Quadrant-Specific Pain in Intravitreal Injection: A Systematic Review and Meta-analysis

Introduction: Patient-reported pain during intravitreal injection (IVI) may vary by injection quadrant and influence adherence to repeated treatments. Hence, this study aimed to quantify whether patient-reported pain differs by IVI quadrant and identify the least-painful approach. Methods: We searched 13 literature databases on 15 October 2025 for clinical studies reporting patient-reported IVI pain stratified by injection quadrant (superotemporal [ST], superonasal [SN], inferotemporal [IT], inferonasal [IN]). Random-effects meta-analyses synthesized mean differences (MD) in 0–10 visual analogue scale (VAS) pain across all six pairwise quadrant contrasts. All eligible studies were included for a qualitative review and a meta-analysis. The review was prospectively registered (PROSPERO CRD420251164189). Results: Seven studies comprising 2048 IVI were included (ST 611, SN 469, IT 556, IN 412). Most injections involved anti-VEGF agents. All injections were performed under topical anesthesia (100%; drops or gel), with no subconjunctival anesthesia reported (0%), and pain was recorded immediately post-procedure using VAS-derived scales. Across all six pairwise contrasts, pooled mean differences between quadrants were small (typically < 1 VAS unit on a 0–10 scale), and all 95% confidence intervals crossed zero. Across quadrant comparisons, pooled pain differences were small and inconsistent; none of the pairwise pooled estimates demonstrated a statistically consistent difference, and between-study heterogeneity was substantial to considerable (I² generally > 80%). Conclusions: Current evidence does not demonstrate a clearly less painful quadrant for intravitreal injections. Estimates varied across studies and heterogeneity was substantial, limiting confidence in any single average quadrant effect. Efforts to minimize IVI-related pain should prioritize optimized anesthesia protocols, communication, and injection technique, while future studies should standardize pain measurement and quadrant allocation to clarify whether subtle quadrant effects exist. Trial Registration: PROSPERO registration: CRD420251164189.