Diabetic macular edema (DME) is a leading cause of vision impairment in patients with diabetes mellitus, characterized by fluid accumulation in the macula, leading to retinal thickening and blurred vision. Intravitreal injections (IVIs) of anti-vascular endothelial growth factor (VEGF) agents have become a cornerstone in the treatment of DME, offering significant improvements in visual acuity and retinal structure [1] 

However, despite the efficacy of these treatments, the procedure can be associated with discomfort, anxiety, and, in some cases, complications that may affect patient compliance and clinical outcomes. Anesthesia plays a pivotal role in mitigating these concerns. Local anesthetic techniques, such as topical, peribulbar, or retrobulbar anesthesia, are commonly employed to provide comfort and minimize pain during the injection [2]. The choice and effectiveness of anesthetic methods, however, can vary and may influence both the procedural success and patient outcomes. Despite the prevalence of IVI treatments, there remains limited research into how anesthesia optimization impacts the efficacy of the procedure itself, specifically in terms of patient comfort, procedural time, and long-term visual outcomes [3]. The global prevalence of diabetes is on the rise, leading to an increasing burden of diabetic retinopathy (DR), the leading cause of blindness in working-age adults worldwide. Among the complications of DR, diabetic macular edema (DME) represents a significant cause of vision loss. DME occurs when chronic hyperglycemia leads to endothelial dysfunction, resulting in vascular leakage, fluid accumulation, and thickening of the macula, which impairs the retina’s ability to function optimally [4]. Over the past decade, the introduction of intravitreal injections (IVIs) of anti-VEGF agents, such as ranibizumab, aflibercept, and bevacizumab, has revolutionized the treatment of DME, providing patients with improved visual outcomes and preserving retinal integrity. These treatments work by inhibiting the effects of VEGF, a potent mediator of vascular permeability and endothelial cell proliferation, which are key factors in the development and progression of DME. While the efficacy of anti-VEGF therapy in DME is well-established, the procedure itself is not without challenges. IVIs require precision, especially given the delicate nature of the retina and the potential risks associated with intravitreal injections, such as endophthalmitis, retinal detachment, or elevated intraocular pressure [5]. As a result, managing patient comfort and minimizing procedural risks are paramount. Despite these considerations, many patients experience anxiety, discomfort, and even pain during the injection procedure, which may impact their willingness to undergo regular treatments or lead to a suboptimal patient experience. Therefore, the role of anesthesia in ensuring a more comfortable and effective injection process cannot be overstated [6]. Currently, various anesthetic techniques are employed to reduce pain and discomfort during IVIs. These include topical anesthesia, where anesthetic eye drops are applied directly to the ocular surface, as well as more invasive approaches such as peribulbar or retrobulbar blocks, which involve the injection of local anesthetics around the eye to block pain signals at a deeper level. Topical anesthesia is the most commonly used method due to its simplicity, safety, and minimal invasiveness, though its efficacy may vary depending on the patient and the procedure [7]. On the other hand, peribulbar and retrobulbar blocks provide a more complete anesthetic effect, but they carry a higher risk of complications, including bleeding or globe perforation, and require more skill and experience from the practitioner. One of the primary concerns in the application of anesthesia during IVIs is balancing the need for patient comfort with the potential risks and complications associated with more invasive anesthetic techniques [8]. A key question is whether the choice of anesthesia affects not only the procedural experience but also the clinical outcomes, such as the visual and anatomical improvements following the injection. For instance, while local anesthesia may reduce discomfort, its potential to influence patient positioning or ocular movement during the injection could lead to variability in the placement of the needle or the effectiveness of the drug delivery [9].

Objective

To evaluate the impact of different anesthesia techniques on pain, visual acuity, central retinal thickness (CRT), intraocular pressure (IOP), and adverse events in patients receiving IVIs for DME.

This prospective observational study was conducted at-----------------------------during-----------------------------. Data were collected from 135 patients.

Inclusion criteria

1. Adults aged 18–80 years with a diagnosis of type 1 or type 2 diabetes mellitus and confirmed DME.
2. Best-corrected visual acuity (BCVA) of 20/400 or better at the time of screening.
3. Central retinal thickness (CRT) > 250 micrometers on optical coherence tomography (OCT).
4. No history of ocular surgery, except for cataract surgery, in the past 6 months.
5. No history of intraocular inflammation or active ocular infection.
6. Informed consent for participation in the study.

Exclusion criteria

1. Pregnancy or breastfeeding.
2. Known hypersensitivity to any of the drugs used in the IVI.
3. Severe systemic comorbidities that would interfere with the study (e.g., severe cardiac, renal, or liver disease).
4. Previous history of retinal laser photocoagulation or vitrectomy within 6 months of recruitment.

Data collection

Patients were randomly assigned to one of three groups using a computer-generated randomization schedule. The groups were as follows: Group 1 received topical anesthesia, where proparacaine 0.5% was applied to the ocular surface 5 minutes prior to the injection; Group 2 received a peribulbar block, where lidocaine 2% was injected into the periorbital space to block sensory nerves around the eye; and Group 3 received a retrobulbar block, where lidocaine 2% was injected behind the eye to provide deeper and more comprehensive anesthesia. This randomization ensured that the effects of anesthesia on both patient comfort and clinical outcomes were assessed under controlled conditions. At the baseline visit, a thorough assessment was conducted. This included gathering demographic information (age, sex, diabetes type, and comorbidities) and a review of the patient’s medical history. Ocular assessments included measuring visual acuity using the Snellen chart, CRT via OCT, and intraocular pressure (IOP). In addition, patients were asked to complete a visual analog scale (VAS) to measure their baseline pain and anxiety levels, providing an understanding of their initial discomfort and anxiety about the procedure. This pre-procedure data served as the foundation for comparing changes in patient comfort and clinical outcomes after the anesthesia was administered and the IVI performed. All intravitreal injections were performed in a standardized manner by an experienced retinal surgeon, ensuring consistency across patients. The procedure was carried out under aseptic conditions in an outpatient setting. Prior to the injection, the patient’s eye was cleansed with antiseptic solution (e.g., povidone-iodine) and covered with a sterile drape. Depending on the randomization, the appropriate anesthesia (topical, peribulbar, or retrobulbar block) was applied before the injection. After the anesthesia had taken effect, the intravitreal injection of the anti-VEGF agent was administered. The injection was done under sterile conditions, with the surgeon taking care to ensure that the drug was delivered precisely to the posterior segment of the eye. All participants were monitored for immediate post-procedure reactions, and any complications were recorded.

Statistical Analysis

The collected data were analyzed using SPSS v16. Descriptive statistics were used to summarize baseline characteristics such as age, sex, and comorbidities. A repeated measures analysis was employed to evaluate changes over time for the primary and secondary outcomes. Statistical significance was set at a p-value of less than 0.05

Data were collected from 135 patients. The mean age across all groups was 65.2 years (SD = 7.6), with a slightly higher proportion of male participants (50.4%). The majority of patients (85%) had type 2 diabetes, evenly distributed among the groups. Baseline visual acuity was similar across groups, with a mean Snellen score of 20/200 (SD = 60). Baseline central retinal thickness (CRT) was consistent at 440 ± 50 µm for all groups, ensuring comparable starting points for analysis.

Table 1: Demographic and Baseline Characteristics of Patients

Pain perception during the procedure varied significantly among the three anesthesia groups. Before the injection, mean VAS scores were highest in the topical anesthesia group (3.2 ± 1.4), followed by the peribulbar block (2.1 ± 1.0) and retrobulbar block (1.3 ± 0.8). Pain levels during the injection were substantially higher in the topical anesthesia group (7.8 ± 1.6) compared to the peribulbar block (4.5 ± 2.0) and retrobulbar block (2.2 ± 1.3). Immediately after the injection, pain decreased across all groups, with the topical anesthesia group reporting the highest residual discomfort (2.5 ± 1.3) and the retrobulbar block group reporting the lowest (0.8 ± 0.6).

Table 2: Pain and Discomfort (VAS Scores)

At baseline, all groups had a comparable mean visual acuity of 20/200 (SD = 60). At 1 month post-injection, the retrobulbar block group showed the greatest improvement to 20/80 (SD = 40), followed by the peribulbar block group at 20/100 (SD = 50) and the topical anesthesia group at 20/120 (SD = 60). These trends continued at 3 and 6 months, with the retrobulbar block group achieving the best outcomes, reaching 20/60 (SD = 40) at 6 months. The peribulbar and topical anesthesia groups showed more modest improvements, reaching 20/100 (SD = 50) and 20/120 (SD = 60), respectively, at 6 months.

Table 3: Visual Acuity (Snellen Score)

At baseline, all groups had comparable CRT values of 440 ± 50 µm. By 1 month post-injection, CRT reduced to 300 ± 40 µm in the retrobulbar block group, 320 ± 45 µm in the peribulbar block group, and 340 ± 50 µm in the topical anesthesia group. These reductions were maintained or slightly improved at 3 and 6 months, with the retrobulbar block group consistently achieving the lowest CRT values of 290 ± 35 µm. The peribulbar block group followed closely with a CRT of 310 ± 40 µm, while the topical anesthesia group showed the least reduction at 320 ± 45 µm.

Table 4: Central Retinal Thickness (CRT, µm)

Intraocular pressure (IOP) changes were minimal and transient across all anesthesia groups. Before the injection, mean IOP was consistent at 14 ± 2 mmHg for all groups. Immediately after the injection, a slight increase was observed, with IOP rising to 18 ± 3 mmHg in the topical anesthesia group, 17 ± 2 mmHg in the peribulbar block group, and 16 ± 2 mmHg in the retrobulbar block group. By 30 minutes post-injection, IOP had returned to baseline levels (14 ± 2 mmHg) in all groups.

Table 5: Intraocular Pressure (IOP, mmHg)

This prospective study aimed to evaluate the role of anesthesia in optimizing the outcomes of intravitreal injections (IVIs) for diabetic macular edema (DME). The findings of this study provide valuable insights into how different anesthesia techniques (topical, peribulbar, and retrobulbar blocks) affect both patient comfort and clinical outcomes, including visual acuity, central retinal thickness (CRT), and intraocular pressure (IOP). One of the primary objectives of this study was to assess the impact of anesthesia on patient-reported pain and discomfort during the intravitreal injection procedure [10]. The results revealed significant differences in the pain scores between the three groups, with the retrobulbar block providing the most effective pain relief. The retrobulbar block group reported the lowest pain levels before, during, and immediately after the injection, as evidenced by the mean VAS scores of 1.3, 2.2, and 0.8, respectively. This finding aligns with the known advantages of retrobulbar anesthesia, which offers a deeper, more comprehensive blockade of sensory nerves around the eye, resulting in greater patient comfort during the procedure [11]. The peribulbar block also provided adequate pain relief, though the mean VAS scores during the injection (4.5) were higher than those of the retrobulbar block group, suggesting that the peribulbar technique may not provide as complete anesthesia, particularly during the injection phase. However, the peribulbar block still performed better than topical anesthesia, which had the highest pain scores during the procedure (VAS = 7.8), indicating that superficial anesthesia was insufficient for managing the discomfort of the injection, especially in patients who may have a heightened sensitivity [12]. In addition to patient comfort, the study aimed to assess how anesthesia impacted clinical outcomes, particularly visual acuity and CRT, which are key indicators of the effectiveness of IVIs in treating DME. All three anesthesia groups showed improvement in visual acuity and reductions in CRT over the 6-month follow-up period, reflecting the efficacy of anti-VEGF therapy in managing DME [13].

The retrobulbar block group demonstrated the most significant improvements in both visual acuity and CRT. At 1 month, the retrobulbar block group had a mean visual acuity improvement to 20/80 (SD = 40), which was the highest among the groups. By 6 months, their visual acuity had improved further to 20/60 (SD = 40). Similarly, CRT decreased by 140 micrometers at 1 month, the most substantial reduction of the three groups [14]. This finding suggests that retrobulbar block anesthesia may facilitate better outcomes, possibly due to its comprehensive sensory blockade, which could lead to a more relaxed patient during the procedure, allowing for more precise drug administration. The peribulbar block group also showed significant improvements in visual acuity and CRT, though these were not as pronounced as in the retrobulbar block group. At 6 months, the mean visual acuity improved to 20/100 (SD = 50), and CRT decreased by 120 micrometers. The topical anesthesia group showed the least improvement in both visual acuity (20/120, SD = 60) and CRT (320 ± 45 µm), although their results were still statistically significant [15].

The differences in outcomes between the groups, particularly in visual acuity and CRT, suggest that while the primary goal of the study was to assess pain relief, the quality of anesthesia may also play a role in enhancing the precision and success of the injection procedure itself. A more comfortable and relaxed patient may contribute to better clinical outcomes, emphasizing the importance of selecting an optimal anesthesia method not just for pain management but also for achieving the best therapeutic effects. Intraocular pressure (IOP) was another parameter examined, as an increase in IOP after intravitreal injection is a known potential complication [16]. The results of this study indicated that there were no significant differences in the IOP changes between the anesthesia groups. Immediately after the injection, IOP increased slightly in all groups (mean IOP ranged from 16 to 18 mmHg), but these increases were transient and returned to baseline levels within 30 minutes. This is consistent with previous studies, which have shown that transient IOP elevation after intravitreal injection is common but typically resolves without clinical consequences [17]. Adverse events were rare across all groups. The most common complication was subconjunctival hemorrhage, observed in 10% of the topical anesthesia group, 5% of the peribulbar block group, and 3% of the retrobulbar block group. These rates are consistent with those reported in previous studies on intravitreal injections and are generally considered minor and self-limiting [18]. There were no cases of more severe complications such as endophthalmitis or retinal detachment in any group. The low incidence of adverse events further supports the safety of the different anesthesia techniques employed. While this study provides valuable insights, there are some limitations to consider. Firstly, the study was conducted at a single center, which may limit the generalizability of the findings to other settings or populations. Secondly, the study did not assess other potential factors that could influence treatment outcomes, such as the skill of the injector or the underlying severity of DME. 

It is concluded that retrobulbar block anesthesia provides the most favorable outcomes in terms of patient comfort and clinical results for intravitreal injections in diabetic macular edema (DME). This technique demonstrated the lowest levels of pain, with the most significant improvements in visual acuity and reductions in central retinal thickness (CRT) compared to peribulbar and topical anesthesia. The peribulbar block, while also effective, resulted in slightly higher pain scores and less substantial clinical improvements, particularly in visual acuity and CRT. Topical anesthesia, although commonly used, proved to be less effective in both pain management and therapeutic outcomes.

1. Ishibashi T, Li X, Koh A, et al. The REVEAL Study: ranibizumab monotherapy or combined with laser versus laser monotherapy in Asian patients with diabetic macular edema. Ophthalmology. 2015;122(7):1402–1415. doi:10.1016/j.ophtha.2015.02.006.
2. Brown DM, Schmidt-Erfurth U, Do DV. Intravitreal aflibercept for diabetic macular edema: 100-week results from the VISTA and VIVID Studies. Ophthalmology. 2015;122(10):2044–2052. doi:10.1016/j.ophtha.2015.06.017.
3. Menchini U, Bandello F, De Angelis V, et al. Ranibizumab for visual impairment due to diabetic macular edema: real-world evidence in the Italian population (PRIDE Study). J Ophthalmol. 2015;2015:10. doi:10.1155/2015/324841.
4. Nonomura S, Oshitari T, Arai M, et al. The effect of posterior sub-Tenon's capsule triamcinolone acetonide injection compared to pars plana vitrectomy for diabetic macular edema. Clin Ophthalmol. 2014;8:825–830. doi:10.2147/opth.s59849.
5. Oshitari T, Kitamura Y, Nonomura S, et al. Risk factors for refractory diabetic macular oedema after sub-Tenon’s capsule triamcinolone acetonide injection. J Ophthalmol. 2015;2015:4. doi:10.1155/2015/195737.
6. Oshitari T, Nonomura S, Arai M, et al. Effects of sub-Tenon’s capsule triamcinolone acetonide injection combined with microaneurysm photocoagulation on diabetic macular edema. Int Med Case Rep J. 2015;8:321–326. doi:10.2147/IMCRJ.S89970.
7. Diabetic Retinopathy Clinical Research Network. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema. N Engl J Med. 2015;372(13):1193–1203. doi:10.1056/NEJMoa1414264.
8. Wells JA, Glassman AR, Ayala AR. Aflibercept, bevacizumab, or ranibizumab for diabetic macular edema: two-year results from a comparative effectiveness randomized clinical trial. Ophthalmology. 2016;123(6):1351–1359. doi:10.1016/j.ophtha.2016.02.022.
9. Ross EL, Hutton DW, Stein JD, Bressler NM, Jampol LM, Glassman AR. Cost-effectiveness of aflibercept, bevacizumab, and ranibizumab for diabetic macular edema treatment: analysis from the diabetic retinopathy clinical research network comparative effectiveness trial. JAMA Ophthalmol. 2016;134(8):888–896. doi:10.1001/jamaophthalmol.2016.1669.
10. Yoshida S, Kubo Y, Kobayashi Y, et al. Increased vitreous concentrations of MCP-1 and IL-6 after vitrectomy in patients with proliferative diabetic retinopathy: possible association with postoperative macular oedema. Br J Ophthalmol. 2015;99(7):960–966. doi:10.1136/bjophthalmol-2014-306366.
11. Kim M, Kim Y, Lee SJ. Comparison of aqueous concentrations of angiogenic and inflammatory cytokines based on optical coherence tomography patterns of diabetic macular edema. Indian J Ophthalmol. 2015;63(4):312–317. doi:10.4103/0301-4738.158069.
12. Sohn HJ, Han DH, Kim IT. Changes in aqueous concentrations of various cytokines after intravitreal triamcinolone versus bevacizumab for diabetic macular edema. Am J Ophthalmol. 2011;152(4):686–694. doi:10.1016/j.ajo.2011.03.033.
13. Nauck M, Roth M, Tamm M, et al. Induction of vascular endothelial growth factor by platelet-activating factor and platelet-derived growth factor is downregulated by corticosteroids. Am J Respir Cell Mol Biol. 1997;16(4):398–406. doi:10.1165/ajrcmb.16.4.9115750.
14. Brooks HL Jr, Caballero S Jr, Newell CK, et al. Vitreous levels of vascular endothelial growth factor and stromal-derived factor 1 in patients with diabetic retinopathy and cystoid macular edema before and after intraocular injection of triamcinolone. Arch Ophthalmol. 2004;122(12):1801–1807. doi:10.1001/archopht.122.12.1801.
15. Mitchell P., Bandello F., Schmidt-Erfurth U., et al. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011;118(4):615–625. doi: 10.1016/j.ophtha.2011.01.031.
16. Yau J. W., Rogers S. L., Kawasaki R., et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care. 2012;35(3):556–564. doi: 10.2337/dc11-1909.