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Nadyr A Damasceno,1,2 Juliana Angélica Estevão Oliveira,2 Nicolas A Yannuzzi,3 Harry Flynn Jr,3 Mauricio Maia,2 Eduardo F Damasceno,4 Michel Eid Farah2 1HNMD, Hospital Naval Marcilio Dias, Department of Ophthalmology, Rio de Janeiro, RJ, Brazil; 2UNIFESP, Universidade Federal de São Paulo, Department of Ophthalmology, São Paulo, SP, Brazil; 3BPEI, Bascom Palmer Eye Institute, Department of Ophthalmology, Miami, FL, USA; 4UFF, School of Medicine, Universidade Federal Fluminense, Department of Ophthalmology, Niteroi, RJ, BrazilCorrespondence: Eduardo F Damasceno, School of Medicine, Universidade Federal Fluminense, Department of Ophthalmology, Marques Do Paraná 303, Niterói, RJ, 2550-030, Brazil, Email e_damasceno@yahoo.comPurpose: To assess ocular pain in patients undergoing multiple intravitreal injections of anti-vascular endothelial growth factor (anti-VEGF) who have previous factors that may influence pain sensitivity.Methodology: This is a prospective, observational, case series study involving patients who underwent multiple (≥ 3) pro re nata intravitreal injections of ranibizumab or aflibercept to treat any cause of chorioretinal vascular disease. Ocular pain was assessed by the numerical analog scale during intravitreal injection. For this study, the main variable was ocular pain and the secondary variables included age, sex, previous history of glaucoma, primary retinal vascular disease, severe dry eye history, trigeminal pain, scleral buckle surgery, collagen diseases, fibromyalgia, severe migraine history, pars plana vitrectomy, scleral thickness measurements, and type of anti-VEGF.Results: In a total of 894 patients, 948 eyes (4822 intravitreal injections), 793 patients (88.6%) had ocular pain sensitivity between no pain to mild pain, 80 patients (8.9%) had moderate ocular pain, 15 patients (1.6%) had severe ocular pain, and 6 patients (0.7%) had extremely severe ocular pain. Patients with severe dry eye (p = 0.01) and previous history of scleral buckle surgery (p = 0.01) showed a significant correlation with ocular pain during intravitreal injection. Pars plana scleral thickness (> 550 um) and diabetic neuropathy were associated with ocular pain but did not meet the criteria for statistical significance (p = 0.09 and p = 0.06, respectively).Conclusion: Dry eye and prior scleral buckle surgery may contribute to pain associated with intravitreal injection. These issues should be taken into consideration in patients undergoing multiple intravitreal injections.Keywords: Ocular pain, multiple intravitreal injections, anti-VEGF, special risk factors