Background
Melasma is an acquired symmetrical pigmentary disorder where confluent grey‐brown patches typically appear on the face. Available treatments for melasma are unsatisfactory.
Objectives
To assess interventions used in the management of all types of melasma: epidermal, dermal, and mixed.
Search methods
In May 2010 we searched the Cochrane Skin Group Specialised Register, the Cochrane Central Register of Controlled Trials (Clinical Trials) in The Cochrane Library, MEDLINE, EMBASE, PsycINFO, and LILACS. Reference lists of articles and ongoing trials registries were also searched.
Selection criteria
Randomised controlled trials that evaluated topical and systemic interventions for melasma.
Data collection and analysis
Study selection, assessment of methodological quality, data extraction, and analysis was carried out by two authors independently.
Main results
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.
Authors' conclusions
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.
Author(s)
Ratna Rajaratnam, James Halpern, Asad Salim, Charis Emmett
Plain language summary
Treatments for melasma (darker than normal skin occurring in patches)
Melasma is a psychologically distressing skin disorder also known as ‘chloasma’ or ‘mask of pregnancy’. Darker patches of skin gradually develop on the cheeks, forehead, nose, and upper lip. It is more common in women and is associated with pregnancy and medication containing hormones. Melasma is divided into three types: epidermal, dermal, and mixed melasma. Epidermal melasma is the most superficial with an increase in the skin pigment (melanin) in the top layer of skin (epidermis). In dermal melasma, there is increased skin pigment in the second deeper layer of the skin (the dermis). Mixed melasma is a combination of epidermal and dermal melasma.
Conventional treatments for melasma include sunscreens, bleaching creams (e.g. hydroquinone), acne creams (e.g. azelaic acid), topical retinoids (e.g. tretinoin), and facial peels where an acid solution is used to remove outer layers of the skin (e.g. glycolic acid peels). Some treatments incorporate a combination approach such as triple‐combination cream (hydroquinone, tretinoin, and steroid). There is inadequate information available at present to determine the best treatment for melasma.
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.
Author(s)
Ratna Rajaratnam, James Halpern, Asad Salim, Charis Emmett
Authors' conclusions
Implications for practice
The evidence from this review is insufficient to provide clear guidelines for practice. We found low‐quality RCT evidence for a number of different interventions producing varying degrees of skin lightening. All comparisons were evaluated in only one study each apart from the comparison of tretinoin versus placebo (two studies). Tretinoin was beneficial in both white and dark skin participants with a higher proportion of dermal melasma, though in the latter group, the effect was less marked. Triple‐combination cream may be more effective than hydroquinone alone or when compared to any of the individual constituents as a dual combination.
Our review also found limited evidence for other combination creams. Hydroquinone combined with a sunscreen, or hydroquinone combined with glycolic acid, vitamins, and sunscreen are more effective than a sunscreen alone. There is also limited evidence for the combination therapy of hydroquinone cream combined with intense pulsed light being more effective than hydroquinone cream alone.
Rucinol serum and a skin‐whitening complex, Thiospot, may also be useful. In four trials comparing vitamin C iontophoresis to distilled water iontophoresis, Gigawhite botanical extract to placebo, 4% hydroquinone to 5% ascorbic acid, and 20% azelaic acid to 2% hydroquinone, evidence of significant differences between the interventions was less clear. This was because by some of the outcome measures no differences were found whereas with other outcome measures significant differences were noted. In the study by Huh 2003 comparing vitamin C iontophoresis to distilled water iontophoresis, statistically significant results were found on the colorimeter analysis, but the participants in the study could not tell the difference between the sides treated. Similarly, in Francisco‐Diaz 2004, the physician‐assessed MASI for the Gigawhite‐treated side was not significantly different to placebo, but colorimeter analysis showed significantly lighter melasma on the side treated with Gigawhite. The clinical benefit of improvement on objective measures only without taking into account improvement noted subjectively by the participants or physicians is questionable.
For the other comparisons (six studies) the results for the interventions studied were not significantly different and maybe equally effective.
Implications for research
Melasma affects many people around the world, yet there is a paucity of well‐conducted RCTs. Most of the trials conducted were of poor methodological quality and short duration. Melasma is a chronic and relapsing disorder. We therefore recommend that trials should have an intervention period of at least 6 months and there should be long‐term follow up for at least 12 months following the intervention to assess the maintenance of response. Future trials should clearly define participants at baseline. Variation in participant features such as age, duration, or type of melasma are important considerations in assessing the differing response to the interventions and should be provided for each group. Well‐designed RCTs investigating the benefit of sunscreen are needed. If sunscreen is recommended as a co‐intervention there should be details on the SPF, frequency of application and ideally, the sunscreen should be provided along with the study products. In poorer countries, adequate application of a sunscreen may be costly and if not equal between the groups could lead to confounding.
Participant perception of the severity of disease and degree of improvement can be different to the clinical trial investigators, and participant‐assessed outcomes should be incorporated into the study design. There is also a need for trials to include quality of life measures in view of the considerable effect that melasma has on sufferers. The inclusion of the quality of life measures such as the Dermatology Quality of Life Index or the new melasma specific MELASQOL developed for women with melasma would improve relevance of trials and allow comparison between trials using different interventions. Trial investigators should avoid individual made‐up scores to assess response and instead use uniform outcome measures such as the subjective measures of MASI or the melasma severity scale as well as objective measures, e.g. reflectance spectroscopy or corneomelametry. Finally, trials should include a more systematic approach to adverse event reporting including grading of the severity of the adverse event by participants and it should be noted whether the adverse event is related to the study product.