Comparison of the Tolerability of Diclofenac and Nepafenac

Abstract

Purpose:

Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the prevention and treatment of inflammation and pain following cataract surgery. Preservative-free diclofenac and nepafenac drops are commonly used ophthalmic NSAIDs. The purpose of this study was to compare the tolerability of diclofenac to that of nepafenac.

Methods:

In this prospective patient-blinded study, consecutive patients undergoing cataract surgery were included. One drop of nepafenac 0.1% and diclofenac sodium 0.1% were instilled in the right and left eyes, respectively, one immediately after the other, 1 day before surgery. Visual analog scale (scale 0–10) was used to measure patient discomfort, itching, burning, and pain at 1 second (s), 15 s, 1 minute (min), and 5 min postadministration.

Results:

Overall, 44 eyes of 22 patients were included in this study. Diclofenac and nepafenac had high and similar tolerability at all time points with no significant difference regarding all aspects of tolerability. A vast majority of patients (72%) did not prefer 1 drop over the other in terms of overall comfort.

Conclusions:

Both diclofenac and nepafenac seem to have similar high tolerability. Diclofenac may be an affordable alternative to nepafenac and therefore should be considered by prescribing physicians, specifically in preoperative cataract patients.

Introduction

Cataract surgery induces a surgical inflammatory response.^1–3 Uncontrolled inflammation may lead to serious ocular side effects, such as corneal edema, cystoid macular edema (CME), posterior synechia, and secondary glaucoma.¹ Management of postoperative inflammation is thus a mainstay in modern surgery. Topical nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used preoperatively for the prevention and treatment of inflammation and pain following cataract surgery.^2–4 The NSAIDs anti-inflammatory activity is mainly derived by inhibition of the cyclooxygenase enzyme pathway and prevention of the formation of prostaglandins.⁴

Various studies have compared between 2 or more ophthalmic NSAIDs to determine their effectiveness in reducing pain and inflammation associated with cataract surgery.^5–9 More often than not, the studied ophthalmic NSAIDs demonstrated similar effectiveness, with minimal differences observed in regard to final visual results and prevalence of CME. Commercially available topical ophthalmic NSAIDs vary based on inclusion of inactive components such as preservatives, surfactants, tonicity agents, viscosity enhancers, and buffers,¹⁰ which may affect their tolerability. Postcataract treatment with NSAIDs may last for several weeks and lower tolerability may lead to lower compliance of patients.³ Since ophthalmic NSAIDs have demonstrated similar effectiveness, identifying differences in tolerability is of interest.

In Israel, diclofenac sodium and Nevanac are the only registered ocular NSAIDs. The former is priced at 45 New Israeli Shekels [NIS; approximately 13 US dollars (USD)], while the latter is priced at 124 NIS (approximately 35 USD). The structural formulas of diclofenac and nepafenac can be seen in Fig. 1. Diclofenac sodium is a sterile topical ophthalmic solution, buffered at pH 7.2 and commercially available with (Voltaren^® Ophtha Eye Drops; Novartis Pharma AG.) and without (Dicloftil^®; Farmigea SpA) benzalkonium chloride or thimerosal preservatives. Recently, the preservative-free diclofenac preparation was shown to have improved tolerability when compared to its counterpart.¹¹ Nepafenac ophthalmic suspension 0.1% (Nevanac^®; Alcon Laboratories, Inc.) is designated chemically as 2-amino-3-benzoylbenzeneacetamide with a pH of ∼7.4 and contains benzalkonium chloride as a preservative. It is an NSAIDs suspension prodrug, which after corneal penetration is converted by ocular hydrolases to amfenac, the active metabolite. Acosta et al.¹² compared the corneal analgesic efficacy of nepafenac and diclofenac, and found that nepafenac exhibited a more rapid and pronounced effect on thin myelinated nociceptor nerve fibers (responsible to acidic stimulation) than did diclofenac but did not affect the responsiveness of corneal mechanonociceptors or cold receptors. They concluded that while diclofenac exhibits local anesthetic effects, nepafenac does not, a trait that can, in itself, affect patients' tolerability. To the best of our knowledge, to date, no study has compared the tolerability of preservative-free diclofenac with that of nepafenac.

FIG. 1.

Structural formulas of diclofenac and nepafenac.

Methods

This consecutive, patient-blinded study was conducted in accordance with the Declaration of Helsinki. All necessary authorizations were obtained from the Institutional Review Board of the Wolfson Medical Center. No grants, funds, or benefits were received by the authors.

Subjects

Patients undergoing cataract surgery at the Department of Ophthalmology of the Wolfson Medical Center between June 1, 2015, and June 30, 2015, were included in this study. Following informed consent, each preoperative patient received a drop of nepafenac 0.1% in the right eye (Nevanac) and a drop of preservative-free diclofenac sodium 0.1% (Dicloftil) in the left eye. The drops were instilled within 2 seconds (s) of each other, in a single-blind manner. In half of the patients, the drops were instilled in the right eye first and in the other half of the patients, in the left eye first. Patients were blinded to the type of NSAIDs used.

The visual analog scale (VAS) was used to measure patient discomfort, itching, burning, and pain (Likert-type scale 0–10) as it was shown to be a reliable tool in evaluating and quantifying ocular discomfort.^13,14 Following an explanation to the patients about how to use the VAS grading, the VAS was obtained immediately, 15 s, 1 minute (min), and 5 min after drop instillation. The 5 min time point was chosen as the final one based on a previous report which found that no patient discomfort was reported 5 min postinstillation of NSAIDs.¹¹ The total tolerability score was calculated by averaging discomfort, itching, burning, and pain at each time point. Charts of each patient were reviewed and the following data were collected: age, gender, education level, systemic and ocular comorbidities, and known allergies. Every patient considered for the study went through a comprehensive eye examination and a detailed anamnesis was taken. We excluded eyes of patients treated for ocular surface disease, with a tear break up time of <10 s, with diabetic neuropathy, with a history of herpetic keratitis, with signs of posterior or anterior blepharitis, and patients who received topical therapy for any ocular disease at any time point in the past. The cost of the NSAIDS was calculated based on an average of 2 Israeli pharmacy price lists. Prices were converted to USD from NIS based on the conversion rate of ILS/USD = 3.50.

Statistical analyses

Data were analyzed with the Minitab Software, version 16 (Minitab, Inc.). Variables were tested for normality using the Shapiro–Wilk test. Groups were compared by the t-test or Mann–Whitney U test as appropriate. Changes over time following instillation of drops were evaluated using the repeated measures analysis of variance (ANOVA) and Friedman test (nonparametric repeated measurements) as appropriate. Bonferroni correction was used for multiple comparisons. Continuous data are presented as mean ± standard deviation. Nominal data are presented as numbers and percentage. A P-value of <0.05 was considered statistically significant. With a sample size of 25 eyes per group, a power of 0.8, α = 0.05, and an estimated standard deviation of +/−10 at 1 min on the VAS,¹¹ a significant difference in VAS scores between the 2 groups would have been found at a difference of 5.8 (out of 100).

Results

Overall, 44 eyes of 22 patients were included in this study. The mean ± standard deviation age was 72.2 ± 15.3 years and 72.7% (n = 16) were female. The VAS scores for all aspects of tolerability over time are portrayed in Table 1 and in Fig. 2.

FIG. 2.

Discomfort (A), burning (B), itching (C), and pain (D) VAS scores over time. VAS, visual analog scale.

Table 1.

Tolerability at All Time Points Using the Visual Analog Scale

	Nepafenac	Preservative-free Diclofenac	P^a
1 second
Discomfort	0.03 ± 0.09	0.01 ± 0.04	0.38
Itching	0.07 ± 0.26	0.04 ± 0.07	0.54
Burning	0.12 ± 0.32	0.17 ± 0.32	0.66
Pain	0.02 ± 0.04	0.04 ± 0.06	0.24
15 seconds
Discomfort	0.03 ± 0.09	0.13 ± 0.29	0.16
Itching	0.20 ± 0.47	0.16 ± 0.34	0.73
Burning	0.21 ± 0.52	0.16 ± 0.34	0.71
Pain	0.03 ± 0.05	0.15 ± 0.39	0.16
1 minute
Discomfort	0.07 ± 0.22	0.01 ± 0.03	0.24
Itching	0.14 ± 0.32	0.02 ± 0.04	0.11
Burning	0.06 ± 0.24	0.04 ± 0.06	0.66
Pain	0.02 ± 0.04	0.05 ± 0.10	0.32
5 minutes
Discomfort	0.09 ± 0.33	0.04 ± 0.09	0.52
Itching	0.11 ± 0.28	0.04 ± 0.11	0.28
Burning	0.10 ± 0.28	0.05 ± 0.09	0.38
Pain	0.07 ± 0.08	0.07 ± 0.09	1
Preference, %^b	13.6	13.6

Paired t-test.

Most patients (72.8%) stated that they did not prefer 1 drug over the other.

Discomfort

At 1 s after instillation, the discomfort level in eyes treated with nepafenac was 0.03 ± 0.09 and 0.01 ± 0.04 in eyes treated with diclofenac (P = 0.38). At 15 s after instillation, the discomfort level in eyes treated with nepafenac stayed the same, whereas discomfort increased to 0.13 ± 0.29 in the eyes treated with diclofenac (P = 0.16). At 1 min after instillation, discomfort level in the nepafenac group rose to 0.07 ± 0.22, whereas in the diclofenac group it declined to 0.01 ± 0.03 (P = 0.24). At the 5 min time point, discomfort levels were 0.09 ± 0.33 and 0.04 ± 0.09, respectively (P = 0.52).

Burning

At 1 s after instillation, the burning level in eyes treated with nepafenac was 0.12 ± 0.32 and 0.07 ± 0.32 in eyes treated with diclofenac (P = 0.66). At 15 s after instillation, the burning level in eyes treated with nepafenac increased to 0.21 ± 0.52, whereas it almost has not changed in the eyes treated with diclofenac and stood at 0.16 ± 0.34 (P = 0.71). At 1 min after instillation, burning levels reduced in both groups to 0.06 ± 0.24 and 0.04 ± 0.06, respectively (P = 0.66). At the 5 min time point, burning levels were 0.10 ± 0.28 and 0.05 ± 0.09, respectively (P = 0.38).

Itching

At 1 s after instillation, the itching level in eyes treated with nepafenac was 0.07 ± 0.26 and 0.04 ± 0.07 in eyes treated with diclofenac (P = 0.54). At 15 s after instillation, itching levels increased in both groups to 0.20 ± 0.47 and 0.16 ± 0.34, respectively (P = 0.73). At 1 min after instillation, itching levels reduced in both groups to 0.14 ± 0.32 and 0.02 ± 0.04, respectively (P = 0.11). At the 5 min time point, itching levels were 0.11 ± 0.28 and 0.04 ± 0.11, respectively (P = 0.28).

Pain

At 1 s after instillation, the pain level in eyes treated with nepafenac was 0.02 ± 0.04 and 0.04 ± 0.06 in eyes treated with diclofenac (P = 0.24). At 15 s after instillation, the pain level was stable in the eyes treated with nepafenac and was 0.03 ± 0.05, whereas it increased in the eyes treated with diclofenac to 0.15 ± 0.39 (P = 0.16). At 1 min after instillation, pain levels reduced in both groups to 0.02 ± 0.04 and 0.05 ± 0.10, respectively (P = 0.32). At the 5 min time point, pain levels were 0.07 ± 0.08 and 0.07 ± 0.09, respectively (P = 1).

Summary

At no time point was there a significant difference between diclofenac and nepafenac regarding all aspects of tolerability (Fig. 3), with both displaying very low and similar levels of discomfort, pain, itching, and burning scores. Repeated measures ANOVA for nepafenac showed significant difference between measurements over time only for pain (P = 0.01) but not for discomfort (P = 0.51), itching (P = 0.32), or burning (P = 0.15). For diclofenac, ANOVA revealed no significant difference between measurements for all parameters: discomfort (P = 0.08), itching (P = 0.11), burning (P = 0.18), or pain (P = 0.25). A vast majority of patients (72.8%) did not prefer 1 drop over the other in terms of overall comfort; 13.6% favored diclofenac and 13.6% favored nepafenac. We calculated at a power of 0.8 that 1,229 participants would be required in each group for differences to reach the 0.05 significance level (eg, burning at 1 min postinstillation).

FIG. 3.

Total tolerability score.

Discussion

To our knowledge, this study is the first to compare tolerability between the use of a single drop of preservative-free diclofenac sodium and nepafenac drops. Our results indicate that both preservative-free diclofenac and nepafenac seem to have similar high tolerability and that there is no significant difference between them in terms of discomfort, itching, burning, and pain.

Topically applied NSAIDs are commonly used and play a significant role in the management and prevention of noninfectious postoperative inflammation and CME following cataract surgery, as well as to manage pain postoperatively.^3,4 However, most studies comparing NSAIDs drops focused on their efficacy more than on their tolerability.^5–9 Preservative-free drops have been shown to be more tolerable than drops with benzalkonium chloride or thimerosal preservatives.^8,13 Moisseiev and Varssano compared the tolerability of preserved diclofenac sodium 0.1% and preservative-free diclofenac on 30 healthy volunteers and showed that the latter was preferable with better pain, discomfort, itching, and burning scores.¹¹ When comparing their results to our own, it is evident that the mean VAS scores of the preservative-free diclofenac are lower in our research at every category. This can be explained by the mean age of our subjects, which was about 40 years older than theirs, as it was shown that there is a decrease in corneal sensation with aging that correlates with microstructure modifications in the aging cornea.^15–17

Cataract surgery is the most commonly performed surgical procedure in the world, and while life expectancy increases greatly incessantly, the volume of cataract surgery required rises as well.^18,19 The economic impact of cataract surgery in the United States alone is enormous. It is estimated that among Americans, the economic burden of age-related cataract is 6.8 billion USD.²⁰ Since the burden of the cost of Nevanac is higher than preservative-free diclofenac (almost 3 times more expensive), it is necessary to justify its cost by comparing these drugs in terms of patient tolerability and preference. As seen in this study, no difference was found in terms of tolerability, and as we found in the literature review, there is no difference in efficacy between these 2 drops.^21,22 Thus, preferring the cheaper diclofenac might decrease the great toll of cataract surgeries on the healthcare system.

In our study, both diclofenac and nepafenac displayed similar and low scores in all aspects of tolerability, including discomfort, pain, itching, and burning. Not only was there no clinical or statistical difference between the groups at any time point but also a vast majority of the subjects (72.8%) did not prefer 1 drop over the other in terms of overall comfort, and the remaining subjects' preferences were split evenly between the 2 drops. For the difference between both study groups to become significant, it would have required a sample size of 2,458 participants (1,229 in each group), an enterprise that would be unrealistic in view of the very little clinical difference between the 2 groups.

The only statistical significant change over time was observed for pain induced by nepafenac. However, this change has no real clinical meaning as the pain levels were very low and showed a 0.4% VAS score increase from baseline to endpoint (from 0.02 to 0.06, P = 0.02).

The minute levels of discomfort, pain, itching, and burning, which were described repeatedly by our patients using the VAS score, may be attributed to their increased age.^15–17

This study had several limitations. First of which is its small sample size. Second, tolerability was checked at only 4 time points (up to 5 min postinstillation) and did not test for differences after longer periods of use, which may have resulted in the emergence of various symptoms such as ocular surface dryness and burning sensations, which can occur with repeated administration and can be a major cause for low compliance in these patients. Third, Nevanac contains benzalkonium chloride as a preservative, whereas Dicloftil is a preservative-free formulation. As shown in previous studies,^11,13 patients may report higher VAS scores for burning when using a preserved formulation, which by itself could cause local toxicity. With that in mind, we found no difference between the 2 topical drugs.

Further studies with a larger population should be conducted to validate our research.

Nevertheless, this is the first study to evaluate and compare tolerability between the use of a single drop of preservative-free diclofenac sodium and nepafenac drops. Both were similarly and very well tolerated. Therefore, diclofenac may be considered a cost-effective alternative to nepafenac by prescribing physicians, specifically in preoperative cataract patients.

Footnotes

Acknowledgments

No author has any proprietary interest in the publication of this article. No grants or funds were received for this study.

Author Disclosure Statement

No competing financial interests exist.

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