholone did not significantly alter prostaglandin E2 levels but did markedly inhibit leukocyte infiltration. Nassaralla et al. 9 compared the inhibitory effects of a topical NSAID (diclofenac sodium 0.3%) and ste-
roids (fluorometholone 0.1 %) to those of no treatment on the development of corneal haze after photoablative keratectomy in rabbits. Both drugs reduced corneal haze but did not influence refractive outcome. No additive effect was obtained by combining the drugs, which the authors speculate was due to toxicity of the cumulative effect of preservatives or drug interactions. Arshinoff et al. IO studied post-PRK myopic regression in 68 consecutive patients and found that flurbiprofen sodium 0.1 %, when added to topical steroid protocols (fluorometholone 0.25%), reduced myopic regression for 1 year postoperatively significantly more than steroids alone or steroids and diclofenac sodium. In 4 eyes of 2 patients with a severe postoperative glaucomatous response to steroids, the topical steroids were discontinued and the eyes were treated with a topical NSAID alone. Three eyes were initially assigned to the flurbiprofen group and were overcorrected at 1 year, resulting in 0.50 to 1.00 D of hyperopia. All had transient trace corneal haze. Another eye treated with diclofenac began to develop myopic regression and haze at 3 months; the eye eventually stabilized at -4.00 D with moderate haze after the patient began using flurbiprofen. Arshinoff et al. concluded that flurbiprofen alone seemed to be a consistent, potent inhibitor of myopic regression and stromal haze and suggested that the diverse actions of topical NSAIDs are probably mediated through different, although similar, receptors. In the current study, we compared the effects of topical NSAIDs and steroids on myopic regression and corneal haze according to the degree of myopia. In the low to moderate myopia group, the drugs led to significant differences in manifest refraction only at
2 and 4 months, at which time the difference between the steroid and diclofenac subgroups was significantly different. The subjective haze grades were consistently lower in the steroid subgroup after 2 months. In addition, the NSAID subgroups (flurbiprofen and diclofenac) showed severe myopic regression more frequently than the steroid subgroup (22.2 and 33.3% vs. 5.0%); however, the difference did not reach statistical significance. This could be an effect of our small population, and further study is needed. In the high myopia group, the only significant difference in the incidence of the severe myopic regression, corneal haze, or both was between the high myopia group's steroid subgroup and the two NSAID
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EFFECTS OF FLURBIPROFEN AND DICLOFENAC AFTER PRJ(
subgroups. The steroid subgroup had less myopic regression and corneal haze and fewer occurrences of vision-reducing myopic regression or haze. Thus, corticosteroids appeared to be more effective than NSAIDs in reducing myopic regression and haze, especially in eyes with high myopia. Our results were somewhat different from those of Nassaralla et al.,9 who found in an animal experiment that corneal healing response to anti-inflammatory therapy can differ among species. However, they found no difference in keratometric change, and they did not know the preoperative and postoperative manifest refractions. The refractive changes in our study differ from those in Arshinoff et al.'s study.lO However, they used topical NSAIDs only in combination with steroids at the beginning and they used topical NSAIDs for a longer period than our regimen. The mean preoperative refraction (- 5.02 ± 2.63 D) was lower than that in our high myopia group. The greater amount of attempted correction in our high myopia group might induce more regression and haze, 6 and a more potent agent would be required to reduce them (i.e., corticosteroids rather than an NSAID alone). Numerous questions remain to be answered with respect to the ideal post-PRK pharmacologic therapy of the patients. Gartry and coauthors4 reported that topical corticosteroids had transient effects on regression only during their administration and no effect on corneal haze. A study of Canadian surgeons performing excimer laser PRK found 28 reports of subepithelial corneal infiltrates in association with preoperative and postoperative use of topical NSAIDs and contact lens occlusion,7 an incidence of approximately 1 in 250 treated eyes. None of these patients received topical steroids after PRK but had been given topical ketorolac or topical diclofenac before, during, and four times a day after surgery. More than 90% of eyes were left with some stromal scarring and a one or two line reduction in BCVA despite treatment with topical antibiotics, topical corticosteroids, or both. Topical NSAIDs might be used only with topical steroids. In light of our data, we believe that topical NSAIDs would be less effective than topical corticosteroids in reducing myopic regression and haze after PRK, especially in eyes with high myopia. We recently began using topical steroids only in patients with myopia greater than 6.00 D. Although there has been 1322
much controversy about the effect of topical NSAIDs used as painkillers, we use topical diclofenac postoperatively for pain control only until complete closure of epithelial defect. We do not use them for corneal haze . . or myopIC regreSSion.
References 1. Gartry DS, Kerr Muir MG, Marshall ]. Excimer laser photorefractive keratectomy: 18-month follow-up. Ophthalmology 1992; 99: 1209-1219 2. Tuft 5], Ganry DS, Rawe 1M, Meek KM. Photorefractive keratectomy: implications of corneal wound healing. Br ] Ophthalmol 1993; 77:243-247 3. Campos M, Abed HM, McDonnell P]. Topical fluorometholone reduces stromal inflammation after photorefractive keratectomy. Ophthalmic Surg 1993; 24:654657 4. Gartry DS, Kerr Muir MG, Marshall ]. The effect of topical corticosteroids on refraction and corneal haze following excimer laser treatment of myopia: an update. A prospective, randomised, double-masked study. Eye 1993; 7:584-590 5. Fagerholm P, Hamberg-Nystrom H, Tengroth B, Epstein D. Effect of postoperative steroids on the refractive outcome of photorefractive keratectomy for myopia with the Summit excimer laser. ] Cataract Refract Surg 1994; 20:212-215 6. Seiler T, Holschbach A, Derse M, et al. Complications of myopic photorefractive keratectomy with the excimer laser. Ophthalmology 1994; 101:153-160 7. Sher NA, Krueger RR, Teal P, et al. Role of topical steroids, corticosteroids and nonsteroidal anti-inflammatory drugs in the etiology of stromal infiltrates after excimer photorefractive keratectomy (letter). ] Refract Corneal Surg 1994; 10:587-588 8. Phillips AF, Szerenyi K, Campos M, et al. Arachidonic acid metabolites after excimer laser corneal surgery. Arch Ophthalmol 1993; 111:1273-1278 9. Nassaralla BA, Szerenyi K, Wang xw, et al. Effect of diclofenac on corneal haze after photo refractive keratectomy in rabbits. Ophthalmology 1995; 102:469--474 10. Arshinoff S, D'Addario D, Sadler C, et al. Use of topical nonsteroidal anti-inflammatory drugs in excimer laser photorefractive keratectomy. ] Cataract Refract Surg 1994; 20:216-222 11. O'Brart DPS, Lohmann CP, Klonos G, et al. The effects of topical corticosteroids and plasmin inhibitors on refractive outcome, haze, and visual performance after photo refractive keratectomy; a prospective, randomized, observer-masked study. Ophthalmology 1994; 101:15651574 12. Talamo ]H, Gollamudi 5, Green WR, et al. Modulation of corneal wound healing after excimer laser kerato-
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13.
14.
15. 16.
17.
mileusis using topical mitomycin C and steroids. Arch Ophthalmol 1991; 109:1141-1146 Modet N, Gillies MC, Crouch R, Maloof A. Effect of topical interferon a 2b on corneal haze after excimer laser photo refractive keratectomy in rabbits. Refract Corneal Surg 1993; 9:443-451 Fantes FE, Hanna KD, Waring GO III, et al. Wound healing after excimer laser keratomileusis (photo refractive keratectomy) in monkeys. Arch Ophthalmol 1990; 108:665-675 Flach AJ. Cyclo-oxygenase inhibitors in ophthalmology. Surv Ophthalmol 1992; 36:259-284 Priesley Gc. Effects of corticosteroids on the growth and metabolism of fibroblasts cultured from human skin. Br J Dermatol 1978; 99:253-261 Lu KL, Wee WR, McDonnell PJ. Comparison of in vitro antiproliferative effects of steroids and NSAlDs on
human keratocyte. ARVO abstract 3973 Invest Ophthalmol Vis Sci 1995; 36(4):S867 18. Hirata F, Schiffmann E, Venkatasubramanian K, et al. A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids. Proc Natl Acad Sci USA 1980; 77:2533-2536 19. Hersh PS, Rice BA, Baer JC, et al. Topical nonsteroidal agents and corneal wound healing. Arch Ophthalmol 1990; 108:577-583 From the Department of Ophthalmology, Seoul National University College ofMedicine, Seoul Korea. Presented in part at the Symposium on Cataract, IOL and Refractive Surgery, Seattle, Washington, USA, June 1996. None of the authors has a commercial or proprietary interest in any company or product mentioned.
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E
xcimer laser photorefractive keratectomy (PRK) for myopia involves surface photoablation of the anterior central corneal stroma to change its radius of curvature. It has been accepted as safe and effective for the correction of low to moderate myopia. However, Reprint requests to Jin-Hak Lee, MD, Department of Ophthalmology, Seoul National University College of Medicine, #28 Yeongun-dong, Chongro-ku, Seoul 110-744, Korea.
undercorrection, mainly resulting from refractive regression, and corneal haze, which can produce glare and a loss of best corrected visual acuity (BCVA), have been reported as major complications that seem more problematic in eyes with high myopia. 1 These phenomena are the result of corneal wound healing after PRK. Thus, there has been considerable interest in pharmacologic modification of the healing process? Corticosteroids,l-6 nonsteroidal anti-inflam-
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EFFECTS OF FLURBIPROFEN AND DICLOFENAC AFTER PRK
matory drugs (NSAIDs),7-1O plasmin inhibitors,lI antimetabolites,12 and cytokines 13 have been used after excimer laser PRK in animal experiments and clinical trials. Topical NSAIDs can reduce severe pain after PRK.7,10 However, the effect of the various pharmacologic agents on regression and corneal haze remains controversial. Photo refractive keratectomy for high myopia is thought to induce more regression and haze. 6 Thus, those with high myopia may benefit from topical pharmacologic agent therapy. We conducted this study to assess the effects of topical NSAIDs and compared the results with those of topical steroids used after excimer laser PRK for myopia.
Patients and Methods This prospective study was designed to compare the effects of three topical agents on refraction and haze according to the degree of myopia treated. An institutional review board approved the project, and prospective patients were sent background information. Eighty-five eyes of 51 patients had PRK to correct myopia. Mean myopia of the 16 men and 35 women was 6.01 diopters (D) (range 2.13 to 9.90 D spherical equivalent [SE]). Patients with extremely high myopia (10.00 D or more) were excluded; therefore, emmetropia was the aim in every case. All patients had visual acuities correctable to 20/30 or better with spectacles. Refractive astigmatism did not exceed 2.00 D. Patients younger than 18 years or with abnormal corneas or a history of ophthalmic disease or surgery were excluded. Mean patient age was 27.5 years (range 19 to 42 years). Patients were divided into two groups according to the preoperative SE: low to moderate myopia (6.00 D or less) and high myopia (greater than 6.00 D). The low to moderate myopia group comprised 44 eyes of 29 patients (7 men, 22 women) with a mean myopia of 4.34 D (range 2.13 to 6.00 D SE). The high myopia group comprised 41 eyes of 26 patients (11 men, 15 women) with a mean myopia of7.81 D (range 6.25 to 9.75 D SE). The patients were then randomly assigned to one of three subgroups based on topical agent regimen: steroid (fluorometholone 0.1 %) (n = 43); flurbiprofen sodium 0.03% (Ocufen®) (n = 20); diclofenac sodium 0.1 % (Decrol®) (n = 22). Tables 1 and 2 show the preoperative status in each group. 1318
Preoperatively, all patients had a complete ophthalmic examination including slitlamp biomicroscopy, Goldmann applanation tonometry, subjective refraction and visual acuity, cycloplegic refraction, corneal pachymetry, and computerized corneal topography.
Surgical Procedure An OmniMed excimer laser (Summit Technology) with a wavelength of 193 nm, fixed pulse repetition rate of 10 Hz, and radiant exposure of 180 mJ/cm2 at the corneal plane was used. Patients received topical pilocarpine 2% before surgery three times at 5 minute intervals. After topical anesthesia was obtained with proparacaine hydrochloride 0.5%, the central corneal epithelium was removed mechanically. A fixed ablation Table 1. Preoperative status of the low to moderate myopia group (6.00 D or less). Group Steroid (n = 20)
Flurbiprofen (n = 9)
Age Mean SD
27.5 6.0
25.6 8.9
Sex Male Female
5
2
15
7
Characteristic
Spherical equivalent (D) Mean SD
-4.33
-4.04
1.03
1.41
Diclofenac (n = 15) P-value 26.2
0.18
3.4 4 11
0.97
-4.55 0.89
0.65
Table 2. Preoperative status of the high myopia group (greater than 6.00 D).
Group Steroid (n = 23)
Flurbiprofen (n = 11)
Age Mean SD
27.8 6.1
26.4 4.1
33.3
Sex Male Female
7 16
9 2
1 6
Spherical equivalent (D) Mean SD
-7.80 1.11
Characteristic
-7.69 1.06
*Statistically significant; chi-square test
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Diclofenac (n = 7) P-value 0.11
7.0
-8.05 1.02
0.005*
0.24
EFFECTS OF FLURBIPROFEN AND DICLOFENAC AFTER PRK
rate (0.25 J.lm per pulse) and a 5.0 mm ablation zone diameter were used. The number of pulses was computed by the laser's ablation algorithm. A single-zone treatment was done in every case. Postoperatively, topical homatropine 2% and ofloxacin ointment were instilled and a pressure patch was applied once a day until the epithelium healed completely. Oral analgesics and antibiotics were given for 3 days. Postoperative examinations were done 1 day after PRK and then daily until complete epithelial healing and then at 1 and 3 weeks and 2, 4, and 6 months. Manifest refraction and slitlamp examination were done at each visit from postoperative week 1. Subepithelial haze was graded clinically on a scale of a to +4.14 Intraocular pressure (lOP) was measured at 1 week and 3 months.
Postoperative Topical Agent Regimen Patients in the steroid subgroup had the following postoperative regimen: fluorometholone 0.1 % four times a day for 1 month; three times a day for 1 month; twice a day for 1 month; once a day for 1 month; discontinued. Patients in the two NSAID subgroups (flurbiprofen and diclofenac) received one drop of their assigned drug every 15 minutes four times preoperatively and one drop postoperatively before patching and then began the same postoperative tapering schedule as in the steroid group.
Statistical Analysis The data were not normally distributed, and the sample sizes were quite small. Thus, Kruskal-Wallis tests were used to compare age, preoperative refraction, postoperative refractive changes, and haze gradings. Chi-square tests were used to compare sex distribution and percentages of severe myopic regression or haze in each group. A P-value of less than 0.05 was considered statistically significant. When the postoperative refractive changes and haze gradings showed a statistically significant difference between the three subgroups by the Kruskal-Wallis test, the Wilcoxon rank-sum test was used to compare two of the three subgroups, yielding three combinations of two subgroups for the original three subgroups. Because an a-error could affect these combinations, a Wilcoxon rank-sum test was done only when the original groups showed a significant difference by the Kruskal-Wallis test. Thus, a P-value less than 0.05 was considered to indicate a possible trend of the changes in each subgroup.
Results Refractive Outcome Mean postoperative manifest refractions (SE) over time in the low to moderate and high groups are shown in Figures 1 and 2. In the low to moderate myopia group, the mean SE in the three subgroups was statistically significantly different at 2 and 4 months (P = .01
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Figure 1. (Baek) Mean refraction (SE) after PRK in the low to
Figure 2. (Baek) Mean refraction (SE) after PRK in the high
moderate myopia group (6.00 D or less). Extended bars represent standard error. Differences were considered statistically significant at P < .05; P < .05 is compared with similar marks (_a__. = steroid group; ... 0-.. = flurbiprofen group; ---/:x-- = diclofenac group).
myopia group (greater than 6.00 D). Extended bars represent standard error. Differences were considered statistically significant at P < .05; P < .05 is compared with similar marks (_a__. = steroid group; .. ·0··· = flurbiprofen group; ---6--- = diclofenac group).
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EFFECfS OF FLURBIPROFEN AND DICLOFENAC AFTER PRK
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Figure 3. (Baek) Mean subjective corneal haze grading after PRK in the low to moderate myopia group (6.00 D or less). Extended bars represent standard error. Differences were considered statistically significant at P < .05; P < .05 is compared with similar marks (___ = steroid group; ···0·· = flurbiprofen group; ---l::,.--- = diclofenac group).
and .047, respectively); there was no difference at 6 months (Figure 1). At 2 and 4 months, the mean SE in the steroid subgroup was significantly different from that in the didofenac subgroup (P = .007 and .015, respectively). The differences in results in the flurbiprofen and didofenac subgroups were not significant at any time. Two eyes (22.2%) in the flurbiprofen subgroup and five (33.3%) in the didofenac subgroup had severe myopic regression (greater than 2.00 D), whereas one eye (5.0%) in the steroid subgroup did. In the high myopia group, the mean SE of the three subgroups was significantly different after 3 weeks (P < .006; Figure 2). The flurbiprofen and didofenac subgroups showed no significant difference at any point. Three eyes (13.0%) in the steroid subgroup, seven (63.6%) in the flurbiprofen subgroup, and five (71.4%) in the didofenac subgroup showed severe myopic regression (greater than 2.00 D). The percentage of eyes with severe myopic regression in each subgroup was statistically significantly different (P < .002). The steroid subgroup showed severe myopic regression less frequently than the NSAID subgroups.
Subjective Haze The time course for the development of anterior stromal haze, as subjectively assessed at the slitlamp, is shown in Figures 3 and 4. In the low to moderate myopia (Figure 3) and high myopia (Figure 4) groups, 1320
4
5
Time (month)
Figure 4. (Baek) Mean subjective corneal haze grading after PRK in the high myopia group (greater than 6.00 D). Extended bars represent standard error. Differences were considered statistically significant at P < .05; P < .05 is compared with similar marks (___ = steroid group; .. ·0'" = flurbiprofen group; ---l::,.--= diclofenac group).
the difference in haze gradings between the three subgroups was statistically significant. In both groups, the haze gradings in the steroid subgroup were consistently lower than in the NSAID subgroups after 2 months (P < .004). The difference between the two NSAID subgroups was not significant at any point. In the low to moderate myopia group, no eye had severe corneal haze (greater than grade 2) with a two or more line decrease in BCVA. In the high myopia group, two eyes (8.7%) in the steroid subgroup, seven (63.6%) in the flurbiprofen subgroup, and six (85.7%) in the didofenac subgroup had haze greater than grade 2 with a two line or more decrease in BCVA. The steroid subgroup developed severe corneal haze less frequently than the NSAID subgroups.
Complications There were two cases of complications associated with the treatment drug. The first was a 24-year-old man who had increased lOP 2 weeks after steroid instillation. The steroids were stopped immediately, and lOP was normal at the next visit. The second was a 42-year-old woman in the didofenac subgroup, high myopia group, who had myopic regression after 2 months. Two months after steroid instillation, a dendrite-like lesion appeared on her cornea. The steroids were stopped and trifluorothymidine eyedrops prescribed. The lesion had resolved by the next visit.
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Discussion Regression and corneal haze are the results of corneal wound healing after excimer laser PRK. Corneal wound healing passes through a series of welldefined stages: epithelial hyperplasia with epithelial wound healing, stromal regeneration, and wound remodeling (R.E Steinert, MD, "Phase III Two-Year Results of the Summit Technology Laser," presented at the Symposium on Cataract, 10L and Refractive Surgery, San Diego, California, USA, April 1995). Because aggressive wound-healing responses may produce unwanted effects, much effort has been focused on reducing these responses. Nonsteroidal anti-inflammatory drugs inhibit the formation of inflammatory mediators at a later step in the arachidonic acid pathway and have fewer widespread cellular effects than corticosteroids.1 5 They also retard fibroblast growth and proliferation. 16.17 Fluorometholone belongs to the class of corticosteroids that induce production of lipomodulin,18 a glycoprotein that functions as a specific phospholipase ~ inhibitor. This decreases arachidonic acid and, consequently, reduces lipoxygenase and cyclo-oxygenase metabolites. Flurbiprofen sodium, a propionic acid derivative, and diclofenac sodium, a phenylacetyl acid derivative, have well-defined abilities to disrupt the function of cyclo-oxygenase and hence the production of prostaglandins.1 5 Diclofenac sodium can reduce the availability of intracellular arachidonic acid by enhancing its uptake into triglyceride pools and thus influences the production of lipoxygenase as well as cyclooxygenase products. Hersh et al. 19 studied the effects on corneal wound healing of two NSAIDs, flurbiprofen sodium 0.03% and diclofenac sodium 0.1 %, and a topical corticosteroid, prednisolone sodium phosphate 1%. They found that all three decreased early epithelialization of corneal scrape wounds; however, they had no apparent effect on healing of the corneal stroma. Phillips et al. 8 showed that topical application of diclofenac after PRK caused a significant decrease in prostaglandin E2 levels but a significant increase in polymorphonuclear leukocytes in the anterior stroma. In contrast, fluorometholone did not significantly alter prostaglandin E2 levels but did markedly inhibit leukocyte infiltration. Nassaralla et al. 9 compared the inhibitory effects of a topical NSAID (diclofenac sodium 0.3%) and ste-
roids (fluorometholone 0.1 %) to those of no treatment on the development of corneal haze after photoablative keratectomy in rabbits. Both drugs reduced corneal haze but did not influence refractive outcome. No additive effect was obtained by combining the drugs, which the authors speculate was due to toxicity of the cumulative effect of preservatives or drug interactions. Arshinoff et al. IO studied post-PRK myopic regression in 68 consecutive patients and found that flurbiprofen sodium 0.1 %, when added to topical steroid protocols (fluorometholone 0.25%), reduced myopic regression for 1 year postoperatively significantly more than steroids alone or steroids and diclofenac sodium. In 4 eyes of 2 patients with a severe postoperative glaucomatous response to steroids, the topical steroids were discontinued and the eyes were treated with a topical NSAID alone. Three eyes were initially assigned to the flurbiprofen group and were overcorrected at 1 year, resulting in 0.50 to 1.00 D of hyperopia. All had transient trace corneal haze. Another eye treated with diclofenac began to develop myopic regression and haze at 3 months; the eye eventually stabilized at -4.00 D with moderate haze after the patient began using flurbiprofen. Arshinoff et al. concluded that flurbiprofen alone seemed to be a consistent, potent inhibitor of myopic regression and stromal haze and suggested that the diverse actions of topical NSAIDs are probably mediated through different, although similar, receptors. In the current study, we compared the effects of topical NSAIDs and steroids on myopic regression and corneal haze according to the degree of myopia. In the low to moderate myopia group, the drugs led to significant differences in manifest refraction only at
2 and 4 months, at which time the difference between the steroid and diclofenac subgroups was significantly different. The subjective haze grades were consistently lower in the steroid subgroup after 2 months. In addition, the NSAID subgroups (flurbiprofen and diclofenac) showed severe myopic regression more frequently than the steroid subgroup (22.2 and 33.3% vs. 5.0%); however, the difference did not reach statistical significance. This could be an effect of our small population, and further study is needed. In the high myopia group, the only significant difference in the incidence of the severe myopic regression, corneal haze, or both was between the high myopia group's steroid subgroup and the two NSAID
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subgroups. The steroid subgroup had less myopic regression and corneal haze and fewer occurrences of vision-reducing myopic regression or haze. Thus, corticosteroids appeared to be more effective than NSAIDs in reducing myopic regression and haze, especially in eyes with high myopia. Our results were somewhat different from those of Nassaralla et al.,9 who found in an animal experiment that corneal healing response to anti-inflammatory therapy can differ among species. However, they found no difference in keratometric change, and they did not know the preoperative and postoperative manifest refractions. The refractive changes in our study differ from those in Arshinoff et al.'s study.lO However, they used topical NSAIDs only in combination with steroids at the beginning and they used topical NSAIDs for a longer period than our regimen. The mean preoperative refraction (- 5.02 ± 2.63 D) was lower than that in our high myopia group. The greater amount of attempted correction in our high myopia group might induce more regression and haze, 6 and a more potent agent would be required to reduce them (i.e., corticosteroids rather than an NSAID alone). Numerous questions remain to be answered with respect to the ideal post-PRK pharmacologic therapy of the patients. Gartry and coauthors4 reported that topical corticosteroids had transient effects on regression only during their administration and no effect on corneal haze. A study of Canadian surgeons performing excimer laser PRK found 28 reports of subepithelial corneal infiltrates in association with preoperative and postoperative use of topical NSAIDs and contact lens occlusion,7 an incidence of approximately 1 in 250 treated eyes. None of these patients received topical steroids after PRK but had been given topical ketorolac or topical diclofenac before, during, and four times a day after surgery. More than 90% of eyes were left with some stromal scarring and a one or two line reduction in BCVA despite treatment with topical antibiotics, topical corticosteroids, or both. Topical NSAIDs might be used only with topical steroids. In light of our data, we believe that topical NSAIDs would be less effective than topical corticosteroids in reducing myopic regression and haze after PRK, especially in eyes with high myopia. We recently began using topical steroids only in patients with myopia greater than 6.00 D. Although there has been 1322
much controversy about the effect of topical NSAIDs used as painkillers, we use topical diclofenac postoperatively for pain control only until complete closure of epithelial defect. We do not use them for corneal haze . . or myopIC regreSSion.
References 1. Gartry DS, Kerr Muir MG, Marshall ]. Excimer laser photorefractive keratectomy: 18-month follow-up. Ophthalmology 1992; 99: 1209-1219 2. Tuft 5], Ganry DS, Rawe 1M, Meek KM. Photorefractive keratectomy: implications of corneal wound healing. Br ] Ophthalmol 1993; 77:243-247 3. Campos M, Abed HM, McDonnell P]. Topical fluorometholone reduces stromal inflammation after photorefractive keratectomy. Ophthalmic Surg 1993; 24:654657 4. Gartry DS, Kerr Muir MG, Marshall ]. The effect of topical corticosteroids on refraction and corneal haze following excimer laser treatment of myopia: an update. A prospective, randomised, double-masked study. Eye 1993; 7:584-590 5. Fagerholm P, Hamberg-Nystrom H, Tengroth B, Epstein D. Effect of postoperative steroids on the refractive outcome of photorefractive keratectomy for myopia with the Summit excimer laser. ] Cataract Refract Surg 1994; 20:212-215 6. Seiler T, Holschbach A, Derse M, et al. Complications of myopic photorefractive keratectomy with the excimer laser. Ophthalmology 1994; 101:153-160 7. Sher NA, Krueger RR, Teal P, et al. Role of topical steroids, corticosteroids and nonsteroidal anti-inflammatory drugs in the etiology of stromal infiltrates after excimer photorefractive keratectomy (letter). ] Refract Corneal Surg 1994; 10:587-588 8. Phillips AF, Szerenyi K, Campos M, et al. Arachidonic acid metabolites after excimer laser corneal surgery. Arch Ophthalmol 1993; 111:1273-1278 9. Nassaralla BA, Szerenyi K, Wang xw, et al. Effect of diclofenac on corneal haze after photo refractive keratectomy in rabbits. Ophthalmology 1995; 102:469--474 10. Arshinoff S, D'Addario D, Sadler C, et al. Use of topical nonsteroidal anti-inflammatory drugs in excimer laser photorefractive keratectomy. ] Cataract Refract Surg 1994; 20:216-222 11. O'Brart DPS, Lohmann CP, Klonos G, et al. The effects of topical corticosteroids and plasmin inhibitors on refractive outcome, haze, and visual performance after photo refractive keratectomy; a prospective, randomized, observer-masked study. Ophthalmology 1994; 101:15651574 12. Talamo ]H, Gollamudi 5, Green WR, et al. Modulation of corneal wound healing after excimer laser kerato-
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mileusis using topical mitomycin C and steroids. Arch Ophthalmol 1991; 109:1141-1146 Modet N, Gillies MC, Crouch R, Maloof A. Effect of topical interferon a 2b on corneal haze after excimer laser photo refractive keratectomy in rabbits. Refract Corneal Surg 1993; 9:443-451 Fantes FE, Hanna KD, Waring GO III, et al. Wound healing after excimer laser keratomileusis (photo refractive keratectomy) in monkeys. Arch Ophthalmol 1990; 108:665-675 Flach AJ. Cyclo-oxygenase inhibitors in ophthalmology. Surv Ophthalmol 1992; 36:259-284 Priesley Gc. Effects of corticosteroids on the growth and metabolism of fibroblasts cultured from human skin. Br J Dermatol 1978; 99:253-261 Lu KL, Wee WR, McDonnell PJ. Comparison of in vitro antiproliferative effects of steroids and NSAlDs on
human keratocyte. ARVO abstract 3973 Invest Ophthalmol Vis Sci 1995; 36(4):S867 18. Hirata F, Schiffmann E, Venkatasubramanian K, et al. A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids. Proc Natl Acad Sci USA 1980; 77:2533-2536 19. Hersh PS, Rice BA, Baer JC, et al. Topical nonsteroidal agents and corneal wound healing. Arch Ophthalmol 1990; 108:577-583 From the Department of Ophthalmology, Seoul National University College ofMedicine, Seoul Korea. Presented in part at the Symposium on Cataract, IOL and Refractive Surgery, Seattle, Washington, USA, June 1996. None of the authors has a commercial or proprietary interest in any company or product mentioned.
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