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IADVL-SIG PIGMENTARY DISORDERS SYMPOSIUM ARTICLE
Year : 2017  |  Volume : 8  |  Issue : 6  |  Page : 406-442  

Evidence-based review, grade of recommendation, and suggested treatment recommendations for melasma


1 Department of Dermatology, Dr B C Roy Post Graduate Institute of Pediatric Science, Kolkata, West Bengal, India
2 Department of Dermatology, R G Kar Medical College, Kolkata, West Bengal, India
3 Department of Dermatology, K J Somaiya Medical College, Mumbai, Maharashtra, India
4 Consultant Dermatologist, Siliguri, India
5 Department of Dermatology, Post Graduate Institute of Medical Education and Research, Chandigarh, India
6 Department of Dermatology, Velammal Medical College Hospital and Research Institute, Madurai, Tamil Nadu, India
7 Department of Dermatology, Dr. Somervell Memorial CSI Medical College, Karakonam, Trivandrum, Kerala, India
8 Department of Dermatology, Maulana Azad Medical College and Lok Nayak Hospital, Basaidarapur, New Delhi, India
9 ESI- Post Graduate Institute of Medical Science and Research, Basaidarapur, New Delhi, India

Date of Web Publication14-Nov-2017

Correspondence Address:
Nilendu Sarma
P N Colony, Sapui Para, Bally, Howrah, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/idoj.IDOJ_187_17

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   Abstract 


Treatment of melasma is known to be less satisfactory, often incomplete, and relapse is frequent. Although many treatment options are available, they are either known to be unsafe on long-term use or their long-term safety profile is unknown. Patients often use various drugs, even topical steroid-based preparation without any medical supervision for long period of time, making the skin unsuitable for many of the drugs available. Thus, there has been gross disparity among the treating physician about what drugs and what regimen are best suitable for various categories of melasma patients and in different situations. With this background, numerous newer drugs, mostly combinations of some proprietary molecules or even unknown plant extracts, have flooded the market for the management of melasma. Information on efficacy or safety of these products are almost unknown. Studies on Asian people, especially Indian population, are far less commonly available. Therapeutic guideline for use on Indian patients with melasma is almost missing. Extrapolation of data from Caucasian people for use on Asian people may not be scientifically justifiable because Caucasian and Asian people are known to have inherent difference in their response as well as tolerance to the drugs used for melasma. With this background, we have extensively evaluated, following a strict, scientifically designed protocol, all the available studies on melasma management till May 2016 and prepared this document on level of evidence, grade of recommendation and suggested therapeutic guideline for melasma as per the method proposed by Oxford Centre of Evidence-Based Medicine. Various ethical, social, logical, regional, and economic issues in the context of Indian and similar populations were given due importance while preparing the suggested therapeutic recommendation.

Keywords: Guideline, hydroquinone, India, melasma, treatment, triple combination


How to cite this article:
Sarma N, Chakraborty S, Poojary SA, Rathi S, Kumaran S, Nirmal B, Felicita J, Sarkar R, Jaiswal P, D'Souza P, Donthula N, Sethi S, Ailawadi P, Joseph B. Evidence-based review, grade of recommendation, and suggested treatment recommendations for melasma. Indian Dermatol Online J 2017;8:406-42

How to cite this URL:
Sarma N, Chakraborty S, Poojary SA, Rathi S, Kumaran S, Nirmal B, Felicita J, Sarkar R, Jaiswal P, D'Souza P, Donthula N, Sethi S, Ailawadi P, Joseph B. Evidence-based review, grade of recommendation, and suggested treatment recommendations for melasma. Indian Dermatol Online J [serial online] 2017 [cited 2017 Nov 23];8:406-42. Available from: http://www.idoj.in/text.asp?2017/8/6/406/218324




   Introduction Top


Melasma is a common disorder characterized with brown, dark brown to grey pigmentation most commonly on face and sometimes on extra-facial areas such as forearm. Although no systemic involvement is known for this condition, it imparts significant psychological stress on the affected individual. Females are more commonly affected and seek treatment. Various aggravating and precipitating conditions are known to be related, but none has been proven. Hormonal factors, pregnancy, oral contraceptive pills are frequently reported to be intimately associated. Sun exposure, like all pigmentation, aggravates the intensity of pigmentation.

Numerous newer drugs, mostly combinations containing some proprietary molecules and unknown plant extracts, have flooded the market for the management of melasma. This has happened with the background that well-designed studies and thus documented information are lacking on the efficacy, safety, and right dosage on both the age-old drugs that are in use for significantly long time.

Treatment of this condition is less satisfactory. Relapse is frequent. Thus,the latter study was done only on a requirement for long-term therapy is often required. Unfortunately, most of the drugs with known good efficacy have some adverse effects (AEs) on skin on long-term use, limiting their use beyond a period. Thus, there has been gross disparity among the treating physician about what drugs and what regimen are best suitable for various categories of melasma patients and in different situations.

Studies on Asian people, especially Indian population, are far less commonly available. Therapeutic guideline for use on Indian patients with melasma is almost missing. Extrapolation of data from Caucasian people for use on Asian people may not be scientifically justifiable because Caucasian and Asian people are known to have inherent difference in their response as well as tolerance to the drugs used for melasma. This project was undertaken by “IADVL-Special Interest Group (SIG)—Pigmentary Disorders (2014–16).” Members outside the group were also included. The team was headed by the SIG coordinator (NS). Two face-to-face meeting among the SIG members were arranged; one at the beginning and another during the study, to discuss various aspects such as the search strategies, methodology for evaluation of the literature, preparation of evidence, and grading of recommendation. The project was approved by the IADVL Academy.

Objective

Preparing a scientifically designed, exhaustive document on level of evidence, grade of recommendation, and suggested therapeutic guideline for melasma.

Search period

Relevant articles on management of melasma published from January 2000 to May 2016.

Search strategy and inclusion criteria

All types of literature, including meta-analysis, randomized and nonrandomized trials, case reports, and case series, published only in PubMed and Cochrane database in English language were evaluated.

While calculating total number of participants, reviews were not considered. This was to avoid duplication of data as many of the studies we evaluated were also evaluated by these reviews.

Searches were made using the keyword “melasma.”

Exclusion criteria

Studies were excluded if they were found to have the following: poor methodology and study design, unknown composition of the drug, unpublished studies and personal opinion, and when full text is unavailable. Studies using a combination molecule [additional molecules along with the intended single or combination molecules, e.g. triple combination (TC)] were also excluded.

Sponsored trials were, however, evaluated and categorized based on the study quality and methodology. Detailed information is presented later under individual drugs.

Level of evidence

Level of evidence (LOE) assessed as per “Oxford Centre for Evidence-Based Medicine (OCEBM) 2011.”[1]

Grade of recommendation

Grading of recommendation was done based on OCEBM—Levels of Evidence (March 2009).[2]

Therapeutic guideline

This is a proposal and has been made by the present study team based on level of evidence, grade of recommendation along with consideration of various practical and ethical issues.

Assessment of study parameters

The following parameters were checked in the citations: number of patients, origin of the patients, study modality, study design, duration of study and follow-up, methods used for evaluation, AEs, any obvious fallacies, and other important facts.

Study team unanimously decided to consider following evaluation methods as standard: melasma area severity score (MASI), modified MASI (mMASI), and mexameter.

Limitations

Some new data might be published since the preparation of this article.

Detailed evidence on each drugs and grade of recommendation

Triple combination

Nineteen studies and one Cochrane review were found on TC.[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22] Among these, 14 studies including one review were done with fluocinolone acetonide-based triple combination (FTC) monotherapy,[3],[4],[5],[6],[7],[8],[9],[10],[11],[12],[13],[14],[15],[16] 3 used TC combined with other drugs [17],[18],[19] among which one study used hydrocortisone-based TC. Safety, risk of relapse, and efficacy of longer duration (6 months or longer) FTC were also assessed.[4],[5],[14],[15],[16] Four studies used TC with steroids other than fluocinolone acetonide.[19],[20],[21],[22] Total number of patients evaluated with FTC (excluding the review) was more than 4000 patients [Table 1].
Table 1: Evidence on triple combination

Click here to view


Fluocinolone acetonide-based triple combination monotherapy

FTC [fluocinolone acetonide (FA) 0.01%, hydroquinone (HQ) 4%, tretinoin (RA) 0.05%] was found to have significant efficacy in improving melasma in at least two uncontrolled trials (LOE 3).[3],[4]

In comparison to placebo, FTC was found to be higher in efficacy in reduction of pigmentation in a study that also used sequential intense pulsed light (IPL) in both the groups (Goldman et al.)[7] (LOE 3). In other studies, FTC was found to be superior to 4% HQ monotherapy [8] (LOE 2), dual combinations (RA+HQ, RA+FA, and HQ+FA)[9] (LOE 2), and some proprietary skin lightening product (HQ-based combination product)[10] (LOE 2).

Our findings matched to the one published in 2010 by one Cochrane systematic review that evaluated 20 studies with a total of 2125 participants covering 23 different treatments.[12] It reported that TC cream was significantly more effective at lightening melasma than hydroquinone alone [relative risk (RR) 1.58, 95% confidence interval (CI) 1.26–1.97], dual combinations of tretinoin and hydroquinone (RR 2.75, 95% CI 1.59–4.74), tretinoin and fluocinolone acetonide (RR 14.00, 95% CI 4.43–44.25), or hydroquinone and fluocinolone acetonide (RR 10.50, 95% CI 3.85–28.60).

A subsequent Indian study, however, found FTC to be of equal efficacy to a combination therapy that consisted of glycolic acid (GA) peel (sequentially increased from 20 to 70%) along with azelaic acid 20% cream [12] (LOE 2). More studies are necessary to substantiate this finding.

Recommendation

  1. FA-based TC (FA 0.01%, HQ 4%, RA 0.05%) is recommended in melasma (Grade A recommendation)
  2. FA-based TC (FA 0.01%, HQ 4%, RA 0.05%) is preferable to all other mono and combination topical therapy when potency of the therapy is the priority. This is a typical situation at the initiation of therapy for a short period (Grade A recommendation).


Triple combination in combination therapy

Three studies evaluated TC in combination with other drugs.[17],[18],[19] TC combined with GA peel was reported to be efficacious (LOE 3)[17],[18] but magnitude of the benefit of additional GA peel in comparison to TC alone was not studied. In a small nonrandomized study, additional benefit of GA peel on hydrocortisone containing TC (hydrocortisone 1%, HQ 2%, and RA 0.05%) was assessed.[19] Authors found greater and early improvement with combination treatment (TC and GA peel) (LOE 3).

Recommendation

GA peel can be added to TC to increase the efficacy (Grade of recommendation B).

Duration of therapy (initial therapy phase)

Most of the studies have evaluated TC up to a maximum of 8–12 weeks. There is inconsistencies and significant lack of proper reporting of AE in these studies. Thus, it is difficult to conclusively recommend the most safe and effective duration.

Recommendation

  • Initial daily therapy with FB TC should be limited to 8 weeks. However, this may be extended carefully up to 12 weeks (Grade of recommendation D).


Long-term therapy with triple combination

Relapse was noted among almost all cases who improved after treatment for 12 weeks (LOE 3). This called for reinstitution of daily therapy.[14]

Another study, however, noted a longer disease-free period during 6 months of intermittent maintenance therapy after initial 8 weeks of daily therapy. It was reported that 53% of patients remained relapse-free with improved quality of life with median time to melasma relapse as 190 days and it was similar between the groups [15] (LOE 2).

Studies have used daily [4] as well as intermittent regimens [5],[14],[15],[16] with TC for extended period (6 months to 1 year). Common AEs were erythema and skin irritation. Incidence of significant AE such as skin atrophy, telangiectasia was reported to be very low in all these studies. No incidence of exogenous ochronosis was detected in any of these long-term studies. Withdrawal due to AE was also very low.

High degree of safety was reported after 12 months daily use of FTC [4] (LOE 3). However, in contrast to intermittent therapy, one study reported significantly higher incidence of AE when TC was used daily as long-term therapy [14] (LOE 3).

Among the two intermittent regimens (twice weekly versus tapering dose) up to 6 months, there was no significant difference between efficacy in maintaining a disease-free period and the risk of AE [15],[16] (LOE 2). However, none of the studies were done among Indian population. Chance of AE among Asians is often reported to be higher than Caucasians.

Recommendation

  • Till further evidence on Indian population is available, long-term use of TC as maintenance therapy is not recommended (Grade of recommendation D)
  • If used, FTC may be used as twice weekly maintenance therapy very carefully under supervision up to 6 months (Grade of recommendation A).


Triple combination using steroids other than fluocinolone acetonide

AEs were noticed among 43.3% patients in one retrospective study that used mometasone containing TC (mometasone 0.1%, 2% HQ, and 0.025% RA) for one year. Steroid-induced telangiectasia was the commonest finding. Atrophy, hypertrichosis, and acneiform eruption were also seen [20] (LOE 4).

Only one study was found that compared FA and triamcinolone (0.02%) containing TC. Both were found to be similar in efficacy [21] (LOE 2). Difference in AE was also not reported. Follow-up was missing in many of these studies. Thus, comparative risk of relapse or AE is unknown.

One recent study compared dexamethasone containing TC (original Kligman's formula, dexamethasone acetate 0.1%, HQ 5%, and RA 0.1%) with copper bromide laser and reported this TC to be better than laser [21] (LOE 2). However, sample size was very less (only 16 patients completed the trial).

Recommendation

There is significant lack of evidence on TC using steroids other that fluocinolone acetonide-based TC (FTC). Thus, despite lack of direct comparative study between FTC and TC containing other steroids, FTC is preferable as TC (Grade of recommendation D).

Hydroquinone

Evidence

The literature search yielded 122 citations using the key phrase topical hydroquinone in melasma. The articles which were excluded had poor methodology of evaluation. Few studies were excluded as full text were not available. Finally, 11 studies, including 9 randomized controlled trials (RCTs), were evaluated that used 4% HQ among 735 subjects [22],[23],[24],[25],[26],[27],[28],[29],[30],[31],[32],[33] [Table 2].
Table 2: Evidence on hydroquinone

Click here to view


HQ 4% was found to be more effective than placebo in the treatment of melasma.[22],[23] In addition, HQ 4% was reported to be significantly superior to 5% ascorbic acid [24] (LOE 2). Although 4% HQ resulted in higher efficacy than kojic acid (0.75%)[25] (LOE 3) and 4% niacinamide [26] (LOE 2), difference was not statistically significant.

One Cochrane review reported azelaic acid (20%) was superior to HQ 2% but not when compared to 4% hydroquinone (RR 1.11, 95% CI 0.94–1.32)[12] (LOE 1). Since that review was published, only one study reported 20% AA as significantly more efficacious than 4% HQ [27] (LOE 3).

A single study reported lesser efficacy when compared to 3% rumex occidentalis [28] (LOE-2) and 1% flutamide [29] (LOE-2). No further studies substantiated these findings however. All the three RCTs comparing efficacy of 4% HQ with TC (two fluocinolone-based [8],[32] and one dexamethasone-based [33]) confirmed significantly superior efficacy of TC (LOE 2). However, posttreatment follow-up data beyond 12 weeks of therapy was not available.

Pigment lightening effect of HQ is mostly evident after 8–12 weeks.[22],[23] Some studies have continued till 24 weeks without any report of AE.[27],[28] None of the studies included dermal melasma in study subjects.

Irritation is the main AE with HQ.[22],[23],[26] Overall, reporting of AE appeared to be lower than expected. No report of exogenous ochronosis was reported with 4% HQ on using it more than 3 months.

Conclusion and recommendation

HQ 4% is a known effective drug in melasma. Considering its long track record of use and satisfactory efficacy, the evidence appears grossly lacking.

Evaluating the available studies, we recommend HQ 4% in melasma (Grade A recommendation).

The maximum recommended duration is 16 weeks. It is superior to many available therapies except TC, which proved to be more efficacious and azelaic acid 20%, which may be equal in efficacy.

Hydroquinone with tretinoin

Three uncontrolled studies evaluated efficacy of the 4% HQ with tretinoin (0.025–0.05%) mostly for 12–24 weeks [Table 3]. All these studies reported efficacy of such combination. However, all the three studies used proprietary product. AEs such as burning, irritation, redness, and dryness were reported (LOE 3).[34],[35],[36]
Table 3: Evidence on retinoids in melasma

Click here to view


Recommendation

No recommendation possible unless further studies are available.

Retinoids

Evidence

Literature search yielded 94 articles. After primary screening, 90 articles were excluded as these used combination therapies. Finally, four articles were assessed, including one Cochrane systematic review [12],[35],[36],[37] [Table 3].

Two studies used 0.1% RA (tretinoin) and the other one 0.05% isotretinoin gel.[35],[36],[37] Both tretinoin and isotretinoin were compared with vehicle, and the mask study was uncontrolled.

Improvement with tretinoin was higher than vehicle (LOE 2). Overall improvement in MASI (in one of these two) was only 32%.[36] Objective improvements in the studies were mentioned to be significant in both the studies. However, participants rated their improvement as significant in one study only.

These studies had many weaknesses. Sample size was too small. The largest one was done among 38 subjects. One study was not evaluated with standard assessment method such as MASI, and both these studies had no follow-up. Retinoid dermatitis was noted in large number of cases.

Topical isotretinoin was not found to be superior even to the vehicle. In an uncontrolled study on only 20 patients, retinoid mask was found to offer significant improvement in MASI from baseline and the improvement persisted during one year of follow-up.[37]

Conclusion and Recommendation

Overall, the high-quality evidence is lacking in favor of retinoid monotherapy in melasma. Comparative studies with standard treatment options like TC or HQ are unavailable.

Retinoid monotherapy results in only mild improvement. It has known adverse effects also. It may be used in some selected cases of melasma (Grade B recommendation).

Vitamin C

Evidence

Twelve studies were sorted out where vitamin C was used in melasma. One study was excluded as it was done before 2000. Six other studies were excluded because of the weaknesses in study design. Finally, five studies matched the selection criteria [24],[38],[39],[40],[41] [Table 4]. Three studies evaluated vitamin C as monotherapy and compared with other modalities.[24],[38],[39]
Table 4: Evidence on Vitamin C

Click here to view


Vitamin C was reported to be more efficacious than distilled water iontophoresis [38] (LOE 2). Also, vitamin C was found to result in higher improvement (statistically insignificant) than 70% GA peel. However, the study was done only among 14 patients and follow-up was missing [39] (LOE 2).

It was, however, found to be inferior to HQ 4%[24] (LOE 2).

Two studies found significant additional benefit of adding vitamin C to other modalities such as 20% trichloroacetic acid (TCA) peel [40] (LOE 3) and 1064-nm Q-switched Nd:YAG laser [41] (LOE 2). However, the latter study was done only on 8 patients and evaluated the response with VASI and the former study had a complex study design without any follow-up.

Recommendation

Vitamin C is an expensive drug. Stability is an issue. At present, there is insufficient evidence to recommend the drug either as monotherapy or as adjuvant. Larger studies are necessary to assess its efficacy.

Vitamin E

Evidence

Two studies used vitamin E in melasma.[42],[43] None of these two studies used vitamin as monotherapy.

Recommendation

Presently, there is lack of evidence to recommend vitamin E as monotherapy in melasma.

Glycolic acid cream

Evidence

Most of the available studies on GA were done on the GA peel and has been mentioned somewhere else in this document. Only two studies were found that evaluated GA cream formulation [44],[45] [Table 5].
Table 5: Evidence on glycolic acid cream

Click here to view


Among these, one open label uncontrolled study used a novel proprietary synthetic oligopeptide cream also containing GA as one of the ingredient and reported complete clearance of melasma after 6 weeks.[44] Thus it was not rejected.

One RCT evaluated GA cream as an adjuvant to 4% HQ.[45] The study compared five groups where each group had 4% HQ and efficacy of additional drugs such as 10% GA and 0.01% hyaluronic acid was assessed. Efficacy of additional GA cream to HQ was not proven in this study (LOE 2).

Recommendation

There is lack of evidence to recommend use of glycolic acid cream in melasma.

Azelaic acid

Evidence

Seven studies including one systematic review (Cochrane review) were found to evaluate efficacy of azelaic acid in melasma.[12],[27],[28],[29],[52],[53],[54],[55],[56] Total patients evaluated were 383 (excluding the review) [Table 6].
Table 6: Evidence on azalaic acid

Click here to view


One Cochrane review, published in 2010, reported equal efficacy of AA 20% to that of HQ 4%[12] (LOE 1). One RCT published after that review even reported higher efficacy of AA 20% than HQ 4% (LOE 2). However, the number of patients was only 29.[27]

That Cochrane systematic review reported significantly higher efficacy of AA 20% than HQ 2%[12] (LOE 1). No other study was found since 2000.

Combination of Nd:YAG laser with AA 20% cream was also found to be better than the laser monotherapy among 60 patients [49] (LOE 3).

No significant AEs were reported. Long-term AE is unknown. Thus, evidence is limited but suggests efficacy comparable to HQ 4% and short-term safety profile. Long-term safety of data is, however, lacking. More studies are required.

Recommendation

Azelaic acid 20% cream monotherapy is recommended in melasma (Recommendation Grade A).

Azelaic acid 20% cream is recommended as adjuvant to Nd:YAG laser therapy in melasma (Recommendation Grade B).

Arbutin

Evidence

Four studies were found that evaluated arbutin in melasma [50],[51],[52],[53] [Table 7]. In two studies, arbutin was used either in a proprietary cream that also had other drugs or along with Nd:YAG laser. These were thus excluded.[50],[51]
Table 7: Evidence on arbutin

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One study (54 melasma patents, 8 weeks) compared arbutin with a placebo and reported statistically significant difference. However, evaluation was not done using a standard method [50] (LOE 2).

In another study, it was compared with two formulations of elagic acid. All the drugs were effective in significantly improving from baseline, but there was no difference among them [53] (LOE 2).

In summary, efficacy of arbutin is yet to be understood due to gross lack of high-quality comparative studies with standard drugs used in melasma. There is no data on the possible AE.

Recommendation

However, this may be used in melasma for short term. (Grade D recommendation).

Kojic acid

Evidence

Four RCTs were found on use of kojic acid (KA) in melasma. However, sample sizes were less, and strengths of KA were variable (0.75–2%)[25],[54],[55],[56] [Table 8].
Table 8: Evidence on kojic acid

Click here to view


One RCT compared 2% KA with HQ 2% among 39 patients (only one male) in a split-face manner where both sides were also treated with 5% GA. There was no difference between the two drugs [54] (LOE 2).

Another study found KA (0.75%) (along with vitamin C, 2.5%) was inferior to 4% HQ that showed faster and significantly higher improvement in MASI [25] (LOE 2).

Study by Deo et al.[55] reported 58.72% improvement in MASI with 1% KA monotherapy and 71.87% response with combination of KA and 2% HQ (LOE 2).

Role of additional KA (2%) over a combination therapy containing 2% HQ, 10% GA in another randomized single-blind 12-week study produced a mixed result. A dramatic reduction was reported among 17 patients but no additional benefit was found among other 18 patients. However, evaluation was not done using standard method such as MASI [56] (LOE 2).

In summary, studies are limited and there are heterogeneity in the available studies with KA. Most studies have used it along with other drugs. Combination with 2% HQ may offer highest possible benefit from this drug. It appears that 2% KA may have an efficacy similar to 2% HQ. Strength lower than 1% may not be effective. Larger and more designed studies are necessary to understand its true efficacy. Long-term safety of data is also largely lacking.

Recommendation

Kojic acid (preferably 2%) is recommended in melasma (LOE 2, Grade A recommendation).

This may be combined with 2% HQ for a better result (LOE 2, Grade A recommendation).


   Chemical Peels Top


Glycolic acid

Evidence

Totally, 389 patients were assessed in nine studies including five RCTs [13],[57],[58],[59],[60],[61],[62],[63],[64] [Table 9]. Two studies compared efficacy of GA peel in variable percentages (20–70%) with other drugs. One of these studies compared efficacy of GA (20–70%) peel with TC (HQ 2%, RA 0.05%, FA 0.01%). Both GA peel (along with azelaic acid cream) and TC significantly improved MASI and there was no statistically significant difference in efficacy between them [13] (LOE 2). However, sample size was small. No other studies were done to validate these findings.
Table 9: Evidence on chemical peels in melasma

Click here to view


GA peel (70%) was found to be similar in efficacy with tretinoin 1% peel but tretinoin peel was more tolerable by the patients [57],[58] (LOE 2, 4). Combining other drugs like HQ 2% or 0.25% tretinoin was found to be superior to GA peel alone in a RCT with small sample size (20 patients in each arm)[59] (LOE 2). It was a long duration study (6 months study and 3 months follow-up).

GA peel with HQ 2% was better than GA peel with 0.25% tretinoin.[59] In a small RCT involving 25 patients with recalcitrant melasma, the group receiving chemical peel along with topical 20% AA and 0.1% adapalene showed better response than the group receiving topical formulation alone [50] (LOE 2). However, in another small RCT, combining HQ 4% with GA peel was not found to be superior to HQ monotherapy [61] (LOE 2). Whether such combination was better than GA peel was, however, not studied.

In an open study, combining serial GA peel (30–40%) every 3 weeks with modified Kligmann formula for 21 weeks resulted in faster response, but overall efficacy was similar to TC alone [62] (LOE 3).

GA peel was compared with TCA peel in two studies. Efficacy was found to be equal [63],[64] (LOE 3). However, speed of response as well as relapse was faster with TCA, indicating GA to be a better option than TCA.[63]

Overall, most studies had very small sample size and there were lack of uniformity regarding the strength of GA peel used. Only one study directly compared efficacy of GA peel with TC. The result was encouraging. Larger studies of this kind where it has been directly compared with TC or HQ are required to understand its exact efficacy.

Potency of the GA peel in comparison to HQ or TC is mostly unknown. Possibly, it has lesser efficacy. Studies are necessary in this regard. No significant long-term AE is reported. Its potency may be somewhat similar to other strong peels such as TCA peel.

Recommendation

  1. GA peel may be used in melasma (Grade A recommendation)
  2. Its efficacy can be increased combining HQ 2% or 0.25% tretinoin. Also, it can be added to other therapies like azelaic acid or even TC to increase the overall efficacy or the speed of improvement, respectively (Grade B recommendation).


Trichloroacetic acid peel

Evidence

Four studies evaluated efficacy of TCA (10–20%) peel. Two studies compared TCA with GA peel [Table 9]. As discussed in the section of GA peel, TCA peel was found to be of similar efficacy with different strengths of GA peel used (20–75%). Both of these drugs resulted in significant response in comparison to baseline [63],[64] (LOE 3). Response with TCA peels was faster but relapse was also commoner.[63]

Addition of a topical agent, such as ascorbic acid, yields better result than in comparison with using it singly as found in a small study [40] (LOE 2).

The other study compared 15% TCA and modified Jessner's solution with 15% TCA where modified Jessner's solution proved to be useful as an adjuvant treatment with TCA in the treatment of melasma [65] (LOE 3).

Overall, the study design was poor in most of these studies. Larger and properly designed studies remained a necessity. Relapse may be high and its use requires expertise. Care must be taken to avoid AE.

Recommendation

TCA peel can be used in melasma as monotherapy, or combined with other peel like modified Jessner's solution (Grade B recommendation).

Tretinoin peel

There is still a paucity of literature on the peel formulation of the agent which has shown favorable results in a few of the recent studies. The mechanism of action of tretinoin peels is proposed to be similar to that of topical tretinoin, that is, via changes in the epidermis and dispersion of melanin.

There was no significant difference in efficacy between tretinoin 1% peel group and 70% glycolic acid in a RCT and one small study [57],[58] (LOE 2, 4). However, tretinoin peel was more tolerable than GA [Table 9].

Recommendation

Tretinoin peel (1%) may be used in melasma (Grade of recommendation B).

Salicylic acid peels

Only two RCTs (80 patients) were found that evaluated efficacy of salicylic acid peel in melasma [Table 9]. One study compared the efficacy of 30% salicylic acid peel with Jessner's solution (14% salicylic acid, 14% lactic acid, 14% resorcinol in alcohol). There was no difference between these groups [66] (LOE 2).

Another group found no difference between SA peel and HQ 4%. However, the study was done in just 20 patients [67] (LOE 2).

Overall, evidence is significantly lacking. No significant AE is reported. More studies are required to understand its true efficacy and AE.

Recommendation

Salicylic acid peels may be used in melasma (Grade of recommendation B).

Lactic acid peel

Two nonrandomized studies evaluated efficacy of pure lactic acid in melasma [Table 9]. One of these was uncontrolled and another compared lactic acid peel with Jessner's peel. Both these studies reported significant improvement from baseline and no difference was observed in comparison to Jessner's solution [68],[69] (LOE 4, 3).

Recommendation

Lactic acid peel may be used in melasma (Grade of recommendation B).

Jessner's peel

Two studies, one RCT and one nonrandomized trial, evaluated Jessner's solution in the treatment of melasma [Table 9].

Ejaz et al.[66] evaluated Jessner's solution in comparison with 30% salicylic acid where it was found that both the peels are effective in reducing melasma but the difference in efficacy was not statistically significant (LOE 2).

The other study compared 15% TCA and modified Jessner's solution with 15% TCA where modified Jessner's solution proved to be useful as an adjuvant treatment with TCA in the treatment of melasma [65] (LOE 3).

In summary, the evidence as mentioned above indicates that this peel has efficacy equal to salicylic acid peel and lactic acid peel monotherapy. However, both lactic acid (92%; pH 3.5) and salicylic acid (30%) were used in higher strength when used singly than when used in Jessner's peel. Considering the equal efficacy, Jessner's peel may be safer that the individual peel used in higher strength. However, any comment in this regard needs larger and more studies that should address both efficacy and AEs of the drugs. Overall, studies showed that Jessner's solution have yielded significant reduction in pigmentation when used alone as well as adjuvant to other peels such as TCA peel.

Recommendation

Jessner's peel may be used in melasma (Grade of recommendation B).

Overall recommendation on chemical peels

Potency of the chemical peels has never been shown to be more efficacious than standard therapies such as TC or HQ 4% in well-designed studies. In an evidence-based review by Rivas et al.[77] involving 40 studies and 2912 patients, it was found that GA peels are not more effective than HQ. In most of the studies, one peel has been compared with another peel. No peel has also been proven to be consistently better that other.

Different strengths of a single peel have never been compared to find the most effective yet safest strength. One Cochrane review found no difference in efficacy between Jessner's peel and salicylic acid peels both with tretinoin priming [12] (LOE 1). They also opined that meta-analysis was not possible as there was absence of homogeneity in study components. They concluded that no comment could be made on the efficacy of TCA peels, GA peels, salicylic peels or comparison between the peels.

The above-mentioned Cochrane review could not find any benefit of adding GA peel with a combination of HQ and glycolic acid cream.

Peels can have significant AE especially the strong peels such as TCA or other peels used at higher concentration. Even addition of peels such as salicylic acid peel with other agents added no additional benefit, but increased the risk of AE such as postinflammatory hyperpigmentation.[12]

Overall recommendation

  1. All peels may be used in melasma (Grade of recommendation B)
  2. All these peels may be used as an additional therapy to other therapy or as maintenance therapy expecting only a mild to moderate efficacy (Grade of recommendation D)
  3. There is no significant advantage of one peel over another. Selection of the peel and its strength should be done based on the comfort level and experience of the treating dermatologists and the safest strength may be selected. Only experienced dermatologists should use these.


Oral tranexamic acid

Introduction

Evidence

Ten studies,[71],[72],[73],[74],[75],[76],[77],[78],[79],[80] including one systematic review,[71] three RCTs, three uncontrolled studies, were found. Total patients evaluated with these studies excluding the systematic review were 1050, and almost all were of Asian origin [Table 10]. Dosage ranged from 500 to 750 mg daily, usually in divided doses. All these studies, including the review, reported the efficacy in the majority of the patients, although the degree of response was variable (LOE 1, 2, 3, 4).
Table 10: Evidence on oral tranexamic acid

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Improvement was noticed as early as 4 weeks in a systematic review. Three uncontrolled studies also reported response within 4 weeks.[74],[75],[76] Some studies reported a longer median time of 2 months.[72]

None of the studies reported any significant AE except one case of deep vein thrombosis in a patient who had existing protein S deficiency.[72] Follow-up data is lacking in many of these. Maximum safe duration of treatment and minimum effective dosage are yet unknown. Relapse rates in studies varied from 7.5% to as high as 75% (in refractory melasma).[72],[73]

Role of oral tranexamic acid (TXA) as adjuvant to other therapies such as TC, HQ, and laser were assessed in RCTs. One RCT evaluated addition of oral TXA on topical HQ (% unknown) and found sustained improvement at 12 weeks when TXA was added [77] (LOE 2). Three studies (2 RCTs and 1 case–control study) evaluated additional efficacy of oral TXA on Nd:YAG laser,[78] FTC,[79] and IPL.[80] All these studies reported significantly enhanced efficacy with addition of TXA to TC (LOE 2), IPL and LASER treatment (LOE 2, 4) in melasma.

Histological and immunohistochemical evaluation following oral TXA has shown decrease in epidermal pigmentation as well as melasma-associated dermal changes such as number of vessels and mast cells.[74]

Direct head-on comparison with standard therapies, such as TC and HQ, is lacking. However, such comparative studies between oral and topicals are difficult to design. Use of oral TXA has resulted in benefit among majority of the patients and addition of oral TXA with other modalities was also found to be beneficial. Importantly, most studies have been done in Asians. So far, significant AE is unknown but evaluation of coagulation profile is recommended. More studies are necessary to understand its comparative potency, relapse rates, and long-term safety.

Recommendation

Oral TXA 500–750 mg/day in a divided dose may be used in melasma expecting a mild to moderate response for a maximum period of 6 months (Grade A recommendation).

Pretreatment laboratory evaluation and monitoring during treatment is necessary.

Oral TXA can be used along with other topical therapies or IPL/Nd:YAG laser (Grade A recommendation).

Lasers

Lasers used in melasma include:

  1. Pigment-specific lasers (Q-switched, long-pulsed lasers, IPL)
  2. Vascular lasers (pulsed dye, Copper bromide)
  3. Fractional lasers
  4. Ablative lasers.


Nd:YAG laser monotherapy

Low fluence Q-switched (LFQS) Nd:YAG laser has been the most commonly evaluated laser in melasma. However, comparative efficacy of Q-switched Nd:YAG laser (532 nm) with TC or HQ is not available.

Sixteen citations were found that evaluated Nd:YAG laser in melasma and matched our initial screening specific to this topic. Two citations were excluded as they used combination drugs;[81],[82] three studies were excluded as these studies actually assessed adjuvant role of oral TXA,[78] GA peel [83] and vitamin C [41] on Nd:YAG laser. Another article has been excluded because this has been retracted from PubMed.[84] Finally, 10 studies evaluated LFQS Nd:YAG laser on 446 patients [85],[86],[87],[88],[89],[90],[91],[92],[93],[94] [Table 11].
Table 11: Evidence on lasers in melasma

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Among these, six were RCTs, three were nonrandomized uncontrolled studies, and one case–control study. All the three uncontrolled studies (92 patients) reported improvement with LFQS Nd:YAG laser monotherapy (LOE 3).[85],[86],[87] Assessment was not done with standard modality in one of these.[87] Patient number was small.

Studies have documented efficacy of Nd:YAG laser as inferior to 25% TCA peel [88] and low-power fractional CO2 laser [89] and equal to LFQS alexandrite laser (755nm)[90] (LOE 2).

LFQS Nd:YAG laser (1064-nm) was found to result in significantly higher response when combined with IPL in comparison to IPL alone (LOE 2). However, number of patients was less and follow-up was for 2 months only.[91] Another retrospective analysis also reported similar findings [94] (LOE 4).

Various parameters of LFQS Nd:YAG laser have been tried to find out the best one. No significant difference was found between the pulse duration of 5 and 50 ns [93] (LOE 2). Combination of LFQS and long-pulse Nd:YAG resulted in higher decrease in mMASI (3.6 versus 3.0) and significantly lower AEs such as mottled hypopigmentation and rebound hyperpigmentation in comparison to LFQS Nd:YAG laser [94] (LOE 4).

Overall, most of the studies had methodological limitations. Sample size was small and follow-up was limited. Randomized, blinded comparative study with standard drugs such as TC or HQ could be of help to assess its real efficacy.

Recommendation

LFQS Nd:YAG laser (1064 nm) monotherapy is not recommended in melasma.

Nd:YAG laser combination therapy

Efficacy of LFQS Nd:YAG laser was found to be increased when adjuvants such as oral TXA (48 patients, LOE 2),[78] GA peel [83] (15 patients, LOE 2), and vitamin C [41] (8 patients, LOE 3) were added. All such combinations were better than the laser monotherapy. Thus, it may be prudent to use such combination instead of laser monotherapy (Grade D recommendation). However, small number of patients has limited these results to be translated into recommendation. More studies are necessary. See other sections for more details.

Alexandrite laser

Alexandrite laser, though being more pigment-specific compared to Q switched Nd:YAG laser, is expected to have lesser postinflammatory hyperpigmentation. Statistically insignificant, yet higher efficacy of LFQS Nd:YAG laser in comparison to LFQS alexandrite laser (755nm) was reported in a study by Fabi et al. in a very small split-face double-blinded RCT among 20 patients [90] (LOE 2).

Recommendation

Not recommended until further evidence is available.

Q-switched ruby laser

No single study was found that evaluated QSRL monotherapy in melasma. Only one uncontrolled study evaluated 694-nm fractional Q-switched ruby laser (fluence 2.5–3.5 J/cm 2, 7.1 × 7.1 mm spot size, 27.7% area coverage) combined with sonophoresis on levorotatory vitamin C.[81] After four sessions at 2 weeks interval, MASI score decreased by 35% from baseline at follow-up of 3 months after last session.

Recommendation

Not recommended until further evidence is available.

Ablative lasers

Fractional and ablative lasers as single therapies are no longer used due to higher incidence of postinflammatory hyperpigmentation. These have been used with lower fluences.

Fractional CO2 laser

In a split-face double-blinded RCT among 40 patients, low-power fractional CO2 laser was compared to low-fluence Q-switch 1064 nm Nd:YAG laser.[89] Fractional CO2 resulted in significantly higher decrease in melanin index in fractional CO2 side (15.09 ± 13.39 versus 5.97 ± 7.66) and mMASI (8.15 ± 6.53 versus 2.3 ± 3.73) (LOE 2). However, there are many issues in considering this study in recommending this laser in Indian population. Apart from the cost, low-power fractional CO2 laser is an ablative laser. The study was done in non-Asian population. Patient population was only 40. Follow-up was short.

Recommendation

Not recommended in melasma.

Er:YAG laser

Only one study (uncontrolled) on Er:YAG laser (fluence 1 J/cm 2, 5 mm spot size, 2 passes) reported significant improvement in MASI among 15 patients.[95] However, postinflammatory hyperpigmentation was universal (LOE 3).

Recommendation

Not recommended.

Er:Glass laser 107

Only one nonrandomized follow-up study was found that reported marked improvement of more than 75% decrease in MASI in 67.1% patients after 1 month of therapy.[82] However, on follow-up, this became 21.1% at 6 months follow-up.

Recommendation

Not recommended.

Vascular laser

These lasers have an indirect effect in melasma by targeting epidermal vascular endothelial growth factor and dermal vasculature and are more useful in angiogenic melasma.

Copper bromide laser

One nonrandomized study on copper bromide laser (dual-wavelength 511 and 578 nm, fluence 7–19 J/cm 2, 1 mm spot size, 2 passes) could not find any significant improvement among 24 patients in Thailand.[95]

In a split-face RCT among just 20 patients, copper bromide laser was not found superior to TC.[21]

Recommendation

Not recommended until further evidence is available.

Photoprotection in melasma

Evidence

There has been no study among Asians. Four studies were found and all were done among Caucasians. Three out of these four were RCT. Total patients evaluated were 339. Effect was assessed with MASI or calorimetrically [Table 12].
Table 12: Evidence on sun protection

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Role of broadband sunscreen was found to be beneficial in melasma management [97],[98] (LOE 2, LOE 4). Broad spectrum sunscreen along with protection against visible light was found to be better than when visible light was not guarded [99],[100] (LOE 2).

Recommendation

Broad spectrum sunscreen along with visible light protection is recommended in any melasma management strategy (Grade A recommendation).

Miscellaneous drugs

Lignin peroxidase

Only three publications (1 RCT and 2 uncontrolled studies) were found among 142 subjects. All these three studies were done using the product from a single company. More studies among larger number of subjects are necessary to recommend this drug [Table 13].
Table 13: Evidence on lignin peroxidase

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One RCT on 51 Asian patients compared LP with HQ 2% or placebo in a split-face style that reported significantly higher efficacy than HQ 2%. Improvement was seen as early as 7 days [101] (LOE 2). However, it was a very short duration study (31 days).

One nonrandomized study among 60 subjects reported equal efficacy with HQ 4% and higher efficacy than placebo.[102] LP was, however, reported to be superior in improving skin texture and roughness as compared to 4% HQ [102] (LOE 3).

Another uncontrolled open label study also reported significant benefit in melasma [103] (LOE 3). More studies are necessary to assess the efficacy, long-term AE, and relapse rate.

Recommendation

Lignin peroxidase is recommended in melasma (Grade B recommendation).

N-acetyl glucosamine

In the only available study, which is a randomized, double-blinded, split-face study done in 30 females (aged 20–50 years) and compared cream A (4% NAG and 2% nicotinamide) and cream B (4% HQ) for 12 weeks, efficacy of NAG and nicotinamide was found to be slightly more and the side efforts were slightly less than HQ group. However, the difference in mMASI was not statistically significant at the end of the study [104] (LOE 2). The limitations of that study were small sample size, short duration trial, and the absence of NAG monotherapy [Table 14].
Table 14: Evidence on evidence on NAG, LA, silymarin, pidobenzone, and methimazole

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Recommendation

NAG cannot be recommended due to lack of evidence.

Linoleic acid

In a 6-week, double-blind, RCT among 60 patients, linoleic acid (LA) in combination with lincomycin and betamethasone valerate was found to result in higher improvement than a combination of the latter two or vehicle [105] (LOE 2). Addition of LA did not produce any significant AE [Table 14].

Recommendation

There is not enough evidence to recommend use of linoleic acid in melasma.

Silymarin

Only one study was found to evaluate the efficacy of topical silymarin among 60 females [106] [Table 14]. It was compared with intradermal TXA injection and 50% GA peeling. Topical silymarin showed only moderate benefit in melasma with efficacy insignificantly less than GA peel but superior to intradermal TXA (LOE 3).

Recommendation

There is not enough evidence to recommend the use of topical silymarin in melasma.

Pidobenzone

The treatment with pidobenzone 4% (K5 lipogel) twice per day for 16 weeks caused significant reduction in MASI scores by at least 50% in as many as 70% patients without any major AE [107] (LOE 4) [Table 14].

Recommendation

There is not enough evidence to recommend use of pidobenzone cream in melasma.

Methimazole 5%

In two HQ-resistant melasma patients, application of 5% methimazole cream once daily resulted in significant improvement of melasma in both patients after 8 weeks and was well tolerated [108] (LOE 4) [Table 14].

There is a theoretical risk of systemic AE of methimazole. A single study did not show any AE on thyroid but more studies are required to confirm this.[109]

Recommendation

There is not enough evidence to recommend the use of methimazole cream in melasma.

Rucinol

Three double-blind vehicle controlled small RCTs (including one that used liposomal rucinol) evaluated rucinol (0.1–0.3%) in total 75 patients with melasma. All the studies found significantly better response than vehicle [110],[111],[112] (LOE 2). Follow-up was absent and information on relapse was unavailable. None of the study compared this with standard drugs such as HQ. Moderate-to-severe AE was also reported [110] [Table 15]. One uncontrolled open cohort among 52 Indian patients also reported moderate efficacy [113] (LOE 3).
Table 15: Evidence on rucinol

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Recommendation

Rucinol is not recommended in melasma till further evidence suggests advantage over AE.

4-Hydroxyanisol (mequinol)

There are many studies on its beneficial role in solar lentigines.[114],[115],[116],[117],[118] However, only one study is available on melasma and this is a case series on 5 male patients (3 Hispanic and 2 white)[131] [Table 16].
Table 16: Evidence on mequinol and niacinamide

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Mequinol 2% was used along with tretinoin 0.01% topical solution. Four of 5 patients achieved complete clearance of melasma at 12 weeks, and 1 patient showed moderate improvement [119] (LOE 4).

Side effects were minimal. There was an uncontrolled study without any proper evaluation method. Moreover, mequinol was used along with tretinoin. However, all patients were initially resistant to HQ.

Recommendation

There is not enough evidence to recommend the use of topical mequinol in melasma.

Niacinamide

Four RCTs were found that assessed niacinamide.[26],[120],[121],[122] However, two studies included patients with different causes of facial hyperpigmentation in addition to melasma [121],[122] and another one evaluated a combination cream with niacinamide as one ingredient.[1] Thus, only one double-blind RCT evaluated efficacy of niacinamide monotherapy in melasma, and it compared the efficacy with 4% HQ [Table 16].

This study, done among only 27 females, showed good to excellent reduction in pigmentation in 44% of nicotinamide-treated areas compared to 55% with 4% HQ [26] (LOE 2). Side effects of erythema, pruritus, and burning were less frequent and milder with nicotinamide compared to hydroquinone (18% versus 29%). However, there was no follow-up.

Thus, currently, there is significant lack of evidence. More and larger studies are needed.

Recommendation

Niacinamide can be used in melasma (Grade B recommendation).

Triamcinolone injection

One RCT among 42 patients found sub-epidermal triamcinolone injection to be superior to Kligman's formula in improving melasma but AE such as telangiectasia and atrophy were observed [123] (LOE 2).

Recommendation

Not recommended.

Topical betamethasone 17-valerate

No publication was found within the period searched (year 2000 onwards).

Clobetasol propionate

In an uncontrolled study, 10 patients of melasma were treated with topical clobetasol propionate (0.05%) for 8 weeks. After 6–8 weeks 80–90% clearance of pigmentation was observed in 7 patients [125] (LOE 3). However, pigmentation reappeared 2–3 weeks after stopping treatment, even reaching pretreatment state during the next 4–6 months of follow-up. Three patients had to stop therapy after 4 weeks because of local atrophy and striae.[47]

In another single-blind pilot study, split-face comparison study among 30 Indian patients with melasma, initial 8 weeks of 0.05% clobetasol propionate cream followed by 20% azelaic acid cream for the next 16 weeks resulted in higher improvement than azelaic acid monotherapy [125] (LOE 2).

Recommendation

Not recommended.

N-acetyl-4-S-cysteaminylphenol

In a retrospective case series of 12 patients of melasma, 4% N-acetyl-4-S-cysteaminylphenol was applied twice daily for up to 6 months. There was marked improvement in 8 patients, moderate improvement in 3 patients, and almost complete clearance of melasma in 1 patient. Acneiform eruptions were noted in 1 patient [126] (LOE 4).

However, there were many weakness of the study protocol. Apart from the small sample size, no standard evaluation criteria were used; biopsy was done in 2 patients; control was there in just 3 patients; and follow-up duration was variable.

Recommendation

There is not enough evidence to recommend the use of topical N-acetyl cysteaminylphenol in melasma.

Magnolignan

A single, uncontrolled study evaluated a specific product containing 0.5% Magnolignan® on 51 female patients with facial pigmentation (not exclusively melasma after 6 months, authors reported improvement)[127] (LOE 3). However, evaluation method was not standard [Table 17].
Table 17: Evidence on Magnolignan, orchid extract, and dioic acid

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Recommendation

There is not enough evidence to recommend the use of topical Magnolignan in melasma.

Orchid extracts

Only single study was found and it was an open, split-face 8-week trial. Plant extracts (orchid extracts) were compared with vitamin C among 48 Japanese female adult volunteers (30–60 years) with melasma and/or lentigosenilis. The extract was found to be efficacious clinically, in colorimetric measurements and subjectively using a questionnaire [128] (LOE 3) [Table 17].

The extract contained various components, evaluation method was not standard, and comparison was done with vitamin C, which in itself is a weak depigmenting agent.

Recommendation

There is not enough evidence to recommend the use of topical orchid extract in melasma.

Dioic acid

In the only available study done among 96 Mexican females, 1% dioic acid cream was found to improve melasma significantly (MASI) and similar in efficacy to that of 2% HQ cream [129] (LOE 3) [Table 17].

Recommendation

There is not enough evidence to recommend the use of topical dioic acid in melasma.

Octadienedioic acid

No study in melasma available. One Chinese study compared 1% ODA cream with 2% arbutin in forearm for 8 weeks to evaluate its ability to reduce melanin index.[130]

Recommendation

Not possible.

B-carotene

Only single-cohort study done long back is available. Among the 31 Indian patients (26 females and 5 males), clinical improvement was noticed in all except 2 at 8 weeks. Nine patients who continued the drug had further improvement of lower grade [131] (LOE 3). No major AE reported [Table 18].
Table 18: Evidence on B-carotene and licorice

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Recommendation

There is not enough evidence to recommend the use of topical beta-carotene in melasma.

Licorice

No study on licorice monotherapy available. A single RCT among 56 female subjects (89% concluded the study) compared the efficacy of a combination of emblica, licorice, and belides 7% with 2% HQ. Both the group had similar efficacy [132] (LOE 2) [Table 18].

There were many weaknesses of the study. It was a complex combination of licorice; there was no follow-up and evaluation method was poorly defined. Mild burning sensation is reported.

Recommendation

There is not enough evidence to recommend the use of topical licorice in melasma.

Other drugs

There were some reports of improvement in pigmentation but no human clinical studies in melasma were found for the following molecules/drugs:

Aloesin, ebselen,[133] cinnamic acid,[134],[135] pyronic acrylic acid inhibitors,[136] zinc dihydrolipoylhistidinate,[137] resveratrol, 8-methoxycinnamaldehyde, soy, flavonoids, and alpha tocopherol ferulate.

Recommendation

There is not enough evidence to recommend the use of any of these drugs in melasma.

Suggested therapeutic recommendation for melasma

Before a step-ladder treatment protocol is suggested, it may be prudent to classify the available melasma drugs. The classification has been done based on the potency, safety, and the type of therapy. Evidence (whenever available, see the earlier section) and opinion of the team members have been utilized to prepare this classification.

Classification of melasma drugs

  1. Class 1: Daily TC*. Maximum allowable duration for daily therapy is 12 weeks
  2. Class 2: HQ 4% (Maximum allowable duration for daily therapy 3 months), azelaic acid 20% cream (Maximum allowable duration for daily therapy 6 months)
  3. Class 3: HQ 2%, KA 2%, topical retinoids, chemical peels, and various other drugs with known efficacy (see the previous text). Most of these drugs are safer and less potent than the first and second line. It is considered to be safer than those without any strong evidence in this regard. Although most of the studies have recommended the use for 3 months, maximum allowable duration may be longer. However, no definite information is available at least for some of these
  4. Class 4: Oral TXA (500–750 mg/day) for a maximum period of 6 months
  5. Class 5: Laser. LFQS Nd:YAG laser is most preferred Most studies have used up to 6 sessions and some up to 15 sessions.


Outside any category: Sunscreen6.

*TC, unless specifically mentioned, usually means fluocinolone acetonide-based TC (FTC).

Step-wise treatment protocol for melasma

Flowcharts [Figure 1] and [Figure 2] have been presented for understanding step-wise management protocol of melasma. It must be understood that there may be various situations outside the purview of this protocol. Entire previous sections will help the physician to take right decision in any such special situation.
Figure 1: Step-wise management plan for “new patients” or “patients who were treated long back”

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Figure 2: Step-wise management of “relapsed cases”

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Some rules for using the flow chart

  1. In the flowchart, change from one drug to another should ideally be done when it reaches the maximum allowable period (if available) for that particular drug or earlier if there is an AE
  2. Sunscreen should be used in all cases
  3. TC indicates fluocinolone-based TC
  4. Combination treatment indicates all possible combinations with drugs that can be used. Treating physician should select various combinations according to the evidence cited in earlier section and use his/her clinical knowledge
  5. One drug may not be used when there is known information of poor response in the recent past, presence of signs of AE that might be due to same/similar drug or might be aggravated by this drug, and when the maximum allowable limit for a continuous therapy has crossed
  6. The starting point of treatment for a particular patient in the step ladder has to be judged by the physician
  7. Drug holiday, even for many months, after most of the options have been exhausted is a logical step before reinitiating of the treatment.



   Conclusion Top


A therapeutic guideline for melasma that will be universally acceptable is difficult to design even when it is evidence based. Generally, a step-ladder therapeutic protocol follows a principle where efficacy is the primary criteria for selecting a drug over other. However, practically, efficacy may not be the priority in many cases of melasma. Due to the availability of almost all topical formulations over-the-counter in India, it is not uncommon to find patient who has already applied TC, HQ, and other topical steroid formulations, even much beyond the safety limit prior to seeking opinion of a dermatologist. These patients usually have obvious manifestations of AE related to these drugs and are unsuitable for any further exposure to similar drugs. Thus, safety becomes the priority in these situations.

Second, there is the large gap between the available and required scientific evidence for the treatment of melasma. Various treatment options are available but well-designed RCTs are lacking. Due to nonhomogenous study parameters, outcome assessment and comparison is extremely difficult. Long-term safety, risk of AE, potency in comparison to the established therapies are unknown for most of the drugs. Significant lack of large studies among Indians is another hindrance to develop a therapeutic guideline for the Indians. Females largely outnumbered the males resulting in lack of evidence for the ideal therapeutic options for males.

Proposed therapeutic guideline is based on, but not exclusively dependent on, the evidence. We have considered various practical aspects while formulating the therapeutic recommendation.

Melasma is a resistant disease and relapse is a rule than a rarity. This, on the backdrop of paucity of evidence on drugs for every practical situation, treatment of this condition should not be very strictly bound by guideline. We are of opinion that the treating physician should use his/her clinical acumen to select various combinations that he/she might consider safe and effective.

It is expected that this publication with detailed evidence on melasma treatment and suggested step-wise treatment recommendation will be helpful for the physicians primarily practicing in India and other neighboring countries having people with similar ethnic origin.

Finally, this is not a legal document. Similar to all other guidelines, nonadherence to this guideline may not be considered as a negligence and adherence may not be considered as a defense to negate negligence.

Financial support and sponsorship

This project was undertaken by “IADVL-Special Interest Group (SIG)—Pigmentary Disorders (2014–2016).” However, there was no financial support.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8], [Table 9], [Table 10], [Table 11], [Table 12], [Table 13], [Table 14], [Table 15], [Table 16], [Table 17], [Table 18]



 

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