|IADVL-SIG PIGMENTARY DISORDERS SYMPOSIUM ARTICLE
|Year : 2017 | Volume
| Issue : 6 | Page : 406-442
Evidence-based review, grade of recommendation, and suggested treatment recommendations for melasma
Nilendu Sarma1, Sayantani Chakraborty2, Shital A Poojary3, Sanjay Rathi4, Sendhil Kumaran5, Balakrishnan Nirmal6, Joan Felicita7, Rashmi Sarkar8, Prashansa Jaiswal9, Paschal D'Souza9, Nagaraju Donthula5, Sumit Sethi8, Pallavi Ailawadi8, Bebisha Joseph7
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 Publication||14-Nov-2017|
P N Colony, Sapui Para, Bally, Howrah, West Bengal
Source of Support: None, Conflict of Interest: None
| 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 2018 Apr 24];8:406-42. Available from: http://www.idoj.in/text.asp?2017/8/6/406/218324
| Introduction|| |
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.
Preparing a scientifically designed, exhaustive document on level of evidence, grade of recommendation, and suggested therapeutic guideline for melasma.
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.”
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.”
Grade of recommendation
Grading of recommendation was done based on OCEBM—Levels of Evidence (March 2009).
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.
Some new data might be published since the preparation of this article.
Detailed evidence on each drugs and grade of recommendation
Nineteen studies and one Cochrane review were found on TC.,,,,,,,,,,,,,,,,,,, Among these, 14 studies including one review were done with fluocinolone acetonide-based triple combination (FTC) monotherapy,,,,,,,,,,,,,, 3 used TC combined with other drugs ,, 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.,,,, Four studies used TC with steroids other than fluocinolone acetonide.,,, Total number of patients evaluated with FTC (excluding the review) was more than 4000 patients [Table 1].
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).,
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.) (LOE 3). In other studies, FTC was found to be superior to 4% HQ monotherapy  (LOE 2), dual combinations (RA+HQ, RA+FA, and HQ+FA) (LOE 2), and some proprietary skin lightening product (HQ-based combination product) (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. 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  (LOE 2). More studies are necessary to substantiate this finding.
- FA-based TC (FA 0.01%, HQ 4%, RA 0.05%) is recommended in melasma (Grade A recommendation)
- 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.,, TC combined with GA peel was reported to be efficacious (LOE 3), 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. Authors found greater and early improvement with combination treatment (TC and GA peel) (LOE 3).
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.
- 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.
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  (LOE 2).
Studies have used daily  as well as intermittent regimens ,,, 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  (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  (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 , (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.
- 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  (LOE 4).
Only one study was found that compared FA and triamcinolone (0.02%) containing TC. Both were found to be similar in efficacy  (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  (LOE 2). However, sample size was very less (only 16 patients completed the trial).
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).
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 ,,,,,,,,,,, [Table 2].
HQ 4% was found to be more effective than placebo in the treatment of melasma., In addition, HQ 4% was reported to be significantly superior to 5% ascorbic acid  (LOE 2). Although 4% HQ resulted in higher efficacy than kojic acid (0.75%) (LOE 3) and 4% niacinamide  (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) (LOE 1). Since that review was published, only one study reported 20% AA as significantly more efficacious than 4% HQ  (LOE 3).
A single study reported lesser efficacy when compared to 3% rumex occidentalis  (LOE-2) and 1% flutamide  (LOE-2). No further studies substantiated these findings however. All the three RCTs comparing efficacy of 4% HQ with TC (two fluocinolone-based , and one dexamethasone-based ) 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., Some studies have continued till 24 weeks without any report of AE., None of the studies included dermal melasma in study subjects.
Irritation is the main AE with HQ.,, 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).,,
No recommendation possible unless further studies are available.
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 ,,, [Table 3].
Two studies used 0.1% RA (tretinoin) and the other one 0.05% isotretinoin gel.,, 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%. 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.
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).
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 ,,,, [Table 4]. Three studies evaluated vitamin C as monotherapy and compared with other modalities.,,
Vitamin C was reported to be more efficacious than distilled water iontophoresis  (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  (LOE 2).
It was, however, found to be inferior to HQ 4% (LOE 2).
Two studies found significant additional benefit of adding vitamin C to other modalities such as 20% trichloroacetic acid (TCA) peel  (LOE 3) and 1064-nm Q-switched Nd:YAG laser  (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.
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.
Two studies used vitamin E in melasma., None of these two studies used vitamin as monotherapy.
Presently, there is lack of evidence to recommend vitamin E as monotherapy in melasma.
Glycolic acid cream
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 , [Table 5].
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. Thus it was not rejected.
One RCT evaluated GA cream as an adjuvant to 4% HQ. 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).
There is lack of evidence to recommend use of glycolic acid cream in melasma.
Seven studies including one systematic review (Cochrane review) were found to evaluate efficacy of azelaic acid in melasma.,,,,,,,, Total patients evaluated were 383 (excluding the review) [Table 6].
One Cochrane review, published in 2010, reported equal efficacy of AA 20% to that of HQ 4% (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.
That Cochrane systematic review reported significantly higher efficacy of AA 20% than HQ 2% (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  (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.
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).
Four studies were found that evaluated arbutin in melasma ,,, [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.,
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  (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  (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.
However, this may be used in melasma for short term. (Grade D recommendation).
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%),,, [Table 8].
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  (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  (LOE 2).
Study by Deo et al. 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  (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.
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|| |
Totally, 389 patients were assessed in nine studies including five RCTs ,,,,,,,, [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  (LOE 2). However, sample size was small. No other studies were done to validate these findings.
GA peel (70%) was found to be similar in efficacy with tretinoin 1% peel but tretinoin peel was more tolerable by the patients , (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) (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. 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  (LOE 2). However, in another small RCT, combining HQ 4% with GA peel was not found to be superior to HQ monotherapy  (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  (LOE 3).
GA peel was compared with TCA peel in two studies. Efficacy was found to be equal , (LOE 3). However, speed of response as well as relapse was faster with TCA, indicating GA to be a better option than TCA.
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.
- GA peel may be used in melasma (Grade A recommendation)
- 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
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 , (LOE 3). Response with TCA peels was faster but relapse was also commoner.
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  (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  (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.
TCA peel can be used in melasma as monotherapy, or combined with other peel like modified Jessner's solution (Grade B recommendation).
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 , (LOE 2, 4). However, tretinoin peel was more tolerable than GA [Table 9].
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  (LOE 2).
Another group found no difference between SA peel and HQ 4%. However, the study was done in just 20 patients  (LOE 2).
Overall, evidence is significantly lacking. No significant AE is reported. More studies are required to understand its true efficacy and AE.
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 , (LOE 4, 3).
Lactic acid peel may be used in melasma (Grade of recommendation B).
Two studies, one RCT and one nonrandomized trial, evaluated Jessner's solution in the treatment of melasma [Table 9].
Ejaz et al. 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  (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.
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. 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  (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.
- All peels may be used in melasma (Grade of recommendation B)
- 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)
- 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
Ten studies,,,,,,,,,, including one systematic review, 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).
Improvement was noticed as early as 4 weeks in a systematic review. Three uncontrolled studies also reported response within 4 weeks.,, Some studies reported a longer median time of 2 months.
None of the studies reported any significant AE except one case of deep vein thrombosis in a patient who had existing protein S deficiency. 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).,
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  (LOE 2). Three studies (2 RCTs and 1 case–control study) evaluated additional efficacy of oral TXA on Nd:YAG laser, FTC, and IPL. 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.
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.
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 used in melasma include:
- Pigment-specific lasers (Q-switched, long-pulsed lasers, IPL)
- Vascular lasers (pulsed dye, Copper bromide)
- Fractional lasers
- 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;, three studies were excluded as these studies actually assessed adjuvant role of oral TXA, GA peel  and vitamin C  on Nd:YAG laser. Another article has been excluded because this has been retracted from PubMed. Finally, 10 studies evaluated LFQS Nd:YAG laser on 446 patients ,,,,,,,,, [Table 11].
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).,, Assessment was not done with standard modality in one of these. Patient number was small.
Studies have documented efficacy of Nd:YAG laser as inferior to 25% TCA peel  and low-power fractional CO2 laser  and equal to LFQS alexandrite laser (755nm) (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. Another retrospective analysis also reported similar findings  (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  (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  (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.
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), GA peel  (15 patients, LOE 2), and vitamin C  (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, 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  (LOE 2).
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. After four sessions at 2 weeks interval, MASI score decreased by 35% from baseline at follow-up of 3 months after last session.
Not recommended until further evidence is available.
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. 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.
Not recommended in melasma.
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. However, postinflammatory hyperpigmentation was universal (LOE 3).
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. However, on follow-up, this became 21.1% at 6 months follow-up.
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.
In a split-face RCT among just 20 patients, copper bromide laser was not found superior to TC.
Not recommended until further evidence is available.
Photoprotection in melasma
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].
Role of broadband sunscreen was found to be beneficial in melasma management , (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 , (LOE 2).
Broad spectrum sunscreen along with visible light protection is recommended in any melasma management strategy (Grade A recommendation).
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].
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  (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. LP was, however, reported to be superior in improving skin texture and roughness as compared to 4% HQ  (LOE 3).
Another uncontrolled open label study also reported significant benefit in melasma  (LOE 3). More studies are necessary to assess the efficacy, long-term AE, and relapse rate.
Lignin peroxidase is recommended in melasma (Grade B recommendation).
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  (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|
Click here to view
NAG cannot be recommended due to lack of evidence.
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  (LOE 2). Addition of LA did not produce any significant AE [Table 14].
There is not enough evidence to recommend use of linoleic acid in melasma.
Only one study was found to evaluate the efficacy of topical silymarin among 60 females  [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).
There is not enough evidence to recommend the use of topical silymarin in melasma.
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  (LOE 4) [Table 14].
There is not enough evidence to recommend use of pidobenzone cream in melasma.
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  (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.
There is not enough evidence to recommend the use of methimazole cream in melasma.
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 ,, (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  [Table 15]. One uncontrolled open cohort among 52 Indian patients also reported moderate efficacy  (LOE 3).
Rucinol is not recommended in melasma till further evidence suggests advantage over AE.
There are many studies on its beneficial role in solar lentigines.,,,, However, only one study is available on melasma and this is a case series on 5 male patients (3 Hispanic and 2 white) [Table 16].
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  (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.
There is not enough evidence to recommend the use of topical mequinol in melasma.
Four RCTs were found that assessed niacinamide.,,, However, two studies included patients with different causes of facial hyperpigmentation in addition to melasma , and another one evaluated a combination cream with niacinamide as one ingredient. 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  (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.
Niacinamide can be used in melasma (Grade B recommendation).
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  (LOE 2).
Topical betamethasone 17-valerate
No publication was found within the period searched (year 2000 onwards).
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  (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.
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  (LOE 2).
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  (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.
There is not enough evidence to recommend the use of topical N-acetyl cysteaminylphenol in melasma.
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) (LOE 3). However, evaluation method was not standard [Table 17].
There is not enough evidence to recommend the use of topical Magnolignan in melasma.
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  (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.
There is not enough evidence to recommend the use of topical orchid extract in melasma.
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  (LOE 3) [Table 17].
There is not enough evidence to recommend the use of topical dioic acid in melasma.
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.
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  (LOE 3). No major AE reported [Table 18].
There is not enough evidence to recommend the use of topical beta-carotene in melasma.
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  (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.
There is not enough evidence to recommend the use of topical licorice in melasma.
There were some reports of improvement in pigmentation but no human clinical studies in melasma were found for the following molecules/drugs:
Aloesin, ebselen, cinnamic acid,, pyronic acrylic acid inhibitors, zinc dihydrolipoylhistidinate, resveratrol, 8-methoxycinnamaldehyde, soy, flavonoids, and alpha tocopherol ferulate.
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
- Class 1: Daily TC*. Maximum allowable duration for daily therapy is 12 weeks
- Class 2: HQ 4% (Maximum allowable duration for daily therapy 3 months), azelaic acid 20% cream (Maximum allowable duration for daily therapy 6 months)
- 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
- Class 4: Oral TXA (500–750 mg/day) for a maximum period of 6 months
- 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”|
Click here to view
Some rules for using the flow chart
- 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
- Sunscreen should be used in all cases
- TC indicates fluocinolone-based TC
- 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
- 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
- The starting point of treatment for a particular patient in the step ladder has to be judged by the physician
- Drug holiday, even for many months, after most of the options have been exhausted is a logical step before reinitiating of the treatment.
| Conclusion|| |
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|| |
Grimes P, Kelly AP, Torok H, Willis I. Community-based trial of a triple-combination agent for the treatment of facial melisma. Cutis 2006;77:177-84.
Cestari TF, Hexsel D, Viegas ML, Azulay L, Hassun K, Almeida AR, et al
. Validation of a melasma quality of life questionnaire for Brazilian Portuguese language: The MelasQoL-BP study and improvement of QoL of melasma patients after triple combination therapy. Br J Dermatol 2007;1561:13-20.
Torok HM, Jones T, Rich P, Smith S, Tschen E. Hydroquinone 4%, tretinoin 0.05%, fluocinolone acetonide 0.01%: A safe and efficacious 12-month treatment for melasma. Cutis 2005;75:57-62.
Torok H, Taylor S, Baumann L, Jones T, Wieder J, Lowe N, et al
. A large 12-month extension study of an 8-week trial to evaluate the safety and efficacy of triple combination (TC) cream in melasma patients previously treated with TC cream or one of its dyads. J Drugs Dermatol 2005;4:592-7.
Goldman MP, Gold MH, Palm MD, Colón LE, Preston N, Johnson LA, et al.
Sequential treatment with triple combination cream and intense pulsed light is more efficacious than sequential treatment with an inactive (control) cream and intense pulsed light in patients with moderate to severe melasma. Dermatol Surg. 2011;37:224-33.
Chan R, Park KC, Lee MH, Lee ES, Chang SE, Leow YH, et al
. A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma. Br J Dermatol 2008;159:697-703.
Taylor SC, Torok H, Jones T, Lowe N, Rich P, Tschen E, et al
. Efficacy and safety of a new triple-combination agent for the treatment of facial melasma. Cutis 2003;72:67-72.
Monheit G, Dreher F. Comparison of a skin-lightening cream targeting melanogenesis on multiple levels to triple combination cream for melasma. J Drugs Dermatol 2013;12:270-4.
Pratchyapruit W, Vashrangsi N, Sindhavananda J, Tagami H. Instrumental analysis of the pattern of improvement and that of recurrence of melasma in Thai females treated with Kligman-Willis triple combination therapy: Confirmation by using its two different formulae. Skin Res Technol. 2011;17:226-33.
Rajaratnam R, Halpern J, Salim A, Emmett C. Interventions for melasma. Cochrane Database Syst Rev 2010:CD003583.
Mahajan R, Kanwar AJ, Parsad D, Kumaran MS, Sharma R. Glycolic acid peels/azelaic acid 20% cream combination and low potency triple combination lead to similar reduction in melasma severity in ethnic skin: Results of a randomized controlled study. Indian J Dermatol 2015;60:147-52.
Grimes PE, Bhawan J, Guevara IL, Colón LE, Johnson LA, Gottschalk RW, et al
. Continuous therapy followed by a maintenance therapy regimen with a triple combination cream for melasma. J Am Acad Dermatol 2010;62:962-7.
Arellano I, Cestari T, Ocampo-Candiani J, Azulay-Abulafia L, Bezerra Trindade Neto P, Hexsel D, et al
. Preventing melasma recurrence: Prescribing a maintenance regimen with an effective triple combination cream based on long-standing clinical severity. J Eur Acad Dermatol Venereol 2012;26:611-8.
Hexsel D, Soirefmann M, Fernandes JD, Siega C. Objective assessment of erythema and pigmentation of melasma lesions and surrounding areas in long-term management regimens with triple combination. J Drugs Dermatol 2014;13:444-8.
Godse KV. Triple combination of hydroquinone, tretinoin and mometasone furoate with glycolic acid peels in melasma. Indian J Dermatol 2009;54:92-3.
] [Full text]
Rendon M, Cardona LM, Bussear EW, Benitez AL, Colón LE, Johnson LA. Successful treatment of moderate to severe melasma with triple-combination cream and glycolic acid peels: A pilot study. Cutis 2008;82:372-8.
Chaudhary S, Dayal S. Efficacy of combination of glycolic acid peeling with topical regimen in treatment of melasma. J Drugs Dermatol 2013;12:1149-53.
Majid I. Mometasone-based triple combination therapy in melasma: Is it really safe? Indian J Dermatol 2010;55:359-62.
] [Full text]
Hammami Ghorbel H, Boukari F, Fontas E, Montaudié H, Bahadoran P, Lacour JP, et al
. Copper bromide laser vs triple-combination cream for the treatment of melasma: A randomized clinical trial. JAMA Dermatol 2015;151:791-2.
Haddad AL, Matos LF, Brunstein F, Ferreira LM, Silva A, Costa D. A clinical, prospective, randomized, double-blind trial comparing skin whitening complex with hydroquinone vs. placebo in the treatment of melasma. Int J Dermatol 2003;42:153-6.
EnnesSBP, RC Paschoalick, M Mota De Avelar Alchorne. A double-blind, comparative, placebo-controlled study of the efficacy and tolerability of 4% hydroquinone as a depigmenting agent in melasma. J Dermatol Treat 2000;11:173-79.
Espinal-Perez LE, Moncada B, Castanedo-Cazares JP. A double-blind randomized trial of 5% ascorbic acid vs. 4% hydroquinone in melasma. Int J Dermatol 2004;43:604-7.
Monteiro RC, Kishore BN, Bhat RM, Sukumar D, Martis J, Ganesh HK. A comparative study of the efficacy of 4% hydroquinone vs 0.75% kojic acid cream in the treatment of facial melasma. Indian J Dermatol 2013;58:157.
] [Full text]
Navarrete-Solís J, Castanedo-Cázares JP, Torres-Álvarez B, Oros-Ovalle C, Fuentes-Ahumada C, González FJ, et al
. A double-blind, randomized clinical trial of niacinamide 4% versus hydroquinone 4% in the treatment of melasma. Dermatol Res Pract 2011;2011:379173.
Farshi S. Comparative study of therapeutic effects of 20% azelaic acid and hydroquinone 4% cream in the treatment of melasma. J Cosmet Dermatol 2011;10:282-7.
Mendoza CG, Singzon IA, Handog EB. A randomized, double-blind, placebo-controlled clinical trial on the efficacy and safety of 3% Rumex occidentalis cream versus 4% hydroquinone cream in the treatment of melasma among Filipinos. Int J Dermatol 2014;53:1412-6.
Adalatkhah H, Sadeghi-Bazargani H. The first clinical experience on efficacy of topical flutamide on melasma compared with topical hydroquinone: A randomized clinical trial. Drug Des Devel Ther 2015;9:4219-25.
Ferreira Cestari T, Hassun K, Sittart A, de Lourdes Viegas M. A comparison of triple combination cream and hydroquinone 4% cream for the treatment of moderate to severe facial melasma. J Cosmet Dermatol 2007;6:36-9.
Astaneh R, Farboud E, Nazemi MJ. 4% Hydroquinone versus 4% hydroquinone, 0.05% dexamethasone and 0.05% tretinoin in the treatment of melasma: A comparative study. Int J Dermatol 2005;44:599-601.
Gold M, Rendon M, Dibernardo B, Bruce S, Lucas-Anthony C, Watson J. Open label treatment of moderate or marked melasma with a 4% hydroquinone skin care system plus 0.05% tretinoin cream. J Clin Aesthet Dermatol 2013;6:32-8.
Grimes P, Watson J. Treating epidermal melasma with a 4% hydroquinone skin care system plus tretinoin cream 0.025%. Cutis 2013;91:47-54.
Rendon M, Dryer L. Investigator-blinded, single-center study to evaluate the efficacy and tolerability of a 4% hydroquinone skin care system plus 0.02% tretinoin cream in mild-to-moderate melasma and photodamage. J Drugs Dermatol 2016;15:466-75.
Griffiths CE, Finkel LJ, Ditre CM, Hamilton TA, Ellis CN, Voorhees JJ. Topical tretinoin (retinoic acid) improves melasma. A vehicle-controlled, clinical trial. Br J Dermatol 1993;129:415-21.
Kimbrough-Green CK, Griffiths CE, Finkel LJ, Hamilton TA, Bulengo Ransby SM, Ellis CN, et al
. Topical retinoic acid (tretinoin) for melasma in black patients. A vehicle-controlled clinical trial. Arch Dermatol 1994;130:727-33.
Leenutaphong V, Nettakul A, Rattanasuwon P. Topical isotretinoin for melasma in Thai patients: A vehicle-controlled clinical trial. J Med Assoc Thai 1999;82:868-75.
Huh CH, Seo KI, Park JY, Lim JG, Eun HC, Park KC. A randomized, double-blind, placebo-controlled trial of vitamin C iontophoresis in melasma. Dermatology 2003;206:316-20.
Sobhi RM, Sobhi AM. A single-blinded comparative study between the use of glycolic acid 70% peel and the use of topical nanosome vitamin C iontophoresis in the treatment of melasma. J Cosmet Dermatol 2012;11:65-71.
Soliman MM, Ramadan SA, Bassiouny DA, Abdelmalek M. Combined trichloroacetic acid peel and topical ascorbic acid versus trichloroacetic acid peel alone in the treatment of melasma: A comparative study. J Cosmet Dermatol 2007;6:89-94.
Lee MC, Chang CS, Huang YL, Chang SL, Chang CH, Lin YF, et al
. Treatment of melasma with mixed parameters of 1,064-nm Q-switched Nd:YAG laser toning and an enhanced effect of ultrasonic application of vitamin C: A split-face study. Lasers Med Sci 2015;30:159-63.
Handog EB, Galang DA, de Leon-Godinez MA, Chan GP. A randomized, double-blind, placebo-controlled trial of oral procyanidin with vitamins A, C, E for melasma among Filipino women. Int J Dermatol 2009;48:896-901.
Guevara IL, Pandya AG. Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and sunscreen in the treatment of melasma. Int J Dermatol 2003;42:966-72.
Hantash BM, Jimenez F. A split-face, double-blind, randomized and placebo-controlled pilot evaluation of a novel oligopeptide for the treatment of recalcitrant melasma. J Drugs Dermatol 2009;8:732-5.
Ibrahim ZA, Gheida SF, El Maghraby GM, Farag ZE. Evaluation of the efficacy and safety of combinations of hydroquinone, glycolic acid, and hyaluronic acid in the treatment of melasma. J Cosmet Dermatol 2015;14:113-23.
Mazurek K, Pierzchala E. Comparison of efficacy of products containing azelaic acid in melasma treatment. J Cosmet Dermatol 2016;15:269-82.
Sarkar R, Bhalla M, Kanwar AJ. A comparative study of 20% azelaic acid cream monotherapy versus a sequential therapy in the treatment of melasma in dark-skinned patients. Dermatology 2002;205:249-54.
Verallo-Rowell VM, Verallo V, Graupe K, Lopez-Villafuerte L, Garcia-Lopez M. Double-blind comparison of azelaic acid and hydroquinone in the treatment of melasma. Acta Derm Venereol Suppl 1989;143:58-61.
Bansal C, Naik H, Kar HK, Chauhan A. A comparison of low-fluence 1064-nm Q-switched Nd:YAG laser with topical 20% azelaic acid cream and their combination in melasma in Indian patients. J Cutan Aesthet Surg 2012;5:266-72.
] [Full text]
Crocco EI, Veasey JV, Boin MF, Lellis RF, Alves RO. A novel cream formulation containing nicotinamide 4%, arbutin 3%, bisabolol 1%, and retinaldehyde 0.05% for treatment of epidermal melasma. Cutis 2015;96:337-42.
Polnikorn N. Treatment of refractory melasma with the MedLite C6 Q-switched Nd:YAG laser and alpha arbutin: A prospective study. J Cosmet Laser Ther 2010;12:126-31.
Morag M, Nawrot J, Siatkowski I, Adamski Z, Fedorowicz T, Dawid-Pac R, et al
. A double-blind, placebo-controlled randomized trial of Serratulae quinque foliae folium, a new source of β-arbutin, in selected skin hyperpigmentations. J Cosmet Dermatol 2015;14:185-90.
Ertam I, Mutlu B, Unal I, Alper S, Kivçak B, Ozer O. Efficiency of ellagic acid and arbutin in melasma: A randomized, prospective, open-label study. J Dermatol 2008;35:570-4.
Garcia A, Fulton JE Jr. The combination of glycolic acid and hydroquinone or kojic acid for the treatment of melasma and related conditions. Dermatol Surg 1996;22:443-7.
Deo KS, Dash KN, Sharma YK, Virmani NC, Oberai C. Kojic acid vis-a-vis its combinations with hydroquinone and betamethasone valerate in melasma: A randomized, single blind, comparative study of efficacy and safety. Indian J Dermatol 2013;58:281-5.
] [Full text]
Lim JT. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Dermatol Surg 1999;25:282-4.
Faghihi G, Shahingohar A, Siadat AH. Comparison between 1% tretinoin peeling versus 70% glycolic acid peeling in the treatment of female patients with melasma. J Drugs Dermatol 2011;10:1439-42.
Khunger N, Sarkar R, Jain RK. Tretinoin peels versus glycolic acid peels in the treatment of melasma in dark-skinned patients. Dermatol Surg 2004;30:756-60.
Garg VK, Sarkar R, Agarwal R. Comparative evaluation of beneficiary effects of priming agents (2% hydroquinone and 0.025% retinoic acid) in the treatment of melasma with glycolic acid peels. Dermatol Surg 2008 Aug; 34:1032-9.
Erbil H, Sezer E, Taştan B, Arca E, Kurumlu Z. Efficacy and safety of serial glycolic acid peels and a topical regimen in the treatment of recalcitrant melasma. J Dermatol 2007;34:25-30.
Hurley ME, Guevara IL, Gonzales RM, Pandya AG. Efficacy of glycolic acid peels in the treatment of melasma. Arch Dermatol 2002;138:1578-82.
Sarkar R, Kaur C, Bhalla M, Kanwar AJ. The combination of glycolic acid peels with a topical regimen in the treatment of melasma in dark-skinned patients: A comparative study. Dermatol Surg 2002 Sep; 28:828-32.
Kalla G, Garg A, Kachhawa D. Chemical peeling—glycolic acid versus trichloroacetic acid in melasma. Indian J Dermatol Venereol Leprol 2001;67:82-4.
] [Full text]
Puri N. Comparative study of 15% TCA peel versus 35% glycolic acid peel for the treatment of melasma. Indian Dermatol Online J 2012;3:109-13.
] [Full text]
Safoury OS, Zaki NM, El Nabarawy EA, Farag EA. A study comparing chemical peeling using modified Jessner's solution and 15% trichloroacetic acid versus 15% trichloroacetic acid in the treatment of melasma. Indian J Dermatol 2009;54:41-5.
] [Full text]
Ejaz A, Raza N, Iftikhar N, Muzzafar F. Comparison of 30% salicylic acid with Jessner's solution for superficial chemical peeling in epidermal melasma. J Coll Physicians Surg Pak 2008;18:205-8.
Kodali S, Guevara IL, Carrigan CR, Daulat S, Blanco G, Boker A, et al.
Aprospective, randomized, split-face, controlled trial of salicylic acid peels in the treatment of melasma in Latin American women. J Am Acad Dermatol 2010;63:1030-5.
Sharquie KE, Al-Tikreety MM, Al-Mashhadani SA. Lactic acid as a new therapeutic peeling agent in melasma. Dermatol Surg 2005;31:149-54.
Sharquie KE, Al-Tikreety MM, Al-Mashhadani SA. Lactic acid chemical peels as a new therapeutic modality in melasma in comparison to Jessner's solution chemical peels. Dermatol Surg 2006;32:1429-36.
Rivas S, Pandya AG. Treatment of melasma with topical agents, peels and lasers: An evidence-based review. Am J Clin Dermatol 2013;14:359-76.
Tse TW, Hui E. Tranexamic acid: An important adjuvant in the treatment of melasma. J Cosmetic Dermatol 2013;12:57-66.
Lee HC, Thng TG, Goh CL. Oral tranexamic acid in the treatment of melasma: A retrospective analysis. J Am Acad Dermatol 2016;75:385-92.
Tan AWM, Sen P, Chua SH, Goh BK. Oral tranexamic acid lightens refractory melasma. Australas J Dermatol 2016 [Epub ahead of print].
Na JI, Choi SY, Yang SH, Choi HR, Kang HY, Park KC. Effect of tranexamic acid on melasma: A clinical trial with histological evaluation. J Eur Acad Dermatol Venereol 2013;27:1035-9.
Li Y, Sun Q, He Z, Fu L, He C, Yan Y. Treatment of melasma with oral administration of compound tranexamic acid: A preliminary clinical trial. J Eur Acad Dermatol Venereol 2014;28:393-4.
Wu S, Shi H, Wu H, Yan S, Guo J, Sun Y, et al
. Treatment of melasma with oral administration of tranexamic acid. Aesthetic Plastic Surg 2012;36:964-70.
Karn D, Kc S, Amatya A, Razouria EA, Timalsina M. Oral tranexamic acid for the treatment of melasma. Kathmandu Univ Med J 2012;10:40-3.
Shin JU, Park J, Oh SH, Lee JH. Oral tranexamic acid enhances the efficacy of low fluence 1064 Nm Q switched Nd:YAG laser treatment for melasma in Koreans: A randomised prospective trial. Dermatol Surg 2013;39:436-42.
Padhi T, Pradhan S. Oral tranexamic acid with fluocinolone-based triple combination cream versus fluocinolone-based triple combination cream alone in melasma: An open labelled randomised comparative trial. Indian J Dermatol 2015;60:520.
] [Full text]
Cho HH, Choi M, Cho S, Lee JH. Role of oral tranexamic acid in melasma patients treated with IPL and low fluence QS Nd:YAG laser. J Dermatol Treat 2013;24:292-6.
Zhou HL, Hu B, Zhang C. Efficacy of 694-nm fractional Q-switched ruby laser (QSRL) combined with sonophoresis on levorotatory vitamin C for treatment of melasma in Chinese patients. Lasers Med Sci 2016;31:991-5.
Tourlaki A, Galimberti MG, Pellacani G, Bencini PL. Combination of fractional erbium-glass laser and topical therapy in melasma resistant to triple-combination cream. J Dermatolog Treat 2014;25:218-22.
Vachiramon V, Sahawatwong S, Sirithanabadeekul P. Treatment of melasma in men with low-fluence Q-switched neodymium-doped yttrium-aluminum-garnet laser versus combined laser and glycolic acid peeling. Dermatol Surg 2015;41:457-65.
Lee DB, Suh HS, Choi YS. A comparative study of low-fluence 1064-nm Q-switched Nd:YAG laser with or without chemical peeling using Jessner's solution in melasma patients. J Dermatolog Treat 2014;25:523-8.
Kim JY, Choi M, Nam CH, Kim JS, Kim MH, Park BC, et al
. Treatment of melasma with the photoacoustic twin pulse mode of low-fluence 1,064 nm Q-switched Nd:YAG laser. Ann Dermatol 2016;28:290-6.
Hofbauer Parra CA, Careta MF, Valente NY, de Sanches Osório NE, Torezan LA. Clinical and histopathologic assessment of facial melasma after low-fluence Q-switched neodymium-doped yttrium aluminium garnet laser. Dermatol Surg 2016;42:507-12.
Sim JH, Park YL, Lee JS, Lee SY, Choi WB, Kim HJ, et al
. Treatment of melasma by low-fluence 1064 nm Q-switched Nd:YAG laser. J Dermatolog Treat. 2014;25:212-7.
Moubasher AE, Youssef EM, Abou-Taleb DA. Q-switched Nd:YAG laser versus trichloroacetic acid peeling in the treatment of melasma among Egyptian patients. Dermatol Surg 2014;40:874-82.
Jalaly NY, Valizadeh N, Barikbin B, Yousefi M. Low-power fractional CO2
laser versus low-fluence Q-switch 1,064 nm Nd:YAG laser for treatment of melasma: A randomized, controlled, split-face study. Am J Clin Dermatol 2014;15:357-63.
Fabi SG, Friedmann DP, Niwa Massaki AB, Goldman MP. A randomized, split-face clinical trial of low-fluence Q-switched neodymium-doped yttrium aluminum garnet (1,064nm) laser versus low-fluence Q-switched alexandrite laser (755nm) for the treatment of facial melasma. Lasers Surg Med 2014;46:531-7.
Yun WJ, Moon HR, Lee MW, Choi JH, Chang SE. Combination treatment of low-fluence 1,064-nm Q-switched Nd:YAG laser with novel intense pulse light in Korean melasma patients: A prospective, randomized, controlled trial. Dermatol Surg 2014;40:842-50.
Vachiramon V, Sirithanabadeekul P, Sahawatwong S. Low-fluence Q-switched Nd:YAG 1064-nm laser and intense pulsed light for the treatment of melasma. J Eur Acad Dermatol Venereol 2015;29:1339-46.
Alsaad SM, Ross EV, Mishra V, Miller L. A split face study to document the safety and efficacy of clearance of melasma with a 5 ns q switched Nd YAG laser versus a 50 ns q switched Nd YAG laser. Lasers Surg Med 2014;46:736-40.
Choi CP, Yim SM, Seo SH, Ahn HH, Kye YC, Choi JE. Retrospective analysis of melasma treatment using a dual mode of low-fluence Q-switched and long-pulse Nd:YAG laser vs. low-fluence Q-switched Nd:YAG laser monotherapy. J Cosmet Laser Ther 2015;17:2-8.
Attwa E, Khater M, Assaf M, Haleem MA. Melasma treatment using an erbium:YAG laser: A clinical, immunohistochemical, and ultrastructural study. Int J Dermatol 2015;54:235-44.
Eimpunth S, Wanitphakdeedecha R, Triwongwaranat D, Varothai S, Manuskiatti W. Therapeutic outcome of melasma treatment by dual-wavelength (511 and 578 nm) laser in patients with skin phototypes III-V. Clin Exp Dermatol 2014;39:292-7.
Lakhdar H, Zouhair K, Khadir K, Essari A, Richard A, Seité S, et al
. Evaluation of the effectiveness of a broad-spectrum sunscreen in the prevention of chloasma in pregnant women. J Eur Acad Dermatol Venereol 2007;21:738-42.
Vázquez M, Sánchez JL. The efficacy of a broad-spectrum sunscreen in the treatment of melasma. Cutis 1983;32:92, 95-6.
Boukari F, Jourdan E, Fontas E, Montaudié H, Castela E, Lacour JP, et al
. Prevention of melasma relapses with sunscreen combining protection against UV and short wavelengths of visible light: A prospective randomized comparative trial. J Am Acad Dermatol 2015;72:189-90.
Castanedo-Cazares JP, Hernandez-Blanco D, Carlos-Ortega B, Fuentes-Ahumada C, Torres-Álvarez B. Near-visible light and UV photoprotection in the treatment of melasma: A double-blind randomized trial. Photodermatol Photoimmunol Photomed 2014;30:35-42.
Mauricio T, Karmon Y, Khaiat A. A randomized and placebo-controlled study to compare the skin-lightening efficacy and safety of lignin peroxidase cream vs. 2% hydroquinone cream. J Cosmet Dermatol 2011;10:253-9.
Draelos ZD. A split-face evaluation of a novel pigment-lightening agent compared with no treatment and hydroquinone. J Am Acad Dermatol 2015;72:105-7.
Zhong SM, Sun N, Liu HX, Niu YQ, Wu Y. Reduction of facial pigmentation of melasma by topical lignin peroxidase: A novel fast-acting skin-lightening agent. Exp Ther Med 2015;9:341-4.
Iraji F, Mehrpour K, Asilian A, Siadat AH, Mohaghegh F. A comparative study to evaluate the efficacy of “4% N-Acetyl Glucosamine + 2% Nicotinamide” cream versus 4% hydroquinone cream in the treatment of facial melasma: A randomized, double-blind, split-face clinical trial. J Cell Tissue Res 2009;9:1767-72.
Lee MH, Kim HJ, Ha DJ, Paik JH, Kim HY. Therapeutic effect of topical application of linoleic acid and lincomycin in combination with betamethasone valerate in melasma patients. J Korean Med Sci 2002;17:518-23.
Elfar NN, El-Maghraby GM. Efficacy of intradermal injection of tranexamic acid, topical silymarin and glycolic acid peeling in treatment of melasma: A comparative study. J Clin Exp Dermatol Res 2015;6:280.
Zanieri F, Assad GB, Campolini P, Lotti T. Melasma: Successful treatment with 4% pidobenzone. Dermatol Ther 2008;21:18-9.
Malek J, Chedraoui A, Nikolic D, Barouti N, Ghosn S, Abbas O. Successful treatment of hydroquinone-resistant melasma using topical methimazole. Dermatol Ther 2013;26:69-72.
Kasraee B, Safaee Ardekani GH, Parhizgar A, Handjani F, Omrani G, Samani M, et al
. Safety of topical methimazole for the treatment of melasma. Transdermal absorption, the effect on thyroid function and cutaneous adverse effects. Skin Pharmacol Physiol 2008;21:300-5.
Khemis A, Kaiafa A, Queille-Roussel C, Duteil L, Ortonne JP. Evaluation of efficacy and safety of rucinol serum in patients with melasma: A randomized controlled trial. Br J Dermatol 2007;156:997-1004.
Huh SY, Shin JW, Na JI, Huh CH, Youn SW, Park KC. Efficacy and safety of liposome-encapsulated 4-n-butylresorcinol 0.1% cream for the treatment of melasma: A randomized controlled split-face trial. J Dermatol 2010;37:311-5.
Huh SY, Shin JW, Na JI, Huh CH, Youn SW, Park KC. The efficacy and safety of 4-n-butylresorcinol 0.1% cream for the treatment of melasma: A randomized controlled split-face trial. Ann Dermatol 2010;22:21-5.
Madan Mohan NT, Gowda A, Jaiswal AK, Sharath Kumar BC, Shilpashree P, Gangaboraiah B, et al
. Assessment of efficacy, safety, and tolerability of 4-n-butylresorcinol 0.3% cream: An Indian multicentric study on melasma. Clin Cosmet Investig Dermatol 2016;9:21-7.
Fleischer AB Jr, Schwartzel EH, Colby SI, Altman DJ. The combination of 2% 4-hydroxyanisole (Mequinol) and 0.01% tretinoin is effective in improving the appearance of solar lentigines and related hyperpigmented lesions in two double-blind multicenter clinical studies. J Am Acad Dermatol 2000;42:459-67.
Jarratt M. Mequinol 2%/tretinoin 0.01% solution: An effective and safe alternative to hydroquinone 3% in the treatment of solar lentigines. Cutis 2004;74:319-22.
Piérard-Franchimont C, Henry F, Quatresooz P, Vroome V, Piérard GE. Analytic quantification of the bleaching effect of a 4-hydroxyanisole-tretinoin combination on actinic lentigines. J Drugs Dermatol 2008;7:873-8.
Ortonne JP, Camacho F, Wainwright N, Bergfelt L, Westerhof W, Roseeuw D. Safety and efficacy of combined use of 4-hydroxyanisole (mequinol) 2%/tretinoin 0.01% solution and sunscreen in solar lentigines. Cutis 2004;74:261-4.
Draelos ZD. The combination of 2% 4-hydroxyanisole (mequinol) and 0.01% tretinoin effectively improves the appearance of solar lentigines in ethnic groups. J Cosmet Dermatol 2006;5:239-44.
Keeling J, Cardona L, Benitez A, Epstein R, Rendon M. Mequinol 2%/tretinoin 0.01% topical solution for the treatment of melasma in men: A case series and review of the literature. Cutis 2008;81:179-83.
Viyoch J, Tengamnuay I, Phetdee K, Tuntijarukorn P, Waranuch N. Effects of trans-4-(aminomethyl) cyclohexanecarboxylic acid/potassium azeloyldiglycinate/niacinamide topical emulsion in Thai adults with melasma: A single-center, randomized, double-blind, controlled study. Curr Ther Res Clin Exp 2010;71:345-59.
Lee do H, Oh IY, Koo KT, Suk JM, Jung SW, Park JO, et al
. Reduction in facial hyperpigmentation after treatment with a combination of topical niacinamide and tranexamic acid: A randomized, double-blind, vehicle-controlled trial. Skin Res Technol 2014;20:208-12.
Bissett DL, Robinson LR, Raleigh PS, Miyamoto K, Hakozaki T, Li J, et al
. Reduction in the appearance of facial hyperpigmentation by topical N-undecyl-10-enoyl-L-phenylalanine and its combination with niacinamide. J Cosmet Dermatol 2009;8:260-6.
Eshghi G, Khezrian L, Esna Ashari F. Comparison between intralesional triamcinolone and Kligman's formula in treatment of melasma. Acta Med Iran 2016;54:67-71.
Neering H. Treatment of melasma (chloasma) by local application of a steroid cream. Dermatologica 1975;151:349-53.
Kanwar AJ, Dhar S, Kaur S. Treatment of melasma with potent topical corticosteroids. Dermatology 1994;188:170.
Jimbow K. N-acetyl-4-S-cysteaminylphenol as a new type of depigmenting agent for the melanoderma of patients with melasma. Arch Dermatol 1991;127:1528-34.
Takeda K, Arase S, Sagawa Y, Shikata Y, Okada H, Watanabe S, et al
. Clinical evaluation of the topical application of Magnolignan® (5, 5′-dipropyl-biphenyl-2, 2′-diol) for hyperpigmentation on the face. Nishinihon J Dermatol 2006;68:293-8.
Tadokoro T, Bonte F, Archambault JC, Cauchard JH, Neveu M, Ozawa K, et al
. Whitening efficacy of plant extracts including orchid extracts on Japanese female skin with melasma and lentigosenilis. J Dermatol 2010;37:522-30.
Tirado-Sanchez A, Santamaria Roman A, Ponce Olivera RM. Efficacy of dioic acid compared with hydroquinone in treatment of melasma. Int J Dermatol 2009;48:893-5.
Wiechers JW, Groenhof FJ, Wortel VAL, Miller RM, Hindle NA, Drewitt Barlow A, et al
. Octadecenedioic acid for a more even skin tone. Cosmetics & Toiletries. Available from: http://www.cosmetics and toiletries.com
. [Last accessed on 2016 Jul 25].
Kar HK. Efficacy of beta-carotene topical application in melasma. An open clinical trial. Indian J Dermatol Venereol Leprol 2002;68:320-2.
] [Full text]
Costa A, Moisés TA, Cordero T, Alves CR, Marmirori J. Association of emblica, licorice and belides as an alternative to hydroquinone in the clinical treatment of melasma. An Bras Dermatol 2010;85:613-20.
Kasraee B, Nikolic DS, Salomon D, Carraux P, Fontao L, Piguet V, et al
. Ebselen is a new skin depigmenting agent that inhibits melanin biosynthesis and melanosomal transfer. Exp Dermatol 2011;21:19-24.
Kong YH, Jo YO, Cho CW, Son D, Park S, Rho J, et al
. Inhibitory effects of cinnamic acid on melanin biosynthesis in skin. Biol Pharm Bull 2008;31:946-8.
Tan C, Zhu W, Lu Y. Aloin, cinnamic acid and sophorcarpidine are potent inhibitors of tyrosinase. Chin Med J (Engl) 2002;115:1859-62.
Kang SS, Kim HJ, Jin C, Lee YS. Synthesis of tyrosinase inhibitory (4-oxo-4-H-pyran-2-yl) acrylic acid derivative. Bioorg Med Chem Lett 2009;19:188-91.
Tsuji-Naito K, Hatani K, Okada K, Tehara T. Modulating effects of a novel skin-lightening agent, alpha-lipoic acid derivative, on melanin production by the formation of DOPA conjugate products. Bioorg Med Chem 2007;15:1967-75.
[Figure 1], [Figure 2]
[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]