Triple combination therapy – strong recommendation
Five RCTs have examined the efficacy of TC agents. One 211 patient double-blind RCT found that 4% HQ, 0.05% tretinoin, and 0.01% fluocinolone acetonide (FA) (Zhejiang Rishengchang Pharmaceutical Co., Ltd, Zhejiang, China) was more effective than placebo at clearing melasma based on the decreased index of total target score.30 Another double-blind RCT of 32 patients found that daily 4% HQ, 0.05% tretinoin, and 0.05% dexamethasone had better investigator-rated outcomes than 4% HQ after 12 weeks.31 Erythema and scaling were more prevalent following TC therapy (87.5% vs 43.7%). An open-label RCT of 119 patients found that once daily TC cream of 4% HQ, 0.05% tretinoin, and 0.01% FA (Tri-Luma®, Galderma, Lausanne, Switzerland) more effectively cleared melasma compared with twice daily 4% HQ, with 35% of patients achieving complete clearance on
TC therapy compared with 5.1% in the HQ group.32 A 242 patient single-blind study evaluating the same treatment regimen similarly demonstrated reduced MASI score compared with 4% HQ.33 Patient photographs were consistent and showed improvement of melasma.33 In a single-blind 641 patient RCT, a TC hydrophilic cream containing 4% HQ, 0.05% tretinoin, and 0.01% FA more effectively cleared melasma compared with dual combination regimens of tretinoin plus HQ, tretinoin plus FA, or HQ plus FA.34 AEs of erythema, skin peeling, burning, and stinging sensation were mild and similar among all treatment arms.34 TC therapy was superior to 4% HQ with a similar AE profile and received a strong recommendation. TC therapies demonstrate the benefit of synergistic treatments in which HQ decreases melanogenesis, tretinoin increases keratinocyte turnover, and steroids reduce inflammation. Evidence from epidemiological studies and case reports has not revealed an increased risk of cancer but clinicians may consider limiting chronic exposure.9 If clinical goals have been achieved, a maintenance regimen of once or twice weekly TC therapy may minimize the risk for ochronosis.35,36 Relapse has been shown to occur in 50% of patients approximately 190 days following the establishment of a maintenance regimen compared with 58 days following abrupt cessation of therapy.35-37 For patients seeking a non-HQ therapeutic approach for the treatment of melasma due to HQ associated safety profile, we recommend against TC.
4-n-butylresorcinol – weak recommendation
Three double-blind, split-face RCTs compared the efficacy of 4-n-butylresorcinol 0.1% cream or 0.3% serum with vehicle.38-40 In all 3 studies, 4-n-butylresorcinol significantly reduced skin pigmentation compared with vehicle based on colorimetric measures and clinical pigmentation score. In one study, the depigmenting effects of 4-n-butylresorcinol 0.3% serum increased until week 8 and then plateaued.40 The other two studies only compared the efficacy until week 8. Adverse events were mild in all three studies. Photographs showed improvement following 4-n-butylresorcinol topical therapies.38-40 4-n-butylresorcinol decreased skin pigmentation and may be a useful as a short-term treatment for melasma, but the longterm efficacy beyond 12 weeks is unclear. In vitro studies have indicated that 4-n-butylresorcinol was the most potent inhibitor of tyrosinase compared with HQ, arbutin, and kojic acid.41 4-nbutylresorcinol received a weak recommendation, as additional studies are needed to compare the efficacy of 4-n-butylresorcinol to establish the duration of effect greater than 8 to 12 weeks, and comparison studies to 4% HQ may provide additional strength of data.
Benefits Closely Balanced With Risks and Burden
Glycolic acid – weak recommendation
Glycolic acid is believed to improve melasma by accelerating desquamation.42 Two RCTs examined the efficacy of combination 10% glycolic acid and 4% HQ for melasma.43,44 In a vehicle-controlled, double-blind RCT of 35 patients, twice daily application of a cream containing 10% buffered glycolic acid with 4% HQ, ascorbic acid, vitamin E, and sunscreen (Glyquin, ICN Pharmaceuticals, Costa Mesa, CA) was applied for 12 weeks.43 The combination 10% glycolic acid product significantly improved melasma compared with sunscreen-only control as determined by MASI and colorimetry.43 Another single-blind RCT compared daily 4% HQ alone with 4% HQ with 0.01% hyaluronic acid; 4% HQ with 10% glycolic acid; 4% HQ with 0.01% hyaluronic and 10% glycolic acid; or placebo.44 All 4 topical treatments improved melasma from baseline. The most significant decrease in melasma was measured following 4% HQ with 0.01% hyaluronic acid and 10% glycolic acid. Topical 4% HQ with supplemental glycolic acid was more irritating to skin than HQ alone. Post-treatment photographs showed localized skin brightening around the treatment site.
Glycolic acid is weakly recommended as a supplement to 4% HQ, as the benefits and risk of skin desquamation should be carefully considered for each patient. Additionally, the RCTs do not directly compare the efficacy of glycolic acid alone with HQ alone. Glycolic acid supplementation had greater efficacy and more severe AEs compared with 4% HQ alone. Skin desquamation from glycolic acid may be minimized if patients apply a moisturizing cream concurrently.9 Glycolic acid appears best suited as adjunct therapy for melasma and not a primary, firstline approach.
Kojic acid – weak recommendation
Kojic acid is a tyrosinase inhibitor produced by several fungi species. Two poorly designed RCTs examined the use of kojic acid for melasma. In an 80-patient single-blind RCT, 4 different formulations of 1% kojic acid alone or in combination with 2% HQ and/or 0.1% betamethasone were tested.45 All 4 treatment groups significantly reduced MASI score after daily treatment for 12 weeks.45 The authors did not statistically compare intertreatment efficacy but concluded that 1% kojic acid with 2% HQ
Five RCTs have examined the efficacy of TC agents. One 211 patient double-blind RCT found that 4% HQ, 0.05% tretinoin, and 0.01% fluocinolone acetonide (FA) (Zhejiang Rishengchang Pharmaceutical Co., Ltd, Zhejiang, China) was more effective than placebo at clearing melasma based on the decreased index of total target score.30 Another double-blind RCT of 32 patients found that daily 4% HQ, 0.05% tretinoin, and 0.05% dexamethasone had better investigator-rated outcomes than 4% HQ after 12 weeks.31 Erythema and scaling were more prevalent following TC therapy (87.5% vs 43.7%). An open-label RCT of 119 patients found that once daily TC cream of 4% HQ, 0.05% tretinoin, and 0.01% FA (Tri-Luma®, Galderma, Lausanne, Switzerland) more effectively cleared melasma compared with twice daily 4% HQ, with 35% of patients achieving complete clearance on
TC therapy compared with 5.1% in the HQ group.32 A 242 patient single-blind study evaluating the same treatment regimen similarly demonstrated reduced MASI score compared with 4% HQ.33 Patient photographs were consistent and showed improvement of melasma.33 In a single-blind 641 patient RCT, a TC hydrophilic cream containing 4% HQ, 0.05% tretinoin, and 0.01% FA more effectively cleared melasma compared with dual combination regimens of tretinoin plus HQ, tretinoin plus FA, or HQ plus FA.34 AEs of erythema, skin peeling, burning, and stinging sensation were mild and similar among all treatment arms.34 TC therapy was superior to 4% HQ with a similar AE profile and received a strong recommendation. TC therapies demonstrate the benefit of synergistic treatments in which HQ decreases melanogenesis, tretinoin increases keratinocyte turnover, and steroids reduce inflammation. Evidence from epidemiological studies and case reports has not revealed an increased risk of cancer but clinicians may consider limiting chronic exposure.9 If clinical goals have been achieved, a maintenance regimen of once or twice weekly TC therapy may minimize the risk for ochronosis.35,36 Relapse has been shown to occur in 50% of patients approximately 190 days following the establishment of a maintenance regimen compared with 58 days following abrupt cessation of therapy.35-37 For patients seeking a non-HQ therapeutic approach for the treatment of melasma due to HQ associated safety profile, we recommend against TC.
4-n-butylresorcinol – weak recommendation
Three double-blind, split-face RCTs compared the efficacy of 4-n-butylresorcinol 0.1% cream or 0.3% serum with vehicle.38-40 In all 3 studies, 4-n-butylresorcinol significantly reduced skin pigmentation compared with vehicle based on colorimetric measures and clinical pigmentation score. In one study, the depigmenting effects of 4-n-butylresorcinol 0.3% serum increased until week 8 and then plateaued.40 The other two studies only compared the efficacy until week 8. Adverse events were mild in all three studies. Photographs showed improvement following 4-n-butylresorcinol topical therapies.38-40 4-n-butylresorcinol decreased skin pigmentation and may be a useful as a short-term treatment for melasma, but the longterm efficacy beyond 12 weeks is unclear. In vitro studies have indicated that 4-n-butylresorcinol was the most potent inhibitor of tyrosinase compared with HQ, arbutin, and kojic acid.41 4-nbutylresorcinol received a weak recommendation, as additional studies are needed to compare the efficacy of 4-n-butylresorcinol to establish the duration of effect greater than 8 to 12 weeks, and comparison studies to 4% HQ may provide additional strength of data.
Benefits Closely Balanced With Risks and Burden
Glycolic acid – weak recommendation
Glycolic acid is believed to improve melasma by accelerating desquamation.42 Two RCTs examined the efficacy of combination 10% glycolic acid and 4% HQ for melasma.43,44 In a vehicle-controlled, double-blind RCT of 35 patients, twice daily application of a cream containing 10% buffered glycolic acid with 4% HQ, ascorbic acid, vitamin E, and sunscreen (Glyquin, ICN Pharmaceuticals, Costa Mesa, CA) was applied for 12 weeks.43 The combination 10% glycolic acid product significantly improved melasma compared with sunscreen-only control as determined by MASI and colorimetry.43 Another single-blind RCT compared daily 4% HQ alone with 4% HQ with 0.01% hyaluronic acid; 4% HQ with 10% glycolic acid; 4% HQ with 0.01% hyaluronic and 10% glycolic acid; or placebo.44 All 4 topical treatments improved melasma from baseline. The most significant decrease in melasma was measured following 4% HQ with 0.01% hyaluronic acid and 10% glycolic acid. Topical 4% HQ with supplemental glycolic acid was more irritating to skin than HQ alone. Post-treatment photographs showed localized skin brightening around the treatment site.
Glycolic acid is weakly recommended as a supplement to 4% HQ, as the benefits and risk of skin desquamation should be carefully considered for each patient. Additionally, the RCTs do not directly compare the efficacy of glycolic acid alone with HQ alone. Glycolic acid supplementation had greater efficacy and more severe AEs compared with 4% HQ alone. Skin desquamation from glycolic acid may be minimized if patients apply a moisturizing cream concurrently.9 Glycolic acid appears best suited as adjunct therapy for melasma and not a primary, firstline approach.
Kojic acid – weak recommendation
Kojic acid is a tyrosinase inhibitor produced by several fungi species. Two poorly designed RCTs examined the use of kojic acid for melasma. In an 80-patient single-blind RCT, 4 different formulations of 1% kojic acid alone or in combination with 2% HQ and/or 0.1% betamethasone were tested.45 All 4 treatment groups significantly reduced MASI score after daily treatment for 12 weeks.45 The authors did not statistically compare intertreatment efficacy but concluded that 1% kojic acid with 2% HQ
