Comparison of analgesic effect of preoperative topical diclofenac and ketorolac on postoperative pain after photorefractive keratectomy

ARTICLE

Comparison of analgesic effect of preoperative topical diclofenac and ketorolac on postoperative pain after photorefractive keratectomy Jin Pyo Hong, MD, Sang Min Nam, MD, Chan Young Im, MD, Sangchul Yoon, MD, Tae-im Kim, MD, PhD, Eung Kweon Kim, MD, PhD, Kyoung Yul Seo, MD, PhD

PURPOSE: To investigate changes in the pain-suppressing potency of 2 preoperatively applied topical nonsteroidal antiinflammatory drugs (NSAIDs) after photorefractive keratectomy (PRK) using a time-serial pain-scoring system. SETTING: Saeyan Eye Center, Seoul, South Korea. DESIGN: Comparative case series. METHODS: Ninety-four patients were randomly assigned to 2 groups: ketorolac group (ketorolac 0.5% in 1 eye and ofloxacin 0.3% in the other eye) and diclofenac group (diclofenac 0.1% in 1 eye and ofloxacin 0.3% in the other eye). One drop of each ophthalmic drug was applied 3 times to each eye 30 minutes before PRK. No other NSAID or steroid was prescribed until 4 days after PRK. The patients were asked to score the postoperative pain in each eye with a visual analog scale at 6, 18, 24, 36, 48, 72, and 96 hours. RESULTS: The natural peak of pain was located between 24 and 36 hours. Initially, the degree of pain reduction was constant for both NSAIDs; it dropped after 24 hours and 36 hours in the ketorolac group and the diclofenac group, respectively. The postoperative time-serial pattern of the pain score changed in the diclofenac group but not in the ketorolac group compared with the pattern in the ofloxacin-treated eye. The visual outcome was not affected by either NSAID, and significant complications were not noticed for a mean of 7 months. CONCLUSIONS: The duration and pattern of the action may vary according to types of NSAIDs. Preemptive topical diclofenac 0.1% was a safe and effective method for post-PRK pain control. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2014; -:-–- Q 2014 ASCRS and ESCRS

Photorefractive keratectomy (PRK) or surface ablation is one of the most widely used surgical procedures to correct myopia, along with laser in situ keratomileusis (LASIK).1,2 In PRK, the corneal epithelium is removed by various techniques such as diluted alcohol, manual debridement, or brush before laser ablation of the corneal stroma.3,4 After PRK, ocular discomfort such as foreign-body sensation or pain can be present for 2 to 3 days.5–7 The postoperative discomfort arises primarily from the exposed corneal nerve endings after removal of the corneal epithelium.8 Various chemical mediators such as prostaglandin, histamine, and Q 2014 ASCRS and ESCRS Published by Elsevier Inc.

substance P are secreted from the corneal tissue damaged by the excimer laser. These mediators stimulate the exposed corneal nerve endings.9 To eliminate ocular pain after PRK, the bandage contact lens, dilute topical anesthetics, oral analgesics, topical morphine, and topical nonsteroidal antiinflammatory drugs (NSAIDs) have been introduced.7,10–14 Topical NSAIDs are commonly prescribed to mitigate inflammation and pain related to ocular surgery.15 Administration of a single drop of topical diclofenac 0.1% 2 hours before PRK has been reported to be helpful in managing postoperative pain.16 Preoperative 0886-3350/$ - see front matter http://dx.doi.org/10.1016/j.jcrs.2014.05.029

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application also decreases pain for 1 day after PRK when topical diclofenac is applied for 2 days postoperatively.16 Recently, diclofenac 0.1% and ketorolac 0.5% instilled in a dose of 1 drop administered 30 minutes before surgery were equally beneficial in preventing post-PRK pain and discomfort for 2 days.17 In that study, a single dose of topically applied NSAID prevented pain without postoperative administration.17 However, topical betamethasone 0.1% was administered postoperatively and may have influenced the postoperative inflammation and pain.17 Postoperative pain control with preoperative topical NSAIDs is clinically important because previous studies suggest that topical NSAIDs decrease corneal epithelium migration and delay wound healing.18 Severe corneal toxicity has been reported with various NSAIDs such as diclofenac 0.1%, ketorolac 0.5%, nepafenac 0.1%, and bromfenac 0.09%.19–24 With a corneal surface disturbed by PRK, the capacity of the corneal epithelium to self-repair may be diminished by topical NSAIDs and cause serious complications, including corneal melting. Ameliorating post-PRK pain with the preoperative application of topical NSAIDs only would be a safe and useful way to treat PRK patients. In our study, no postoperative NSAID or steroid was used so the effect of preoperative topical NSAID treatment could be assessed. In addition, the post-PRK pain was scored at 7 different times for 4 days to provide a detailed report of the duration and intensity of the drug's effect over time. Similar to previous studies,

Submitted: September 2, 2013. Final revision submitted: December 7, 2013. Accepted: January 7, 2014. From the Saeyan Eye Center (Hong), the Ian Eye Center (Im), the Department of Ophthalmology (Yoon, T-i. Kim, E.K. Kim, Seo), Eye and Ear Hospital, Severance Hospital, Institute of Vision Research, Yonsei University College of Medicine, Seoul, and the Department of Ophthalmology (Nam), CHA Bundang Medical Center, CHA University, Seongnam, South Korea. Jin Pyo Hong, MD, and Sang Min Nam, MD, contributed equally to this article. Supported by a grant from the Korea Healthcare Technology R&D Project (Grant number A103001), Ministry of Health & Welfare, South Korea. Presented at the XXX Congress of the European Society of Cataract and Refractive Surgeons, Milan, Italy, September 2012. Corresponding author: Kyoung Yul Seo, MD, PhD, Department of Ophthalmology, Severance Hospital, Yonsei University College of Medicine, 134 Shinchondong, Seodaemungu, Seoul 120-752, South Korea. E-mail: [email protected].

a paired-eye comparison design was used to observe the changes in pain. The action patterns of topical ketorolac and diclofenac were also compared. PATIENTS AND METHODS This randomized double-masked paired-eye comparison single-center trial (No. 4-2012-0440) was approved by the institutional review board of our institution. Informed consent was obtained from all participants, and the study adhered to the tenets of the Declaration of Helsinki. One hundred thirteen patients who had PRK from January 2011 to March 2011 at Saeyan Eye Center were recruited. Preoperative examinations included history, corrected distance visual acuity (CDVA), manifest refraction, intraocular pressure, keratometry, central corneal thickness, pupil size, slitlamp examination, topography (Orbscan II, Bausch & Lomb), and higher-order aberration (HOA) analysis (WASCA Analyzer, Carl Zeiss Meditec AG). The inclusion criteria were age of at least 19 years, simultaneous bilateral PRK, a greater than 400 mm (including epithelium) postoperative corneal thickness, and a thinner than 150 mm ablation depth. The exclusion criteria were a history of ocular surgery or trauma, 2.0 diopters (D) greater difference in spherical equivalent (SE) between the eyes, keratoconus or other corneal pathology, use of systemic or topical NSAIDs within 1 month of the surgery, history of allergic reaction to aspirin or other NSAIDs, glaucoma or ocular hypertension (O20 mm Hg), collagen vascular disease, diabetic retinopathy, pregnancy or lactation, and intraoperative complications. Recruited patients were excluded if they replaced their contact lenses, took analgesics arbitrarily, used a topical steroid irregularly, stopped arbitrarily, or were followed for fewer than 3 months.

Randomization and Preoperative Treatment On the day of surgery, the patients were randomly assigned to one of 2 groups by a lottery drawn by a nurse who was unrelated to this research. The ketorolac group applied topical ketorolac 0.5% (Acular) in 1 eye and topical ofloxacin 0.3% (Ocuflox) in the other eye preoperatively. The diclofenac group applied topical diclofenac 0.1% (Voltaren) in 1 eye and ofloxacin 0.3% in the other eye preoperatively. Neither the surgeon nor the patients knew which ophthalmic drug went into which eye. A randomly assigned ophthalmic drug was first instilled into the right eye 3 times at 1-minute intervals 30 minutes before surgery, and the other ophthalmic drug was instilled into the left eye in the same manner 10 minutes later.

Surgical Method All eyes (the right eye first, then the left eye) were operated on by a single surgeon (J.P.H). Before surgery, topical proparacaine hydrochloride 0.5% (Alcaine) was applied 3 times to both eyes. Then 20% alcohol was applied to an 8.0 mm diameter well for 30 seconds and rinsed from the eye using a cold balanced salt solution (BSS, Alcon Laboratories, Inc.). The corneal epithelial layer was then removed with a micro hoe. The exposed corneal stroma was ablated with a Mel80 excimer laser (Carl Zeiss Meditec AG) and irrigated again with cold balanced salt solution for 30 seconds. A cellulose sponge soaked with mitomycin 0.02% was applied to the ablated stroma for 20 to 30 seconds before irrigation in cases

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Table 1. Comparison of preoperative characteristics of patients in the 2 groups.a Characteristic

Group KO (n Z 49)

Group DO (n Z 45)

95% CI or P value

Age (y) Men:Women

29 G 7 17:32

29 G 7 12:33

2 to 3b 0.536c

Manifest refraction (diopter) Sphere Cylinder SE CDVA (log MAR) HOA (mm)f

Ketorolac

Ofloxacin

95% CId

Diclofenac

Ofloxacin

95% CId

4.41 G 1.95 0.91 G 0.70 4.87 G 2.08 0.03G 0.05 0.36 G 0.13

4.47 G 2.07 1.05 G 0.85 4.99G 2.11 0.03G 0.06 0.38 G 0.16

0.18 to 0.28 0.01 to 0.28 0.11 to 0.34 0.02 to 0.02 0.07 to 0.03

4.18 G 1.88 0.83 G 0.75 4.60 G 2.00 0.04G 0.05 0.38 G 0.22

4.04 G 1.61 0.89 G 0.76 4.49 G 1.68 0.04G 0.06 0.39 G 0.19

0.40 to 0.11 0.09 to 0.21 0.37 to 0.14 0.01 to 0.01 0.06 to 0.04

1.0 to 0.56e 0.38 to 0.22e 1.11 to 0.57e 0.02 to 0.02e 0.11 to 0.07e

CDVA Z corrected distance visual acuity; CI Z confidence interval; DO Z doclofenac–ofloxacin; HOA Z higher-order aberration; KO Z ketorolac–ofloxacin; SE Z spherical equivalent a All values are expressed as mean G SD except gender ratio. b CI for T-test c P value of chi-square test; Chi-sqaure with Yates correction Z 0.4 d Paired t-test e CI for the difference of the means between ketorolac and diclofenac (t-test). f The subject numbers were 34 in group KO and 30 in group DO.

with more than 6.0 D of correction. After surgery, a bandage contact lens (Acuvue Oasis, Johnson & Johnson Vision Care, Inc.) was placed over both eyes.

Assessment of Pain and Postoperative Protocol Only moxifloxacin hydrochloride 0.5% (Vigamox) was used in both eyes 4 times daily until the bandage contact lenses were removed. No oral analgesic was prescribed with consent of the patients after the purpose of the study had been explained. If patients felt intolerable pain, they could take oral analgesics and were excluded from the study without penalty. The patients were asked to score the level of postoperative pain in each eye separately at 6, 18, 24, 36, 48, 72, and 96 hours postoperatively using a visual analog scale (VAS),25 which rates the pain on a scale of 0 (no pain) to 10 (the most excruciating pain). The pain prevention of preoperative ophthalmic drugs was assessed with the pain reduction score; ie, the pain score after topical ofloxacin is subtracted from the pain score after the topical NSAID in the same patient at a specific postoperative time. On postoperative day 5, the bandage contact lenses were removed if the corneal epithelium was completely regenerated and moxifloxacin hydrochloride 0.5% was discontinued. Thereafter, fluorometholone 0.1% (Flumetholon) was applied 4 times daily for 1 month and tapered over the next 2 months. Postoperative examinations included uncorrected visual acuity and retinoscopy.

Statistical Analysis Repeated measures multivariate analysis of variance (MANOVA) and the power calculation were carried out by IBM SPSS (version 20, International Business Machines Corp.). Multiple comparisons versus the control group of repeated measures MANOVA were performed by Sigma Plot (version 12.0, Systat Software, Inc.). The sample size for multivariate repeated measures MANOVA was estimated with G*power 3 (version

3.1.5.1).26 The sample size for paired t test was calculated with Sigma Plot. Other statistical calculations were performed with IBM SPSS. The sample sizes for multivariate repeated measures MANOVA on pain reduction scores of the ketorolac and diclofenac groups were estimated in the power of 0.8, the a of 0.05, Pillai V, and O'Brien-Shieh algorithm. The ketorolac group and diclofenac group required 21 patients with the effect size f(V) of 1 and 20 patients with the effect size f(V) of 1.03, respectively. The sample sizes for paired t tests of the difference between the preoperative spherical SE in the ketorolac and diclofenac groups were calculated with a power of 0.8, a of 0.05, and 0.35 D difference to be detected. The estimated numbers for the ketorolac group and the diclofenac group were 41 patients with 0.776 standard deviation (SD) of difference and 48 patients with 0.842 SD of difference, respectively.

RESULTS One hundred thirteen patients were initially enrolled in the study. Eleven patients were excluded because they took an oral analgesic. Another 8 patients were excluded because of premature bandage contact lens removal or not submitting their questionnaire in a timely manner. Finally, 94 patients (188 eyes), 29 men and 65 women, were analyzed and were randomly allocated to the ketorolac group or the diclofenac group. There were no statistically significant differences in the age or sex ratio in the 2 groups. Manifest refraction, CDVA, and HOAs were statistically the same in the 4 subgroups of the ketorolac and diclofenac groups (Table 1). First, the natural pain curve after PRK was obtained from the ofloxacin-treated eyes. Postoperative pain scores showed a similar pattern in ofloxacin-treated eyes in the ketorolac and diclofenac groups

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Figure 1. Time-serial changes in the pain score of ofloxacin-treated eyes. The pain score was not different between the 2 groups (PZ.603, a Z 0.05, power Z 0.081, repeated measures MANOVA). The postoperative pain score changed according to the postoperative time (P!.001, a Z 0.05, power Z 1.000, repeated measures MANOVA), but there was no interaction between the postoperative time and groups (PZ.872, a Z 0.05, power Z 0.162, repeated measures MANOVA). In both groups, the mean pain scores at postoperative 24, 36, 72, and 96 hours were different from the pain score at postoperative 6 hours (indicated by asterisks) (P!.001 except for the 24-hour period of the diclofenac-ofloxacin group, PZ.002; multiple comparison versus control group, Holm-Sidak method). Error bars represent 95% CIs of the mean.

(Figure 1). The peak of the pain scores was in the postoperative period of 24 to 36 hours (Figure 1). The overall pain score of ketorolac-treated eyes was less than that of ofloxacin-treated eye (Figure 2). However, there was no interaction effect between ketorolac and postoperative time. This meant the time-serial pattern of pain of ketorolac did not change (Figure 2). The pain reduction score of ketorolac was maintained at the same level from 6 to 24 hours (Figure 3). The overall pain score of the diclofenac-treated eyes was less than that of ofloxacin-treated eyes (Figure 4). In addition, diclofenac showed an interaction effect with the postoperative time and the time-serial pattern of pain changed significantly in diclofenac-treated eyes (Figure 4). From 36 to 48 hours, the pain score decreased in ofloxacin-treated eyes (P!.001, a Z 0.05, power Z 1.000, paired t test) but did not change in diclofenac-treated eyes (PZ.275, a Z 0.05, power Z 0.191, paired t test). The pain reduction score of diclofenac was at the same level for 6 to 36 hours (Figure 5). However, the maximum pain score decreased at the same rate, an average of 2 units (2 to 3 units, 95% confidence interval [CI]) in ketorolac-treated and diclofenac-treated eyes. After the preoperative treatment of topical NSAIDs, no serious complications including corneal melt or

Figure 2. Time-serial changes in the pain score in the ketorolac group. The pain score varied according to the postoperative time (P!.001, a Z 0.05, power Z 1.000, multivariate repeated measures MANOVA) and the preoperative treatment (PZ.031, a Z 0.05, power Z 0.584, repeated measures MANOVA). There was no interaction effect between the postoperative time and the preoperative treatment (PZ.193, a Z 0.05, power Z 0.549, repeated measures MANOVA). Error bars represent 95% CIs of the mean.

perforation were noticed during the mean period of 7 months G 4 (SD) in the ketorolac group and 7 G 5 months in the diclofenac group ( 2 to 2 months, 95% CI of difference; t test). The visual outcomes were not affected by preoperative treatment with ketorolac or diclofenac in comparison with ofloxacin (Table 2).

Figure 3. Time-serial changes in the pain reduction score of preoperatively administered ketorolac. A smaller pain reduction score means a greater reduction of pain. Pain reduction score changed with postoperative time (P!.001, a Z 0.05, power Z 0.999, repeated measures MANOVA). Asterisk indicates significance at P!.05 relative to the score at postoperative 6 hours (PZ.740, PZ1.000, PZ.004, PZ.003, P!.001, and P!.001 at 12, 24, 36, 48, 72, and 96 hours, respectively; multiple comparison versus control group, Holm-Sidak method). Error bars represent 95% CIs of the mean.

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Figure 4. Time-serial changes in the pain score in the diclofenac group. The pain score varied according to the postoperative time (P!.001, a Z 0.05, power Z 1.000, repeated measures MANOVA) and the preoperative treatment (PZ.029, a Z 0.05, power Z 0.594, repeated measures MANOVA). The time effect on the pain score was influenced by the preoperative treatment (PZ.005, a Z 0.05, power Z 0.927, repeated measures MANOVA). Error bars represent 95% CIs of the mean.

Figure 5. Time-serial changes in the pain reduction score of preoperatively administered diclofenac. A smaller pain reduction score means a greater reduction of pain. Pain reduction score changed with postoperative time (P!.001, a Z 0.05, power Z 0.998, repeated measures MANOVA). Asterisk indicates significance at P!.05 relative to the score at postoperative 6 hours (PZ0.944, PZ.595, PZ.881, P!.001, P!.001, and P!.001 at 12, 24, 36, 48, 72, and 96 hours, respectively; multiple comparison versus control group, Holm-Sidak method). Error bars represent 95% CIs of the mean.

DISCUSSION The post-PRK pain was described as a typical peak curve (Figure 1). Similar pain curves were obtained from the ofloxacin-treated eyes of the ketorolac and diclofenac groups. Pain should be controlled for more than 36 hours because peak pain occurred between 24 and 36 hours (Figure 1). In this study, preoperative topical ketorolac and diclofenac suppressed postoperative pain with a constant intensity for 24 hours and 36 hours, respectively (Figures 3 and 5). The intensity of pain reduction was represented by the pain reduction score. The pain reduction score was the difference in pain scores between the NSAID-treated and the ofloxacin-treated paired eyes in the same patient. Because the minimum clinically significant VAS difference for paired simultaneous

comparisons is about 0.5 cm or less, the pain reduction scores were not only statistically significant but also clinically noticeable by the patients (Figures 3 and 5).27 The constant intensity of the pain-reducing action for postoperative 24 or 36 hours was not well explained by the pharmacokinetics. Various topical NSAIDs are known to reach their peak aqueous concentrations at 0.5 to 4.0 hours after instillation; thereafter the concentration decreases.28,29 However, in this study, the pain reduction effect persisted for a longer time despite the expected decline of ketorolac or diclofenac concentration in the corneal tissue (Figures 3 and 5). Preemptive analgesia is one possible mechanism that explains this phenomenon.30 The perception of

Table 2. Visual outcomes after preoperative treatment of ketorolac or diclofenac.a Group KO (n Z 49)

Retinoscopy (diopter) Sphere Cylinder SE UDVA

Group DO (n Z 45) b

Ketorolac

Ofloxacin

95% CI

Diclofenac

Ofloxacin

95% CIb

0.07 G 0.41 0.33 G 0.27 0.24 G 0.45 0.10 G 0.09

0.01 G 0.41 0.34 G 0.24 0.18 G 0.43 0.09 G 0.09

0.18 to 0.05 0.08 to 0.09 0.17 to 0.06 0.02 to 0.02

0.02 G 0.40 0.36 G 0.28 0.20 G 0.41 0.08 G 0.15

0.04 G 0.38 0.32 G 0.29 0.12 G 0.43 0.07 G 0.15

0.20 to 0.07 0.12 to 0.04 0.21 to 0.05 0.02 to 0.05

CI Z confidence interval; DO Z diclofenac–ofloxacin; KO Z ketorolac–ofloxacin; SE Z spherical equivalent; UDVA Z uncorrected distance visual acuity a All values are expressed as mean G SD. b Paired t-test

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pain is potentiated by surgery through the peripheral and central sensitization.30–32 When the peripheral terminals of primary sensory neurons are exposed to inflammatory mediators and other chemicals by the surgery, the sensitivity of high threshold nociceptor increases (peripheral sensitization).33 Then, the related neurons in the spinal cord become more excitable by continuous nociceptive afferent input (central sensitization).33 Because NSAIDs have an analgesic property, preemptive topical NSAIDs may weaken the corneal nerve sensitization by PRK. The analgesic property of NSAIDs is mediated by the inhibiting prostaglandin synthesis or by directly interfering with the excitability of the nerve endings.33–36 Pain reduction for 24 or 36 hours was not sufficient because substantial postoperative pain was observed up to 48 hours in the ofloxacin-treated eyes (Figure 1). In addition to surgical injury, postoperative inflammation also acts as nociceptive input,30 and the preemptive-only treatment of a topical NSAID seems insufficient to completely eliminate postoperative pain hypersensitivity. In a previous study, 17 a topical steroid was added postoperatively and may have inhibited postoperative inflammation and made it possible to reduce the pain for 2 days in patients exposed to preoperative topical ketorolac or diclofenac. However, we did not use a topical steroid until the bandage contact lens was removed because use of a steroid immediately after PRK can delay corneal epithelial healing.37–39 In addition, preemptive diclofenac seemed to have a longer effect than ketorolac (Figures 3 and 5). Although both diclofenac and ketorolac alleviated post-PRK pain, the time-serial pattern of the pain was changed by diclofenac but not by ketorolac (Figures 2 and 4). There are several differences in penetrability into the aqueous humor and concentration in the aqueous humor,28,29 cyclooxygenase 2 (COX2) inhibitory potency,40,41 and COX2 selectivity42 between diclofenac and ketorolac. According to a previous report, 36 topical diclofenac 0.1% shows the corneal hypoanesthetic effect, but topical ketorolac 0.5% fails to demonstrate such an effect. The distinctions might make a difference in the duration and the action pattern of preemptive diclofenac and ketorolac. Although the preemptive treatment of topical diclofenac did not cover the entire period of postoperative pain, it was clinically useful because the pain rapidly decreased after 36 hours (Figure 1). Ketorolac and diclofenac were not directly compared, and the mean difference in myopic correction for each subgroup would have reached 1.11 D in this study (Table 1). To confirm the efficacy difference between ketorolac and diclofenac, a direct comparison with a larger sample size is required.

Another clinical benefit of the preemptive treatment of a topical NSAID was safety. In preemptive treatment, because the topical NSAIDs are used only preoperatively and the disturbed epithelial corneal surface after PRK is not exposed to topical NSAIDs, the possibility of complications is lowered. As in previous reports, no significant complications were noticed for a mean of 7 months (Table 2). In contrast to prior reports, no postoperative NSAID or steroid was applied in this study to show the action of preoperative topical NSAIDs only. Eleven patients (9.7%) were excluded from the study because they took a postoperative oral analgesic. To decrease the number of excluded patients, we carefully treated the corneal tissue and used cold balanced salt solution to minimize postoperative pain. As a result, only preemptive analgesia was assessed, removing the possibility of an oral analgesic effect. However, surgical efforts to ameliorate pain should be considered when interpreting our results. In conclusion, the preoperative treatment of a topical NSAID in PRK functioned as preemptive analgesia. Topical ketorolac and diclofenac showed similar potencies for pain prevention, but the duration of action appeared to be longer with topical diclofenac. WHAT WAS KNOWN  Preoperative topical NSAIDs reduce postoperative pain in PRK when they are continued or combined with a topical steroid postoperatively. WHAT THIS PAPER ADDS  Only preoperative topical NSAIDs can ameliorate postPRK pain without postoperative topical steroids.  The effect of preoperative NSAIDs was dose independent and might be explained as preemptive analgesia.  Topical diclofenac 0.1% was more effective than topical ketorolac 0.5% in preemptive analgesia.

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First author: Jin Pyo Hong, MD Saeyan Eye Center, Seoul, South Korea