Comparative Efficacy of Oral Tranexamic Acid, Intradermal Tranexamic Acid, and Fractional Er: YAG Laser Combined With Hydroquinone in Refractory Melasma: A Randomized Clinical Trial

Abstract

ABSTRACT Background Refractory melasma is difficult to treat because of its chronic relapsing behavior and complex pathophysiology. Combination treatment may improve outcomes over topical depigmenting treatment alone. Objective To compare the efficacy and safety of oral tranexamic acid (TXA), fractional Er:YAG laser, and intradermal TXA, each combined with topical 4% hydroquinone in patients with refractory melasma. Methods This randomized clinical trial included 45 patients with refractory melasma who were assigned equally to three treatment groups: oral TXA plus hydroquinone, fractional Er:YAG laser plus hydroquinone, or intradermal TXA plus hydroquinone. Clinical response was evaluated using the Melasma Area and Severity Index (MASI). All groups received background hydroquinone and photoprotection; therefore, the study compares adjunctive treatment strategies rather than isolating the independent effect of hydroquinone. Results All groups exhibited a significant improvement in the total MASI score after treatment. Oral TXA showed the greatest reduction from 23.61 +/− 1.9 to 9.30 +/− 1.6, followed by fractional Er:YAG laser from 18.91 +/− 2.1 to 11.56 +/− 1.9 and intradermal TXA from 20.41 +/− 1.7 to 13.48 +/− 2.3. Adverse events were mild and transient, and no thromboembolic events or treatment discontinuations occurred. The largest percentage improvement was achieved with oral TXA. Conclusion Oral TXA combined with hydroquinone produced the greatest short‐term MASI improvement in refractory melasma, while fractional Er:YAG laser and intradermal TXA remained useful alternatives. Because follow‐up was limited to 3 months, recurrence rates, durability of response, and long‐term safety require confirmation in longer studies. Trial Registration ClinicalTrials.gov registration number: NCT06522984