Efficacy and Safety of Topical Famotidine Combined With Thulium 1927 nm Fractional Laser in the Treatment of Melasma: A Split-Face Randomized, Single-Blind, Vehicle-Controlled Clinical Trial With Long-Term Follow-Up

Background: Melasma is a common hyperpigmentation skin disorder with a high recurrence rate. Mast cell activation plays a role in its pathogenesis, with melanocyte activation via histamine receptor 2 (H2R) considered a potential mechanism. This study aims to evaluate the efficacy of topical famotidine combined with 1927 nm thulium fractional laser in treating melasma and reducing recurrence. Methods: The study was designed as a split-face, randomized-controlled, single-blind trial. Participants underwent four full-face 1927 nm fractional laser treatments at 4-week intervals and applied 2% famotidine solution on a randomly assigned side and control solution on the opposite side of the face twice daily for 16 weeks. Skin assessments including VISIA imaging, modified melasma area severity index (mMASI) score, and DermaLab skin color detection were conducted by blinded dermatologists at Weeks 0, 4, 8, 12, and 16. Self-assessment scores and the melasma quality of life (MELASQoL) index were collected at baseline and Week 16. Long-term follow-up was performed at Week 64. All side effects were recorded. Statistical analyses included paired t-tests, repeated measures ANOVA, and Wilcoxon and Friedman tests. Results: A total of 16 patients were enrolled in the study. At Week 16, the famotidine-treated side showed significant reductions in mMASI (p = 0.019, (Formula presented.) = 0.598) and melanin index (MI) (p = 0.006, (Formula presented.) = 0.672), with a slight improvement in erythema index (EI). ∆MI was significantly lower on the famotidine-treated side than the control (p = 0.012, Cohen’s d = 0.710). Both MELASQoL scores and patient self-assessments improved, with no obvious adverse effects observed. Long-term evaluation at Week 64 revealed sustained improvement in mMASI on the famotidine-treated side compared to the control side (p = 0.029, Cohen’s d = 0.686). Conclusions: This study provides clinical evidence supporting H2R blockade as a potential melasma treatment. Famotidine may enhance laser efficacy and modulate histamine-mediated melanogenesis, offering long-term benefits in reducing recurrence. Trial Registration: ClinicalTrials.gov identifier: NCT06313307.