had the best efficacy and 1% kojic acid with 0.1% betamethasone was the least effective. 1% kojic acid, 2% HQ, and 0.1% betamethasone was associated with acneiform eruptions. In another RCT, daily 0.75% kojic acid with 2.5% ascorbic acid for 12 weeks was inferior to 4% HQ.46 Photographs demonstrated minimal efficacy for kojic acid as a stand-alone treatment. Anecdotal clinical evidence suggests that compounding 12% HQ with 6% kojic acid may be an effective treatment not associated with diffuse skin brightening, but this formulation has not been studied in an RCT. Based upon the available published literature reviewed, kojic acid received a weak recommendation when combined with other agents, and evidence does not support recommendation as a stand-alone treatment for melasma.
Risks and Burden Outweigh Benefits
Parsley – weak recommendation
In a poorly designed double-blind RCT, patients applied parsley or 4% HQ daily for 8 weeks.47 The patients in the parsley group had to self-brew 2.5 g of parsley in 125 ml of water. Both treatments significantly improved MASI from baseline. AEs in the parsley and 4% HQ group included irritation, redness, and itching. As patients were required to self-prepare parsley extract to prevent treatment expiration, the use of parsley was weakly recommended. Additionally, differences in sample preparation may lead to variability in treatment results.
Zinc sulfate – strong recommendation
Zinc sulfate has been used to treat numerous skin conditions including acne vulgaris and warts. Two RCTs examined the use of once or twice daily 10% zinc sulfate for melasma.48,49 In both studies, topical application of 10% zinc sulfate reduced MASI score less effectively than 4% HQ. One study noted that patients treated with 4% HQ alone complained of greater skin irritation. However, 10% zinc sulfate resulted in PIH in 2 patients that resolved with topical tretinoin treatment.49 As zinc sulfate was inferior to 4% HQ and carried a risk of PIH, we strongly do not recommend zinc sulfate for the treatment of melasma.
Insufficient Evidence to Determine Net Benefit
Aloe vera – no strength of recommendation
One double-blind study compared the efficacy of 2 aloe vera formulations (0.5% gel extract or 0.25% liposome-encapsulated gel extract) in 180 pregnant patients with pre-existing melasma.50 After 5 weeks, liposome-encapsulated aloe vera significantly improved patient MASI compared with the standard gel formulation. As there was no placebo or HQ control group, it is difficult to determine the relative efficacy of aloe vera. However, the net risk of AEs is likely low as the treatment was used in pregnant patients. The study did not describe the frequency of aloe vera application.
Ascorbic acid – no strength of recommendation
In a 16 patient, split-face, double-blind RCT, patients were less satisfied with 5% L-ascorbic acid (La Roche-Posay, France) compared with 4% HQ after 16 weeks.51 Colorimetric analysis demonstrated no difference between treatment arms, and HQ was more irritating to the skin. Ascorbic acid is readily oxidized, which limits its use as a stand-alone treatment but may be combined with other topical agents.9
Dioic acid – no strength of recommendation
One open-label RCT of 96 patients compared twice daily 1% dioic acid with 2% HQ for 12 weeks. 1% dioic acid and 2% HQ improved MASI scores from baseline, but there was no significant difference between dioic acid and HQ.52 Patients treated with dioic acid had a higher incidence of acneiform reaction, which the authors attributed to an oily vehicle. An open-label design limited the strength of this study.
Ellagic acid and arbutin – no strength of recommendation
In an open-label RCT involving 29 patients, twice daily treatment with 1% synthetic ellagic acid, 1% arbutin, or plant extract with 1% natural ellagic acid significantly improved skin pigmentation after 6 months without the occurrence of AEs.53 Limitations in the study design included the lack of blinding and lack of a placebo-control. Thus, additional research is needed before conclusions can be drawn about ellagic acid and arbutin therapy for melasma.
Flutamide – no strength of recommendation
One double-blind study compared the efficacy of daily topical 1% flutamide, an anti-androgenic drug, with 4% HQ over 4 months.54 Both treatments reduced MASI compared with baseline. Flutamide was more effective than HQ according to MASI and patient satisfaction but there was no difference between treatments when assessed using colorimetric analysis. The AE profile was not provided, and the safety of hormonal therapy should be evaluated before a recommendation can be made.
Risks and Burden Outweigh Benefits
Parsley – weak recommendation
In a poorly designed double-blind RCT, patients applied parsley or 4% HQ daily for 8 weeks.47 The patients in the parsley group had to self-brew 2.5 g of parsley in 125 ml of water. Both treatments significantly improved MASI from baseline. AEs in the parsley and 4% HQ group included irritation, redness, and itching. As patients were required to self-prepare parsley extract to prevent treatment expiration, the use of parsley was weakly recommended. Additionally, differences in sample preparation may lead to variability in treatment results.
Zinc sulfate – strong recommendation
Zinc sulfate has been used to treat numerous skin conditions including acne vulgaris and warts. Two RCTs examined the use of once or twice daily 10% zinc sulfate for melasma.48,49 In both studies, topical application of 10% zinc sulfate reduced MASI score less effectively than 4% HQ. One study noted that patients treated with 4% HQ alone complained of greater skin irritation. However, 10% zinc sulfate resulted in PIH in 2 patients that resolved with topical tretinoin treatment.49 As zinc sulfate was inferior to 4% HQ and carried a risk of PIH, we strongly do not recommend zinc sulfate for the treatment of melasma.
Insufficient Evidence to Determine Net Benefit
Aloe vera – no strength of recommendation
One double-blind study compared the efficacy of 2 aloe vera formulations (0.5% gel extract or 0.25% liposome-encapsulated gel extract) in 180 pregnant patients with pre-existing melasma.50 After 5 weeks, liposome-encapsulated aloe vera significantly improved patient MASI compared with the standard gel formulation. As there was no placebo or HQ control group, it is difficult to determine the relative efficacy of aloe vera. However, the net risk of AEs is likely low as the treatment was used in pregnant patients. The study did not describe the frequency of aloe vera application.
Ascorbic acid – no strength of recommendation
In a 16 patient, split-face, double-blind RCT, patients were less satisfied with 5% L-ascorbic acid (La Roche-Posay, France) compared with 4% HQ after 16 weeks.51 Colorimetric analysis demonstrated no difference between treatment arms, and HQ was more irritating to the skin. Ascorbic acid is readily oxidized, which limits its use as a stand-alone treatment but may be combined with other topical agents.9
Dioic acid – no strength of recommendation
One open-label RCT of 96 patients compared twice daily 1% dioic acid with 2% HQ for 12 weeks. 1% dioic acid and 2% HQ improved MASI scores from baseline, but there was no significant difference between dioic acid and HQ.52 Patients treated with dioic acid had a higher incidence of acneiform reaction, which the authors attributed to an oily vehicle. An open-label design limited the strength of this study.
Ellagic acid and arbutin – no strength of recommendation
In an open-label RCT involving 29 patients, twice daily treatment with 1% synthetic ellagic acid, 1% arbutin, or plant extract with 1% natural ellagic acid significantly improved skin pigmentation after 6 months without the occurrence of AEs.53 Limitations in the study design included the lack of blinding and lack of a placebo-control. Thus, additional research is needed before conclusions can be drawn about ellagic acid and arbutin therapy for melasma.
Flutamide – no strength of recommendation
One double-blind study compared the efficacy of daily topical 1% flutamide, an anti-androgenic drug, with 4% HQ over 4 months.54 Both treatments reduced MASI compared with baseline. Flutamide was more effective than HQ according to MASI and patient satisfaction but there was no difference between treatments when assessed using colorimetric analysis. The AE profile was not provided, and the safety of hormonal therapy should be evaluated before a recommendation can be made.
LIMITATIONS
Currently, there is no universally effective treatment for melasma, and some established topical agents carry significant safety risks that may reduce patient compliance and satisfaction. Topical HQ, the basis for many combination therapies, may be less effective in patients with darker skin phenotypes and is associated with ochronosis.9,55 Other novel agents have shown promising results, but are limited by small sample sizes, poor study design, and limited high quality published RCTs. When evaluating naturally-derived or compounded topical therapies, it is essential to consider the reproducibility of the chemical composition. Differences in treatment concentration or secondary ingredients may have a significant impact on therapeutic efficacy. Additionally, several RCTs used natural agents published in non-English languages. These studies may have added to the literature, but we were unable to
