Comparison of the efficacy of nepafenac with or without dexamethasone for preventing pseudophakic cystoid macular edema

Authors

Abstract

Aim To compare the efficacy of nepafenac monotherapy with the combination of nepafenac and dexamethasone for preventing pseudophakic cystoid macular edema (PCME), one of the most common complications after cataract surgery.
Methods This retrospective study included patients who underwent uncomplicated cataract surgery. They were divided into two groups: Group 1 (Monotherapy) received nepafenac alone, while Group 2 (Combination Therapy) received nepafenac with dexamethasone. Postoperative central macular thickness and cystoid changes were monitored using optical coherence tomography (OCT). Statistical analyses were performed to compare the efficacy of both regimens in preventing PCME.
Results Both treatment groups were effective in reducing macular thickening and lowering the risk of clinically significant PCME. However, no statistically significant difference in efficacy was found between nepafenac monotherapy and combination therapy. This finding suggests that adding dexamethasone did not provide a measurable superiority in preventing PCME compared to nepafenac alone.
Conclusion Our study demonstrates that nepafenac monotherapy is as effective as combination therapy for PCME prophylaxis. The lack of additional benefit from the combination suggests that monotherapy may be a more practical approach, as it can improve patient compliance, reduce side effects, and simplify the treatment regimen. Although our study has limitations, including a small sample size and the use of only one type of NSAID, our findings contribute to the literature supporting NSAID monotherapy in postoperative cataract management. Larger, randomized controlled trials are needed to confirm these results.

Keywords

Introduction

Cataract surgery is the most frequently performed intraocular procedure ¹. One of the common complications is PCME, which can cause a significant decrease in visual acuity ². Cystoid macular edema, first reported by Irvine in 1953, was demonstrated by Gass with fluorescein fundus angiography (FFA) 13 years later, and thus, CM developing following cataract surgery was named Irvine-Gass syndrome (IGS) ^3,4. The incidence of clinically significant pseudophakic cystoid macular edema varies between 1% and 2% ⁵. In most of the patients, edema resolves spontaneously within the first year ⁶. Various treatment options include NSAIDs and corticosteroids. Pseudophakic cystoid macular edema can also be seen after complicated and uncomplicated cataract surgery. Underlying predisposing causes, such as diabetes, retinal vein occlusion, epiretinal membrane, uveitis, and posterior capsule rupture, may increase the incidence of PCME ¹. The pathogenesis of PCME is still fully elucidated ⁷. However, it has been reported that inflammation is the underlying cause ⁸. Inflammatory mediators released during cataract surgery break down the blood-retinal barrier and cause the development of cystoid macular edema (CME). Topical nonsteroidal anti-inflammatory drops are known to be effective in the prevention and treatment of cystoid macular edema ^9,10,11. Nevanac® (nepafenac 0.1%) has received approval from the Food and Drug Administration (FDA) for managing pain and inflammation related to phacoemulsification ¹². Nepafenac, a prodrug, converts into an active metabolite called amfenac through hydrolysis within various ocular structures such as the iris, retina, and choroid ^13,14. It exhibits better corneal permeability, leading to higher concentrations of the drug within the eye compared to other NSAIDs ^13,14.
Importantly, nepafenac provides long-lasting inhibition of prostaglandin synthesis when compared to other NSAIDs ¹³. Both steroids and non-steroids suppress inflammation by blocking the arachidonic acid pathway through Cox inhibition ¹⁵. In addition to that, steroids also inhibit the lipoxygenase pathway ¹⁵. Corticosteroids are effective in suppressing postoperative inflammation and, therefore, are topically used for approximately 4-6 weeks after cataract surgery ¹⁵. However, despite this, they may be insufficient in suppressing PCME ^16,17,18. When steroids and nonsteroidal drugs are used together, they reduce postoperative inflammation with a synergistic effect ^9,10. This study aims to compare the efficacy of nepafenac alone or in combination with dexamethasone in reducing PCME incidence.

Materials and Methods

A retrospective analysis was conducted on patients undergoing cataract surgery at the Department of Ophthalmology, Çanakkale Onsekiz Mart University, between March 2022 and February 2023. A total of 47 patients were included in the study.
Drug Information● Nepafenac (Nevanac® 0.1%): Manufactured by Alcon, it is an NSAID used to reduce pain and inflammation post-surgery.
● Dexamethasone (Maxidex® 0.1%): Manufactured by Alcon, it is a corticosteroid used to control inflammation.
Patients were divided into two groups:
-Group 1: Nepafenac monotherapy (26 patients)
-Group 2: Combination therapy with Nepafenac and Dexamethasone (21 patients)
Cases of uncomplicated cataract surgery were included in the study, regardless of whether they were performed by residents or experienced surgeons. Postoperative follow-ups were conducted at day 1, week 1, and month 1. The primary outcome measure was the reduction in macular edema based on Optical Coherence Tomography (OCT) ¹⁷. Statistical analyses were conducted using SPSS version 26.0.12 In addition, patients with vitreomacular interface disorders such as epiretinal membrane and vitreomacular traction were excluded from the study. The study enrolled healthy participants without systemic diseases (e.g., hypertension or diabetes), ocular conditions (e.g., glaucoma or uveitis), prior intraocular surgery, or use of topical/systemic medications ¹⁷. All types of age-related cataract, including nuclear, cortical, or posterior subcapsular, were included in the study; however, cataracts caused by trauma or uveitis, which could increase the risk of cystoid macular edema (CME), were excluded ¹⁶. Intraocular pressure measurement with Goldman applanation tonometry, optical coherence tomography (OCT), best corrected visual acuity with Snellen chart, and complete biomicroscopic and funduscopic examination with dilated fundus examination were performed in all patients before and after surgery ¹⁵. All patients received routine antibiotics and corticosteroid topical eye drops after surgery. Nepafenac 0.1% and/or prednisolone acetate eye drops topically four times daily for one month were started in patients who presented cystoid edema on optic coherence tomography at the 1st month postoperative examination ¹⁰. The diagnosis of macular edema in OCT was evaluated by a single ophthalmologist (C.Ö.). A 10% increase in central macular thickness was accepted as the cutoff value for macular edema ¹⁸. Exclusion criteria included patients with systemic diseases (e.g., diabetes, hypertension), prior intraocular surgeries, or ocular conditions (e.g., glaucoma, uveitis) ¹⁷.
Statistical analysis was done using SPSS version 26.0 (IBM Corp. USA) ¹². All continuous variables were expressed as means ± standard deviations, and categorical variables were expressed as proportions. As the data were not normally distributed, non-parametric tests were conducted to determine statistical significance. Between-group analyses were performed using the Mann–Whitney test. For correlation analysis between functional and anatomical differences, Spearman’s correlation test was used.
Ethical ApprovalThe study is retrospective in nature and does not involve any experimental intervention or identifiable patient data. Therefore, ethical committee approval was not required in accordance with institutional and national guidelines.

Results

In this study, patients were divided into 2 groups. Group 1 consisted of 26 patients who received only topical 0.1% nepafenac sterile eye drop treatment, and Group 2 consisted of 21 patients who received a combination of 0.1% nepafenac and 0.1% dexamethasone sterile eye drops. Group 1 consists of 26 patients; nineteen (73.07%) cases were male, and 7 cases ( 26.92%) were female. Group 2 consists of 21 patients; twelve (57.14%) cases were male and nine (42.85%) cases were female. The mean age of group 1 was 72,6 ± 6.3, and group 2 was 68,3 ± 6.2. In group 1, ten (38.46%) eyes were right and sixteen eyes were left (61.53%), in group 2, ten eyes were right ( 47.61%) and eleven eyes were left (52.38%) (Table 1). No statistically significant difference was found in the reduction of macular edema between Group 1 and Group 2 (p > 0.05). While the mean value of edema (anatomical) in group 1, 1st month, and 3rd months was 118.46 μm (SD 142.23), the mean value in group 2 was 129.33 μm (SD 89.23). Baseline demographic and clinical characteristics of patients in both treatment groups (Table 1). A very weak inverse correlation was found between the 3rd month visual acuity increase and the decrease in edema level (p value < 0.37). The difference in visual acuity improvement between the two treatments was not statistically significant in patients who received Group 1 and Group 2 (p-value 0.59). There was no statistically significant correlation between anatomical and functional differences (Table 2). Table 2 presents the mean anatomical and functional differences between Group 1 and Group 2. The measurements are given in micrometers (m) for anatomical differences and in standardized units for functional differences. Comparison of mean central macular thickness (CMT) between Group 1 and Group 2 at baseline, 1 month, and 3 months postoperatively. Data are presented as mean ± standard deviation. No statistically significant difference was observed between the groups (p > 0.05).

Discussion

This study aligns with previous research indicating that NSAIDs and corticosteroids can reduce PCME ^10,16,19. Despite the high visual expectations following uneventful cataract surgery, the occurrence of cystoid macular edema remains a prominent source of patient dissatisfaction despite favorable surgical outcomes ². Despite this, the purpose of this study was to assess the efficacy of topical nepafenac, both as monotherapy and in combination with steroids, in patients who developed cystoid macular edema following an uneventful cataract surgery procedure. Understanding the underlying cause and pathophysiology of retinal macular edema is essential for effective treatment ⁶. In the study published by Kessel et al. in 1996, in which the effect of NSAIDs and steroids on PCME was investigated, they found low evidence that NSAIDs were more effective than steroids, and also, intraocular pressure was increased in the group receiving topical steroids ²⁰. In our study, no significant difference was found between the use of topical steroids and nonsteroids in PCME. Another shortcoming of our study is that intraocular pressures were not controlled after the use of topical steroids. Also, patients using only topical steroids were not compared with patients receiving topical nonsteroidal and combined therapy.
Russo et al. concluded that NSAIDs and steroids are synergistically effective in the treatment of PCME ¹⁹. In our study, however, it did not indicate a synergistic effect. The small number of patients included in the study may have affected the results. Walter et al., in accordance with the literature, showed that NSAIDs were superior to steroids alone ²¹.
In our study, nonsteroids were found to be superior, but a patient group in which only steroids were used was not formed. The difference of this study is that it has been shown that topical NSAIDs, which are started a few days before the preoperative period and applied for 1 month postoperatively, are advantageous when compared to the use of only NSAIDs and/or steroids postoperatively. Although bromfenac was the NSAID used in some studies prior to surgery, pharmacokinetic studies suggest that nepafenac achieves higher intraocular concentrations and may offer superior bioavailability ¹⁴. Therefore, considering the side effect profile of nepafenac, there are studies showing that it is more effective than other NSAIDs ^22,23. It has been shown that nepafenac reaches peak concentration in aqueous humor in a shorter time than bromfenac and ketorolac, and its ocular bioavailability is higher than other drugs ^13,14. The absence of a statistically significant difference between the two groups in our study allowed us to conclude that a single treatment would be sufficient. In a previously published case series, functional and anatomical improvement was reported in three patients with acute pseudophakic cystoid macular edema (PCME) who were treated with topical NSAIDs alone or in combination with corticosteroids ²⁴. Clinical recovery was observed in all patients except one, who had chronic hemorrhagic edema. All patients received topical nepafenac 0.1%, which was associated with notable therapeutic benefit. Topical nepafenac 0.3% has been shown to be more effective than placebo in preventing PCME among patients with perioperative risk factors; however, no significant difference was observed in patients without such risk factors ¹⁶. In our study, 0.1% nepafenac was used to treat acute pseudophakic cystoid macular edema (PCME), and patients with known risk factors were excluded. In contrast, another study included a group receiving 0.3% nepafenac, allowing comparison of its efficacy relative to the 0.1% concentration. Both studies demonstrated improvements in functional and anatomical outcomes. Also, the benefits of perioperative use of NSAIDs are that they do not cause perioperative mydriasis, do not cause an increase in intraocular pressure, and reduce endothelial cell loss ²³. In conclusion, it is well established that increasing the number of prescribed topical medications negatively impacts patient adherence to treatment regimens ²⁵. As the number of drugs used increases, the side effect profile expands ²⁵. Although some differences have been reported between the efficacy of Nevanac (nepafenac) monotherapy and its combination with Maxidex (dexamethasone), the use of Nevanac alone remains beneficial and is consistent with findings reported in the literature ^10,16,25. This study is one of the few to comparatively assess the efficacy of nepafenac monotherapy versus its combination with dexamethasone in patients developing pseudophakic cystoid macular edema (PCME) after uneventful cataract surgery ^19,20,21. Although no statistically significant difference was observed between the two treatment approaches, the findings highlight that nepafenac monotherapy may offer a sufficient and simplified therapeutic strategy by reducing drug load and minimizing potential side effects. There are four main limitations of our study. First, in our study, all drops were started in patients with PCME on OCT at the 1st month after surgery. Therefore, no comment can be made regarding the effectiveness of starting it in the early period before or after surgery. Although several studies in the literature suggest that preoperative administration of NSAIDs may be beneficial in preventing PCME, there is currently no clear consensus regarding the optimal timing, duration, or dosage of such prophylaxis ²⁰. Secondly, one type of topical NSAID (nepafenac) was preferred for treatment. Thirdly, a small number of patients were included in the study due to exclusion criteria. Fourth, PCME was defined solely based on OCT. Patients who could not be detected on OCT but may have been diagnosed via fluorescein angiography (FFA) were excluded from the study. However, using a single standardized diagnostic method may be more useful to define PCME clearly.

Declarations

References

1. Chu CJ, Johnston RL, Buscombe C, et al. Risk factors and ıncidence of macular edema after cataract surgery: a database study of 81,984 eyes. Ophthalmology. 2016;123:316-23.
   PubMed Google Scholar
2. Flach AJ. The incidence, pathogenesis and treatment of cystoid macular edema following cataract surgery. Trans Am Ophthalmol Soc. 1998;96:557-634.
   PubMed Google Scholar
3. Irvine SR. A newly defined vitreous syndrome following cataract surgery. Am J Ophthalmol. 1953;36:599-619.
   PubMed Google Scholar
4. Gass JDM, Norton EWD. Cystoid macular edema and papilledema following cataract extraction: a fluorescein fundoscopic and angiographic study. Arch Ophthalmol. 1966;76:646-61.
   PubMed Google Scholar
5. Henderson BA, Kim JY, Ament CS, et al. Clinical pseudophakic cystoid macular edema. Risk factors for development and duration after treatment. J Cataract Refract Surg. 2007;33:1550-8.
   PubMed Google Scholar
6. Shelsta HN, Jampol LM. Pharmacologic therapy of pseudophakic cystoid macular edema: 2010 update. Retina. 2011;31:4-12.
   PubMed Google Scholar
7. Milch FA, Yannuzzi LA. Medical and surgical treatment of aphakic cystoid macular edema. Int Ophthalmol Clin. 1987;27:205-17.
   PubMed Google Scholar
8. Benitah NR, Arroyo JG. Pseudophakic cystoid macular edema. Int Ophthalmol Clin. 2010;50:139-53.
   PubMed Google Scholar
9. Laurell CG, Zetterström C. Effects of dexamethasone, diclofenac, or placebo on the inflammatory response after cataract surgery. Br J Ophthalmol. 2002;86:1380–4.
   PubMed Google Scholar
10. Zaczek A, Artzen D, Laurell CG, et al. Nepafenac 0.1% plus dexamethasone 0.1% versus dexamethasone alone: effect on macular swelling after cataract surgery. J Cataract Refract Surg. 2014;40:1498-505.
    PubMed Google Scholar
11. Flach AJ, Stegman RC, Graham J, et al. Prophylaxis of aphakic cystoid macular edema without corticosteroids. A paired-comparison, placebo-controlled double-masked study. Ophthalmology. 1990;97:1253-8.
    PubMed Google Scholar
12. Sarfraz MH, Haq RI, Mehboob MA. Effect of topical nepafenac in prevention of macular edema after cataract surgery in patients with non-proliferative diabetic retinopathy. Pak J Med Sci. 2017;33(1):210-4.
    PubMed Google Scholar
13. Ke TL, Graff G, Spellman JM, et al. Nepafenac, a unique nonsteroidal prodrug with potential utility in the treatment of trauma-induced ocular inflammation: II. In vitro bioactivation and permeation of external ocular barriers. Inflammation. 2000;24:371-84.
    PubMed Google Scholar
14. Walters T, Raizman M, Ernest P, et al. In vivo pharmacokinetics and in vitro pharmacodynamics of nepafenac, amfenac, ketorolac, and bromfenac. J Cataract Refract Surg. 2007;33:1539-45.
    PubMed Google Scholar
15. El-Harazi SM, Feldman RM. Control of intra-ocular inflammation associated with cataract surgery. Curr Opin Ophthalmol. 2001;12(1):4-8.
    PubMed Google Scholar
16. McCafferty S, Harris A, Kew C, et al. Pseudophakic cystoid macular edema prevention and risk factors: prospective study with adjunctive once daily topical nepafenac 0.3% versus placebo. BMC Ophthalmol. 2017;17(1):16.
    PubMed Google Scholar
17. Singh R, Alpern L, Jaffe GJ, et al. Evaluation of nepafenac in prevention of macular edema following cataract surgery in patients with diabetic retinopathy. Clin Ophthalmol. 2012;6:1259-69.
    PubMed Google Scholar
18. Pollack A, Staurenghi G, Sager D, et al. Prospective randomised clinical trial to evaluate the safety and efficacy of nepafenac 0.1% treatment for the prevention of macular oedema associated with cataract surgery in patients with diabetic retinopathy. Br J Ophthalmol. 2017;101:423-7.
    PubMed Google Scholar
19. Tzelikis PF, Vieira M, Hida WT, et al. Comparison of ketorolac 0.4% and nepafenac 0.1% for the prevention of cystoid macular oedema after phacoemulsification: prospective placebo-controlled randomised study. Br J Ophthalmol. 2015;99(5):654-8.
    PubMed Google Scholar
20. Kessel L, Tendal B, Jørgensen KJ, et al. Post-cataract prevention of inflammation and macular edema by steroid and nonsteroidal anti-inflammatory eye drops: a systematic review. Ophthalmology. 2014;121:1915-24.
    PubMed Google Scholar
21. Walter KA, Lee RY, Chen K, Komanski C. Incidence of cystoid macular edema following routine cataract surgery using NSAIDs alone or with corticosteroids. Arq Bras Oftalmol. 2020;83(1):55-61.
    PubMed Google Scholar
22. Hovanesian J, Holland E. Tolerability and toxicity of topically applied nepafenac 0.3% compared with generic ketorolac 0.5%. J Cataract Refract Surg. 2019;45:174-80.
    PubMed Google Scholar
23. Nardi M, Lobo C, Bereczki A, et al. Analgesic and anti-inflammatory effectiveness of nepafenac 0.1% for cataract surgery. Clin Ophthalmol. 2007;1(4):527-33.
    PubMed Google Scholar
24. Hariprasad SM, Callanan D, Gainey S, et al. Cystoid and diabetic macular edema treated with nepafenac 0.1%. J Ocul Pharmacol Ther. 2007;23:585-9.
    PubMed Google Scholar
25. Modi SS, Lehmann RP, Walters TR, et al. Once-daily nepafenac ophthalmic suspension 0.3% to prevent and treat ocular inflammation and pain after cataract surgery: phase 3 study. J Cataract Refract Surg. 2014;40:203-11.
    PubMed Google Scholar

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About This Article

Received:

September 1, 2025

Accepted:

November 3, 2025

Published Online:

March 11, 2026