A comparative study of various topical nonsteroidal anti-inflammatory drugs to steroid drops for control of post cataract surgery inflammation.

BACKGROUND: Postoperative inflammation continues to be a cause of patient discomfort, delayed recovery, and in some cases, suboptimal visual results. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) and steroid are commonly used in the management and prevention of noninfectious ocular inflammation following cataract surgery. AIMS: The aim was to study the safety and efficacy of various NSAIDs drops for control of postoperative inflammation following cataract surgery and compare with steroid eye drops in a patient following cataract surgery. SUBJECTS AND METHODS: Totally, 200 patients undergoing phacoemulsification with posterior chamber intraocular lens implantation were randomly assigned to receive either nepafenac 0.1% 3 times daily, bromfenac 0.09% twice daily, ketorolac 0.5% 4 times daily for 1 month or 1% prednisolone eye drops as their postoperative anti-inflammatory medication with 50 cases in each group. The patients were examined at the 1st day (baseline), 1st week, 2nd week, and 4th week after surgery. Postoperative inflammation was evaluated subjectively by intraocular pressure, slit-lamp assessment of signs of inflammation, including conjunctival hyperemia, ocular pain, and aqueous cells and flare. STATISTICAL ANALYSIS: Statistical analysis was performed by the SPSS program for Windows, version 17.0. RESULTS AND
CONCLUSIONS: In our study, we found that prednisolone 1% was more effective in controlling postoperative intraocular inflammation in terms of reducing anterior chamber cells and flare. We found that ketorolac 0.5% and nepafenac 0.1% were equally effective in controlling postoperative ocular pain and inflammation. All four drugs are effective in controlling post cataract surgery ocular inflammation. Intraocular inflammation is best controlled with prednisolone 1%, while ocular pain and hyperemia are better controlled with NSAIDs in the early postoperative periods.

RCT Entities:   Population Interventions Outcomes

Introduction

Recent advances in cataract surgery, with improvement in surgical instruments and techniques such as phacoemulsification, have resulted in the decrease of physical surgical trauma with a decrease in the release of prostaglandins which are the main players in postoperative ocular inflammation. However, postoperative inflammation continues to be a cause of patient discomfort, delayed recovery, and in some cases, suboptimal visual results. Left untreated, this inflammation might interfere with patients' rehabilitation and/or contribute to the development of another complication such as cystoid macular edema (CME). Topical nonsteroidal anti-inflammatory drugs (NSAIDs) and steroid are commonly used in the management and prevention of noninfectious ocular inflammation following cataract surgery. Clinical evidence suggests that the combined use of NSAIDs and steroids is synergistic.[1]

While the anti-inflammatory actions of corticosteroids are in part from inhibition of phospholipase A2 preventing the release of arachidonic acid from membrane-bound phospholipids, NSAIDs act more downstream in the cascade and directly inhibit cyclooxygenase-1 (COX-1) and COX-2 enzymes.[2] The purpose of this study is to review the use of steroids and NSAIDs in the treatment of postsurgical inflammation following cataract surgery.

This study was designed to compare the effectiveness of prednisolone acetate 1%, nepafenac 0.1%, bromfenac 0.09%, and ketorolac 0.5% for the prevention and treatment of pain and inflammation following cataract surgery.

Subjects and Methods

This prospective randomized study has been conducted on 200 patients attending the ophthalmology OPD of a tertiary care hospital with a clinical diagnosis of ocular cataract requiring surgical removal with 50 cases in each group. The study was approved by the Ethical Committee, and the authors did not have any financial interest in the products used in the study. All patients who had undergone phacoemulsification with posterior chamber intraocular lens implantation have been randomized to receive NSAIDs drops or steroid drops.

Inclusion criteria

Inclusion criteria were carriers of senile cataract (>40 years of age) with an indication for cataract extraction with implantation of the intraocular lens and uncomplicated cataract surgery.

Exclusion criteria

Exclusion criteria were topical/inhaled/systemic steroid 14 days before surgery, topical/inhaled/systemic NSAIDs within 7 days of surgery, eyes with cells and flare and ocular pain in preoperative baseline examination, corneal opacity, suspected hypersensitivity to NSAIDs, chronic or recurrent inflammatory eye disease, diabetic patient, severe dry eye patient, cases in which there is intraoperative complications, glaucoma patient, patient having macular pathology.

A detailed history of patients was taken and was asked for a history of diabetes mellitus, hypertension or coronary artery disease, or any other systemic illness. Specific ocular history was asked regarding ocular trauma or previous ocular surgery, history of any chronic pathology, history of usage of spectacles, and history of prolonged medication in the eyes.

Before the surgery, patients were informed of the risks, benefits, and alternatives to the procedure. The allotment of the patients in the four groups was done by randomization. Simple randomization method was used, in which patients were chosen by assigning random numbers taken from a random numbers table of a statistical textbook. Any sign of active ocular inflammation (redness, edema, tearing, or discharge) was documented. Conjunctival hyperemia was evaluated by slit-lamp examination and classified from 0 (no edema) to 4+.

Grading of anterior chamber cells was done using the narrowest slit of the slit lamp (1-mm wide, 1-mm high), the number of cells per high-power field in the anterior chamber was counted and recorded on a scale, where Grade 0 represented ≤5 cells, Grade 1 represented 5–10 cells, Grade 2 represented 11–20 cells, Grade 3 represented 21–50 cells, and Grade 4 represented ≥50 cells.

Grading of aqueous flare

Five-point scale from 0: Nil (media clear), +1: Iris details, just detectable, +2: Moderate (iris and lens details clear), +3: Marked (iris and lens details not clear), +4: Intense (fibrinous exudate).

Ocular pain

Patients were asked to subjectively rank their eye pain on a six-point scale from 0 (none) to 5 (severe). They were also asked about photophobia, burning sensation, itching, and foreign body sensation.

Treatment failure was defined as a patient presenting at any postoperative visit with more than 15 cells, very dense flare, or investigator-assessed ocular pain score of Grade 4 or 5 on a 6-point ordered categorical scale from 0 (none) to 5 (severe). Patients were considered cured if the sum of their aqueous cells and flare ratings was 0 (i.e., 0–5 cells and clear media) at the current and all subsequent study visits. Clinical success was defined as an aqueous cells rating of 0 (<5) or 1 (5–10 cells) and an aqueous flare rating of 0 (none) at the current and all subsequent study visits. All the cases were implanted with a single-make lens to maintain uniformity. All operations were performed by a single surgeon, and the same surgical technique was employed to ensure uniformity and to minimize variations.

Evaluation

Group A of 50 patients, in which the study medication, that is, prednisolone acetate 1% was used. 1 to 2 drops 4 times daily for the 1st week, 3 times daily for the 2nd week, and 2 times daily for the 3rd and 4th week.

Group B of 50 patients, in which the study medication agent nepafenac 0.1% was used; 1 drop 3 times daily for 1 month.

Group C of 50 patients, in which the study medication agent bromfenac 0.09% was used; 1 drop twice daily for 1 month.

Group D of 50 patients, in which the study medication agent ketorolac 0.5% was used; 1 drop 4 times daily for 1 month.

The intraocular pressure (IOP), visual acuity, slit-lamp examination, and fundoscopy were done at each visit. The measurement of IOP was done by Goldmann applanation tonometer available in the department. Patients in four groups were followed postoperatively for any intraocular inflammation on the 1st day, 1st week, 2nd week, and 4th week.

Statistical analysis

Statistical analysis was performed by the SPSS program for Windows, version 17.0 (SPSS Inc. Released 2008. SPSS Statistics for Windows, Version 17.0. Chicago: SPSS Inc.). Continuous variables are presented as a mean ± standard deviation, and categorical variables are presented as absolute numbers and percentage. Data were checked for normality before statistical analysis using Shapiro–Wilk test. Normally distributed continuous variables were compared using ANOVA. Multiple comparison tests like Bonferroni or Tamhane's T2 test were used to assess the differences between the individual groups. Categorical variables were analyzed using the Chi-square test. For all statistical tests, a P < 0.05 was taken to indicate a significant difference.

Results

It was observed that Group C had the maximum mean age of 62.60 years with a standard deviation of 8.64, while Group D had the minimum mean age of 58.30 years with a standard deviation of 7.89. Group A had the mean age of 59.54 years with standard deviation of 9.49 and Group B had the mean age of 59.42 with standard deviation of 8.56. The correlation between the mean ages among the four groups was not significant [Table 1].

Table 1

Age distribution among the groups

Group A comprised 52% of females and 48% of males. Similarly, Group B comprised 68% of females and 32% of males; Group C had 62% of females and 38% of males and Group D had 66% of females and 34% of females.

There were no differences in vision findings in the patients under the study at various time intervals across all the four groups [Table 2].

Table 2

Vision among the groups

The mean IOP at various time intervals was comparable in all the groups under our study. Further, it was observed that the comparison of IOP at various time intervals among the four groups was not significant [Table 3].

Table 3

Intraocular pressure

Ocular pain score

The overall ocular pain score was comparable between Group A and Group B (P = 0.108) and Group B and Group C (P = 0.685); however, there was significant difference observed between Group A and Groups C and D (P < 0.05, respectively) and Group D and Groups B and C (P < 0.001). There was a significant correlation between the ocular pain score at the 1st week among the four groups. It was observed that there was a significant correlation between the ocular pain score at the 2nd week among the four groups [Tables 4a–d].

Table 4a

Comparison of ocular pain score at the 1st day

Table 4d

Comparison of ocular pain score at the 4th week

The overall ocular pain score at the 4th week was comparable between Group A and Group B and Group D; however, there was a significant difference observed between Group A and Group C (P = 0.117), Group B and Group C (P = 0.806), and Group C and Group D (P = 0.117).

Conjunctival hyperemia

The overall conjunctival hyperemia grades at the 1st day were comparable between Group A and Groups B and C (P = 0.086 and 0.234, respectively) and Group B and Group C (P = 0.211). However, there was a significant difference observed between Group A and Group D (P < 0.001), Group B and Group D (P < 0.001), and Group C and Group D (P < 0.001).

Conjunctival hyperemia grade at the 1st week was comparable between Group C and Group D (P = 0.213). However, there was a significant difference observed between Group A and Groups B, C, and D (P < 0.001, 0.023, and 0.028, respectively); Group B and Groups C and D (P = 0.001 and 0.001, respectively) [Tables 5a–d].

Table 5a

Comparison of conjunctival hyperemia grade at the 1st day

Table 5d

Comparison of conjunctival hyperemia grade at the 4th week

There was no significant correlation between the conjunctival hyperemia score at the 4th week among the four groups [Table 5d].

Anterior chamber cells

There was a significant correlation between the anterior chamber cell grades at the 1st day among the four groups. It was observed that there was a significant correlation between the anterior chamber cell grades at the 1st week among the four groups. However, it was observed that there was a significant difference between Group A and all the other three groups (P < 0.001) and Group C and Group D (P = 0.023) [Table 6].

Table 6a

Comparison of anterior chamber cells grade at the 1st day

It was observed that there was a significant correlation between the anterior chamber cell grades at the 2nd week among the four groups. The overall anterior chamber cells grades at the 2nd week were not comparable, and there was a significant difference observed between all the groups.

There was a significant difference observed between Group A and Group C (P < 0.001), Group B and Group C (P < 0.001), and Group C and Group D (P < 0.001).

Anterior chamber flare grade

The overall anterior chamber flare grade at the 1st day was not comparable, and there was a significant difference observed between all the groups.

The overall anterior chamber flare grade at the 2nd week was comparable between Group A and Group D (P = 0.242) and Group C and Group D (P = 0.142). However, it was observed that there was a significant difference between Group A and Groups C and D (P < 0.001 each), Group B and Groups C and D (P = 0.006 and <0.001, respectively) [Tables 7a–d].

Table 7a

Comparison of anterior chamber flare grade at the 1st day

Table 7d

Comparison of anterior chamber flare grade at the 4th week

The overall anterior chamber flare grades at the 4th week were comparable between Group A and Groups B and D, and Group B and Group D. There was a significant difference between Group A and Group C (P = 0.006), Group B and Group C (P = 0.006), and Group C and Group D (P = 0.006).

Fundus

It was observed that there were no significant fundus findings in patients under the Fundus 90D examination at various time intervals across all the four groups.

Discussion

The efficacies of the drugs used in this study were assessed by comparing the IOP, signs of inflammation, including conjunctival hyperemia, ocular pain, and aqueous cells and flare.

The main effectiveness criterion was the rate of anterior chamber cell decrease. A progressive decrease in anterior chamber cell count after the 1st postoperative day was found on slit-lamp examination, suggesting that the inflammatory reaction was controlled in four groups.

The previous studies have demonstrated that ocular rebound inflammation may develop secondary to rapid tapering or abrupt discontinuation of topical ocular steroid use and is best prevented with gradual tapering.[3] The mechanisms by which rebounds in ocular disease may follow steroid withdrawal are still uncertain.[3]

Topical corticosteroids are commonly used as a routine treatment over several weeks to reduce the inflammatory reaction after cataract surgery.[4]

In a group in which prednisolone acetate 1% was used, we found that there was a normal IOP in all patients in all four visits. In this study in prednisolone group, we found that ocular pain, conjunctival hyperemia, aqueous cells, and aqueous flare all were 100% relieved by the end of the 4th week. In Demco et al.'s[5] study, it was found that diclofenac sodium 0.01% ophthalmic solution was as effective, safe, and well-tolerated overall as prednisolone acetate 1.0% ophthalmic suspension. In el-Harazi et al.'s[6] study, they have found that ketorolac tromethamine 0.5% and diclofenac sodium 0.1% may be as effective and safe as prednisolone acetate 1% in controlling inflammation following cataract extraction.

In the group in which nepafenac 0.1% was used, we found that there was a normal IOP in 100% of patients in all four visits. Further, we found that nepafenac was effective and safe in controlling postoperative ocular pain and inflammation. In a study conducted by Lane et al.[7] and Stewart et al.,[8] they found that nepafenac 0.1% was effective in the prevention and treatment of ocular inflammation as compared to the placebo group.

In a group in which bromfenac 0.09% was used, we found that IOP remains in the normal range in all visits in 100% of patients. In our study, we found that bromfenac 0.09% was effective in controlling postoperative ocular pain and inflammation which was similar to study done by Donnenfeld et al.,[9] who found that bromfenac 0.09% ophthalmic solution was effective for the rapid resolution of ocular pain after cataract surgery.

Kawaguchi et al.[10] found that bromfenac has a more rapid onset of anti-inflammatory activity than diclofenac on measuring aqueous flare levels; they had noted that at each time, flare was lower in the bromfenac group than in the diclofenac group. In the group in which ketorolac 0.5% was used, we found normal IOP among all patients in all four visits. We also found that ketorolac 0.5% was more effective in controlling of ocular pain as compared to nepafenac 0.1%, bromfenac 0.09%, and prednisolone 1%. Although we found that ketorolac was effective and safe in controlling postoperative inflammation, el-Harazi et al.[6] found that ketorolac tromethamine 0.5% and diclofenac sodium 0.1% may be as effective and safe as prednisolone acetate 1% in controlling inflammation following cataract extraction.

In our study, we found that prednisolone 1% was more effective in controlling postoperative intraocular inflammation in terms of reducing anterior chamber cells and flare. In a study conducted by Simone et al.,[11] observed that prednisolone acetate was more effective at reducing intraocular inflammation by day 7 after cataract surgery than ketorolac although this difference resolved by day 28. In a study by el-Harazi et al.,[6] it was found that ketorolac tromethamine 0.5% may be as effective and safe as prednisolone acetate 1% in controlling inflammation following cataract extraction.

In our study, we have found that ketorolac 0.5% and nepafenac 0.1% were equally effective in controlling postoperative ocular pain and inflammation. In a study conducted by Duong et al.,[12] they found that ketorolac 0.4% and nepafenac 0.1% were equally effective in controlling intraocular inflammation.

Conclusion

It is concluded that NSAIDs such as nepafenac 0.1%, bromfenac 0.09%, and ketorolac 0.5% are a good alternative to steroids in controlling postoperative ocular inflammation in patients undergoing cataract surgery. All four drugs are effective in controlling postcataract surgery ocular inflammation. Intraocular inflammation is best controlled with prednisolone 1%, while ocular pain and hyperemia are better controlled with NSAIDs in the early postoperative periods.

Lacunae in the study

The sample size was relatively small, consisting of fifty patients in each of the four groups

Due to nonavailability of optical coherence tomography in our hospital, postoperative CME could not be assessed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Table 4b

Comparison of ocular pain score at the 1st week

Table 4c

Comparison of ocular pain score at the 2nd week

Table 5b

Comparison of conjunctival hyperemia grade at the 1st week

Table 5c

Comparison of conjunctival hyperemia grade at the 2nd week

Table 6b

Comparison of anterior chamber cells score at the 1st week

Table 6c

Comparison of anterior chamber cells grade at the 2nd week

Table 6d

Comparison of anterior chamber cells grade at the 4th week

Table 7b

Comparison of anterior chamber flare grade at the 1st week

Table 7c

Comparison of anterior chamber flare grade at the 2nd week