Effects of Topical Bromfenac Solution on Macular Thickness in Cataract Patients Undergoing Phacoemulsification Surgery

Introduction

The cataract is a degenerative alteration in the metabolism of the lens.¹ it is characterized by opacification² and clouding³ of the transparent and crystalline lens inside the eyes,⁴ which greatly impairs vision.² It is associated mainly with the aging process and is more common as people get older.^5–7 It can develop in either one or both eyes.⁵ Despite being nearly always treatable, cataracts remain one of the primary indications of vision impairment globally and in Iraq.^5,8

Although modern phacoemulsification is considered highly safe, pseudophakic cystoid macular edema (CME) commonly contributes to poor visual results following successful surgery.^9,10 CME might be caused by cataract surgery, an intrusive operation that produces inflammatory mediators. These mediators flow from the anterior chamber to the posterior segment, leading to the disruption of blood-aqueous and blood-retinal barriers (BRB). CME results from fluid buildup in the retina due to the increased permeability of the perifoveal capillaries resulting from the disruption of the corneal retinal barrier (BRB). The increase in macular thickness following cataract surgery is well recognized as potentially resulting in CME.¹¹

Topical preparations, are the dosage forms that are most frequently chosen for the treatment of ocular diseases. They are a non-invasive method of administration.¹²

Nonsteroidal anti-inflammatory drugs (NSAIDs) mainly exert their anti-inflammatory and analgesic effects by non-selectively inhibition of cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) enzymes by blocking the COX pathway and restrict arachidonic acid conversion to prostaglandins. The pivotal function of prostaglandins is to induce pain and facilitate miosis, vasodilation, leukocyte migration and disruption of the blood-ocular barrier.¹³

Topical NSAIDs are more frequently utilized to avoid post-operative CME after cataract surgery and multiple meta-analyses on the role of NSAIDs like ketorolac, nepafenac, and diclofenac, have shown evidence of their effectiveness and proposed that their usage, either alone or in conjunction with topical steroids may be more advantageous than using steroids alone and their utility may also extend to the management of pseudophakic CME.¹⁴

The sole brominated ophthalmic NSAID now available is bromfenac.¹³ The presence of bromine in the chemical structure of bromfenac improves the molecule’s ability to dissolve in the blood and permeate the cornea, intraocular tissue and vitreous fluid. The bromination at the forth positions of the phenyl group prolongs the drug’s analgesic and anti-inflammatory effects.¹⁵ This substance’s activity is mediated by its binding to and inhibition of cyclooxygenase II (COX II). Therefore, it prevents the transformation of arachidonic acid into cyclic endoperoxides, which serve as prostaglandins (PG) precursors.¹⁶

Nonsteroidal anti-inflammatory drugs (NSAIDs) differ in their capacity to inhibit cyclooxygenases 1 and 2. While the precise plasma levels of bromfenac after ocular administration is unrecognized, its relative potency is evaluated by calculating the concentration of drug required to block 50% of the COX enzyme activity (inhibitory concentration 50% or IC50). A lower value for IC50 indicates a higher enzyme’s level of inhibition. Comparative in vitro experiments showed that bromfenac inhibits COX-2 18 times more potent than ketorolac, 6.5 times more potent than amfenac and 3.7 times more effective than diclofenac.¹⁷

Bromfenac 0.09% has been approved by the US Food and Drug Administration (FDA) for use in cataract surgery patients to avoid ocular pain and minimize post-operative inflammation.¹⁴

Methods

This prospective study was conducted in an Ophthalmic Center in Baghdad, Iraq, between May 2023 and January 2024. Eighty-seven (87) eyes were enrolled from eighty-seven (87) Iraqi patients diagnosed with cataracts.

Results

Eighty-seven Iraqi patients with cataracts were divided into two groups: group one (n=forty-five patients) underwent phacoemulsification surgery with the administration of bromfenac postoperatively, and group two (n=forty-two patients) underwent phacoemulsification surgery without administration of bromfenac post operatively.

The demographic data between both groups show no significant differences between both groups regarding age, gender, diabetes mellitus, and hypertension, as shown in Table 1. The average age of group one was 66.44±8.7 years ranging from 45 years to 86 years; 17 (37.7%) were in their 60s and 70s, more than half of the cases 25 (55.5%) were male, 27 (60%) had diabetes and 20 (44.4%) had hypertension, while group two had the mean age was 61.3±9.3 years ranging from 40 years to 76 years, 17 (40.4%) were in their 60s, 22 (52.3%) were female, 14 (33.3%) had diabetes and 19 (45.2%) had hypertension.

For the central retinal thickness, the preoperative mean of CRT in group one and group two were 248.53±35.6 μm and 262.40±20.7 μm, respectively, with a p-value of 0.029, while the postoperative mean of CRT in group one and group two was 255.78±36.6 μm, 278.18±29.06 μm respectively with p-value was 0.004, and all these are clinically significant as shown in Table 2.

Table 3 illustrates the percentage changes of the CRT in the two groups post-operatively. Five patients (11.90%) had an increase of more than 100 μm in group two and none in group one. Those five patients had significant macular edema, four of them had diabetes, and two had hypertension.

There were forty-one patients with diabetes, and the pre-operative mean of CRT was 257.74±74 μm and 264.07±34.65 μm, respectively, in group one and group two, with a p-value=0.983. For the postoperative CRT, the mean was 266.6±39.4 μm and 287.6±37.4 μm, respectively, in group one and group two, with a p-value=0.042, which was clinically significant, as shown in Table 4.

There were thirty-nine patients with hypertension, and the pre-operative means of CRT were 241.80±42.85 μm and 260.36±25.72 μm, respectively, in groups one and two with p-value=0.218, while for the postoperative CRT, the mean was 251.8±38.8 μm, 276.5±32.6 μm respectively in group one and two with p-value=0.022 which are also clinically significant as shown in Table 5.

There were forty-five males in this study, and the pre-operative mean of CRT was 243.96±36.79 μm and 260.7±17.18 μm, respectively, in group one and group two, with a p-value=0.090. The postoperative mean of CRT was 245.2±31.9 μm and 273.99±24.1 μm, respectively, in group one and group two, with a p-value=0.016, which are clinically significant, as shown in Table 6.

Regarding the females, there were forty-two females. The pre-operative mean of CRT was 254.25±34.11 μm, and 263.95±26.37 μm respectively, in group one and group two with p-value=0.099, while the post-operative mean of CRT was 268.2±38.9 μm and 287.62±37.4 μm respectively in group one and group two with p-value=0.047 which are also clinically significant as shown in Table 7.

Five patients in group one developed Punctuate Epithelial Erosions (PEE) or Superficial Punctate Keratitis (SPK) post-operatively. At the same time, there were no patients with corneal changes in group two, and no other side effects were reported. Five patients developed cystoid macular edema in group two as a complication of phacoemulsification surgery, and no cystoid macular edema was noted in group one.

Discussion

Postoperatively, both groups exhibited a rise in central retinal thickness (CRT), as seen in Table 2. Nevertheless, group two experienced a more pronounced rise, and the difference remained statistically significant. The observed increase in CRT in the group that did not receive bromfenac can be attributed to the inflammatory process following cataract surgery, which is a predisposing factor for the occurrence of CME.¹⁹ A mechanical trauma-induced series of inflammatory processes, resulting in the production of prostaglandins (PGs) and other inflammatory mediators in the anterior segment, characterizes the pathophysiology of post-operative CME. The inflammatory Mediators induce the disruption of the blood-retinal barrier, causing the buildup of fluid within the retina and thickening and swelling of the macular tissue. Furthermore, prostaglandins in the eye induce vasodilation and leukocyte migration.²⁰

Among group one, Bromfenac probably inhibited the postoperative inflammatory process. This explanation aligns with the findings of Song SH et al. whose study demonstrated that NSAIDs, including bromfenac, are frequently used before and after cataract surgery to mitigate macular edema due to their analgesic, anti-inflammatory, anticoagulant and antipyretic characteristics. Bromfenac specifically blocks COX-2, the primary enzyme responsible for eye inflammation. Its enhanced lipophilic properties enable it to penetrate the cornea more effectively, leading to faster and efficacious analgesic and anti-inflammatory effects relative to other NSAID ophthalmic drops.¹⁵

Table 3 presents data indicating a 5.75% incidence of a significant increment in CRT of higher than 100 μm and CME, which aligns with the results reported by De Almeida L et al., who reported a 6.4% occurrence.¹⁰ Nevertheless, another study suggested that the prevalence of CME in the general population varies between 0.1% and 2.35%, usually occurring 4 to 6 weeks after the surgery.²¹ Other studies have demonstrated a broader range in the prevalence of CME, ranging from 0.2% to 20%.²² This variability is probably influenced by whether the diagnosis was established by clinical examination or verified using fluorescein angiography or optical coherence tomography (OCT).^10,22 Other variables that affect the prevalence of CME following the surgery of cataract include surgical techniques and the presence of related comorbidities.¹⁰ Also, all the patients who had CME were in group two, and none in group one, which indicates the protective effect of bromfenac in preventing CME.

Diabetes mellitus (DM) is the most common metabolic condition.²³ In the industrialized world, it is one of the leading causes of vision loss.²⁴ Among the general population, type 2 diabetes is more common (95%) than type I diabetes (5%).²⁵ and the data presented in Table 4 indicates a significant difference between the two groups. Group one had a lower mean central retinal thickness postoperatively (266.6 μm) than group two (287.6 μm), with a statistically significant difference (p-value=0.042). These findings indicate that bromfenac could be efficacious in decreasing the thickness of the central retina after surgery in individuals with diabetes. This goes in line with the previous studies that indicate that the administration of a steroid ophthalmic solution alone in post-cataract surgery is inadequate for preventing macular edema in diabetic patients and should be augmented with NSAIDs.¹⁵

Table 5 shows that group one had a lower mean central retinal thickness postoperatively (251.8 μm) compared to group two (276.5 μm) with a p-value equal to 0.022. This suggests that bromfenac might effectively reduce central retinal thickness postoperatively in hypertensive patients. Ocular alterations in people with very high blood pressure can be substantial and encompass optic neuropathy, retinopathy and choroidopathy.²⁶ Although most studies do not specifically target hypertensive patients, the general results indicate that bromfenac’s effectiveness in decreasing retinal thickness and preventing cystoid macular edema (CME) can be advantageous for various patient groups, including those with hypertension.

In both males and females, Tables 6 and 7 show that Group 2 consistently experienced a greater increase in CRT postoperatively compared to Group 1, with both groups showing a statistically significant difference postoperatively. The differences were not statistically significant preoperatively in either gender, meaning the groups were relatively comparable before surgery. The statistically significant increase in Group Two’s CRT postoperatively in both genders may suggest that this group experienced more inflammation, potentially due to surgery,¹⁹ and the absence of preventive treatment by bromfenac. This pattern supports the hypothesis that bromfenac, which reduces inflammation, may help in limiting CRT increase and preventing conditions like cystoid macular edema¹⁵ regardless of the gender.

Studies have shown that males and females can have different baseline retinal thicknesses and responses to ocular treatments due to hormonal and anatomical differences. Males also have greater foveal and mean macular thickness.^27,28 In this study, female patients experienced a larger increase in CRT than male patients. However, the sample size is not large enough to be representative of the general population.

Five patients from group one had Punctate Epithelial Erosions (PEE), also known as Superficial Punctate Keratitis (SPK), and many studies reported corneal toxicity from NSAID, especially when combined with steroids.^29,30

Conclusion

This study demonstrated that bromfenac has shown significant efficacy in preventing cystoid macular edema (CME) following cataract surgery as compared to corticosteroids alone but might cause punctate epithelium corneal erosion in some patients.

Ethical consideration and consent

The study was conducted based on the declaration of Baghdad University’s Ethical Committee, College of Medicine, and according to the ministry of health ethical policy (ethical permission letter No.03-33 in 2024-9-17). Written informed consent was obtained from all participants before inclusion in the study. The study was conducted in accordance with the Helsinki Treaty.