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DOI: https://doi.org/10.21203/rs.3.rs-1608629/v1
Purpose: To assess the effects of nepafenac ophthalmic suspension 0.1% for the control of pain experienced after dexamethasone intravitreal implant (Ozurdex) injections.
Methods: This randomized, double-masked, placebo-controlled study included 68 adults receiving Ozurdex injection. Patients were randomly assigned to receive nepafenac ophthalmic suspension 0.1% or balanced salt solution placebo. They were asked to assess the level of pain using a visual analog scale (VAS) for pain, at 1, 6 and 24 hours following the injection.
Results: At 1 hour after the injection, there was a course toward less pain scores in the nepafenac group; however, statistical significance was not reached. At 6 and 24 hours, the nepafenac group had significantly lower pain scores than those receiving placebo.
Conclusion: Nepafenac ophthalmic suspension 0.1% is effective in reducing pain experienced after Ozurdex injections.
Ozurdex (Ozurdex 0.7mg, Allergan, CA, USA) is a biodegradable, slow-release dexamethasone implant delivered by intravitreal injection and is now emerging as a potential treatment for macular edema arising from retinal vein occlusion, diabetic retinopathy, uveitis and Irvine-Gass syndrome [1–4] .
Patients frequently report ocular discomfort for up to 24 hours after the intravitreal injections but not quantified in any way. As the majority of patients require multiple injections, exploring the pain associated after this procedure is important to overcome patient discomfort and maintain compliance [5]. Topical non-steroidal anti-inflammatory drugs (NSAIDs) and more recently nepafenac ophthalmic suspension has been utilized to reduce patient’s discomfort after many ocular surgeries [6, 7]. Nepafenac ophthalmic suspension has become increasingly popular among ophthalmic surgeons due to the fact that, it has more neutral and less polarized structure with superior corneal permeability characteristics compared to other available topical NSAIDs [8].
Analgesic effect of nepafenac was studied in intravitreal injections of anti-vascular endothelial growth factor (anti-vegf) with reporting beneficial effect [9]. Currently rare studies are designed to evaluate and quantify pain during Ozurdex injection [10]. However, studies are very limited in this era [5, 11, 12] .
This study was designed to determine the effectiveness of nepafenac ophthalmic suspension 0.1% for the control of pain experienced after Ozurdex injections.
This was a randomized, double-masked, placebo-controlled study conducted at an ophthalmology clinic of a tertiarry referral center. The study protocol was approved by the local ethics committee and followed the guidelines of the Declaration of Helsinki. Patients were recruited from the retina service and prior to being included in the study, they gave their written informed consent.
Indications for injection included macular edema secondary to central retinal vein occlusion (CRVO), branch retinal vein occlusion (BRVO), or diabetic retinopathy (DR). Exclusion criteria included any previous ocular surgery other than cataract extraction. Any known allergy or sensitivity to the study medications, its components, or other agents required for the study procedures (e.g., povidone–iodine) were excluded. Patients using systemic analgesic or sedative medications were also excluded.
Ozurdex injections were administered under topical anesthesia in standardized fashion. All patients were prepared for injection by the same nurse and injected by the same retina specialist (M.O). The retina specialist opened a randomized envelope with a bottle of nepafenac ophthalmic suspension 0.1% (Nevanac; Novartis, Basel, Switzerland) or balanced salt solution placebo to determine treatment allocation. Both topical agents were given in camouflaged bottles. The patients were distributed into two groups. Group 1, consisting of 34 eyes, received topical 0.1% nepafenac and group 2, consisting of 34 eyes, received placebo (balanced salt solution) as per randomization 5 minutes later by the retina specialist who was not masked to the drop allocated.
Proparacaine Hydrochloride 0.5% (Alcaine; Alcon, TX, USA) eye drops were used for topical anesthesia 5 min and immediately before injection. No sedation was administered to any patients. A lid speculum was inserted and 5% of povidone–iodine (Isosol; Merkez Lab, Turkey) was instilled. The injection was performed at 3.5 mm (pseudophakic patients) or 4 mm (phakic patients) posterior to the limbus in the superotemporal quadrant by a tunneled injection technique using the customized applicator that has a 22-gauge needle. After removing the applicator, mild pressure was applied with a cotton swab over the injection site to reduce vitreal reflux and subconjunctival hemorrhage. Sterile balanced salt solution (BSS; Alcon, TX, USA) was used to rinse out excess povidone–iodine and all patients received a drop of moxifloxacin (Vigamox; Alcon, TX, USA) immediately after the intravitreal injection after which patients were instructed to self-administer every hours for 2 days. Parameters such as age, sex, the underlying retinal cause for the injection, injection side and lens status were recorded for the participants.
The primary study outcome was subjectively reported pain. Patients were asked to rate their pain level in each eye on a visual analog scale (VAS) at 1, 6 and 24 hours following the injection. The pain VAS is a continuous scale comprised of a horizontal or vertical line, usually 10 centimeters (100 mm) in length, anchored by 2 verbal descriptors, with 0 being no pain and 10 being excruciating pain [13]. A trained examiner recorded the VAS measurements after explaining this method to the patients. Neither the examiner nor the patient knew which drop was applied.
Statistical analysis was performed with SPSS version 15 (SPSS Science, Chicago, IL). Pain scores and baseline characteristics in each group were expressed as mean ± standard deviation (SD). Demographic and patient characteristics were compared using descriptive statistics and categorical parameters were analyzed using Chi-square test. Continuous parameters were analyzed by Mann–Whitney U test. Friedman test was used to test the pain score differences among 1, 6 and 24 hours. When the analysis showed significant differences among the groups, post hoc analysis utilizing the Wilcoxon-signed rank test was used to analyze the difference among the groups. P-value of less than 0.05 was considered statistically significant.
Sixty eight consecutive patients receiving intravitreal Ozurdex injections were enrolled, and pain scores were obtained in all patients. There were no differences between the treatment and placebo group in regards to demographic features, and type of underlying pathology (Table 1). No adverse events other than mild transient subconjunctival hemorrhage were encountered during the study.
Pain scores are presented in Table 2 and Fig. 1. At 1 hour after the injection, there was a course toward less pain in the nepafenac group; however, statistical significance was not reached. At 6 and 24 hours, the nepafenac group had significantly lower pain scores. A comparison of all combined scores between the groups demonstrated significantly lower pain scores in the eyes receiving nepafenac. There was a significant difference among the groups when Friedman test was used. Post hoc analysis utilizing Wilcoxon-signed rank demonstrated that the difference was significant between 1 hour and 24 hours, and 6 hours and 24 hours in both nepafenac and placebo groups.
Dexamethasone implant injection is definitely an unpleasant experience for patients and it was our awareness that many suffer pain in variable degrees. Pain at the site of injection can cause distress for patients which may result in reduction in patient compliance with the treatment [14, 15]. In view of this, we decided to test the effectiveness of nepafenac in terms of reducing the pain after the injection as nepafenac has been proven to have an acceptably great margin of safety and a very good analgesic effect in many ocular surgeries [6, 7].
There are several studies in literature evaluating pain either during or after anti-vegf injection however there is still controversy regarding the most effective procedure of anesthesia for lessening pain related avti-vegf injection [4, 16–18]. There are also limited studies that evaluates pain during Ozurdex injection [10]. Differently, in present study we aimed to investigate reducing the ocular pain especially after Ozurdex injection. In this way we may be able to encourage the patients to the treatment who will need multiple injections to get a desirable treatment effect [17–19].
In the present study nepafenac demonstrated a significant reduction of pain after Ozurdex injection at 6 and 24 hours compared with placebo. Although statistical significance was not reached, there was a tendency to less pain in the nepafenac group at 1 hour after the injection. Following topical application the onset of nepafenac activity was reported to be around 15 minutes and duration of action was greater than 8 hours [20].The rapid onset of activity, and a highly effective non-selective cyclooxygenase inhibitor feature of nepafenac may contribute to a significant reduction of the pain at 6 hours [8].
Ogurel and colleagues [10] reported that topical 0.1% nepafenac had an additive analgesic effect during intravitreal Ozurdex injection when combined with topical anesthesia. Makri and colleagues [12] reported that a single drop of nepafenac before intravitreal injection was effective in reducing injection-related pain immediately and up to 6h after the injection which supports our results.
Ozurdex is in an applicator with a relatively large 22-gauge needle compared with other needles. Therefore, patients may experience more pain than other procedures performed by a smaller sized needles [21, 22]. In a large trial, Ozurdex was observed to be well tolerated and eye pain was reported as the third most seen adverse effect [3]. However in a study, an interesting outcome was added to the literature that intravitreal injection of Ozurdex was not associated with more pain than bevacizumab injections, despite larger needle gauge and longer scleral route [4]. Similar to the latter study a very recent study by Ertan and colleagues [23] supports this article as they concluded that there was no significant difference in pain between intravitreal injections of dexamethasone implant, ranibizumab or aflibercept.
Interestingly, the mean VAS pain score at 6 hours in the placebo group was slightly higher than those at 1 hour after the injection. This can be attributed to ocular surface irritation caused by topical application of povidone–iodine and topical anesthetics during the procedure [24, 25]. We observed that the pain scores in both nepafenac and placebo groups at 1 hour after the injection were similar which may also be attributed to the corneal epithelial damage.
Indeed, data concerning pain after intravitreal Ozurdex injection is limited, however, a study, with the similar application technique of the drug, by Urlich demonstrated that a single drop of nepafenac reduced the ocular discomfort after intravitreal injection [24]. Although the results of our study were similar to those reported by Urlich, they were not completely consistent. The pain scores were also lower at 24 hours in that trial; however, no statistical significance was reached, probably due to the investigator using systane ultra as a placebo. Specifically, systane ultra provides sustained lubrication to the eye and protects the ocular surface from further damage while the surface epithelial cells undergo repair and renewal [26]. We, therefore, avoided using any artificial tears as a placebo to minimize potential bias.
A limitation of our study includes the difficulty of objectively comparing pain levels. However, the study design and administration of the Ozurdex by a single ophthalmologist are strengths of this study.
In conclusion, nepafenac ophthalmic suspension 0.1% was effective in reducing pain after intravitreal Ozurdex injection and may offer patient comfort and patient adherence to the treatment.
Author Disclosure Statement
The authors have no financial or proprietary interest in any material or method mentioned. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of article.
Author Disclosure Statement
The authors have no financial or proprietary interest in any material or method mentioned. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of article.