Topical and Systemic Therapies in Melasma: A Systematic Review

Abstract

Introduction:

Melasma is an acquired disorder, which presents with well-demarcated, brown-colored hyperpigmented macules, commonly involving the sun-exposed areas such as the face. It is a chronic and distressing condition, affecting the patients' quality of life, and has been conventionally treated with “first-line” agents including hydroquinone (HQ) alone or as a part of a triple combination cream (TCC), while “second-line” options include chemical peels, and third line options include laser therapy.

Materials and Methods:

A systematic search was performed for all topical and systemic treatments for melasma up till May 4, 2021, using the PubMed and EMBASE databases, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol. The search terms “melasma” and “treatment” were used to search for the relevant articles on both these databases, and a total of 4020 articles were identified. After removing the duplicate entries and screening the titles, abstracts, and full-text articles, we identified 174 randomized controlled trials (RCTs) or controlled clinical trials.

Results:

Based on our review, HQ, TCCs, sunscreens, kojic acid (KA), and azelaic acid receive grade A recommendation. Further large-scale studies are required to clearly establish the efficacy of topical vitamin C, resorcinol, and topical tranexamic acid (TXA). Several newer topical agents may play a role only as an add-on or second-line drugs or as maintenance therapy. Oral TXA has a strong recommendation, provided there are no contraindications. Procyanidins, Polypodium leucotomos (PL), and even synbiotics may be taken as adjuncts.

Discussion:

Several newer topical and systemic agents with multimodal mechanisms of action have now become available, and the balance seems to be tipping in favor of these innovative modalities. However, it is worth mentioning that the choice of agent should be individualized and subject to availability in a particular country.

Introduction

Melasma is an acquired disorder which presents with symmetrical hyperpigmentation, commonly involving the face. Conventionally, melasma has been treated with first-line agents including hydroquinone (HQ) alone or as part of a triple combination cream (TCC), while second-line options include oral drugs and chemical peels, and third-line options include laser therapy.[1,2,3] Several newer topical and systemic agents with multimodal mechanisms of action have now become available, and the balance seems to be tipping in favor of these innovative modalities.[4]

We performed this review in an attempt to study the safety and efficacy profile of the presently available topical and systemic therapeutic agents for melasma and provide clinical recommendations based on the current evidence to guide the treatment protocol for melasma.

Materials and Methods

We performed a systematic search for topical and systemic treatments for melasma on May 4, 2021, using the PubMed and EMBASE databases, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol. The search terms “melasma” and “treatment” were used to search both these databases [Figure 1]. We included studies with a sample size of ten or more, had a controlled arm, and had utilized clinically measurable parameters (melasma area severity index (MASI), modified MASI, Patient Global Assessment (PGA), erythema index (EI), and melanin index (MI)) for evaluation of the response. Only articles published within the last 20 years (since May 4, 2001) were included in the study.

Figure 1.

We performed a systematic search for novel and currently used topical and systemic treatments for melasma on May 4, 2021, using the PubMed and EMBASE databases, according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) protocol. The search terms “melasma” and “treatment” were used to search for the relevant articles on both these databases

In phase 1, two reviewers independently read the titles and abstracts of all identified electronic database citations. Any studies that did not fulfill the inclusion criteria were discarded. In phase 2, the same selection criteria were applied to the full articles to confirm their eligibility. Seven reviewers participated independently in phase 2, and any disagreements were resolved by consensus. If it was not possible to reach consensus, the coordinator made the final decision and the final selection was based on the full text of the publication and subsequent assessment.

The references and bibliographies of the included studies and literature reviews were checked to confirm that all relevant articles were included in the systematic search. Grading of recommendation was carried out as per Oxford Centre for Evidence-Based Medicine (OCEBM)–level of evidence (LOE) (March 2009).

Results

We identified a total of 4020 articles from the PubMed and EMBASE databases, using the search terms mentioned above. After removing the duplicate entries and screening the titles, abstracts, and full-text articles, we identified 174 randomized controlled trials (RCTs) or controlled clinical trials.

A wide variation in patient inclusion was observed in the studies evaluated, in terms of severity of melasma, type of melasma, skin phototypes, duration of follow-up, and recurrence rates. Furthermore, heterogeneity was noted regarding the analysis of therapeutic outcomes according to phototype, melasma subtype, or the usage of previous melasma treatments. Outcome measures utilized by various studies included different scoring systems: MASI, mMASI, PGA, MI, and EI. A summary of the study design, treatment groups, primary and secondary outcomes, results, and side effects of the topical and systemic agents has been outlined in supplementary Tables 1 ^{(614.3KB, pdf)} and 2 ^{(249.3KB, pdf)} , respectively.

Discussion

Sunscreen

A broad-spectrum sunscreen with a sun protection factor (SPF) of at least 30, which covers ultraviolet A (UVA) (minimum protection grade of UVA [PA]+++), UVB, and visible light (VL)—strength of recommendation A, LOE 1.

In multiple trials, sunscreens have been found to be a promising modality of therapy in melasma. It should be remembered that UV and VL both should be targeted to provide wholesome protection. In a double-blind randomized trial, UV-VL sunscreen was found to enhance the depigmenting efficacy of HQ compared with UV-only sunscreen in the treatment of melasma. Developing more effective filters against the wavelengths of VL could provide even better protection in the future.[5,6]

Triple combination

Triple combination of 4% HQ + 0.05% retinoic acid + 0.01% fluocinolone acetonide cream—strength of recommendation A, LOE 1.

Triple combination creams (TCC) remain the gold standard therapy for melasma and is more effective than dual combination therapy and HQ or kojic acid (KA) alone.[7,8,9,10,11,12,13,14,15,16] Improvement in pigmentation reaches a nadir at around 6 weeks, necessitating the need for an effective maintenance therapy.[8] A twice-weekly maintenance regimen has been found to be comparable or more effective in postponing relapse in severe melasma as compared to the tapering regimen.[9,10]

The long-term use of TCC as maintenance therapy is not recommended (strength of recommendation D), and if used as maintenance therapy, it is given twice weekly, very carefully up to 6 months to 1 year (strength of recommendation A) beyond which there is a risk of atrophy, telangiectasias, and other cutaneous side effects with daily usage.

Topical corticosteroids as monotherapy for melasma are usually not preferred for their atrophogenic potential and other adverse effects, although fluticasone is less atrophogenic than others.

Multiple RCTs have been conducted comparing TCCs with placebo, monotherapy with HQ, formulations consisting of 4% HQ and 0.02% triamcinolone acetonide in hydrophilic cream, tretinoin plus HQ (RA + HQ), tretinoin plus fluocinolone acetonide (RA + FA), and HQ plus fluocinolone acetonide (HQ + FA), and the combination containing 2% KA plus octinoxate and allantoin. Treatment with TCC is found to be superior to the rest.[11,12,13,14,15,16]

TCC in combination with chemical peels yields better results than either therapy alone.[17,18,19,20]

TCC is found to be comparable in efficacy to intralesional tranexamic acid (TXA) and intralesional triamcinolone acetonide[21,22,23] TCC in combination with laser therapy yields better results than either therapy alone.[24,25,26,27,28,29,30,31,32]

HQ cream

HQ 4% cream—strength of recommendation B, LOE 1.

Multiple RCTs have been conducted, comparing HQ creams (of different percentages) with several topical agents, and variable results have been reported.[33,34,35,36,37,38,39,40,41,42,43,44] HQ is one of the most effective therapies for melasma, when compared with other agents. However, TCCs and 3% Rumex occidentalis (RO) cream score higher when a head-to-head comparison is performed.[12,13,14,34]

It is worth mentioning that liposomal HQ cream was not found to be better than the conventional HQ cream, in terms of effectiveness in an Iranian RCT published in 2019.[41]

An Asian study evaluated the role of Q-switched Nd: YAG laser as an add-on therapy, apart from HQ 2% cream, and the combination group was found to show significantly better results. Another trial reported that patients receiving Er: YAG (erbium: yttrium–aluminum–garnet) laser plus HQ 4% cream showed a higher reduction in MASI score, in comparison with the group who received HQ 4% cream alone. A French study reported that 90% of the subjects who received the combination products (vs 79% in HQ-only group) had better results.[45]

The results of other comparative trials of HQ with miscellaneous molecules have been detailed in the supplementary file 1.[46,47,48,49,50,51,52,53,54,55,56,57,58,59]

KA

KA 2% cream—strength of recommendation A, LOE 2.

KA is one of the nonsteroidal and non-HQ alternatives for the treatment of melasma. KA 0.75% cream was inferior to HQ 4% cream and KA 2% cream was inferior to modified Kligman's formula (MKF), and the combination of KA 1% cream and HQ 2% cream was superior to either formulation.[16,60,61] Combination of 4% KA with 5% methimazole did not yield better results.[62] Therefore, the clinical improvement in melasma patients is more with MKF and topical HQ 4% compared with KA, and the combination of KA and HQ provides superior improvement compared to KA alone.

Azelaic acid

Azelaic acid 20% cream—strength of recommendation A, LOE 1.

The available evidence suggests that azelaic acid is a good depigmenting agent in melasma as a stand-alone therapy. Its efficacy is comparable to HQ 4% and TXA 10%. However, its efficacy is improved when used in combination with a Q-switched Nd: YAG laser and sequential glycolic acid peels.[58,63,64,65,66,67,68,69]

A recent study by Akl et al. has demonstrated the superior efficacy of liposomal 20% azelaic acid cream, compared with HQ 4% cream, when used as an adjuvant along with oral TXA to treat melasma.[57] Another interesting pilot study has demonstrated the effectiveness and safety of a novel combination containing tazarotene 0.075%, azelaic acid 20%, tacrolimus 0.1%, and (microfine) zinc oxide 10% in treating moderate-to-severe melasma (once daily application for 20 weeks).[70]

Arbutin

Arbutin cream—strength of recommendation D, LOE 2.

In a double-blind RCT, Morag et al. compared 2.51% arbutin with a placebo in 50 melasma patients of Polish origin. Clinical improvement was observed in 22 melasma patients, representing 75.86% of the study group.[71] Another randomized, open-label study compared the skin lightening effect of arbutin 1% gel, ellagic acid 1% gel, and ellagic acid plus plant extracts (1% gel) in mixed melasma, twice daily application for 6 months. They found arbutin gel to be more effective, which reduced the MI to 71% of baseline, compared with 79% and 76% with ellagic acid and ellagic acid–plant extract combinations, respectively. The only limitation of this study was the absence of a control group.[72] Additionally, several studies have highlighted the skin- depigmenting property of arbutin, when used in combination with other similar topical products such as nicotinamide, bisabolol, retinaldehyde, vitamin C, and TXA.[73] Besides, 7% arbutin cream has also demonstrated efficacy when used in combination with a Q-switched Nd-YAG laser to reduce the severity of melasma.[74]

Retinoids

Tretinoin 0.05% or 0.025% cream—strength of recommendation B, LOE 1.

As per the literature review, topical retinoids are better than placebo in a reduction in MASI score in melasma patients. Topical adapalene is better tolerated than topical retinoic acid. There is no advantage of combining microneedling (MN) with topical retinoids to treat melasma. HQ is a better priming agent for trichloroacetic acid (TCA) peel compared with topical tretinoin.[75,76,77,78]

Vitamin C

Insufficient evidence to recommend it as monotherapy or as adjuvant therapy.

Vitamin C is one of the novel therapeutic options for the management of melasma. Iontophoresis with vitamin C has been found to be superior to mineral water iontophoresis.[79] Besides, a combination of 1064 nm Q-switched Nd: YAG laser toning along with topical vitamin C, TXA, and glutathione has been shown to deliver better results when compared to laser toning alone.[80] In another study by Menon et al. which compared MN with TXA and MN with 20% vitamin C solution on either side of the face, improvement in MASI was mild with vitamin C and moderate with TXA.[81] Currently, there is insufficient evidence to recommend it as monotherapy or as adjuvant therapy.

Cysteamine (CA)

5% CA cream—strength of recommendation B, LOE 2.

5% CA cream has been compared with placebo cream applied daily, in two well-designed double-blind RCTs, among 50 and 40 patients of melasma over 4 months with a significant reduction in MASI scores reported in both the studies as compared with placebo.[82,83] CA cream has also been compared with 4% HQ cream, placebo cream, MKF, and TXA mesotherapy. It is inferior to HQ, but superior to a placebo preparation.[82,83,84,85] In a double-blind RCT, Karrabi et al. compared CA cream with MKF, and CA treatment was able to decrease the mMASI score to a greater degree.[80] Reduction in MASI was also found comparable to TXA mesotherapy with less complications observed with the CA group.[86] CA cream with a good efficacy and safety profile may be considered an alternative treatment option for melasma.

Resorcinol

0.1% liposome-encapsulated rucinol and 0.3% rucinol cream—LOE 2.

Resorcinol 0.3% serum is superior to vehicle, as concluded in a double-blind, randomized, vehicle-controlled split-face comparative trial (LOE 2).[87] In another double-blind split-face RCT, 4-n-butylresorcinol (4-n-BLR) 0.1% cream was better than vehicle.[88] Similar results have been documented when a preparation of liposome-encapsulated 4-n-BLR 0.1% cream was compared with vehicle.[89]

Tranexamic acid

Efficacious alternative to HQ products, with comparable results. LOE 2

TXA has been widely studied, in the management of melasma. Formulations such as 6.5% TXA and 5% TXA have been found to be superior to vehicle alone and comparable in efficacy to HQ.[90] TXA 5% cream has been found to deliver better results than HQ cream (both 2% and 4%).[91,92,93] However, in a split-face double-blind study, 5% liposomal TXA had similar efficacy in reducing patient score compared with 4% HQ.[88] TXA has also been compared with other agents besides HQ.[94,95,96] In a split-face double-blind study of twice daily 3% TXA vs 3% HQ and 0.01% dexamethasone, both treatments significantly reduced pigmentation.[94] In an interventional comparative study, a combination of oral and topical 3% TXA showed significantly better results than oral TXA with 20% azelaic acid for the treatment of melasma.[97] TXA can also be given as microinjections (MI) and with MN. In an open-label comparative study, 4 mg/ml TA with MN monthly showed more improvement in MASI score in comparison with 4 mg/ml TA MI monthly at end of 3-month follow-up.[98] Several other studies have compared TA MI with conventional melasma treatments with variable efficacy with injection-related side effects being a limiting factor.[99,100,101,102,103] MN with TXA has not shown promising results in most of the studies.[104,105,106,107,108] A combination of TXA with lasers has shown better results than lasers alone in treating melasma. No serious adverse events were reported.[109,110,111,112,113] Current evidence suggests that 5% TXA may be an efficacious alternative to HQ products, with comparable results, in patients without predispositions to thrombotic events.

Miscellaneous topical agents

Insufficient evidence to recommend it as monotherapy. May be used in combination therapy or as maintenance agent.

A variety of miscellaneous topical agents have been used either singly, or in conjunction with other established topical therapeutic options such as sunscreen, 4% HQ cream, and 20% TCA peel. Among the newer agents, 3% RO cream, undecylenoyl phenylalanine (UP) 2% cream, 30% metformin lotion, cream containing 0.05% tomato lycopene, and 3.45% wheat bran extract, 2% lincomycin +2% linoleic acid, 5% topical magnesium ascorbyl phosphate cream, 5% lignin peroxidase, Petroselinum crispum solution, 4% diacetyl boldine (DAB) serum, topical olive extract, 4% liquiritin cream, 10% zinc sulfate solution, 1% flutamide, and 0.2% thiamidol cream have high-to-moderate efficacy (grades A-B) and seem to be an efficacious alternative to HQ products, with comparable results. Topical epidermal growth factor (EGF) serum, topical mometasone fractional Er: YAG laser, 5% picolinamide cream, and 5% methimazole cream have low-to-very low or insufficient evidence (grades C-D).[34,62,114,115,116,117,118,119,120,121,122,123,124,125]

The details of these agents are summarized in the supplementary Table 2 ^{(249.3KB, pdf)} . In a study evaluating dioic acid (DA), which interferes with melanosome transfer, it was found to be as efficient and safe as 2% HQ; however, further large-scale-controlled, multicenter studies are required to support these results.[125] A novel topical hypopigmenting product containing ethyl linoleate, thioctic acid, octadecenedioic acid, lactic acid, and ethylhexyl methoxycinnamate was observed to have a significant skin lightening effect as compared to the control group.[126]

10% solution of zinc sulfate when compared to 4% HQ solution was not found to be as effective as the latter, although the frequency of irritation was significantly higher with HQ.[120]

Magnesium-L-ascorbyl-2-phosphate (MAP) is a stable derivative of ascorbic acid, known to inhibit melanin synthesis. Murtaza et al. reported that the combination of TCA peel and 5% topical MAP cream was significantly more effective than TCA peel alone.[118]

Hormonal influence is shown to exist in the pathogenesis of melasma, and flutamide, an antiandrogenic agent as a 1% topical cream was found to be as effective as 4% topical HQ with a better MASI improvement and higher patient satisfaction with the former.[127]

DAB stabilizes tyrosinase in its inactive form, while TGF-b1 biomimetic oligopeptide-68 inhibits tyrosinase activity. A combination of DAB serum at night and DAB/TGF-b1 biomimetic oligopeptide-68/sunscreen cream in the morning and at noon was observed to be as efficacious and safe for facial melasma.[128]

Mulberry is a novel whitening agent with antioxidant properties, and the efficacy of 75% mulberry extract oil (MEO) was assessed by Alvin et al. who reported a superior reduction in MASI, mexameter reading, and melasma quality of life score (MELASQoL) with MEO as compared to placebo with fewer adverse effects.[129] Individual studies have evaluated the efficacy of novel agents such as trifecting night cream, combination cream containing KA, phytic acid, and butyl methoxydibenzoylmethane, and trans-4-(aminomethyl) cyclohexanecarboxylic acid/potassium azeloyl diglycinate/niacinamide have shown superior results, but further large-scale studies are required to establish their efficacy.[129,130,131,132]

Recommendation for topical agents

Topical agents are recommended as first-line therapy for melasma.

• Start with fixed TCC (4% HQ + 0.05% RA + 0.01% FA) cream—daily, once at night application for a maximum period of 8 weeks is recommended (grade A recommendation).

• HQ alone (2-4%) may be used as monotherapy (more effective than KA, 20% azelaic acid), and it can be continued for 3 months (up to 1 year).

• Maintain with any of the following topicals:

  • KA 2% cream, azelaic acid 20% cream, arbutin cream, ascorbic acid, or newer agents.

  • Fixed TCC: twice weekly for up to 6 months (or 1 year) (grade of recommendation A).

Systemic Agents

TXA

Oral TXA 500–750 mg/day in a divided dose, for a maximum period of 6 months (strength of recommendation A, LOE 2–4).

The efficacy and safety of oral TXA for melasma were first recognized by Nijor in 1979.[133] In general, the sixteen RCTs included in this review had an LOE of 1b based on Individual RCT (with narrow confidence intervals).[134] Subjects were mostly females with skin phototypes between II and VI. TXA was given at a dosage of 250 mg twice a day at a varying duration of 8–20 weeks. Only one study used 250 mg once a day[135] and another used a TXA-based medication at a higher dose of 750 mg/day.[136]

The intervention arm either used oral TXA alone[137,138,139,140,141] or in combination with sunscreen,[133,135,142,143,144,145,146,147,148] triple combination lightening cream,[142,149] HQ cream,[133,144] or QS Nd: YAG laser.[136] Supplementary Table 1 ^{(614.3KB, pdf)} summarizes the interesting results from the different studies as the comparator arms were varied. Early onset of action was seen in 4^th week in different studies.[142,149]

Adverse reactions were seen, albeit not sufficiently serious for the participants to discontinue the trial. Effects on the gastrointestinal system like nausea, vomiting, and diarrhea (5%–19%) were the most commonly encountered side effect.[133,135,137,138,139,140,141,142,143,145,148] Oligomenorrhea and hypomenorrhea (0.3%–14.7%) were experienced by some subjects.[133,135,138,139,140,142,144,145] No thrombotic event was reported. Overall, no serious side effects were noted among the subjects in the studies conducted by Shin, Del Rosario, and Padhi.[136,146,149]

Oral TXA leads to a mild-to-moderate improvement in melasma when used at a dose of 500–750 mg/day in a divided dose, for a maximum period of 6 months (strength of recommendation A). Current evidence suggests that oral TXA may be used alone or as an adjuvant to conventional topical drugs or in cases recalcitrant to conventional topical therapy.

Procyanidin (Pinus pinaster)

Insufficient evidence to recommend it as monotherapy. May be used in combination therapy or as maintenance agents.

Saliou et al. confirmed that procyanidin administered at a dose of 1.10 mg/kg for 4–8 weeks significantly prevented UV radiation-induced erythema in humans.[150]

The extract of French maritime pine bark (Pinus pinaster) contains flavonoids such as procyanidin. Kohama et al. showed that procyanidin possesses antioxidant and anti-inflammatory actions.[151,152] Procyanidin's capacity to decrease melasma pigmentation has been documented in multiple studies. The studies conducted by Handog et al.[153] and Lima et al.[154] are included in this review.

Polypodium leucotomos (PL)

Insufficient evidence to recommend it as monotherapy.

PL is a tropical species of fern that possesses antioxidant and photoprotective properties, apart from its antimutagenic and immunoregulatory properties.[155]

Previously published studies by Martin et al. and Ahmed et al. had conflicting results, and the number of subjects was low.[156,157] In the study by Goh et al., no significant differences were observed between the two groups.[158]

Synbiotics

Insufficient evidence to recommend it as monotherapy.

Synbiotics are health products defined as a mixture of probiotics and prebiotics intended to increase the survival and activity of the beneficial microorganisms in the digestive system to as high as sevenfold.[159] Probiotics may help improve skin disorders, possibly including melasma, because of their anti-inflammatory, antioxidative, anti-tyrosinase, and ultraviolet protection capacities. The evaluation of synbiotic supplementation in the treatment of melasma was conducted by Piyavantin et al. in a 12-week RCT, wherein the mMASI score, MI, and EI between the two groups were significantly different (P ≤ 0.001), in favor of the synbiotic treatment group. No untoward reactions were noted [Supplementary Table 2 ^{(249.3KB, pdf)} ].[160]

Finasteride

Insufficient evidence to recommend it as monotherapy.

Finasteride is a synthetic 4-azasteroid compound whose antiandrogenic effect stems from its capacity to inhibit 5-alpha reductase, which is accountable for the conversion of testosterone to dihydrotestosterone (DHT).

In the RCT by Rassai and Mehrjui, it is interesting to note that among the patients included in the study, androgenetic features concurred with their melasma: 63.3% had androgenetic alopecia, 13.3% had acne, and hirsutism was noted in 20%. The thirty females with melasma were divided into two groups. For 12 weeks, all applied sunscreen with SPF 60 every morning, and 4% HQ cream on pigmented spots every night. Subjects in group A were given 5 mg finasteride tablet at night, while those in group B, a placebo tablet. At the end of the treatment period, although a higher number of patients in group A attained more than 50% reduction in MASI score compared with that of group B, there was no significant statistical difference observed between the two groups. Intake of finasteride by the female subjects did not produce any untoward reaction.[161]

Recommendation for systemic agents

• Oral TXA—leads to a mild-to-moderate improvement in melasma when used at a dose of 500–750 mg/day in divided doses, for a maximum period of 6 months (grade of recommendation A).

• Oral procyanidin/pycnogenol—available RCTs have reported a good-to-moderate LEV for oral procyanidin or pycnogenol use in melasma. Currently, there is insufficient evidence to recommend oral procyanidin or pycnogenol as monotherapy in melasma.

• Oral PL extract—previously published reports showed conflicting results, and the number of subjects evaluated is low. There is insufficient evidence to recommend it as monotherapy in melasma.

Conclusion

HQ, TCC (4% HQ + 0.05% retinoic acid + 0.01% fluocinolone acetonide), sunscreens, KA, and azelaic acid receive a grade A recommendation, and TCC is preferable to all other topical therapies when the potency of the therapy is the priority, such as for the initiation of therapy for a short period (strength of recommendation A).

However, it is worth mentioning that the choice of agent should be individualized and subject to availability in a particular country. Also, combinations work better with TCC making treatment durations shorter. Among the newer agents, 3% RO cream, UP 2% cream, 30% metformin lotion, cream containing 0.05% tomato lycopene, and 3.45% wheat bran extract, 2% lincomycin + 2% linoleic acid, 5% topical MAP cream, 5% lignin peroxidase, Petroselinum crispum solution, 4% DAB serum, topical olive extract, 4% liquiritin cream, 10% zinc sulfate solution, 1% flutamide, and 0.2% thiamidol cream have high-to-moderate efficacy (grades A–B) and seem to be efficacious alternatives to HQ products, with comparable results.

Few studies that did not fulfill our inclusion criteria have reported the usefulness of mequinol 2%, topical and oral glutathione, topical and oral tocopherol, and several plant extracts as effective therapies for melasma, and large controlled trials are needed to establish efficacy and safety for wider acceptance of these agents.

Oral TXA leads to a mild-to-moderate improvement in melasma when used at a dose of 500–750 mg/day in a divided dose, for a maximum period of 6 months (strength of recommendation A) and may be used alone or as an adjuvant to conventional topical drugs or in cases recalcitrant to conventional topical therapy. Procyanidins, PL, and even synbiotics may be taken as adjuncts. Finasteride, however, may work in melasma accompanied by androgenic concerns. The strength of recommendation and LOE of the various topical and systemic agents has been summarized in [Table 1].

Table 1.

Strength of recommendation and level of evidence

Drug/therapy	Strength of recommendation/level of evidence (LOE)
A broad-spectrum sunscreen with a sun protection factor (SPF) of at least 30, which covers ultraviolet A (UVA) (minimum protection grade of UVA [PA]+++), UVB, and visible light	Strength of recommendation A, LOE 1
Triple combination of 4% HQ+0.05% retinoic acid+0.01% fluocinolone acetonide cream	Strength of recommendation A, LOE 1
Hydroquinone (HQ) 4% cream	Strength of recommendation B, LOE 1
Kojic acid 2% cream	Strength of recommendation A, LOE 2
Azelaic acid 20% cream	Strength of recommendation A, LOE 1
Tretinoin 0.05% or 0.025% cream	Strength of recommendation B, LOE 1
Arbutin cream	Strength of recommendation D, LOE 2
Vitamin C (ascorbic acid)	Insufficient evidence to recommend it as monotherapy or as adjuvant therapy
5% cysteamine cream	Strength of recommendation B, LOE 2
Resorcinol 0.1% liposome-encapsulated rucinol and 0.3% rucinol cream	Insufficient evidence to recommend it as monotherapy. May be used in combination therapy or as maintenance agents LOE 2
Tranexamic acid (topical)	Efficacious alternative to HQ products, with comparable results
Miscellaneous topical agents	Insufficient evidence to recommend it as monotherapy. May be used in combination therapy or as maintenance agents.
Oral tranexamic acid leads to a mild-to-moderate improvement in melasma when used at a dose of 500–750 mg/day in a divided dose, for a maximum period of 6 months	Strength of recommendation A, LOE 2–4
Other oral agents	Insufficient evidence to recommend it as monotherapy. May be used in combination therapy or as maintenance agents

Grading of recommendation as per OCEBM – levels of evidence (March 2009). Level of evidence as per OCEBM 2011 – 1: systematic review of randomized trials, 2: randomized trial, 3: nonrandomized controlled cohort/follow-up study, 4: case series; case–control; or historically controlled studies. OCEBM: Oxford Centre for Evidence-Based Medicine 134

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

Supplementary File

Supplementary Table 1

Summary of the studies included : Topical agents

Supplementary Table 2

Summary of the studies included: systemic agents