Abstract: We included 20 studies with a total of 2125 participants covering 23 different treatments. Statistical pooling of the data was not possible due to the heterogeneity of treatments. Each study involved a different set of interventions. They can be grouped into those including a bleaching agent such as hydroquinone, triple-combination creams (hydroquinone, tretinoin, and fluocinolone acetonide), and combination therapies (hydroquinone cream and glycolic acid peels), as well as less conventional therapies including rucinol, vitamin C iontophoresis, and skin-lightening complexes like Thiospot and Gigawhite. Triple-combination cream was significantly more effective at lightening melasma than hydroquinone alone (RR 1.58, 95% CI 1.26 to 1.97) or when compared to the dual combinations of tretinoin and hydroquinone (RR 2.75, 95% CI 1.59 to 4.74), tretinoin and fluocinolone acetonide (RR 14.00, 95% CI 4.43 to 44.25), or hydroquinone and fluocinolone acetonide (RR 10.50, 95% CI 3.85 to 28.60). Azelaic acid (20%) was significantly more effective than 2% hydroquinone (RR 1.25, 95% CI 1.06 to 1.48) at lightening melasma but not when compared to 4% hydroquinone (RR 1.11, 95% CI 0.94 to 1.32). In two studies where tretinoin was compared to placebo, participants rated their melasma as significantly improved in one (RR 13, 95% CI 1.88 to 89.74) but not the other. In both studies by other objective measures tretinoin treatment significantly reduced the severity of melasma. Thiospot was more effective than placebo (SMD -2.61, 95% CI -3.76 to -1.47). The adverse events most commonly reported were mild and transient such as skin irritation, itching, burning, and stinging. The quality of studies evaluating melasma treatments was generally poor and available treatments inadequate. High-quality randomised controlled trials on well-defined participants with long-term outcomes to determine the duration of response are needed.

Plain-language summary: We included 20 studies with a total of 2125 participants covering 23 different treatments. Triple-combination cream was significantly more effective at lightening melasma when compared to hydroquinone alone or to dual combinations such as tretinoin and hydroquinone, tretinoin and fluocinolone acetonide, or hydroquinone and fluocinolone acetonide. Tretinoin was more effective at lightening melasma compared to placebo, as was the skin-whitening complex Thiospot. However, many studies were of a poor quality with a only small number of participants. The side-effects reported most frequently by both participants and clinicians were dry, red, and sore skin. No serious side-effects were seen. More evidence is needed on other treatments which are widely used, including the role of sunscreens which were recommended in almost all studies. There is a need for high-quality studies comparing the treatments for this difficult to manage condition. For example, studies should have a minimum follow-up period of 6 months and should clearly categorise participant groups such as age, type of melasma, and duration of the condition at the start of the trial so that these differences can be considered when assessing results. Addtionally, study outcomes should include participants' views in a standardised manner because they may perceive the degree of skin lightening differently to the trial investigators.