there was an improvement in the melasma in 73.4% of patients on the EGF-treated side vs 13% on the placebo side. The average Melasma Quality of Life questionnaire score decreased from 42 to 33, with 73% of patients having an improvement in their score. No AEs were reported with use of either treatment.
While the authors concluded that topical EGF is a safe and effective treatment for melasma, additional RCTs with greater power and validated outcome measures are needed to evaluate the efficacy of topical EGF for melasma. Thus, topical EGF received a weak recommendation.
Hydroquinone (Liposomal) – weak recommendation
One double-blind RCT compared once daily treatment with 4% liposomal HQ (prepared by fusion method) to standard formulations of 4% HQ for 12 weeks, and demonstrated similar efficacy between the treatment regimens at week 4 following the end of the treatment course.18 AEs for liposomal HQ were not reported. As a result, any added benefit of liposomal vehicle is minimal.
Lignin peroxidase – weak recommendation
One split-face RCT compared the efficacy of twice daily lignin peroxidase (elure, Syneron Medical Ltd, Yokneam, Israel) in two cohorts of 30 patients over 12 weeks.19 In the first cohort, lignin peroxidase significantly improved MASI compared with no treatment. In the second cohort, there was no difference in MASI score between the lignin peroxidase and 4% HQ groups. Investigator grading indicated that lignin peroxidase resulted in improved skin texture. There were no AEs from either treatment. Lignin peroxidase improved patient melasma compared with no treatment.
Mulberry extract – weak recommendation
One single-blind RCT found that twice daily 75% mulberry extract oil for 8 weeks significantly improved patient MASI compared with placebo.20 Clinical photographs were consistent and showed decreased pigmentation following mulberry extract treatment. Patients treated with mulberry extract reported fewer AEs than the control group. Mulberry extract received a weak recommendation, as additional research is needed to establish the efficacy of mulberry extract for periods greater than 8 weeks and compared with HQ.
Niacinamide – weak recommendation
Niacinamide, also known as vitamin B3, may decrease skin pigmentation by preventing melanosome transfer.21 One double- blind, split-face RCT of 27 patients compared the efficacy of 4% niacinamide (Nicomide-T Cream 4%, DUSA Pharmaceuticals Inc, Wilmington, MA) with 4% HQ every 3 hours during the daytime for 8 weeks.22 Both treatments reduced MASI significantly at week 8 compared with baseline. Niacinamide was associated with fewer and milder AEs. Colorimetric measures did not show statistical differences between both sides. However, according to the IGA, good to excellent improvement was observed with niacinamide in 44% of patients compared with 55% with HQ. Niacinamide received a weak recommendation, but there is promising efficacy from a single study.
Rumex occidentalis (Western Dock) – weak recommendation
One double-blind RCT compared the efficacy of twice daily 3% Rumex occidentalis (a perennial herb), 4% HQ, and placebo for 8 weeks in 45 patients.23 The placebo had no significant effect, while the 3% Rumex occidentalis and 4% HQ significantly decreased MASI scores and colorimetric measures. Patients treated with Rumex occidentalis reported mild peeling. Clinical photographs demonstrated decreased pigmentation and diffuse skin brightening.23 Rumex occidentalis reduced patient melasma and may be worthy of future research.
Tranexamic acid – strong recommendation
Five RCTs examined the use of topical TXA for patients with melasma. In one study of 60 patients, twice daily treatment with 6.5% TXA (Pazana Laboratory Asia Co., Ltd, Bangkok, Thailand) significantly improved melasma compared with vehicle at week 8.24 Clinical photographs showed improvement following TXA treatment, but mild pre-treatment severity. However, in another double-blind, split-face RCT, 5% TXA performed no better than the vehicle.25 Both treatment and control reduced melasma, but there was no difference in efficacy as determined by MASI and colorimetry. In a 60 patient double-blind study, 5% TXA vs 2% HQ twice daily both significantly decreased MASI.26 5% TXA was associated with higher patient satisfaction and less skin irritation. 26 In another split-face, double-blind study, 5% liposomal TXA (prepared by fusion method) had similar efficacy in reducing patient MASI score compared with 4% HQ after twice daily treatment for 12 weeks.27 Skin irritation only occurred in the 4% HQ treated group.27 In a split-face, double-blind study of twice daily 3% TXA vs 3% HQ and 0.01% dexamethasone, both treatments significantly reduced MASI scores.28 Photographs showed decreased pigmentation. There was no difference in treatment efficacy between groups, but topical application of 3% HQ and 0.01% dexamethasone was associated with an increased incidence of AEs.28
TXA had similar efficacy to HQ with a milder AE profile and received a strong recommendation. The efficacy of TXA is dependent on concentration dose when used as monotherapy. TXA is a lysine analogue and carries a theoretical risk for thrombosis due to the anti-fibrinolytic effects. However, no evidence of increased clotting in low-risk patients was found in a recently published review of the safety and efficacy of oral TXA for melasma. 29 Topical TXA likely has decreased vasculature circulation compared with oral administration, but the theoretical risk of blood clots remains. Clinicians may consider topical TXA as an alternative to HQ in patients without predispositions to thrombotic events.
While the authors concluded that topical EGF is a safe and effective treatment for melasma, additional RCTs with greater power and validated outcome measures are needed to evaluate the efficacy of topical EGF for melasma. Thus, topical EGF received a weak recommendation.
Hydroquinone (Liposomal) – weak recommendation
One double-blind RCT compared once daily treatment with 4% liposomal HQ (prepared by fusion method) to standard formulations of 4% HQ for 12 weeks, and demonstrated similar efficacy between the treatment regimens at week 4 following the end of the treatment course.18 AEs for liposomal HQ were not reported. As a result, any added benefit of liposomal vehicle is minimal.
Lignin peroxidase – weak recommendation
One split-face RCT compared the efficacy of twice daily lignin peroxidase (elure, Syneron Medical Ltd, Yokneam, Israel) in two cohorts of 30 patients over 12 weeks.19 In the first cohort, lignin peroxidase significantly improved MASI compared with no treatment. In the second cohort, there was no difference in MASI score between the lignin peroxidase and 4% HQ groups. Investigator grading indicated that lignin peroxidase resulted in improved skin texture. There were no AEs from either treatment. Lignin peroxidase improved patient melasma compared with no treatment.
Mulberry extract – weak recommendation
One single-blind RCT found that twice daily 75% mulberry extract oil for 8 weeks significantly improved patient MASI compared with placebo.20 Clinical photographs were consistent and showed decreased pigmentation following mulberry extract treatment. Patients treated with mulberry extract reported fewer AEs than the control group. Mulberry extract received a weak recommendation, as additional research is needed to establish the efficacy of mulberry extract for periods greater than 8 weeks and compared with HQ.
Niacinamide – weak recommendation
Niacinamide, also known as vitamin B3, may decrease skin pigmentation by preventing melanosome transfer.21 One double- blind, split-face RCT of 27 patients compared the efficacy of 4% niacinamide (Nicomide-T Cream 4%, DUSA Pharmaceuticals Inc, Wilmington, MA) with 4% HQ every 3 hours during the daytime for 8 weeks.22 Both treatments reduced MASI significantly at week 8 compared with baseline. Niacinamide was associated with fewer and milder AEs. Colorimetric measures did not show statistical differences between both sides. However, according to the IGA, good to excellent improvement was observed with niacinamide in 44% of patients compared with 55% with HQ. Niacinamide received a weak recommendation, but there is promising efficacy from a single study.
Rumex occidentalis (Western Dock) – weak recommendation
One double-blind RCT compared the efficacy of twice daily 3% Rumex occidentalis (a perennial herb), 4% HQ, and placebo for 8 weeks in 45 patients.23 The placebo had no significant effect, while the 3% Rumex occidentalis and 4% HQ significantly decreased MASI scores and colorimetric measures. Patients treated with Rumex occidentalis reported mild peeling. Clinical photographs demonstrated decreased pigmentation and diffuse skin brightening.23 Rumex occidentalis reduced patient melasma and may be worthy of future research.
Tranexamic acid – strong recommendation
Five RCTs examined the use of topical TXA for patients with melasma. In one study of 60 patients, twice daily treatment with 6.5% TXA (Pazana Laboratory Asia Co., Ltd, Bangkok, Thailand) significantly improved melasma compared with vehicle at week 8.24 Clinical photographs showed improvement following TXA treatment, but mild pre-treatment severity. However, in another double-blind, split-face RCT, 5% TXA performed no better than the vehicle.25 Both treatment and control reduced melasma, but there was no difference in efficacy as determined by MASI and colorimetry. In a 60 patient double-blind study, 5% TXA vs 2% HQ twice daily both significantly decreased MASI.26 5% TXA was associated with higher patient satisfaction and less skin irritation. 26 In another split-face, double-blind study, 5% liposomal TXA (prepared by fusion method) had similar efficacy in reducing patient MASI score compared with 4% HQ after twice daily treatment for 12 weeks.27 Skin irritation only occurred in the 4% HQ treated group.27 In a split-face, double-blind study of twice daily 3% TXA vs 3% HQ and 0.01% dexamethasone, both treatments significantly reduced MASI scores.28 Photographs showed decreased pigmentation. There was no difference in treatment efficacy between groups, but topical application of 3% HQ and 0.01% dexamethasone was associated with an increased incidence of AEs.28
TXA had similar efficacy to HQ with a milder AE profile and received a strong recommendation. The efficacy of TXA is dependent on concentration dose when used as monotherapy. TXA is a lysine analogue and carries a theoretical risk for thrombosis due to the anti-fibrinolytic effects. However, no evidence of increased clotting in low-risk patients was found in a recently published review of the safety and efficacy of oral TXA for melasma. 29 Topical TXA likely has decreased vasculature circulation compared with oral administration, but the theoretical risk of blood clots remains. Clinicians may consider topical TXA as an alternative to HQ in patients without predispositions to thrombotic events.
