Impact of ocular pressure on pain scores during intravitreal injections with topical anesthetic applications

INTRODUCTION

Intravitreal injection (IVI) is a procedure used to deliver medication into the vitreous cavity. After the advent of anti-vascular endothelial growth factor as an effective treatment for age-related macular degeneration (AMD), IVI became a very common procedure in ophthalmology, often requiring multiple injections.^[1,2] Other pharmacological agents that are injected into the vitreous humor include antibiotics, antivirals, and steroids. Diabetic macular edema, retinal vein occlusion, and ocular infections are other common indications for IVI. Most patients will experience pain and discomfort while undergoing the procedure, and different topical anesthetic agents have been used to eliminate or decrease pain on injection. This is crucial for patient comfort and compliance with the treatment as well as to avoid complications due to sudden eye or head movement.^[3] A subconjunctival hemorrhage is a common complication of IVI, occurring in nearly 36% of cases.^[4] Other possible complications include cataract formation, increased intraocular pressure, and endophthalmitis.^[5]

Topical anesthetic drops, lidocaine gel, and sub-conjunctival injection of lidocaine are the most frequently used anesthetics in this procedure. Many studies have compared various anesthetic agents and injection techniques to evaluate the pain experienced during injection, with no good agreement on the best option for IVI.^[1,6-10] A current study concluded that subconjunctival lidocaine is the most effective method for reducing pain and eye movement during IVI.^[9] Another study examined the effect of different anesthetic methods, including lidocaine gel, lidocaine-soaked pledgets, and topical proparacaine drops, and found no statistical difference among them. However, it recommended the use of topical drops due to their cost-effectiveness.^[1] The present study aimed to evaluate the effectiveness of manual pressure at the injection site in addition to topical anesthetic in minimizing patients’ experience of pain during IVI compared to topical anesthetic drops alone.

MATERIALS AND METHODS

This prospective randomized comparative study was conducted between October and November 2020. It was halted due to the COVID-19 pandemic and resumed from August to September 2023 at the Eye Care Center in Qassim, Saudi Arabia. The study adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from all participants and ethical approval was given by the research and ethics committees of Qassim Health Affairs, Ministry of Health. Patients who required frequent IVI as part of their routine clinical care for retinal disease and were scheduled to receive IVI of bevacizumab (Avastin, Genentech) or aflibercept (Eylea, Bayer) were included in the study. All participants had previously received at least one IVI. Patients who had undergone surgery for conditions other than cataracts, glaucoma, conjunctivitis, herpetic eye diseases, uveitis, keratitis, and bullous keratopathy were excluded from the study. These conditions may influence the patient’s eye pain sensitivity. Patients using systemic sedatives or analgesic drugs were also excluded. Demographic data, ocular indications for IVI, type of the injected drug, and complications of the procedure were recorded.

Each patient was allocated randomly to receive one of two anesthetic methods before IVI and then to receive the alternative method on their consecutive visit for IVI. The two methods involved: (1) Manual ocular pressure being applied at the site of injection using a cotton swab soaked with topical anesthetic drops and (2) applying topical anesthetic drops without a swab or ocular pressure. Patients were asked immediately after each IVI to score their pain using a Visual Analog Scale (VAS). To ensure consistency in applying ocular pressure and standardization of the technique, a single physician administered the anesthetic and ocular pressure and performed the IVI procedure.

Patients underwent IVI in the supine position under sterile conditions. One drop of topical anesthesia (tetracaine hydrochloride 1%, preservative-free, Bausch and Lomb) was instilled into the eye, and a sterile ophthalmic drape was applied after the periocular area was cleaned with 10% povidone-iodine. A sterile lid speculum was used to open the eyelid, and 5% povidone-iodine solution was applied to the superotemporal quadrant. One minute before IVI, three drops of topical anesthesia were applied either directly or on a sterile cotton swab stick with moderate pressure to the site of injection. The appropriate level of ocular compression was determined by observing a visible indentation at the site where the cotton swab was applied. A 30G needle syringe was used to inject the drugs into the vitreous cavity 3.5-mm posterior to the limbus. The vitreal reflux was reduced by applying mild pressure over the injected site using a sterile cotton swab soaked with 5% povidone-iodine. Topical antibiotic drops were instilled into the eye in all cases at the end of the procedure.

Immediately after the IVI procedure, the patient was asked to evaluate the pain experienced during the injection using the Visual Analog Scale (VAS). VAS is a grading scale for subjective measurement of pain experience in which 0 represents no pain, and 10 represents the worst pain the patient had ever felt. This scale has been used in many studies and found to be a valid and reliable approach to evaluate pain and other symptoms.^[11-14]

IBM Statistical Package for the Social Sciences version 25.0 was used for statistical analysis. A P < 0.05 was considered significant. Student’s t-test, Chi-square test, and one-way analysis of variance were used to investigate factors associated with the pain score following IVI.

RESULTS

A total of 20 eyes of 20 patients were included in the study, 12 (60.0%) males and eight (40.0%) females. The mean age was 60.20 years (standard deviation = 7.93, range 46–75). Indications for IVI were diabetic macular edema (75%), macular edema secondary to retinal vein occlusion (15%), and exudative AMD (10%). The drugs used for IVI were bevacizumab in 17 patients (85%) and aflibercept in three patients (15%) [Table 1].

The mean VAS pain scores with and without ocular pressure, at 1.90 ± 0.72 and 2.30 ± 0.92, respectively (out of a maximum of 10), were not significantly different (P = 0.134). Subconjunctival hemorrhage occurred in 10 cases (50%) following IVI without ocular pressure, compared to two cases (10%) in IVI with ocular pressure (P = 0.006). No other ocular complications were recorded [Table 2].

Mean pain scores were also analyzed according to gender. In male patients, mean pain scores were 1.75 ± 0.75 with ocular pressure and 2.33 ± 1.07 without (P = 0.138). Pain scores in females were 2.13 ± 0.64 with ocular pressure and 2.25 ± 0.71 without (P = 0.717). No statistically significant difference in pain score was found between male and female participants after either method (P > 0.2). Furthermore, there was no statistically significant difference between pain scores in the two anesthetic methods with respect to IVI drugs, history of cataract surgery, laterality, or the patient’s ocular pathology [Tables 3 and 4].

DISCUSSION

In recent years, IVI, an in-office procedure for delivering therapeutic agents into the vitreous cavity for the management of many ocular diseases, has become increasingly common. Patient comfort and minimal pain are important to ensure compliance with the requirement for repeat procedures. Different forms of anesthesia have been found to be effective in pain management but there is no consensus on the preferred approach.^[15-18] The present study compared patient pain experienced during IVI using two anesthetic approaches, namely one anesthetic agent (tetracaine hydrochloride 1%) with different methods (anesthetic only versus anesthetic plus pressure applied to the injected site). To overcome variations in pain sensitivity between participants, the techniques were applied within patients so that each patient was exposed to both methods at consecutive visits in random order. To minimize the impact of a first ocular injection experience, all patients had undergone at least one prior IVI. To achieve standardization, a single physician administered the anesthetic and performed the IVI procedure, and all IVIs were delivered using the same needle size in the superotemporal quadrant.

The findings of this study suggest that applying ocular pressure, along with topical anesthetic drops during IVI, resulted in less discomfort compared to using topical anesthetic drops alone. However, this result was not statistically significant (mean VAS pain scores = 1.90 vs. 2.30, respectively, P=0.134). To date, few studies have assessed the effect of applying ocular pressure in minimizing pain during IVI with different anesthetic agents. Sofi and Singh used one topical anesthetic agent (0.5% proparacaine) to compare two different anesthetic methods (topical drops only and cotton bud soaked with anesthetic drops applied with pressure at the injection site) and found no statistical difference in mean VAS between the two groups.^[19] In another study, Gregori et al. compared anesthetics using sterile cotton swabs soaked in 4% liquid lidocaine applied with gentle eye pressure and using 3.5% lidocaine ophthalmic gel alone and found similar discomfort with both methods during and after the procedures.^[20]

Subconjunctival hemorrhage is a common complication that can occur after IVI. This condition arises from direct injury to the blood vessels in the conjunctiva caused by the injection needle. While it is typically a harmless side effect, it can result in cosmetic concerns and anxiety for patients. Such feelings may potentially lead to interruptions in the treatment.^[4,21] Numerous studies have been published in the literature aimed at reducing the occurrence of subconjunctival hemorrhage during IVI. One study conducted by Gonzalez-Saldivar et al. found that the use of topical oxymetazoline before IVI significantly decreases the incidence of subconjunctival hemorrhage.^[21] Another study found that using lidocaine gel had a lower incidence of subconjunctival hemorrhage following IVI compared to topical drops.^[20] Our study demonstrated that applying pressure to the injection site significantly reduced the incidence of subconjunctival hemorrhage, thereby enhancing patient comfort and promoting treatment compliance.

Previous studies have compared the degree of pain following IVIs between male and female patients and reported different results. Some studies found that females were more prone to perceive pain due to hormonal, psychosocial, and other factors.^[7,14,22,23] This explains why the current study indicated that males reported lower pain levels, although the difference was not statistically significant. In addition, pain scores were not significantly associated with a history of cataract surgery, laterality, or type of IVI drug.

The study has some limitations, including the subjective assessment of pain and the small sample size. The sample size of 20 participants is relatively small, which may limit the generalizability of the findings. No objective method for pain assessment exists, and the VAS pain score is a validated and widely used method for pain measurement. Another possible limitation of the study is bias due to the patient patient’s awareness of the different anesthetic methods, with one of the anesthetic methods involving pressure on the eye. A specific strength of the present study is its within-subjects design, minimizing the influence of variations in pain sensitivity between participants. Another strength is the standardization of each method, with a single physician administering the anesthetic and performing the IVI procedure. To the best of our knowledge, this is the first within-subjects study to compare patient pain experience during IVI using topical anesthetic drops with and without exertion of ocular pressure to the site of injection. Further studies with larger numbers of participants are required to increase statistical power and to investigate the factors associated with IVI pain.

CONCLUSION

IVI is a common procedure used to manage various eye diseases. This prospective study compared two methods of anesthesia to reduce pain during the procedure. The results showed that applying ocular pressure in conjunction with topical anesthetic drops resulted in lower pain scores compared to using the drops alone; however, this difference was not statistically significant. In addition, the use of ocular pressure significantly decreased the occurrence of subconjunctival hemorrhage. Therefore, we recommend this method as it may enhance patient comfort and improve adherence to treatment.