Abstract / Summary
We aim to evaluate the short-latency tear-secretory effects and symptom responses of infraorbital menthol emulsion in dry eye disease (DED) without intentional ocular-surface instillation. In this randomized, participant- and assessor-masked, vehicle-controlled trial, 128 adults with DED were assigned to bilateral infraorbital application of vehicle (0% menthol), 2% menthol, or 4% menthol emulsion four times daily for 3 weeks. Follow-up measurements were obtained 10 min after supervised application. The available analysis population comprised 95 participants (32, 32, and 31, respectively), and efficacy analyses used the right eye. The primary endpoint was baseline-to-week-3 change in the Schirmer I test without topical anesthesia. Baseline-adjusted mixed models for repeated measures estimated treatment contrasts with 95% confidence intervals (CIs) and Dunnett-adjusted P -values. Mean (standard deviation) week-3 Schirmer changes were 1.90 (7.41), 8.56 (7.95), and 8.72 (6.42) mm/5 min in the vehicle, 2%, and 4% groups, respectively. Adjusted differences versus vehicle were 6.69 mm/5 min for 2% menthol (95% CI 2.59–10.80; P < 0.001) and 6.43 mm/5 min for 4% menthol (95% CI 2.23–10.64; P = 0.002). Corresponding tear meniscus height differences were 0.08 mm (95% CI 0.04–0.13; P < 0.001) and 0.09 mm (95% CI 0.05–0.13; P < 0.001). Fluorescein tear break-up time did not meet the adjusted significance threshold. Exploratory dryness visual analog scale (VAS) scores also favored 2% and 4% menthol, with adjusted differences versus vehicle of −22.07 mm (95% CI −32.56 to −11.58) and −26.09 mm (95% CI −36.72 to −15.47), respectively, although subjective outcomes may have been influenced by functional unmasking. No serious adverse events occurred; one participant developed mild periocular erythema that resolved after treatment discontinuation. In the available analysis population, infraorbital 2% and 4% menthol produced clinically measurable short-latency increases in Schirmer values and tear meniscus height compared with vehicle, supporting further investigation of infraorbital stimulation of endogenous aqueous tear secretion without intentional ocular-surface instillation. The study does not establish persistence of benefit between applications, and confirmation is needed in trials with complete randomized-population follow-up and appropriately designed pre-dose assessments.