Topical Treatments for Melasma: A Systematic Review of Randomized Controlled Trials

November 2019 | Volume 18 | Issue 11 | Original Article | 1156 | Copyright © November 2019

Evan Austin BS,ª Julie K. Nguyen MD,a,b Jared Jagdeo MD MSa,b

ªDepartment of Dermatology, State University of New York, Downstate Medical Center, Brooklyn, NY 

BDermatology Service, VA New York Harbor Healthcare System Brooklyn Campus, Brooklyn, NY


Herein, we provided evidence-based recommendations on the safety and efficacy of topical medications for melasma (Table 2). The topical agents are presented below in alphabetical order in categories according to their risk and benefit to patients with melasma. According to ACP guidelines, a strong recommendation may apply to most patients without reservations, whereas a weak recommendation differs according to an individual patient’s circumstances. As only RCTs were reviewed, all recommendations were supported by moderate-quality (ie, one or more poorly designed RCT) or high quality of evidence (ie, one or more well designed RCT).

Multiple RCTs used 4% topical HQ as an active ingredient in combination therapies or comparison arms, but most of the literature on 4% HQ as a therapeutic modality was published before 2003. Cysteamine, TC, and TXA received the strongest recommendation of benefit. These medications had greater efficacy and/or milder AE profiles compared with topical HQ. A full description of topical treatments is provided below, and the mechanisms of action are provided in Table 3.

Benefits Outweigh Risks and Burden
Azelaic acid – weak recommendation
Two poorly designed RCTs examined the efficacy of azelaic acid. In an open-label study, 29 patients received twice daily 20% azelaic acid or 4% HQ for 8 weeks. 20% azelaic acid was more effective than 4% HQ according to the Melasma Area and Severity Index (MASI) score, but there is a significant bias in this study due to the open-label design.11 The clinical photographs
demonstrated good clinical responses for both treatment arms.

In another open-label RCT, patients received azelaic acid of various concentrations (5%, 10% and 20%) with 3 different supplemental formulations.12 All 3 azelaic acid formulations improved colorimetric scores after 6 months of twice daily application. The most effective formulation contained 20% azelaic acid with 10% mandelic acid, 5% phytic acid, 5% 4-n-butyl resorcinol, and 2% ferulic acid (Sesderma, Valencia, Spain). No AE profile was provided. Azelaic acid received a weak recommendation due to the poor study design of the included articles. Both studies had an open-label study design and one study compared combination formulations without comparing individual ingredients. The 2 identified studies use different concentrations of azelaic acid (range 5% to 20%), which also confounds results.

Cysteamine – strong recommendation
Cysteamine is approved by the U.S. Food and Drug Administration for the treatment of cystinosis and has been shown to inhibit melanogenesis at high concentrations.13,14 In 2 well-designed double-blind RCTs, 50 and 40 patients with melasma were treated with 5% cysteamine (Cysteamine®, Scientis Pharma SA, Geneva, Switzerland) or placebo daily for 4 months.13,14 In both studies, cysteamine significantly reduced MASI scores compared with placebo. In the second study, significant colorimetric differences were found favoring topical cysteamine compared with the placebo at 2 months and 4 months, and the Investigator’s Global Assessment (IGA) and patient feedback indicated positive efficacy of cysteamine. Patients reported erythema, dryness, itching, burning sensation, and irritation following cysteamine therapy. Side effects were associated with prolonged exposure to the topical agent, and removing the cysteamine by washing may decrease these side effects in patients. Clinical photos demonstrated diffuse skin brightening. Cysteamine has not been directly compared with 4% HQ.

Cysteamine is reported to have anti-cancer and anti-melanoma effects, which may be beneficial compared with HQ.15,16 Cysteamine may lead to diffuse skin brightening, and some patients report an unpleasant odor from cysteamine. Cysteamine is widely used in Europe, but is not commercially available in the United States. As a stand-alone agent, cysteamine received a strong recommendation as it has a beneficial efficacy and safety profile.

Epidermal growth factor – weak recommendation
The topical application of EGF has been evaluated for the promotion of wound healing and prevention of post-inflammatory hyperpigmentation (PIH) after laser resurfacing of facial skin.17 In one double-blind, split-face RCT, 50 patients were treated with topical EGF serum (DNARenewal, Beverly Hills, CA) vs placebo on each designated side of the face, twice daily for 8 weeks.17 According to the Physician Global Aesthetic Improvement Scale,