Determinants Of Postoperative Pain Following Corneal Cross-Linking: A Longitudinal Mixed-Effects Analysis

Postoperative pain remains one of the most common and challenging complications following corneal cross-linking despite various anesthesia and analgesia strategies. The aim of this study was to compare different analgesia protocols for postoperative pain control following corneal cross-linking and to evaluate temporal pain profiles as well as clinical and intraoperative factors associated with postoperative pain severity.

This retrospective comparative study was conducted at a tertiary referral ophthalmology center. Patients who underwent standard epithelium-off corneal cross-linking for keratoconus were included. Postoperative pain scores were recorded at predefined postoperative time points during the first 24 hours following surgery.

All patients received standard postoperative artificial tear and topical antibiotic therapy. Patients were divided into four groups according to analgesic protocol. Group 1 received NSAIDs at the 1st postoperative hour; Group 2 received subtenon lidocaine–bupivacaine at surgery completion followed by NSAIDs at the 3rd hour; Group 3 received intravenous tramadol-based analgesia at the 1st postoperative hour; and Group 4 received both subtenon anesthesia and intravenous tramadol at the 3rd hour. Intergroup comparisons were performed using one-way ANOVA. Longitudinal pain changes were analyzed using linear mixed-effects models, and hour-specific predictors were evaluated with multiple linear regression analysis.

Baseline demographic and clinical characteristics were comparable among groups (p>0.05). Postoperative pain scores decreased significantly over time in all groups (p<0.001). Patients receiving subtenon anesthesia showed lower pain scores in the early postoperative period compared with NSAID-only treatment. Linear mixed-effects analysis demonstrated significant effects of time, treatment group, and time–group interaction on postoperative pain (p<0.001). Intraoperative pain score was the only independent predictor of postoperative pain severity. Hour-specific regression analyses showed significant analgesic benefit of subtenon anesthesia during the first and second postoperative hours, which diminished by the fourth hour.

Subtenon anesthesia significantly reduces early postoperative pain following corneal cross-linking; however, this analgesic effect diminishes over time. Systemic tramadol provides additional pain control during later postoperative periods. Intraoperative pain perception was identified as the strongest predictor of postoperative pain severity. These findings suggest that combined perioperative analgesic strategies may provide more effective and sustained postoperative pain control after corneal cross-linking.