Management of pain with diclofenac after femtosecond-assisted laser in situ keratomileusis

ARTICLE Management of pain with diclofenac after femtosecond-assisted laser in situ keratomileusis Jared Parker, MD, Amit Tandon, MD, Roni M. Shtein, MD, H. Kaz Soong, MD, Theresa N. Cooney, MD, David C. Musch, PhD, MPH, Shahzad I. Mian, MD PURPOSE: To evaluate the safety and efficacy of topical diclofenac sodium 0.1% after femtosecond laser assisted laser in situ keratomileusis (LASIK). SETTING: W.K. Kellogg Eye Center, University of Michigan, Ann Arbor, Michigan, USA. DESIGN: Clinical trial. METHODS: Pain was assessed in patients treated with topical diclofenac sodium 0.1% or artificial tears immediately after LASIK using a numeric pain scale and a combined picture numeric pain scale 0, 2, 4, 12, and 24 hours postoperatively. Visual outcomes and complications were noted up to 24 hours. RESULTS: The study enrolled 100 eyes of 50 patients. Patients treated with diclofenac 0.1% reported less pain than the control group on both pain scales 2, 4, 12, and 24 hours after surgery, with the maximum benefit at 4 hours (PZ.02). Fewer patients in the diclofenac group (76.0%) than in the control group (91.3%) used oral pain and/or anxiolytic medications during the first 24 hours after surgery (PZ.25). Ninety-eight eyes had an uncorrected distance visual acuity of 20/40 or better. Mild peripheral diffuse lamellar keratitis accounted for the majority of perioperative complications (n Z 15). CONCLUSION: Pain after femtosecond laser assisted LASIK was mild and was reduced with a single dose of topical diclofenac sodium 0.1% given immediately after surgery. Financial Disclosure: No author has a financial or proprietary interest in any material or method mentioned. J Cataract Refract Surg 2011; 37:569 573 Q 2011 ASCRS and ESCRS Laser in situ keratomileusis (LASIK) has emerged as an effective refractive surgical treatment to correct low to moderate myopia and hyperopia with or without astigmatism. 1,2 The more rapid recovery time and decreased patient pain over that with other corneal refractive procedures, such as photorefractive keratectomy (PRK), has contributed to the popularity of LASIK. However, patient discomfort related to wound healing is common in the early postoperative period. 3,4 This pain is partly due to disruption of the epithelium and dense corneal nerve plexus beneath Bowman layer during creation of the LASIK flap. Postoperative pain typically is most prominent during the first 5 to 6 hours after surgery, with resolution coinciding with healing of the epithelial defect. 4 Topical nonsteroidal antiinflammatory drugs (NSAIDs) regulate pain and inflammation by inhibiting cyclooxygenase, suppressing polymorphonuclear chemotaxis, and decreasing the expression of inflammatory cytokines. 5 The use of NSAIDs to reduce postoperative pain after radial keratotomy, laser-assisted subepithelial keratectomy (LASEK), and PRK is well established. 6 13 However, few studies have evaluated their benefit after LASIK, and no study to date has assessed their use after LASIK performed with a femtosecond laser. 14,15 We evaluated the safety and efficacy of a topical NSAID, specifically a single dose of diclofenac sodium 0.1%, in reducing early postoperative pain after LASIK during which the flap was created with a femtosecond laser. Q 2011 ASCRS and ESCRS Published by Elsevier Inc. 0886-3350/$ - see front matter 569 doi:10.1016/j.jcrs.2010.09.020

570 NSAIDS FOR PAIN AFTER LASIK PATIENTS AND METHODS Study Design This randomized double-masked controlled study was performed at the Cornea and Refractive Surgery Clinic, W.K. Kellogg Eye Center, University of Michigan. Patients of 4 refractive surgeons were recruited between March 2007 and May 2008. Informed consent for study participation was obtained, and the study was approved and monitored by the University of Michigan s Institutional Review Board. Patients Eligible patients were at least 21 years old and scheduled to have bilateral simultaneous LASIK with femtosecond flap creation for primary myopia or hyperopia with or without astigmatism. Only patients with myopia less than 12.00 diopters (D) and astigmatism less than 4.00 D or hyperopia less than 4.00 D and astigmatism less than 2.00 D were recruited. Excluded were patients who were pregnant or nursing, with a medical history of systemic collagen vascular disease or an autoimmune condition, or with a history of hypersensitivity to NSAIDs. Preoperative data collected included the presence of dry eye, corrected distance visual acuity (CDVA), and manifest refraction. Dry eye was defined as superficial punctuate staining during the initial consultation and/or a Schirmer test of less than 10.0 mm after 5 minutes with a topical anesthetic agent. Intraoperative data collected included depth of the excimer laser ablation, diameter of the flap, and presence or absence of an epithelial defect. One-day postoperative data included uncorrected distance visual acuity (UDVA), CDVA if measured, presence of diffuse lamellar keratitis (DLK), epithelial defect, flap striae, and flap edema. Surgical Technique During bilateral simultaneous LASIK, the flap was created with a 60 KHz IntraLase femtosecond laser (Abbott Medical Optics, Inc.) and stromal ablation performed with a Technolas 217 excimer laser (Bausch & Lomb). The femtosecond laser was preprogrammed for each procedure with a planned flap diameter of 9.0 mm, flap thickness of 100 to 120 mm, superior hinge angle of 45 to 50 degrees, raster energy of 1.6 mj, and Submitted: February 15, 2010. Final revision submitted: August 13, 2010. Accepted: September 18, 2010. From the Department of Ophthalmology and Visual Sciences (Parker, Tandon, Shtein, Soong, Cooney, Musch, Mian), W.K. Kellogg Eye Center, University of Michigan Medical School, the Department of Epidemiology (Musch), University of Michigan School of Public Health, Ann Arbor, Michigan, and Ohio State University School of Medicine (Tandon), Columbus, Ohio, USA. Supported in part by a grant from Research to Prevent Blindness, Inc., New York, New York, USA. Corresponding author: Shahzad I. Mian, MD, W.K. Kellogg Eye Center, 1000 Wall Street, Ann Arbor, Michigan 48105, USA. E-mail: smian@umich.edu. side-cut energy of 2.0 mj. The excimer laser stromal ablation was performed using a PlanoScan or Zyoptix treatment plan. Topical prednisolone acetate 1.0% and gatifloxacin 0.3% eyedrops were placed in the eye immediately postoperatively, and the patient was asked to continue use throughout the day of the procedure. Study Protocol A sealed, opaque envelope containing random allocation was opened, and the patient was randomized to receive diclofenac sodium 0.1% (Voltaren) or artificial tears at the end of the LASIK procedure, after the corneal flap was repositioned. The surgical assistant instilled 1 drop of the study medication into each eye; the physician and patient were masked to which type of eyedrop was given. A linear numeric pain scale with scores between 1 and 6, corresponding to a brief description of pain (none, little, some, mild, a lot, severe, terrible), and a combined picture numeric pain scale with scores of 0, 2, 4, 6, 8, and 10, corresponding to pictures of a facial expression and brief description of pain (none, little bit, little more, even more, whole lot, worst), were given to the patient before discharge. 16 Each patient was asked to rate his or her pain immediately after surgery and 2, 4, 12, and 24 hours thereafter by drawing a circle around the appropriate pain score on each of the 2 scales. Patients were allowed to take oral pain medications as needed but were asked to document each type and dose on a provided form. They were also instructed not to use eyedrops other than prednisolone acetate 1% and a fourthgeneration fluoroquinolone, as directed by their physician, in the first 24 hours after surgery. Statistical Analysis The Student t test, Fisher exact test, and mixed regression analysis were used to compare the 2 groups in mean age, sex, dry eye, and mean preoperative spherical equivalent (SE). The Student t test was used to compare pain severity between the 2 groups at each time point. The Fisher exact test was used to compare postoperative pain and the need for anxiolytic medications between the groups. Mixed linear regression was used to adjust for inter-eye correlation. RESULTS The study enrolled 50 patients (100 eyes); the diclofenac group and the control group each comprised 25 patients. Of the 50 patients, 46 completed the pain scales. There were no statistically significant differences in age, sex, presence of preoperative dry eye, or mean SE between the diclofenac group and the control group (Table 1). Efficacy Two, 4, 12, and 24 hours after surgery, the diclofenac group reported less pain than the control group on both pain scales. The only time at which pain was statistically significantly less in the diclofenac group was at the 4-hour time point (PZ.02) (Figure 1). Immediately after surgery (time Z 0), the diclofenac group reported more pain (mean score 2.0 on numeric scale and 2.8 on picture numeric scale) than the control group (mean score 1.7 and 2.5, respectively) (PZ.35). At 4 hours, the mean

NSAIDS FOR PAIN AFTER LASIK 571 Table 1. Comparison of NSAID and control groups after LASIK with a femtosecond laser. Group Patients (n) Mean Age (Y) G SD Women, n (%) Preop Dry Eye, n (%) Mean Preop SE (D) G SD Diclofenac 25 35.5 G 10.7 15 (60) 5 (20) 3.83 G 0.34 Control 25 37.2 G 10.9 21 (84) 8 (32) 3.95 G 0.53 P value d 0.58* 0.11 0.52 0.64 z SE Z spherical equivalent *Student t test Fisher exact test z Mixed-regression analysis pain score on the numeric scale was 1.4 (a little to some pain) in the diclofenac group and 2.4 (some to mild pain) in the control group (PZ.016). The respective scores on the combined picture numeric scale at 4 hours were 2.5 (hurts a little bit) and 4.5 (hurts a little more) (PZ.017). Correlation analysis showed no significant linear relationship between excimer treatment parameters or flap diameter and reported pain. Three eyes had an intraoperative epithelial defect. Fewer patients in the diclofenac group (19 patients; 76.0%) than in the control group (23 patients; 91.3%) used oral pain and/or anxiolytic medications (eg, ibuprofen, diazepam, acetaminophen) during the first 24 hours after surgery, although the difference was not statistically significant (PZ.25). One day postoperatively, the UDVA was 20/20 or better in 62 eyes, 20/40 or better in 98 eyes, and 20/50 in 2 eyes. The mean UDVA was 20/21 in the diclofenac group and 20/24 in the control group. At 1 day, lowgrade peripheral DLK developed in 12 eyes in the diclofenac group and 3 eyes in the control group and central DLK in 2 eyes in the diclofenac group. One eye had an epithelial defect, and 1 eye had flap mild microstriae. No eye had flap edema. No significant adverse events occurred in either group. Figure 1. Pain scale scores (* Z statistically significant). DISCUSSION The use of a single drop of diclofenac sodium 0.1% after the corneal flap was repositioned during LASIK with femtosecond laser flap creation resulted in less postoperativepain(assessedwith2painscales)thanacontrol drop (artificial tears) at most time points, with significant between-group differences at 4 hours (PZ.02). Although LASIK is considered to cause less pain than surface ablation procedures such as PRK and LASEK, pain does occur in the initial postoperative period. In our study, this pain improved with a single dose of the topical NSAID diclofenac given at the time of surgery. Similar outcomes have been reported by Price et al. 4 and Kosrirukvongs et al. 14 with use of a mechanical microkeratome and multiple doses of ketorolac tromethamine postoperatively. Dougherty 15 recently reported decreased postoperative pain after LASIK with the use of a mechanical microkeratome and multiple doses of ketorolac tromethamine before and during surgery. Diclofenac was selected for this study based on its known effect in reducing pain after PRK. 7 11 Results in studies that evaluated pain after surface ablation 12,17,18

572 NSAIDS FOR PAIN AFTER LASIK suggest that other topical NSAIDs may have similar efficacy in managing pain after LASIK. In our study, the diclofenac was given as a single dose at the time of surgery to limit toxicity while providing pain relief because pain after LASIK is primarily limited to the early postoperative period. Diclofenac, along with other topical NSAIDs, has been associated with corneal toxicity and melting. 19 Our single-dose approach also limits the expense of topical NSAIDs to patients. The small increase in pain immediately after surgery in the diclofenac group can be attributed to the known side effect of stinging associated with most topical NSAIDs. The diminished pain reported after 12 hours and 24 hours in both groups likely corresponded to corneal epithelial healing at the LASIK flap edge. Two distinct pain scales were used to increase the confidence in pain assessment in each group. Postoperative prophylactic topical NSAIDs are reported to decrease the incidence of DLK after LASIK. 20 The higher incidence of DLK in our diclofenac group (n Z 15) than in the control group (n Z 3) was unexpected and thought to be unrelated to use of the study medication. The higher incidence of DLK may be associated with the use of the femtosecond laser compared with the incidence when a microkeratome is used. 21 This prospective randomized study assessed the effect of a single NSAID eyedrop to reduce early postoperative pain after LASIK with femtosecond laser flap creation. To our knowledge, this is the first published study assessing NSAID use for pain after femtosecond-assisted LASIK. Also, there are few previous studies of the pain-relieving effect of a single dose of an NSAID eyedrop after LASIK. This study is limited by a small sample size in each group and the failure of 4 patients to return the pain surveys. A potential confounding variable is the concurrent postoperative use of other oral pain and/or anxiolytic medications, which could have affected the reporting of pain in both groups. However, the postoperative use of these medications was less frequent in patients who received diclofenac, although not significantly less. No specific washout period before surgery was enforced, although no patient reported preoperative use of oral analgesic agents. Administration of a single dose of diclofenac 0.1% after femtosecond-assisted LASIK may be a simple, but significant way to reduce early postoperative pain and improve the patient s LASIK experience. REFERENCES 1. Sugar A, Rapuano CJ, Culbertson WW, Huang D, Varley GA, Agapitos PJ, de Luise VP, Koch DD. Laser in situ keratomileusis for myopia and astigmatism: safety and efficacy; a report by the American Academy of Ophthalmology (Ophthalmic Technology Assessment). Ophthalmology 2002; 109:175 187 2. 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