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Year : 2019  |  Volume : 27  |  Issue : 1  |  Page : 1-7

Evaluation of Ocular Pain During and After Intravitreal Injection of Antivascular Endothelial Growth Factors in South-West Nigeria

Department of Ophthalmology, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife, Nigeria

Date of Web Publication4-Jul-2019

Correspondence Address:
Dr. Judith G Akinwande
Department of Ophthalmology, Obafemi Awolowo University Teaching Hospitals Complex, Ile-Ife
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/njo.njo_22_18

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Aim: This article determines pain scores during and after intravitreal injections in black Africans so as to make evidence-based decisions in pain management. Settings and Design: This was a prospective cohort study conducted over 16 months following institutional ethical clearance on adults scheduled for intravitreal antivascular endothelial growth factor (anti-VEGF) therapy. Materials and Methods: Age, sex, indication for therapy, presence of diabetes mellitus, anti-VEGF agent, current dose of anti-VEGF taken, and quadrant of injection were recorded. Pain was measured with visual analog scale during the procedure and 15 min, 30 min, 1 h, and 3 h after procedure. Pain intensity was classified into no pain, mild, moderate, and severe. Data were analyzed using Statistical Package for the Social Sciences version 22.0, P-value below 0.05 was considered statistically significant. Results: A total of 49 eyes of 49 patients with male-to-female ratio of 1.2:1 and mean age of 66.61 ± 11.24 years were studied. Most common indication for anti-VEGF was diabetic retinopathy (17, 34.7%) and most patients (34, 69.4%) received bevacizumab. The mean pain score during injection was 36.33 ± 23.25; this progressively decreased with time to 0.20 ± 1.42 by 3 h postinjection (P < 0.001). Six (12.2%) patients experienced no pain at all during the injection, whereas mean pain score was significantly higher in those who had bevacizumab injections (P = 0.031) and diabetes (P = 0.013). Pain was mainly mild in severity during the injection and female patients tended to have more severe pains. Conclusion: Pain during intravitreal anti-VEGF in black Africans is mild, and it resolves within 3 h of the injection.

Keywords: Anti-VEGF, bevacizumab, intravitreal injection, ocular pain, ranibizumab

How to cite this article:
Onakpoya OH, Akinwande JG. Evaluation of Ocular Pain During and After Intravitreal Injection of Antivascular Endothelial Growth Factors in South-West Nigeria. Niger J Ophthalmol 2019;27:1-7

How to cite this URL:
Onakpoya OH, Akinwande JG. Evaluation of Ocular Pain During and After Intravitreal Injection of Antivascular Endothelial Growth Factors in South-West Nigeria. Niger J Ophthalmol [serial online] 2019 [cited 2020 Jul 6];27:1-7. Available from:

  Introduction Top

Intravitreal injection of antivascular endothelial growth factor (anti-VEGF) agents is widely used for the treatment of a wide variety of retinal diseases, including age-related macular degeneration, diabetic retinopathy, retinal vascular occlusions, and retinopathy of prematurity.[1] Bevacizumab (Avastin; Genentech, San Francisco, California, USA) and ranibizumab (Lucentis; Genentech) are currently the most commonly used intravitreal anti-VEGF and have been found to have equivalent visual outcome.[2] Ranibizumab is a humanized monoclonal antibody Fab fragment that binds to all active VEGF-A isoforms.[3],[4] It was designed for intraocular use. Bevacizumab on the other hand, is a 150-kD humanized monoclonal full-length antibody that binds to all active isoforms of VEGF-A.[5] It is used off-label for ocular diseases with no commercially available form.[6],[7]

Pain at the injection site is one of the common procedure-related complications of intravitreal anti-VEGF. The pain associated with intravitreal injection can lead to sudden eye movement and blepharospam that can result in intraocular complications.[8] Patients who require multiple injections are likely to refuse further treatment after a bad experience.[9] Pain is a subjective perception that cannot be accurately and consistently measured.[10] Several pain scores, which include the visual analog scale (VAS), numeric rating scale, verbal descriptor scale, Wong–Baker faces scale, and McGill pain questionnaire, to mention a few, have however been developed to quantify pain.[11] The VAS is a horizontal line exactly measuring 10 cm (100 mm) as shown in [Figure 1] and has been shown to be a valid, reliable, and reproducible research measure of acute pain measurement.[12],[13] It has found a place in ophthalmological studies and has been used with success for grading pain after intravitreal injection.[14],[15],[16] Jensen et al.[17] recommended rating of VAS pain score into no pain (0–4 mm), mild pain (5–44 mm), moderate pain (45–74 mm), and severe pain (75–100 mm) to reflect the severity of pain.
Figure 1 Visual analog scale (VAS)

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Younger age, male sex, larger needle size, injection in the left eye, and superotemporal quadrant have been associated with higher pain scores after intravitreal injection.[9],[16],[18] Rifkin et al.[18] observed that pain scores decreased with each consecutive injection. Pain scores as well as factors influencing them could differ in different population groups as ethnic/racial differences have been reported in pain threshold.[19] The index study was conducted on homogenous black African population, and authors are not aware of studies evaluating pain in black Africans following intravitreal injections. This study was aimed at determining pain scores during intravitreal injections in black African patients so as to make evidence-based decisions in pain management.

  Patients, Materials, and Methods Top

This prospective cohort study was conducted in the retinal unit of the Department of Ophthalmology, Obafemi Awolowo University Teaching Hospital Complex, Ile-Ife, from January 2016 to April 2017. Ethical clearance was obtained from the Ethics and Research Committee of Obafemi Awolowo University Teaching Hospital. Informed consent was taken from each patient in accordance to the Helsinki Declaration of 1975, as revised in 2000.

All consenting consecutive adult patients aged 18 years and above scheduled for intravitreal anti-VEGF therapy were recruited into the study. Patients who had any previous ocular surgery other than cataract extraction, presence of anterior segment conditions that can affect pain sensation such as bullous keratopathy, patients using systemic analgesics or sedative medications, presence of ocular pain or active ocular infection, and patients with poor cooperation in using the VAS were excluded from the study.

All patients had Snellen visual acuity, slit lamp biomicroscopy (Carl Zeiss Meditec AG, Jena, Germany), applanation tonometry with Perkins (Haag-Streit, Mason, Ohio, USA), fundoscopy with +78D (Volk Optical, Mentor, Ohio, USA), as well as binocular indirect ophthalmoscopy (Keeler, Broomall, Pennsylvania, USA). Demographic and clinical data including age, sex, indication for therapy, laterality, number of previous intravitreal anti-VEGF in the affected eye, presence of diabetes mellitus (DM), lens status, type of anti-VEGF, and quadrant of injection were recorded. Pain was measured by subjective grading on the VAS that was explained to consenting patients before the intravitreal injection. Each patient was asked to mark a vertical line crossing the horizontal line, according to his or her subjective pain assessment during the injection, ranging from no pain at all (0) to maximal/worst pain (100). The distance between the left edge of the horizontal line and the vertical mark made by the patient was later measured with a transparent meter rule and recorded in millimeter. This was transformed into a score between 0 and 100. The severity of pain was further classified into no pain, mild, moderate, and severe.[17]

Intravitreal injections were given by a single surgeon in the operating theater and standard sterile procedure including gowning and masking was followed. Anesthesia was achieved by instilling one drop of tetracaine hydrochloride (Alcon, Fort Worth, Texas, USA) at 30, 15, 5 min, and just before the injection. The periocular skin, eyelid margins, and eyelashes were cleaned with 10% povidone iodine; 5% povidone iodine was instilled in the inferior conjunctival fornix. Wire eyelid speculum was inserted to keep the eyelids parted as well as to direct the eyelashes away from the field; 1.25 mg/0.05 mL of bevacizumab was dispensed into a single-use 27-gauge needle syringe using aseptic technique, patient was instructed to gaze directly opposite the site of injection, and the injection was given in the quadrant of choice. The entry site was 3.5 and 4.0 mm from the limbus in the pseudophakic and phakic patients, respectively, and the needle was inserted perpendicularly through the sclera directed at the center and injection gently pushed into the vitreous. Sterile cotton-tipped applicator was used to apply pressure after injection. Pre- or postinjection paracentesis was not performed in any of the patients. A drop of antibiotic (tobramycin; Alcon) eye drop was immediately instilled after the injection. Ranibizumab (0.5 mg/0.05 mL) in a prefilled syringe was injected with a 30-gauge needle using the same method. Immediately after the injection, the patients were asked to rate their perceived pain during the procedure and subsequently at 15 min, 30 min, 1 h, and 3 h after the injection.

Data were imputed and analysis was conducted using Statistical Package for the Social Sciences version 22.0 (SPSS Inc., Chicago, Illinois, USA) for Windows (Microsoft Corporation, Redmond, Washington, USA). Primary outcome measure was mean pain score; factors influencing pain score and severity of pain were the secondary outcome measures. Comparison of mean pain scores during and after the injection was conducted with paired Student’s t-test. The difference in pain score with regard to patients’ characteristics was compared using analysis of variance. A P value less than 0.05 was considered statistically significant.

  Results Top

A total of 49 eyes of 49 patients were recruited for this study. There were 27 (55.1%) males and 22 (44.9%) females with a male-to-female ratio of 1.2:1. The mean age was 66.6 ± 11.2 years and ranged from 33 to 85 years. Most of them (31, 63.3%) had tertiary education, whereas nine (18.4%) patients had no formal education. A large number (19, 38%) were retirees [[Table 1]]. Twenty-six (53.1%) patients were diabetic, and bevacizumab was the most commonly (34, 69.4%) given anti-VEGF. The most common indication for intravitreal anti-VEGF in this study was diabetic retinopathy (17, 34.7%). Although the index injection number ranged from one to four, most of them (25, 51.0%) received their first dose during the study. Most (46, 93.9%) eyes were phakic and injection site was mainly superotemporal [[Table 2]].
Table 1 Demographic characteristics of study population (49 patients)

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Table 2 Clinical characteristics of study group (49 patients)

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The mean pain score reported by patients during intravitreal injection was 36.3 ± 23.3, 18.6 ± 18.1 at 15 min after the injection, 9.0 ± 11.9 at 30 min postinjection, and 2.5 ± 6.0 at 1 h postinjection. The mean pain score progressively decreased with time after intravitreal anti-VEGF; after 3 h of injection, the mean pain score was 0.2 ± 1.4 with 48 (98.0%) patients feeling no pain [[Figure 2]]. The difference between the mean pain score during the injection and the mean pain scores at various times postinjection was statistically significant [[Table 3]].
Figure 2 The mean pain score trend during and following intravitreal anti-VEGF injection

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Table 3 Relationship between pain score during injection and postinjection pain scores

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The mean pain score experienced by patients during intravitreal injection was significantly higher in patients who had intravitreal bevacizumab injection compared with those who had ranibizumab; the difference was no longer significant at 15 min, 30 min, 1 h, and 3 h after the injection. Mean pain score was significantly higher among diabetic patients (37.3) during the procedure compared with nondiabetic patients (35.2). No significant difference was found in mean pain score during intravitreal injection based on age, indication for injection, laterality, quadrant of injection, number of previous injections, and lens status [[Table 4]].
Table 4 Mean pain score during and after intravitreal injection

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Six (12.2%) patients felt no pain at all during anti-VEGF injection, whereas most of them (85.8%) reported mild and moderate pain. The severity of pain when present was mainly mild or moderate during and after intravitreal anti-VEGF injection [[Table 5]]. Females reported statistically significant higher severity of pain than males during intravitreal anti-VEGF injection (P = 0.002); all patients who reported no pain were males (6, 12.2%), whereas the majority of patients (15, 71.4%) with moderate pain and the only patient (1, 2.0%) with severe pain were females [[Table 6]]. The type of anti-VEGF, presence of DM, and dose had no effect on severity of pain. Subconjunctival hemorrhage was noted in three (6.1%) patients.
Table 5 Ranking of pain severity during intravitreal injection

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Table 6 Factors influencing the severity of pain during intravitreal injection

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  Discussion Top

Intravitreal injection is the most common ophthalmic procedure in the United States,[20] and it is gaining prominence as a mode of treatment for retinal diseases in Nigeria.[21],[22] Pain evaluation in intravitreal injection is useful for assessment and determination of treatment plans so as to reduce the pain as well as discomfort associated with the procedure thus optimizing patients’ compliance.

The mean pain score during intravitreal injection procedure in this study was 36.3 ± 23.3. This mean pain score is high as intravitreal injection is expected to be a relatively pain-free procedure following topical anesthetic agents use. Moisseiev et al.[14] documented a lower mean pain score of 20.8 ± 20.3 in Israel after intravitreal injection of Ozurdex and bevacizumab. A higher value of 44.77 ± 16.42 was reported by Örnek et al.[23] in Turkey following the use of topical levobupivacaine for intravitreal injection. Pain values as low as 2.77 ± 2.12 had been reported among Caucasians.[10] Subconjunctival analgesia has, however, been documented to provide greater pain reduction than topical analgesia.[24]

There was significant difference in the pain scores recorded with bevacizumab and ranibizumab during the injection with patients who had intravitreal bevacizumab recording higher mean pain scores. This difference is probably due to the larger needle caliber. Rodrigues et al.[25] reported that smaller needle types cause less pain following intravitreal injections, and Güler et al.[9] documented a significant difference in the pain scores after intravitreal bevacizumab and ranibizumab with the use of different needle sizes. However, Rifkin et al.[18] and Haas et al.[26] used 27- and 30-gauge needles for injection and reported that the caliber of the needle did not significantly affect the pain score.The presence of diabetes was related to having significantly higher mean pain scores than nondiabetics during intravitreal injection. “The exact reason for this is not known” is the perception of ocular pain heightened in this group of patients, or could the presence of other causes of ocular irritation in diabetics affect patients’ self-reported pain levels? Moisseiev et al.[14] reported no association between intravitreal injection pain scores and presence of DM in their own study. Mean pain scores reduced to near normal levels by 3 h after injection without the use of postoperative analgesia in these patients. Rifkin et al.[15] reported a much longer duration of intravitreal injection pains lasting for days with a range of 3 to 7 days reduced to 2.25 ± 1.22 days with the use of ketorolac eye drops.

The ranking of pain scores in patients who reported any pain was mainly mild in severity with few patients experiencing moderate pain. This is similar to previous reports stating that pain from intravitreal injections are largely mild in intensity.[18],[23] In fact, 12.2% of the patients studied reported no pain at all during the injection. The subjective nature of the VAS and individual differences in nature of pain recall are limitations in the methodology; however, as there is no quantitative technique to evaluate the amount of pain, the VAS was the best option.

  Conclusion Top

Pain during intravitreal anti-VEGF in black Africans is mild, and it resolves within 3 h of the injection without the use of analgesics. Patients who had intravitreal bevacizumab and diabetes reported higher pain scores during intravitreal injection. Females experience more severe pain than males during the injection. This reported trend of pain is useful in preinjection patient counseling and may play a role in improving patients’ compliance. Female patients and patients with DM should be adequately counseled preinjection and may require topical analgesic agent in the first hour postinjection.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Financial support and sponsorship

This study was funded by authors.

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]


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