Melasma Compilation of Articles 1

IJD® SYMPOSIUM EDITORIAL
Treatment of Melasma: The Journey Ahead
Melasma, a commonly acquired hypermelanosis, presents suggests that all melasma is in fact “mixed.”[4,5] Further,
as symmetrical irregular to dark-brown macules on involvement of the dermis has been demonstrated which
sun-exposed areas such as the face, particularly over the includes findings such as increased solar elastosis and
forehead and malar areas, and extrafacial sites such as vascularity in dermis of melasma patients.[5] We have now
the neck and forearms and is undoubtedly one of the begun to acknowledge that melasma, rather than being
top five dermatological referrals we see in everyday a rigid linear epidermal problem, is in fact a complex
practice. Majority of the literature in melasma studies interplay among the epidermal melanocytes, keratinocytes,
the condition in women, but occurrence in men is not dermal fibroblasts, and vascular endothelial cells.[5] The
uncommon. A few studies on melasma in men have elaboration of this newer concept of pathogenesis has
been conducted, and they report the occurrence as high identified several other potential targets for research and
as 10% in Puerto Rico[1] and 25.8% in India.[2] Being a treatment in the field of melasma.
disorder of hyperpigmentation present on exposed areas Recently, studies have suggested that interactions
such as the face, it can be a source of embarrassment for between altered cutaneous vasculature and melanocytes
the patients including the men, resulting in a negative may influence the development of hyperpigmentation
impact on the quality of life. in the overlying epidermis. Vascular endothelial
The major etiological factors include genetic growth factor (VEGF) could have a direct influence on
susceptibility, exposure to ultraviolet (UV) radiation, melanogenesis through its receptor on melanocytes as
and sex hormones. Melasma, as we have all seen in our well as on vascular endothelial cells, which on exposure
experience, is an extremely difficult condition to treat to UV radiation may release cytokines and soluble factors
and notorious for relapse and recurrence. In our quest such as plasminogen, which might be a possible cause of
for treatment, we began with limited but powerful drugs, hyperpigmentation in melasma.[6]
which include hydroquinone (HQ) and the modified These findings led to the use of plasmin inhibitor
Kligman’s regimen combination creams which inhibit tranexamic acid in melasma, in both oral and topical
melanogenesis by inhibiting the rate-limiting enzyme forms. Although some studies have found it to be
tyrosinase. The reduction of pigmentation imparts effective, the results have been mostly inconsistent,
excellent clinical efficacy to these drugs and makes them temporary, and short lived.[7] Further, the vascular theory
the gold standard, even today. However, inconsistent/ does not explain the inconsistent results of copper
incomplete results and considerable adverse effects, bromide or pulsed dye laser in melasma, which are
both on short- and long-term use, make it extremely hypothesized to reduce the VEGF-induced angiogenesis
important to look for alternative drugs which provide and thus the hyperpigmentation. Further research needs
similar results but lesser side effects. to be done to generate more clinical evidence to put
The journey toward demystifying this path begins these drugs and physical modalities to larger clinical use.
with solving the enigmatic puzzle, the mammoth task Among the other causal factors of melasma, role of
of deciphering the pathogenesis of melasma, and the inflammation is garnering much interest. Majority of the
understanding of which has undergone a paradigm shift inflammation in melasma in the epidermis is known to
over the years. In 1981, Sanchez et al., using clinical and be induced by UV radiation. UV induces melanogenesis by
histological characteristics, classically described melasma its direct effect on DNA and melanocyte membranes that
as a linear model and classified on the basis of localization release diacylglycerol and arachidonic acid, which have a
of melanosomes in the skin, as epidermal, dermal, and putative role in melanogenesis. Further, UV light induces
mixed.[3] Moreover, in our practice, we conform to the an increase in cell surface expression of receptors for
notion that epidermal melasma responds well to the topical keratinocyte-derived paracrine melanogenic factors such
depigmenting agents, while the other two variants are as basic fibroblast growth factor, nerve growth factor,
much more challenging to treat. However, with the use of endothelin-1, and the proopiomelanocortin-derived
newer investigational modalities such as in vivo reflectance peptides such as melanocyte-stimulating hormone,
confocal microscopy, immunohistochemistry, and electron adrenocorticotropic hormone, and beta-endorphin.
microscopy, it has been discovered that the distribution of Keratinocytes also secrete nitric oxide in response
melanin and melanophages is heterogeneous and perhaps to UV radiation. These inflammatory mediators are
© 2017 Indian Journal of Dermatology | Published by Wolters Kluwer - Medknow 447

Sarkar and Ailawadi: Treatment of melasma
overexpressed in lesional skin of melasma patients of them have small study groups, short trial period with
and induce local increase of vessels and inflammatory limited follow-up. There are multiple reasons for the
cells, all of which contribute to the hyperpigmentation same like multiple chromophores present in the skin, the
in melasma.[8] This has opened the doors to research variable depth of melanin and melanophages in the skin
on potential efficacy on anti-inflammatory molecules. combined with the act that lasers only accelerate the
Various anti-inflammatory agents such as liquorice pathways for removal of melanin and melanophages but
extract, orchid extract, and mulberry extract are used do not target the melanin production itself. Furthermore,
topically, while oral preparations of proanthocyanidin, they present a risk for PIH or a rebound melasma flare,
pycnogenol, oral Polypodium leucotomos extract, and especially the dark-skinned patients.
Vitamin C have begun to find a foothold as potential
Hence, the treatment of melasma should focus on
treatments for melasma. Most of these have been studied
underlying etiological factors, namely, addressing
largely in vitro with fewer in vivo studies. Although the
endocrinal abnormalities, cessation of suspected drug,
results are encouraging, further studies need to find
evidence of the laboratory results converting to clinical and photoprotection with special emphasis on visible
benefits. Another antioxidant molecule glutathione, both and infrared light. Sunscreens containing inorganic
oral and injectable, has been the talk of the town due to constituents, such as iron oxide, would definitely help
its potential of reducing pigmentation and making the treatment. Time-tested topical HQ and non-HQ therapies
skin shade fairer by a shade or two. Much has been said still remain the first line of treatment for melasma
about its role in melasma, but it is yet to be backed by with adjuvants such as chemical peels and lasers being
even a single study in the same. It shall have to wait for reserved as second line and third line of treatment,
more data on its efficacy on long-term safety. respectively. A group of Indian Pigmentary Experts
from Pigmentary Disorders Society have attempted
While most of the studies have focused on reducing to review and give practical tips in management of
melanogenesis by inhibiting tyrosinase, the concept of melasma,elsewhere in this special issue. The quest for
hyperactive melanocytes has begun to take a footing. a perfect competitor for topical HQ still continues.
In melasma, the lesional melanocytes are found to be There is an increasing excitement and hope associated
more biologically active than those in normal skin, with the newer oral agents, but we need to be cautious
and there is an upregulation of genes involved in regarding their side effects and long-term prevention
melanogenesis-tyrosinase, TYRP1, TYRP2, and MITF in in recalcitrance of melasma. Combination therapies and
melasma lesions.[9] These findings suggest that inhibiting lifelong maintenance of treatment are the way forward
the activity of melanocytes rather than only melanin for treating melasma. The articles in this invited
synthesis would be more effective. Many new agents symposium on melasma discuss available evidence and
such as aloesin, arbutin, ellagic acid, and antisense brings forward a suggested treatment algorithm by
oligonucleotides have been found to act on these experts from Pigmentary Disorders Society (PDS) in a
targets. The in vivo and in vitro studies give favorable collaborative discussion called South Asian Pigmentary
efficacy and safety outcomes and in some studies better Forum (SPF).
than the conventional agents such as HQ. This is an
upcoming concept, but it needs to be backed by more Rashmi Sarkar, Pallavi Ailawadi1
literature for it to be put to widespread use. From the Department of Dermatology, Maulana Azad Medical College,
1
Department of Dermatology, Maulana Azad Medical College and Lok
Moving on from the medical management of melasma, Nayak Hospital, New Delhi, India
the other therapeutic modalities include chemical peels E -mail: rashmisarkar@gmail.com
and laser and light treatments, which are particularly
beneficial for patients less responsive/refractory to References
topical therapy. Chemical peels have largely established 1. Vázquez M, Maldonado H, Benmamán C, Sánchez JL. Melasma
their role in the treatment of hypermelanoses such as in men. A clinical and histologic study. Int J Dermatol
1988;27:25-7.
melasma, but the potential side effects of irritation and
2. Sarkar R, Puri P, Jain RK, Singh A, Desai A. Melasma in men:
postinflammatory hyperpigmentation (PIH), especially A clinical, aetiological and histological study. J Eur Acad
in the dark-skinned individuals, sensitize us to exercise Dermatol Venereol 2010;24:768-72.
caution while using these in melasma patients. 3. Sanchez NP, Pathak MA, Sato S, Fitzpatrick TB, Sanchez JL,
Mihm MC Jr., et al. Melasma: A clinical, light microscopic,
A multitude of laser and light devices have been used in
ultrastructural, and immunofluorescence study. J Am Acad
melasma with varying degree of success. The vast arrays Dermatol 1981;4:698-710.
of machines with multiple protocols that are different 4. Kang HY, Ortonne JP. What should be considered in treatment
among most studies give us a fair idea that no single of melasma. Ann Dermatol 2010;22:373-8.
modality is uniformly effective. It is also difficult to 5. Kwon SH, Hwang YJ, Lee SK, Park KC. Heterogeneous
decipher the results of studies involving lasers as most pathology of melasma and its clinical implications. Int J Mol
448 Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

Sarkar and Ailawadi: Treatment of melasma
Sci 2016;17:824. This is an open access article distributed under the terms of the Creative
6. Kim EJ, Park HY, Yaar M, Gilchrest BA. Modulation of vascular Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows
endothelial growth factor receptors in melanocytes. Exp others to remix, tweak, and build upon the work non-commercially, as long as the
Dermatol 2005;14:625-33. author is credited and the new creations are licensed under the identical terms.
7. Poojary S, Minni K. Tranexamic acid in melasma: A review.
Pigment Disord 2015;2:228. Access this article online
8. Lee AY. An updated review of melasma pathogenesis. Quick Response Code:
Dermatologicasinica 2014;32:233-9. Website: www.e-ijd.org
9. Grimes PE, Yamada N, Bhawan J. Light microscopic,
immunohistochemical, and ultrastructural alterations in
patients with melasma. Am J Dermatopathol 2005;27:96-101.
DOI: 10.4103/ijd.IJD_487_17
How to cite this article: Sarkar R, Ailawadi P. Treatment of melasma:

The journey ahead. Indian J Dermatol 2017;62:447-9.
Received: October, 2017. Accepted: October, 2017.
Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017 449

IJD® SYMPOSIUM
Lasers in Melasma: A Review with Consensus Recommendations by Indian

Pigmentary Expert Group
Rashmi Sarkar, Sanjeev Aurangabadkar1, T Salim2, Anupam Das3, Swapnil Shah4, Imran Majid5,
Mohan Singh6, G Ravichandran7, Kiran Godse8, Shehnaz Arsiwala9, Latika Arya10, Narendra Gokhale11,
Nilendu Sarma12, R G Torsekar13, Sidharth Sonthalia14, V K Somani15
Abstract From the Department of

Lasers have come up as the newest therapeutic modality in dermatological conditions Dermatology, Maulana Azad
including melasma. In this article, as a group of experts from Pigmentary Disorders Society Medical College and Lok Nayak
Hospital, New Delhi, 1Consultant
in collaboration with South Asian Pigmentary Disorders Forum (SPF), we have tried to discuss
Dermatologist, Skin and Laser
the lasers which have been used in melasma and formulate simple consensus guidelines. Clinic, Begumpet, Hyderabad,
Following thorough literature search, we have summarised the rationale of using the lasers 2
Consultant Dermatologist,
and the supporting evidences have also been provided. It is clear that laser cannot be the Cutis Institute of Dermatology
first line treatment for melasma. However, it can be used as an adjuvant therapy in resistant and Aesthetic Sciences, Calicut,
cases, provided the selection of patient and counselling has been done properly. Kerala, 3Dermatology, KPC
Medical College and Hospital,
KEY WORDS: Lasers, melasma, expert opinion, consensus Kolkata, West Bengal, 4Consultant
Dermatologist, Solapur,
Maharashtra, 5Dermatology, Govt
What was known? Medical College, Srinagar, Kashmir,
Numerous lasers and light devices have been used in melasma with unsatisfactory results. Besides, lasers are not advisable 6
as monotherapy in the treatment of melasma. Q-switched lasers (QSL), fractional lasers, ablative lasers, intense pulsed lights Mohan Singh Diseases Hospital,
(IPLs), copper bromide laser, thulium laser, and their combinations have all been used, but response is unpredictable, and Phagwara, Punjab, 7Senior
the pigmentation frequently recurs. Since melanin has a broad absorption spectrum (630–1100 nm) , a variety of lasers Consultant and Coordinator,
and light sources can be used, but the selection of patient, counselling and post-procedural follow-up form the backbone Dermatology, Apollo Hospitals,
of laser therapy. Chennai, 8Dermatology, D Y
Patil Hospital, Navi Mumbai,
9
Introduction Saifee Hospital, Prince Aly Khan
Hospital, Mumbai, 10Consultant
Melasma is a common acquired facial pigmentary disorder and challenging to treat. Dermatologist, L A Skin &
Triple combination (FTC) creams and sunscreens remain the cornerstone of therapy Aesthetic Clinic, New Delhi,
followed by maintenance with hydroquinone (HQ) and non-HQ skin-lightening
11
Consultant Dermatologist, Sklinic
Skin Clinic, Indore, Madhya
agents. Peels have made successful inroads and are used frequently as an adjunct to Pradesh, 12Dermatology, Dr.
medical management. B.C.Roy Postgraduate Institute
of Pediatric Sciences, Kolkata,
A variety of lasers and light devices have been used with varying degrees of success West Bengal, 13Consultant
in melasma. The vast array of devices and combination protocols that have been Dermatologist, Fortis Hospital,
tried in melasma clearly indicate that no single modality is singularly effective. Mulund, Mumbai, 14Consultant
Q-switched lasers (QSL), fractional lasers, ablative lasers, intense pulsed lights (IPLs), Dermatologist, Skinnocence: The
Skin Clinic, Gurgaon, Haryana,
copper bromide laser, thulium laser, and their combinations have all been used, 15
but response is unpredictable, and the pigmentation frequently recurs. Lasers can Skintrendz, Himayat Nagar,
be used in selected patients with resistant melasma after thorough counseling and Hyderabad, India
preferably after conducting test treatments. This article discusses available evidence
and brings forward a suggested treatment algorithm by 15 experts from Pigmentary
Address for correspondence: Dr. Rashmi Sarkar, Department of This is an open access article distributed under the terms of the Creative
Dermatology, Maualna Azad Medical College, New Delhi, India. Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows
E-mail: rashmisarkar@gmail.com others to remix, tweak, and build upon the work non-commercially, as long as the
author is credited and the new creations are licensed under the identical terms.
Access this article online
For reprints contact: reprints@medknow.com
Quick Response Code:
Website: www.e-ijd.org
How to cite this article: Sarkar R, Aurangabadkar S, Salim T, Das A,
Shah S, Majid I, et al. Lasers in melasma: A review with consensus
recommendations by Indian pigmentary expert group. Indian J Dermatol
DOI: 10.4103/ijd.IJD_488_17 2017;62:477-82.
© 2017 Indian Journal of Dermatology | Published by Wolters Kluwer - Medknow 477

Sarkar, et al.: Lasers for melasma: A review and Indian consensus opinion
Disorders Society (PDS) in a collaborative discussion the cell alive. Since fluence used is very less and there is
called South Asian Pigmentary Forum (SPF). no cell death, inflammation and heating is minimum, thus
reducing the chances of recurrence.
The lasers and light-based devices used in melasma
include: Rationale for Use of Lasers in Melasma
[1]
Melanin has a broad absorption spectrum (630–1100 nm)
fractional ablative lasers[2] allowing a variety of lasers and light sources to be
1540 nm/1550 nm Er:Glass laser used. Melanosomes have a short thermal relaxation time
(50–500 nanoseconds). Longer wavelengths penetrate
2940 nm Er:YAG laser
deeper to target the dermal pigment, but melanin
10,600 nm CO2 laser
[3] absorption is better with shorter wavelengths.
QS Nd:YAG laser [(QSNY) 1064 nm] has a pulse
duration of 10 ns. Hence, the QSNY laser seems like a
logical choice for some cases of melasma, especially in
lasers individuals with darker skin tones.
Q-switched Nd:YAG Laser

laser Low-fluence Q-switched (LFQS) Nd-YAG laser is the most
widely studied laser for the treatment of melasma.
However, there are no randomized controlled trials (RCTs)
[4,5]
comparing the effectiveness, safety, and tolerability
of Q-switched Nd-YAG laser (532 nm) versus topical
corticosteroids or hydroquinone.
toning
We have considered 10 studies [Table 1] which evaluated the
role of LFQS Nd:YAG laser on 446 patients of melasma.[7-16]
fractional laser
Out of these 10 studies, 6 were RCTs, 3 were
nonrandomized uncontrolled studies, and 1 of them was
Laser toning has gained immense popularity in Southeast
a simple case–control study. Ninety-two patients were
Asia. The concept of laser toning (low fluence, multipass
evaluated in the three uncontrolled studies and the
technique, multiple sessions at weekly intervals) is based authors concluded that LFQS Nd:YAG laser monotherapy
on the proposed novel theory of subcellular selective had good results in melasma.[7-9]
photothermolysis, proposed by Mun et al. in 2011.[6] They
studied the ultrastructural changes within melanosome, However, the drawback of these studies was the small
using transmission electron microscopy. They found a sample size, which puts a question mark on the
reduction in the dendrites of epidermal melanocytes, effectiveness of LFQS Nd:YAG laser monotherapy in
following laser treatment. Laser treatment caused melasma. The effectiveness of Nd:YAG laser was found to
selective photothermolysis on Stage IV melanosomes, be inferior to low-power fractional CO2 laser[11] and equal
wherein the melanocytes remained intact and only the to that of LFQS alexandrite laser (755 nm).
melanosomes were destroyed. They concluded that laser To note, Chan et al. reported a series of facial
toning was an effective method for treating melasma depigmentation with the use of low-fluence QSNY laser.
through subcellular-selective photothermolysis. They concluded that laser toning with LFQS 1,064 nm
Traditional treatments were based on the principle of Nd:YAG laser for skin rejuvenation and melasma can be
selective photothermolysis which results in destruction and associated with mottled depigmentation. Hence, caution
death of pigment-containing cells. In response to cell death, needs to be exercised while performing this procedure
inflammation follows and results in repigmentation and and the risks need to be explained to patients.[17]
recurrence or in postinflammatory hyperpigmentation (PIH). The results of LFQS Nd:YAG laser (1,064 nm) were found
The adverse effects were attributed to laser-induced to be better when combined with IPL. However, number
basal layer damage and dermal inflammation leading to of patients was less and follow-up period was small.[13]
recurrence of melasma on sun exposure, PIH, rebound
In addition, Na et al. observed that combination treatment
hyperpigmentation, and mottled depigmentation. This
may provide more rapid clinical resolution in mixed-type
is in contrast to the principle of subcellular selective
melasma with possible long-term clinical benefits.[18]
photothermolysis, which uses high-peak power, ultrashort
pulse duration [5ns], and flat-top beam resulting in Besides, LFQS when combined with long-pulse Nd:YAG has
destruction of only melanin in the target cell but leaving shown better results in terms of reduction in melasma area

Table 1: Summary of a few important studies conducted on the safety and effectiveness of various lasers in
melasma
Study Conclusion Level of evidence Comment
Kim et. al. LFQS Nd:YAG laser showed good results III LFQS Nd:YAG laser is not recommended as
Hofbauer et. al. monotherapy. However, it can be combined
Sim et. al. with other lasers, peels, and oral adjuvants
Moubasher et. al. LFQS Nd:YAG laser was inferior to 25% TCA II
peel
Jalaly et. al. LFQS Nd:YAG laser was inferior to II
low-power fractional CO2 laser
Moubasher et. al. LFQS Nd:YAG laser was equally effective as II
LFQS alexandrite laser
Yun et. al. LFQS Nd:YAG laser in combination with IPL IV
was superior to IPL alone
Alsaad et. al. LFQS Nd:YAG laser of pulse durations 5 ns II
and 50 ns was equivocal
Choi et. al. LFQS Nd:YAG laser in combination with IV
long-pulsed Nd:YAG was superior to LFQS
Nd:YAG laser alone
Shin et. al. Efficacy of LFQS Nd:YAG laser is increased II
when combined with oral TXA
Vachiramon et. al. Efficacy of LFQS Nd:YAG laser is increased II
when combined with glycolic acid peel
Lee et. al. Efficacy of LFQS Nd:YAG laser is increased III
when combined with Vitamin C
Zhou et. al. QSRL with sonophoresis on levorotatory III QSRL cannot be recommended until further
Vitamin C showed good results studies are conducted, due to possibility of
postinflammatory hyperpigmentation
Kopera et. al. QSRL showed moderate results, but side II–III Given the risk of postoperative
Taylor et. al. effects were alarming dyspigmentation, the authors concluded that
it was not safe enough to recommend for
Tse et. al.
routine use for melasma in Southeast Asian
population
Fabi et. al. LFQS Nd:YAG laser was better than II Alexandrite laser cannot be recommended
alexandrite laser until further studies are conducted
Jalaly et. al. Low-power fractional CO2 laser showed good II Since the study was conducted in non-Asian
results population and the follow-up was short,
fractional CO2 laser cannot be recommended
Attwa et. al. Er-YAG laser showed good results III Postinflammatory hyperpigmentation was a
significant adverse effect, and thus, this laser
cannot be recommended
Manaloto et. al. Er-YAG laser resurfacing improved melasma II–III Postinflammatory hyperpigmentation
outweighs any benefit. Can be recommended
for refractory cases only
Brauer et. al. Fractional 1550/1540 nm nonablative laser II–III Use of low fluence, variable pulses, and
shows promising results pretreating all patients with hydroquinone for
6 weeks before laser therapy is recommended
LFQS: Low-fluence Q-switched, QSRL: Q-switched ruby laser, IPL: Intense pulsed light, TXA: Tranexamic acid
severity index (MASI) score and significantly less adverse Efficacy of LFQS Nd:YAG laser is increased when combined
effects, when compared with LFQS Nd:YAG laser alone.[16] with oral tranexamic acid, glycolic acid peel, Vitamin C,
Tian et al. reported a novel technique using a combination etc.[20-22]
of fractional 2940-nm Er:YAG and 1064-nm Q-switched
Nd:YAG lasers. Authors reported a rapid improvement Q-switched Ruby Laser
in two cases, within a month of treatment. The novel We did not find any study which has evaluated the
strategy was found to deliver a safe, tolerable, and role of Q-switched ruby laser (QSRL) as a monotherapy
sustained result within a short period of treatment.[19] in the treatment of melasma. Zhou et al. published
a study which was conducted on Chinese patients, Vascular Laser

on the role of 694-nm fractional Q-switched ruby Angiogenic melasma has been shown to respond to
laser (fluence 2.5–3.5 J/cm2, 7.1 × 7.1 mm spot size, vascular lasers, which act by targeting vascular endothelial
27.7% area coverage) in combination with sonophoresis growth factors and the blood vessels of dermis.
on levorotatory Vitamin C. There was a reduction in
MASI score by 35% at the end of the study. However, Copper Bromide Laser
there are no further studies to validate the results in
Copper bromide laser produces 2 wavelengths – 511 nm
Indian population.[23] Besides, previous studies have
green light to treat pigmentary lesions and 578 nm
reported the development of PIH and recurrence of
yellow light to treat vascular lesions. Both wavelengths
melasma following the use of ruby lasers.[24-26] Hence, it
can be used simultaneously to treat melasma, every
is not safe to use QSRL routinely in Southeast Asian
2 weeks for 8 weeks. It may target vascular component
population.
as well as pigmentation in melasma.
Intense Pulsed Light Eimpunth et al. conducted a nonrandomized
IPL, a nonlaser light source that emits light with study in Thailand. They used copper bromide
wavelengths between 515 and 1200 nm, has been laser (dual-wavelength, 511 and 578 nm, fluence
studied alone and in comparison with hydroquinone for 7–19 J/cm2) but could not find any statistically
the treatment of melasma. IPL appears to give modest significant improvement.[29]
improvement as an adjunctive therapy in patients with In another split-face RCT conducted by Hammami et al.,
melasma refractory to topical therapy alone and may be copper bromide laser was not found to be better than
useful in patients who do not mind the 1- to 2-week triple combination creams.[30]
recovery time.
Thulium Fiber Laser
Alexandrite Laser Thulium fiber laser (1927 nm) nonablative laser has
Fabi et al. reported a randomized split-face clinical trial, also shown promise in the management of melasma.
comparing the effectiveness of alexandrite laser and Treatments are performed once a month for 3–4 months.
LFQS Nd:YAG laser. The latter was found to be better, It is a fractionated laser that produces small amount
though statistically insignificant.[12] of epidermal ablation and greater amount of dermal
heating.[31]
Fractional and Ablative Lasers (CO2 Laser)
These are not used as monotherapies on account of the Fractional Nonablative Lasers
high incidence of side effects. However, low-fluence Fractional 1550/1540 nm nonablative laser therapy is
lasers are being used. Jalaly et al. conducted a split-face the only laser treatment for melasma that has been
double-blinded randomized trial and compared low-power approved by the FDA, and it has shown promising
fractional CO2 laser with LFQS 1,064 nm Nd:YAG laser.[11] results. Given the risk for hyperpigmentation, some
Fractional CO2 laser showed good results in terms of authors suggest using lower fluences, variable pulses,
reduction in melanin index and MASI score. However, it is and pretreating all patients with hydroquinone for up to
not wisely to recommend the use of this laser in Indian 6 weeks before laser therapy, especially in patients with
population due to financial constraints, short follow-up a history of PIH.
period, and the fact which cannot be overlooked is that
the study was conducted in non-Asian population. Brauer et al. studied a low energy, low density,
nonablative fractional 1927 nm laser for melasma, PIH,
Er-YAG Laser and photodamage. In this study, favorable outcomes
were demonstrated and results were maintained at the
Attwa et al. conducted an uncontrolled study on the
3-month follow-up.[32]
effectiveness of Er-YAG laser and reported significant
improvement in MASI score. However, PIH was a Acknowledgment
statistically significant side effect.[27] The Consensus Meeting of a group South Asian
Besides, Manaloto et al. concluded that Er-YAG laser can Pigmentary Forum (SPF) with Pigmentary Disorders
be recommended for refractory cases only.[3] Society (PDS) was made possible by an educational grant
by Galderma, India.
Er-Glass Laser Financial support and sponsorship
Tourlaki et al. conducted a nonrandomized study Nil.
on Er-glass laser. The reduction in MASI score was
significant at the end of 1 month, but this was not Conflicts of interest
sustained.[28] There are no conflicts of interest.

What is new? treatment of low-fluence 1,064-nm Q-switched Nd:YAG laser

· Lasers can be used in selected patients with resistant melasma after with novel intense pulse light in Korean melasma patients:
thorough counseling and preferably after conducting test treatments. A prospective, randomized, controlled trial. Dermatol Surg
· Low-fluence Q-switched (LFQS) Nd-YAG laser seems to be the best option 2014;40:842-50.
for refractory cases of melasma, especially in individuals with darker skin
14. Vachiramon V, Sirithanabadeekul P, Sahawatwong S.
tones. However, it is not recommended as monotherapy. It can be combined
with other lasers, peels, and oral adjuvants.
Low-fluence Q-switched Nd:YAG 1064-nm laser and intense
· Q-switched ruby laser and Erbium YAG laser are better avoided, due to the pulsed light for the treatment of melasma. J Eur Acad
risk of developing post-inflammatory hyperpigmentation. Dermatol Venereol 2015;29:1339-46.
· Fractional 1550/1540 nm non-ablative laser therapy is the only laser that 15. Alsaad SM, Ross EV, Mishra V, Miller L. A split face study to
has been approved by the FDA for melasma. To minimise the chances of document the safety and efficacy of clearance of melasma
post-inflammatory hyperpigmentation, it is advisable to use lower fluencies,
with a 5 ns q switched Nd YAG laser versus a 50 ns q switched
variable pulses and pre-treatment with hydroquinone for4- 6 weeks before
laser therapy. Nd YAG laser. Lasers Surg Med 2014;46:736-40.
16. Choi CP, Yim SM, Seo SH, Ahn HH, Kye YC, Choi JE, et al.
Retrospective analysis of melasma treatment using a dual
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1. Wang CC, Hui CY, Sue YM, Wong WR, Hong HS. Intense laser vs. Low-fluence Q-switched Nd: YAG laser monotherapy.
pulsed light for the treatment of refractory melasma in Asian J Cosmet Laser Ther 2015;17:2-8.
persons. Dermatol Surg 2004;30:1196-200. 17. Chan NP, Ho SG, Shek SY, Yeung CK, Chan HH. A case series of
2. Rokhsar CK, Fitzpatrick RE. The treatment of melasma with facial depigmentation associated with low fluence Q-switched
fractional photothermolysis: A pilot study. Dermatol Surg 1,064 nm Nd: YAG laser for skin rejuvenation and melasma.
2005;31:1645-50. Lasers Surg Med 2010;42:712-9.
3. Manaloto RM, Alster T. Erbium:YAG laser resurfacing for 18. Na SY, Cho S, Lee JH. Combinational treatment using intense
refractory melasma. Dermatol Surg 1999;25:121-3. pulsed light and low fluence Q-switched Nd: YAG laser over
4. Nouri K, Bowes L, Chartier T, Romagosa R, Spencer J. laser treatment alone. Lasers Surg Med 2010;42:712-9.
Combination treatment of melasma with pulsed CO2 laser 19. Tian WC. Novel technique to treat melasma in Chinese: The
followed by Q-switched alexandrite laser: A pilot study. combination of 2940-nm fractional Er: YAG and 1064-nm
Dermatol Surg 1999;25:494-7. Q-switched Nd: YAG laser. J Cosmet Laser Ther 2016;18:72-4.
5. Angsuwarangsee S, Polnikorn N. Combined ultrapulse CO2 laser 20. Shin JU, Park J, Oh SH, Lee JH. Oral tranexamic acid enhances
and Q-switched alexandrite laser compared with Q-switched the efficacy of low-fluence 1064-nm quality-switched
alexandrite laser alone for refractory melasma: Split-face neodymium-doped yttrium aluminum garnet laser treatment
design. Dermatol Surg 2003;29:59-64. for melasma in Koreans: A randomized, prospective trial.
6. Mun JY, Jeong SY, Kim JH, Han SS, Kim IH. A low Dermatol Surg 2013;39:435-42.
fluence Q-switched nd:YAG laser modifies the 3D structure 21. Vachiramon V, Sahawatwong S, Sirithanabadeekul P.
of melanocyte and ultrastructure of melanosome by Treatment of melasma in men with low-fluence Q-switched
subcellular-selective photothermolysis. J Electron Microsc neodymium-doped yttrium-aluminum-garnet laser versus
(Tokyo) 2011;60:11-8. combined laser and glycolic acid peeling. Dermatol Surg
7. Kim JY, Choi M, Nam CH, Kim JS, Kim MH, Park BC, et al. 2015;41:457-65.
Treatment of melasma with the photoacoustic twin pulse 22. Lee MC, Chang CS, Huang YL, Chang SL, Chang CH, Lin YF,
mode of low-fluence 1,064 nm Q-switched nd:YAG laser. Ann et al. Treatment of melasma with mixed parameters of
Dermatol 2016;28:290-6. 1,064-nm Q-switched Nd: YAG laser toning and an enhanced
8. Hofbauer Parra CA, Careta MF, Valente NY, de Sanches Osório NE, effect of ultrasonic application of vitamin C: A split-face
Torezan LA. Clinical and histopathologic assessment of facial study. Lasers Med Sci 2015;30:159-63.
melasma after low-fluence Q-switched neodymium-doped 23. Zhou HL, Hu B, Zhang C. Efficacy of 694-nm fractional
yttrium aluminium garnet laser. Dermatol Surg 2016;42:507-12. Q-switched ruby laser (QSRL) combined with sonophoresis on
9. Sim JH, Park YL, Lee JS, Lee SY, Choi WB, Kim HJ, et al. levorotatory vitamin C for treatment of melasma in Chinese
Treatment of melasma by low-fluence 1064 nm Q-switched patients. Lasers Med Sci 2016;31:991-5.
Nd: YAG laser. J Dermatolog Treat 2014;25:212-7. 24. Kopera D, Hohenleutner U. Ruby laser treatment of melasma
10. Moubasher AE, Youssef EM, Abou-Taleb DA. Q-switched Nd:YAG and postinflammatory hyperpigmentation. Dermatol Surg
laser versus trichloroacetic acid peeling in the treatment 1995;21:994.
of melasma among Egyptian patients. Dermatol Surg 25. Taylor CR, Anderson RR. Ineffective treatment of refractory
2014;40:874-82. melasma and postinflammatory hyperpigmentation by
11. Jalaly NY, Valizadeh N, Barikbin B, Yousefi M. Low-power Q-switched ruby laser. J Dermatol Surg Oncol 1994;20:592-7.
fractional CO2 laser versus low-fluence Q-switch 1,064 nm 26. Tse Y, Levine VJ, McClain SA, Ashinoff R. The removal of
Nd: YAG laser for treatment of melasma: A randomized, cutaneous pigmented lesions with the Q-switched ruby laser
controlled, split-face study. Am J Clin Dermatol and the Q-switched neodymium: Yttrium-aluminum-garnet
2014;15:357-63. laser. A comparative study. J Dermatol Surg Oncol
12. Fabi SG, Friedmann DP, Niwa Massaki AB, Goldman MP. 1994;20:795-800.
A randomized, split-face clinical trial of low-fluence Q-switched 27. Attwa E, Khater M, Assaf M, Haleem MA. Melasma
neodymium-doped yttrium aluminum garnet (1,064 nm) laser treatment using an erbium: YAG laser: A clinical,
versus low-fluence Q-switched alexandrite laser (755 nm) immunohistochemical, and ultrastructural study. Int J
for the treatment of facial melasma. Lasers Surg Med Dermatol 2015;54:235-44.
2014;46:531-7. 28. Tourlaki A, Galimberti MG, Pellacani G, Bencini PL.
13. Yun WJ, Moon HR, Lee MW, Choi JH, Chang SE. Combination Combination of fractional erbium-glass laser and topical

therapy in melasma resistant to triple-combination cream. melasma: A Randomized clinical trial. JAMA Dermatol
J Dermatolog Treat 2014;25:218-22. 2015;151:791-2.
29. Eimpunth S, Wanitphakdeedecha R, Triwongwaranat D, 31. Ho SG, Yeung CK, Chan NP, Shek SY, Chan HH. A retrospective
Varothai S, Manuskiatti W. Therapeutic outcome of melasma study of the management of Chinese melasma patients using
treatment by dual-wavelength (511 and 578 nm) laser in a 1927 nm fractional thulium fiber laser. J Cosmet Laser Ther
patients with skin phototypes III-V. Clin Exp Dermatol 2013;15:200-6.
2014;39:292-7. 32. Brauer JA, Alabdulrazzaq H, Bae YS, Geronemus RG. Evaluation
30. Hammami Ghorbel H, Boukari F, Fontas E, of a low energy, low density, non-ablative fractional 1927 nm
Montaudié H, Bahadoran P, Lacour JP, et al. Copper bromide wavelength laser for facial skin resurfacing. J Drugs Dermatol
laser vs. Triple-combination cream for the treatment of 2015;14:1262-7.

IJD® SYMPOSIUM
Medical Management of Melasma: A Review with Consensus

Recommendations by Indian Pigmentary Expert Group
Rashmi Sarkar, Narendra Gokhale1, Kiran Godse2, Pallavi Ailawadi3, Latika Arya4, Nilendu Sarma5,
R G Torsekar6, V K Somani7, Pooja Arora8, Imran Majid9, G Ravichandran10, Mohan Singh11,
Sanjeev Aurangabadkar12, Shehnaz Arsiwala13, Sidharth Sonthalia14, T Salim15, Swapnil Shah16
Abstract From the Dermatology, Maulana

Melasma is one of the most common hyperpigmentary disorders found mainly in women and Azad Medical College and Lok
dark-skinned patients. Sunlight, hormones, pregnancy, and genetics remain the most implicated Nayak Hospital, 3Dermatology,
Maulana Azad Medical College and
in the causation of melasma. Although rather recalcitrant to treatment, topical agents such as
Associated Hospitals, 4Consultant
hydroquinone, modified Kligman’s Regime, azelaic acid, kojic acid, Vitamin C, and arbutin still Dermatologist, L A Skin and
remain the mainstay of therapy with sun protection being a cornerstone of therapy. There are Aesthetic Clinic, 8Dermatology, Dr
several new botanical and non botanical agents and upcoming oral therapies for the future. There RML Hospital and PGIMER, New
is a lack of therapeutic guidelines, more so in the Indian setup. The article discusses available Delhi, 2Dermatology, D Y Patil
evidence and brings forward a suggested treatment algorithm by experts from Pigmentary Hospital, 6Consultant Dermatologist,
Disorders Society (PDS) in a collaborative discussion called South Asian Pigmentary Forum (SPF). Fortis Hospital, 13Consultant
Dermatologist, Saifee Hospital,
Prince Aly Khan Hospital, Mumbai,
KEY WORDS: Expert group, medical treatment, melasma 16
Solapur, Maharashtra, 7Consultant
Dermatologist, Skintrendz,
What was known?
Medical management of melasma with topical hydroquinone or triple combination cream is the most effective
Himayat Nagar, 12Consultant
treatment of melasma,although the last decade or more has seen a lot of side effects due to corticosteroids or
Dermatologist, Skin and Laser
hydroquinone if used unsupervised in Indian patients. Clinic, Begumpet, Hyderabad,
Azelaic acid and kojic acid and vitamic C topically,though weaker gaents,offer an alternative to hydroquinone
1
Consultant Dermatologist, Sklinic
containing creams. Skin Clinic, Indore, Madhya
An initial evaluation and treatment of medical factors,photoprotection and triple combination cream works well and Pradesh, 5Dermatology, Dr B. C.
should be rotated with other non hydroquinone containing agents. Roy Post Graduate Institute of
Pediatric Sciences, Kolkata, West
Bengal, 9Dermatology, Govt Medical
College, Srinagar, Jammu and
Introduction Kashmir, 10Senior Consultant and
Melasma is a common acquired pigmentary skin disorder characterized by a Coordinator, Dermatology, Apollo
Hospitals, Chennai, Tamil Nadu,
symmetrical macular pigmentation of sun-exposed areas like the face. The three 11
Consultant Dermatologist, Mohan
major patterns of pigmentation in melasma are centrofacial (cheeks, forehead, Skin Diseases Hospital, Phagwara,
upper lip, and nose), malar (cheeks and nose), and mandibular (mandibular area Punjab, 14Consultant Dermatologist,
Skinnocence: The Skin Clinic,
of cheeks). Melasma affects females much more commonly than males and majority Gurgaon, Haryana, 15Consultant
of patients are in the third and fourth decades of their life. Several factors such as Dermatologist, Cutis institute of
genetics, sunlight, cosmetics, pregnancy, hormonal treatments, thyroid dysfunction, Dermatology and Aesthetic Sciences,
and drugs have been implicated in the pathogenesis of melasma. Calicut, Kerala, India
The treatment of melasma includes various topical and/or systemic agents. The aim
of this article is to review the evidence available from the existing literature on Address for correspondence:
prevalence and predisposing factors of melasma and suggest management guidelines Dr. Rashmi Sarkar,
Department of Dermatology,
for this common yet challenging skin disorder. This article discusses available Maulana Azad Medical
evidence and brings forward a suggested treatment algorithm by 15 experts from College, New Delhi, India.
Pigmentary Disorders Society (PDS) in a collaborative discussion called South Asian E-mail: rashmisarkar@gmail.com
Pigmentary Disorders Forum (SPF).
This is an open access article distributed under the terms of the Creative
Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows
others to remix, tweak, and build upon the work non-commercially, as long as the
Access this article online author is credited and the new creations are licensed under the identical terms.
Quick Response Code: For reprints contact: reprints@medknow.com
How to cite this article: Sarkar R, Gokhale N, Godse K, Ailawadi P,
Arya L, Sarma N, et al. Medical management of melasma: A review with
consensus recommendations by Indian pigmentary expert group. Indian
DOI: 10.4103/ijd.IJD_489_17 J Dermatol 2017;62:450-69.
450 © 2017 Indian Journal of Dermatology | Published by Wolters Kluwer - Medknow

Sarkar, et al.: Medical management of Melasma-Indian Consensus Recommendations
Methods testosterone in patients as compared to the control group,

A panel comprising of 15 eminent dermatologists form again pointing toward a suppressed gonadal function.[6]
across the country with vast experience and significant Important/key points
academic contribution toward melasma was formed. These
were experts from Pigmentary Disorders Society (PDS) documenting the prevalence of melasma. Majority of
in a collaborative effort called South Asian Pigmentary currently available literature and statistics are from
Disorders Forum (SPF). hospital-based studies
This was followed by an extensive literature search from
the database-PUBMED and COCHRANE LIBRARY. The predisposed individual can lead to the development
keywords used for the search were melasma, treatment, of melasma
management, hydroquinone (HQ), retinoids, sunscreens,
oral drugs, safety, triple combination, chemical peels, between hormones and melasma.
and lasers. The articles published in the past two
Sunprotection for melasma
decades were included in the study. However, few older
There is sufficient literature to prove that light from
publications were included to describe the evolution of
both ultraviolet (UV) and visible spectrum is involved in
treatment over the years. Poorly designed studies and
the pathogenesis of melasma. To assess the efficacy of
those with conflicting results were excluded from the
study. This was followed by day panel discussion during sunscreens in preventing the development of melasma,
which the opinion of the panellists was sought and Lakhdar et al. conducted a study in 200 Moroccan
recorded. females who were <3 months pregnant. They were asked
to use a sunscreen with Sun Protection Factor (SPF) of
Findings 50+ and UVA protection factor of 28 during the day, and
it was seen that only 2.7% of these women developed
Prevalence and predisposing factors melasma during pregnancy.[7]
The reported prevalence of melasma is variable and is
based on the population group studied. It ranges from Boukari et al. in a prospective randomised controlled
8.8% among Latino males to 40% in Southeast Asian trial (RCT), conducted in 40 patients with melasma,
populations.[1] In a prospective study conducted by Sarkar established the efficacy of sunscreen with combined
et al. in a tertiary care hospital in India, the prevalence protection against UV and short wavelengths of visible
of melasma was found to be 20.5% in men.[2] Melasma, light (VL) in preventing melasma relapses.[8] Both the
however, affects women more commonly than men.[2] treatment groups contained the same filters against UV
except that one group received formula containing iron
The major etiological factors involved in melasma are oxides (Visible light absorbing pigment) also. The other
genetic susceptibility, sun exposure, and hormones. group had a significant increase in melasma area severity
Ortonne et al. conducted a larger global survey in 324 index (MASI) from baseline to month 6, as compared to the
women with melasma and found that 50% of patients one having the additional iron oxide, hence emphasizing
had a family history of melasma in at least one family the role of VL in the pathogenesis of melasma.
member. The most common time of onset of melasma
was post pregnancy (42%), whereas 26% of patients This was further confirmed in a study by
developed it during pregnancy.[3] In another study Castanedo-Cazares et al. in a double-blind RCT in
carried out by Tamega Ade et al. in 302 Brazilian 68 patients with melasma to assess the efficacy
patients with melasma, it was found that the most of sunscreen with broad-spectrum UV protection
common precipitating factors were pregnancy (36.4%), containing iron oxide compared with a regular UV-only
oral contraceptives (16.2%), and sun exposure (27.2%).[4] broad-spectrum sunscreen.[9] Patients applied HQ as
a depigmenting agent and were assessed by MASI,
The frequency of thyroid disorders is four times greater
colorimetry and histologic analysis. The group that used
in patients with melasma,[5] In a study conducted by
UV-iron oxide sunscreen had greater improvements than
Lutfi et al., thyroid abnormalities were found in 58.3% of
the UV-only group. Hence, the depigmenting efficacy of
melasma patients.[5] In a recent Indian study conducted
HQ was enhanced with concomitant sunscreen use.
by Gopichandani et al. in melasma patients, levels
of lueienizing hormone, estradiol, and progesterone In a double-blind, placebo-controlled RCT by Vázquez
were lower in cases compared to controls indicating and Sánchez.,[10] among 53 patients who concomitantly
a suppression of hypothalamic-gonadal axis in these used 3% HQ with sunscreen, nearly 96.2% of patients
patients. Other factors that could contribute include: showed improvement as compared to 80.7% of those
estrogens such as estriol and estrone, overexpression using a placebo. Thus, a broad spectrum sunscreen not
of estrogen receptors or increased responsiveness only prevents relapses of melasma but also enhances the
to circulating estrogens. The study also found low efficacy of other topical therapies.

Based on the available literature, the following Pigment lightening by HQ becomes evident after
recommendations can be made for the use of sunscreens 5–7 weeks of the treatment and is recommended to be
[Table 1]. The authors strongly believe that sunscreens continued for at least 3 months and up to 1 year.[22]
should be prescribed to all patients of melasma, as it
has been shown to be effective in reducing pigmentation
Hydroquinone in dual combination
following sun exposure. HQ has been used in combination with other topical
agents such as tretinoin and glycolic acid. Retinoids
Role of camouflage inhibit the transcription of tyrosinase thereby
It can take a long time for the patient to see results with inhibiting melanogenesis. The studies summarising the
the treatment prescribed, during which the option of use of HQ in dual combination have been listed in
cosmetic camouflage should be offered. There are several Table 3.[23-26]
options available in various shades to suit the skin tone.
It is important to choose easy-to-blend formulas that are
Triple combination
nonirritating and provide smooth coverage. One of the first combination topical therapies developed
for the treatment of hyperpigmentation was the
Topical treatment Kligman–Willis formula, consisting of 5% HQ, 0.1%
Phenolic compounds tretinoin, and 0.1% dexamethasone.
Hydroquinone The theory behind the effectiveness of this combination
HQ is the prototype depigmenting agent used in of agents is that tretinoin prevents the oxidation of HQ
melasma that exerts its effect by inhibiting tyrosinase, and improves epidermal penetration while the topical
the rate-limiting enzyme in melanin synthesis. HQ also corticosteroid (TCS) reduces irritation due to the other
affects the membranous structures of melanocytes and two ingredients and decreases cellular metabolism,
causes their apoptosis. further inhibiting melanin synthesis.
HQ 2%–4% is prominently used as mono-therapy and is To suit different skin types, the original Kligman’s
summarized in Table 2.[11-20] formula has been modified in many ways through
In a controlled study (n = 56), both 2% and 5% HQ addition/alteration of one or more of its components.
creams were found to be equally effective, and marked Maximum experimentation has been done with the
improvement was recorded in 80% of the patients.[21] TCS component, namely, the addition of mid to
However, few inflammatory reactions occurred with the high potent, fluorinated/non fluorinated agents and
former. Concentration more than 5% may cause more their concentration. Furthermore, the concentration
irritation and worsening of hyperpigmentation in the of tretinoin and HQ has been kept low in most
form of exogenous ochronosis on prolonged use. formulations. Combination regimes are found to be
more efficacious and faster acting than monotherapies,
thereby shortening the treatment duration and reducing
Table 1: Recommendations for use of sunscreens the AE due to an individual drug.
Serial Recommendatiins
No. The synergistic action of the three topical agents
1 Patients of melasma require a broad spectrum SC (with achieves significantly higher depigmentation than either
SPF of at least 30) which covers UVA, UVB and VL agent alone. According to a Cochrane Collaboration
2 Inorganic SCs are preferred as they provide protection Review (2010), the triple-combination cream (TCC)
from the entire spectrum especially those containing having 4% HQ, 0.05% tretinoin, and 0.01% fluocinolone
iron oxide. Additionally, they provide a camouflage acetonide was significantly more effective in lightening
effect. Since inorganic alone in high concentrations melasma than HQ alone (relative risk [RR] 1.58, 95%
are not cosmetically acceptable, a blend of inorganic confidence interval [CI] 1.26–1.97) or when compared to
and organic is the best. Those patients who would the dual combinations of tretinoin and HQ (RR = 2.75,
like a less visible SC, only organic SCs should be
95% CI 1.59–4.74), tretinoin, and fluocinolone
prescribed
acetonide (RR = 14.00, 95% CI 4.43–44.25), or HQ and
3 The SC needs to be applied liberally (teaspoon rule)
and repeatedly throughout the day (every 2-3 h). fluocinolone acetonide (RR = 10.50, 95% CI 3.85–28.60).
It needs to be emphasized to the patient that they Table 4 summarises the studies which have evaluated
should continue to use SC even when they stay the role of triple combination cream in melasma.[27-32]
indoors, and infrared light can also aggravate melasma
Triple combination cream in long-term and
4 A note should also be made of the coexistent
conditions in the patient like acne and general maintenance treatment of melasma
hydration of skin, occupation, needs and Melasma is a persistent disorder of pigmentation
expectations from the product prescribed and relapse after initial improvement is common.
VL: Visible light, UVA: Ultra violet A, UVB: Ultra violet B, Development of a maintenance regimen after initial
SC: Sunscreen, SPF: Sun protection factor improvement would help in the management.
Table 2: Summary of studies evaluating the role of hydroquinone mono therapy in melasma
References Study type Number of patients Treatment mode Treatmentduration, Method of Results Adverse effects
follow up assessment
Haddad et al., 2003[11] R, DB, SF 30 (25 completed Group 1:4% HQ versus 3 months Clinical Improvement: Group 1: 25%
study) Placebo Follow up - nil evaluation Overall - 72%, AE (irritation)
Divided into 2 groups Group 2: Skin HQ (76.9%) > Group 2: None
Fitzpatrik skin whitening complex skin whitening
type-IV–VI 5% versus placebo complex (66.7%)
Application on either Statistically
half of face nonsignificant
Daily SC (SPF25) in
both groups
Monteiro et al., 2011[12] O, NR 60 patients 4% HQ versus KA 3 months MASI HQ cream superior 6.7% AE (erythema
Indian 0.75% + 2.5% Follow up - nil to KA and mild burning
Vitamin C sensation) HQ
Daily SC SPF15 in 3.3%
both groups AE (erythema)
with KA
Farshi, 2011[13] R, O 29 patients, 4% HQ versus AA 20% 2 months MASI AA significantly AE with HQ>AA
Middle-east twice daily Follow up-nil better than HQ
Baliña and Graupe, 1991[14] R, DB 329 4% HQ versus 20% AA 24 weeks Planimetry (size) Superior results
Epidermal or mixed Follow up - nil 5 point with HQ (73%)
melasma scale (pigment as compared to
intensity) AA (65%)
Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

Piquero Martín et al., 1988[15] R, DB, O 60 patients 4% HQ versus 20%AA 24 weeks Clinical HQ > AA
Follow up - nil photography
Verallo-Rowell et al., 1989[16] R, DB 155 patients 2% HQ versus 20% AA 24 weeks Good to excellent Transient, mild to
Indo-Malay-Hispanic Twice daily Follow up - nil results in moderate irritant
origin application AA (73%) > reaction in both
HQ (19%) groups
Broad spectrum SC
[17]
Espinal-Perez et al., 2004 R, O 16 women 4% HQ versus. 5% 16 weeks Colorimetry, 93% good and 68.7% with HQ and
Mexican ASCA Follow up - nil digital excellent results 6.2% with ASCA
Broad spectrum SC photography, with HQ compared
subjective with 62.5% with
evaluation ASCA
Mendoza et al., 2014[18] R, DB, 45 patients 3% Rumex 8 weeks MASI, Superior results
placebo - controlled Skin type IV occidentalis versus Follow up - nil mexameter with Rumex
4% HQ occidentalis as
Epidermal and mixed
compared to HQ
melasma
453
Contd...
There are controversies regarding the safety of use
29% with with HQ
SF: Split face, O: Open, R: Randomized, DB: Double blind, RCT: Randomised controlled trial, NR: Nonrandomized, AA: Azelaic acid, HQ: Hydroquinone, ASCA: Ascorbic acid, KA: Kojic acid,
of TCS based TCC in long-term treatment of melasma.
niacinamide and
Adverse effects
Apart from a few studies on fluocinolone based TCC,
there is a dearth of studies evaluating the safety of
HQ > Niacinamide 8% with TCC for long-term use. There are three studies where
TCC has been used as a maintenance treatment for
melasma Table 5.[33-35]
infiltrate and solar
improvement and
satisfaction with
but better MASI
The studies in Table 5 show that fluocinolone based
higher patient
on mexameter
Equal efficacy
inflammatory
TCCs can be used as maintenance regimen for more than

decreases in
assessments
flutamide
8 weeks up to a maximum period of 1 year in either
elastosis
Results
daily/intermittent/tapering dose regimen. Adverse

effects such as skin atrophy and telangiectasia were
found to be quite low even on continuing this regimen
for more than 6 months. However, daily treatment in the
chromameter,
photography,
assessment
long term is associated with more AE while intermittent

mexameter
Method of
histology
therapy was associated with higher relapse of melasma

MASI,
MASI,
PGA,
in one study.[35]
In one RCT, objective reduction of melanin and
Treatmentduration,
presence of erythema was assessed in patients

receiving maintenance therapy following initial
Follow up - nil
8 weeks of the treatment regimen. Using narrowband

follow up
reflectance spectrophotometer, it was shown that

16 weeks
8 weeks
there was no difference between melanin levels in

SC: Sunscreen, MASI: Melanin Area and Severity Index, AE: Adverse effect, PGA: Physician global assessment
the melasma lesions in patients following either

Table 2: Contd...
twice weekly or tapering regimen. [36] Adverse effects

were rare in both phases of the study. There was
Treatment mode
borderline reduction in erythema with the tapering

4% Niacinamide
regimen.
versus 4% HQ
HQ 4% versus
1% flutamide
Triple combinations using mid–potent

corticosteroid
Triple combination using mometasone furoate as the
steroidal component was quite popular in our country
Number of patients
until recently. Despite the paucity of supporting evidence

regarding the efficacy and safety of the combination, it
has been used rampantly in the last decade, both as
27 patients
74 patients
physician’s prescription and over-the-counter drug. This

indiscreet usage has resulted in a number of AE in many
patients.
In a retrospective study performed on 60 Indian
Study type
patients of melasma who had used a mometasone-based

R, DB, SF
R, DB
TCC for at least 3 weeks over the past 1 year, it was

found that majority (51.7%) of the patients had used
it well beyond the recommended period.[37] More
than half of the patients showed steroid-related AE
such as atrophy (19/60), telangiectasia (26/60),
Navarrete-Solís et al., 2011[19]
Sadeghi-Bazargani, 2015[20]
hypertrichosis (17/60), and acneiform eruption (11/60)

while using this treatment for more than 2 months and
almost all the patients were affected when they used it
beyond 6 months. In addition, one-third of the patients
Adalatkhah and
complained of worsening of pigmentation and the rest

References
claimed that their disease was the same as before and

no patient rated his/her disease as better than what he/
she had before the initiation of treatment. Furthermore,

Table 3: Summary of the studies where hydroquinone has been used in dual combination
Reference Study type Number of Treatment Treatment Method of Results Adverse effects
patients mode duration assessment
Gold et al., Multicentric, O- 37 4% HQ 24 weeks MASI Significant -
2013[23] + 0.05% Follow melasma reduction in
tretinoin up - nil pigmentation pigmentation from
intensity 4th week onward
Grimes et al., O 20 4% HQ + 12 weeks MASI Significant 3 patients had
2013[24] Fitzpatric 0.025% reduction in erythema, peeling,
skin tretinoin MASI score after stinging
type - III–VI 4 weeks
Rendon SB 39 4% HQ 24 weeks MASI
Significant 2.8% severe
and Dryer, Fitzpatrick + 0.02% improvement in cutaneous
2016[25] skin type tretinoin both objective intolerability
III–VI and subjective
parameters
Guevara R 35 4% HQ + 12 weeks Mexameter, Significant -
and Pandya, 10% GA + MASI, global improvement in
2003[26] SC versus evaluation by both objective
SC patients and subjective
parameters
O: Open, SB: Single blind, R: Randomised, HQ: Hydrquinone, GA: Glycolic acid, SC: Sunscreen, MASI: Melanin Area and Severity Index
Table 4: Summary of the studies where role of triple-combination cream has been evaluated in melasma
Reference Type of Number of Treatment mode Treatment Method of Results Adverse
study patients duration assessment effects
Ferreira Cestari R, O 120 HQ 4% versus 8 weeks Global severity Total clearance Mild AE,
et al., 2007[28] TCC (RA 0.05% + assessment of TCC (35%) > incidence
4% HQ+FA 0.01%) melasma HQ (5.1%) similar in both
group
Taylor R, SB, MC 641 TCC (tretinoin 8 weeks Global TC > DC Mild AE, seen
et al., 2003[29] Skin types I 0.05% + HQ 4% + improvement in (significant) in in all groups
to IV FA 0.01%), versus melasma severity all the groups
DC (tretinoin+HQ,
tretinoin + FA and
HQ +FA)
Grimes MC, O, 1290 0.05% tretinoin + 8 weeks MASI, Significant
et al., 2006[30] Community (1042 HQ 4.% + FA 0.01% Follow up - nil investigator’s improvement in
based, completed) global evaluation MASI
uncontrolled
Fitzpatrick
skin types I
to VI
Chan R, DB 260 patients 4% HQ + 0.05% 8 weeks Melasma GSS, Significant
et al., 2008[31] Asian RA+0.01% FA Follow up - nil MASI reduction
versus 4% HQ in MASI in
TCC (64.2%)
group than
HQ (39.4%)
Gong R, DB 233 4% HQ +0.05% 8 weeks TCC more
et al., 20015[32] RA+0.01% FA Follow up - nil effective
versus placebo
TCC: Triple combination cream, HQ: Hydroquinone, RA: Retinoic acid, FA: Flucinolone acetonide, MASI: Melanin Area and Severity
Index, AE: Adverse effect, SF: Split face, O: Open, R: Randomized, MC: Multicenter, DB: Double blind, GSS: Global severity score
there were complaints of an increase in the area of skin potent TCSs should be used. If properly supervised, this
involvement that had occurred after stoppage of the can be an effective drug in keeping the pigmentation
TCC. Thus, triple combination topical therapy using low under control.

Table 5: Summary of studies evaluating the long term safety of triple-combination cream in melasma
Reference Type of Number of Treatment Duration of Method of Results Adverse effects
study study subjects mode study assessment
Arellano R, DB, SF, 320 patients Daily Daily Primary 78.8% subjects 11.6% AE
et al., 2012[33] MC (308 completed application of 8 weeks f/b efficacy - median had no or mild 0.83% discontinued
initial phase and TCC (FA 0.01% 6 months time to relapse melasma at week treatment due to AE
242 maintenance + HQ 4% + RA maintenance based on GSS 8 and entered
MC: Skin irritation
phase) 0.05%) f/b Secondary maintenance
and erythema
Skin type either of two efficacy phase
maintenance Atrophy and
III and IV variable-GSS, 53% of patients
regimens: telangiectasia
MASI, Subject’s remained
twice weekly minimum
assessment relapse-free in
vs tapering both groups
regimen - 3 week
Twice weekly
- 1st month,
regime better
2 week -
than tapering
2nd month,
egimen in
1 week -
postponing
4th month)
relapse in severe
melasma
Grimes O, Cohort 12 weeks of TCC (HQ 4% 70 (52 Mexameter, Significant Telangiectasia was
et al., 2010[34] initial therapy + RA 0.05% + completed) MASI reduction in all increased in the
f/b 12 weeks FA 0.01%) the parameters group receiving
maintainence Daily once at of efficacy continuous therapy
phase night for first assessment 53% patients
12 weeks reported one or more
Next of AE
12 weeks: None discontinued
Twice weekly
application in
clear to near
clear patient
Daily
treatment in
those patients
who did not
attain clear
state
Torok R, B, MC 569 patients TCC (FA 0.01% 12 months Global >80% of Most common -
et al., 2005[35] (389 and + HQ 4% + assessment patients had erythema (33%) and
327 completed RA+0.05%) clear or near desquamation (29%)
6 and 12 months) clear lesions Skin atrophy-<1%
Telangiectasia- 4%
SF: Split face, O: Open, B: Blind, R: Randomized, MC: Multicentre, TCC: Triple combination cream, HQ: Hydroquinone, RA: Retinoic
acid, FA: Flucinolone acetonide, MASI: Melasma Area and Severity Index, AE: Adverse effect, GSS: Global severity score
Important points of HQ as monotherapy and in combination with other

agents
used as an effective monotherapy. It is found to
be more efficacious than KA and AA. 4% HQ has Kligman’s regimen, the most well-studied formulation
been found to be more efficacious than 2% HQ as is that of 4% HQ, 0.05% tretinoin, and 0.01% FA. It
compared to 20% AA in most of the studies. Pigment has level A quality of evidence in treating melasma
lightening is observed in 3–6 months time. Higher of and is approved by the US FDA
HQ is associated with increased risk of inflammatory
response and long-term use may give rise to AEs like in clearing or near clearing of lesions in several
exogenous ochronosis well-designed RCTs

Table 6: Level and quality of evidence for melasma Due to the paucity of literature, we cannot make a
therapies using hydroquinone alone and in various recommendation for mequinol in melasma.
combinations Nonphenolic compounds
Therapy Level of Quality of Corticosteroids
evidence evidence
2% HQ II C
Corticosteroids reduce pigmentation by decreasing the
4% HQ I B
epidermal turnover and its anti-metabolic effect on
5% HQ1 0.1%-0.4% RA1 7% lactic III C
melanocytes. Both fluorinated and nonfluorinated steroids
acid/10% ascorbic acid have been used in the TCC in various formulations.
3% HQ+0.1% RA III C However, their use as monotherapy is not recommended
4% HQ+0.05% RA+0.01% FA I A due to the plethora of AE and misuse by the patients.
2% HQ1 0.05% RA1 0.1% III C Azelaic acid
dexamethasone (modified kligman)
Azelaic acid (AA) is a nonphenolic dicarboxylic acid
5% HQ, 0.1% RA, and 1% III C
hydrocortisone that acts by competitively inhibiting tyrosinase enzyme.
2% HQ1 0.05% RA1 0.1% III B It inhibits DNA synthesis and mitochondrial enzymes
dexamethasone (modified kligman) causing anti-proliferative and cytotoxic effects on
1: 30%-40% GA peel abnormal melanocytes. It has no effect on the normally
4% HQ+5% GA II B pigmented skin.
2% KA+2% HQ1 10% GA II C
In a prospective, single-blinded, split face comparison
2% HQ+10% GA II C
study, 40 Indian patients with melasma applied AA
4% HQ+20/30% GA I B
cream 20% to one half of the face for 24 weeks and
HQ: Hydroquinone, FA: Flucinolone acetonide, RA: Retinoic acid,
clobetasol 0.05% for eight weeks followed by AzA
GA: Glycolic acid, KA: Kojic acid
cream 20% for the next 16 weeks. Sequential therapy
was associated with more significant improvement than
when used daily is invariably associated with AEs such
monotherapy.[40]
as atrophy and telangiectasia. Although, the incidence
was found to be low in the mentioned studies AA has a good safety profile but may rarely cause
erythema and stinging. By its efficacy and good safety
response and is useful in preventing relapse. However, profile, it is a good option for patients who cannot
the frequency of application (daily/intermittent/ tolerate TCC. Table 7 summarizes the clinical trials with
tapering) determines the safety profile AA.[13,14,41-43]
the safety and efficacy of this regimen as maintenance Level and quality of evidence: IB
therapy and duration of treatment in Indian population Kojic acid
Kojic acid (KA) is hydrophilic fungal derivative that
lightening of pigmentation (within 3 weeks), but inhibits tyrosinase, by chelating copper at the active site
the relapse is also very fast. Further worsening of the enzyme. It is used in a concentration of 1%–4%.
of pigmentation and increase in the area of the
Various studies have been done to evaluate its role in
original lesion has also been experienced by
melasma and these have shown mixed results [Table 8].[12,44-46]
both the patients and physicians. Long-term
KA is less effective when used as monotherapy but shows
use is invariably associated with topical steroid
associated AEs such as atrophy, telangiectasia, good results in combination with HQ and GA.
hirsutism, and acneiform eruption. Level and quality of evidence: B
Mequinol Arbutin
Mequinol, 4-hydroxyanisole, is a phenolic compound that It is a derivative of D-glucopyranoside that competitively
acts as a competitive inhibitor of tyrosinase. It has been inhibits tyrosinase and is cytotoxic to melanocytes.
used in combination with tretinoin in the treatment of Deoxyarbutin is the synthetic derivative of arbutin with
solar lentigines.[38] However, there is only one case series higher efficacy and stability. In a prospective, open-label
that has assessed its role in melasma.,[39] in which 5 male study, a formulation containing nicotinamide 4%, arbutin
patients with melasma were treated with mequinol 2% 3%, bisabolol 1%, and retinaldehyde 0.05% was found to
tretinoin 0.01% topical solution for 16 weeks. Four of be associated with significant reduction in MASI scores.[47]
5 patients achieved complete clearance of melasma at Arbutin has also been used in combination with NdYAG
12 weeks with minimal AE. laser and found to have good results in melasma.[48]

Table 7: Summary of clinical trials with azelaic acid

Reference Study type Patients Treatment Method of Results Side effects
given assessment
Farshi[13] 29 15: 4% HQ + SC MASI Both groups showed
14: AA twice significant improvement. AA
daily + SC for 2 group showed significantly
months greater reduction in MASI
Baliña and DB 329 females 4% HQ AA yielded 65% good or Severe -AE such as
Graupe[14] 20% AA excellent results allergic sensitization or
exogenous ochronosis
were not observed
with AA
Bansal 60 Indian Group A: MASI Significant improvement Group B: Only 1 (5%)
et al.[41] patients Low fluence seen in all three patient had slight burning
QSNL 0.5-1J/ groups. Group C > Group sensation. In combination
cm2 weekly A (P<0.001) and Group group, 1 (5%) patient
intervals B (P<0.001) developed erythema and
Group B: 1 (5%) suffered slight
Twice daily burning sensation
application of
20% AA
Group C:
Combination
of both for
12 weeks
Mahajan Prospective 40 TCC once at night Digital Significant difference from 4 patients in Group A
et al.[42] randomized versus B: GA/ photography, baseline in both the groups. and 3 in Group B had
study AA 20% cream MASI, VAS However, no significant irritation, dryness and
combination for difference between the photosensitivity
3 months groups
Mazurek Comparative 60 females Each Mexameter, All dermocosmetics
K et al.[43] study group with corneometer, containing AA
2016 20 patients reviscometer significantly reduced
each received a pigmentation. Largest
dermocosmetic decrease in pigment
product observed in first 3
containing AA months. combination
for 24 weeks containing 20% AA and
mandelic acid, phytic
acid, 4 N-butyl resorcinol,
and ferulic acid proved
to be the most effective
dermocosmetic III
TCC: Triple combination cream, HQ: Hydroquinone, AA: Azelaic acid, MASI: Melanin Area and Severity Index, AE: Adverse effect,
DB: Double blind, VAS: Visual analog scale, SC: Sunscreen, QSNL: Q Switched Nd Yag Laser
Level and quality of evidence: C Level and quality of evidence IB

Vitamin C Niacinamide
Vitamin C inhibits melanogenesis by acting as a reducing It is the active amide of Vitamin B3 that reduces
agent at various oxidative steps in melanin synthesis. pigmentation by inhibiting the transfer of melanosomes
However, stability is an issue with the Vitamin C to keratinocytes. In a double-blind RCT, 4% niacinamide
preparations due to rapid oxidation. Magnesium ascorbic cream was compared with 4% HQ in 27 melasma patients.
phosphate is a stable esterified derivative of Vitamin C. About 44% of patients showed good to excellent
In a split-face RCT, 16 women with melasma used 5% AA improvement with niacinamide compared to 55% with
and 4% HQ on either side of the face for 16 weeks.[17] HQ. AE was less with niacinamide and histopathology
HQ showed significantly better results but more AE (93% showed decreased inflammatory infiltrate and solar
vs. 62.5%), as compared to Vitamin C. elastosis in the treated lesions.[19]

Table 8: Summary of studies outlining the role of kojic acid in melasma

Reference Study Patients Treatment given Duration Method of Results Adverse effects
type assessment
Deo et al., SB, RCT 80 patients Comparison in 4 groups 12 weeks MASI Efficacy of Group B
2013[44] Indian Group A: KA 1% highest
Group B: KA 1% + HQ B>D>A>C
2%
Group C: KA 1% + BV
0.1%
Group D: KA 1% + HQ
2% + BV 0.1%
Monteiro DB, RCT 60 4% HQ versus 0.75% 12 weeks MASI HQ cream superior
et al., 2013[12] KA + 2.5% Vitamin C Follow up - nil to KA
Lim, 1999[45] DB, SF, 40 Chinese 2% KA + 10% GA + 12 weeks Clinical Side receiving KA did Redness,
RCT women 2% HQ versus 10% evaluation better (60% versus stinging,
GA + 2% HQ 47% improvement) exfoliation in
few patients
Garcia and SF, RCT 39 patients 5% GA+HQ 2% versus 3 months Subjective, 51% responded. KA more
Fulton, 1996[46] 5% GA + KA 2% Follow up - nil wood’s light Equal efficacy of KA irritating
and HQ
SF: Split face, DB: Double-blind, SB: Single blind, RCT: Randomized controlled trial, HQ: Hydroquinone, KA: Kojic Acid, BV:
Betamethasone valerate, MASI: Melasma Area and Severity Index
Level and quality of evidence: IB possible benefits, rigorous controlled trials are mostly
Newer drugs lacking for these agents. Thus, these cannot be strongly
A number of newer derivatives of the conventional recommended for melasma at present and more studies
drugs, synthetic compounds and botanicals derived from are required to further elucidate their role.
natural sources are being studied for their potential Oral drugs for melasma
role in reducing melanogenesis and pigmentation. These Tranexamic acid (TXA) (Trans-4-Aminomethylcyclohexane-
compounds have been found to lighten melasma and carboxylic acid) is a synthetic derivative of the amino
hyperpigmentation induced by UV exposure. They can acid lysine. It binds reversibly to the lysine binding sites
prove to be effective in the treatment of melasma, on plasminogen molecules and inhibits plasminogen
especially as adjuncts to first-line treatments and activator (PA) and thus the conversion of plasminogen
for maintenance. These agents work through various to plasmin. Plasminogen also exists in the basal
mechanisms such as inhibition of activity or maturation epidermal cells and keratinocytes and induction of
of tyrosinase enzyme as well as acceleration of its this keratinocyte-PA system by UV exposure results in
degradation. Other mechanisms include anti-inflammatory, melanogenesis through production of prostaglandins
antioxidant, peroxidase inhibition or breaking down and leukotrienes. It is through prevention of binding
melanin, prevention of transfer of melanosomes
of plasminogen to keratinocyte, TA inhibits UV-induced
from melanocytes to the keratinocytes (niacinamide)
plasmin activity in keratinocytes, thereby decreasing
and stimulation of peroxisome proliferator-activated
melanogenesis through reduced production of PGs.
receptors (octadienedioic acid).
The effect of oral TA in melasma has been studied in
A number of these drugs have been studied in
multiple trials, as summarized in Table 10.[66-74] However,
human trials on melasma, solar lentigines or UV
only two of them are RCTs. Padhi and Pradhan[66]
induced hyperpigmentation with encouraging
evaluated the efficacy of oral TA in 40 Indian patients
results as elucidated in Table 9.[39,49-65] Others such
who were given oral TXA (250 mg twice a day for
as cinnamic acid, green tea extracts, flavonoids,
8 weeks) in addition to a TCC, (fluocinolone acetonide
gentistic acid, pyronic acrylic acid inhibitors, zinc
0.01%, tretinoin 0.05%, and HQ2%). There was a faster
dihydrolipoylhistidinate and resveratrol are in the
reduction in MASI in the combination group and the
process of development and preclinical studies. The
efficacy was maintained throughout the 6 months
knowledge of the properties of these agents enables
follow-up period.
the dermatologist to choose a product that gives the
best benefit to their patients while minimizing the side In another RCT conducted by Karn et al., in
effects Although experimental evidence suggests their 260 patients of melasma, the efficacy of TA was

460
Table 9: Summary of the newer drugs for treatment of melasma
Drug Derived from Mechanism References Type Treatment model Treatmentduration Number of Result Side effect Level of Quality
patients evidence of
evidence
4 Hydroxyanisol Derivative of HQ Inhibition of Keeling Case series Mequinol 2%/ Treatment duration 5 men with Complete Minimal II–III C
tyrosinase et al., 2008[39] tretinoin 0.01% - 12 weeks melasma clearance of adverse effects
topical solution Follow up - upto melisma at
16 week 12 weeks in 4/5
patients. Results
maintained at
the 16-week
follow-up visit
Lignin peroxidase Fungus oxidizing and Mauricio et al., Double-blind , LP versus 2% HQ 31 days 51 Asian LP cream provided Minimal I B
phanerochaete breaking down 2011[49] SF RCT cream or placebo on patients significant adverse effects
chrysosporium melanin either side of face skin-lightening as
compared to HQ
Rapid effect, seen
as early as 7 days
Draelos, Nonrandomized LP versus HQ and 12 weeks 60 women Parity between Minimal
2015[50] cohort, placebo (18-65 years) LP and HQ in adverse effects
SF study Distributed into with facial skin lightening,
2 cohorts (LP versus dyspigmentation whereas, LP
placebo and LP versus including superior to the
HQ) melasma placebo
LP superior in
skin texture and
roughness as
compared to HQ
Magnolignan Biphenyl inhibits the Takeda Cohort study 0.5% Magnolignan® 6 months 51 female Significant No unfavorable II–II C
compound maturation of et al., 2006[51] topical application to patients with improvement of skin reaction
tyrosinase pigmented areas on melasma, senile the melasma
the face lentigo, etc. Lightening of
nonpigmented
healthy skin also
seen

Contd...
Table 9: Contd...
evidence
NAG Monomeric unit of inhibiting the Iraji Double-blind, Combination of 12 weeks 30 females Although Minimal I B
chitin conversion of et al., 2009[52] split-face RCT 4% NAG and 2% (aged 20-50 statistically adverse effects
protyrosinase to nicotinamide versus years) nonsignificant,
tyrosinase 4% HQ on each side efficacy of
of face NAG+nicotinamide
slightly more
than HQ
Side efforts of
NAG+nicotinamide
slightly less than
HQ
Orchid extracts Contains antioxidant Tadokoro O, SF study Plant extracts 8 weeks 48 Japanese Significant Minimal II–II C
flavanoids et al., 2010[53] including orchid females improvement with adverse effects
extracts versus 3% (30-60 years) plant extracts
Vitamin C derivative With melasma (orchid extracts)
and/or lentigo formulation,
senilis parity with
Vitamin C

Dioic acid Biofermentation affects tyrosinase Tirado-Sanchez O, comparative 1% dioic acid versus 12 weeks 96 Mexican Significant Lesser side II–II C
of oleic acid transcriptiona et al., 2009[54] study 2% HQ female patients reduction in effects than
and melanosome pigmentation, HQ
transfer parity with HQ
Octadienedioic Structural Stimulation Wiechers Comparative 1% ODA versus 2% Treatment duration 21 Chinese Mild to moderate Minimal II–II C
acid similarity to AA of PPARs, et al.[55] study arbutin, were both - 8 weeks volunteers benefit in skin adverse effects
modulatesynthesis applied on either Follow up - 4 weeks lightening
of tyrosinase forearm
mRNA
B-Carotene Structural analog Saturates Kar, 2002[56] Open study B-carotene lotion on 8 weeks 31 adults Moderate benefit Minimal II–II C
of Vitamin A melanocyte melasma (26 female and in melasma adverse effects
receptors and 5 male)
reduce melanin
production
461
Contd...
462
Table 9: Contd...
evidence
Linoleic acid Derived from Accelerate Lee Double-blind 2% LM with 0.05% 6 weeks 2% LM mixed Minimal I B
hydroxylated tyrosinase et al., 2002[57] RCT BV versus 2% LM with with 0.05% adverse effects
botanical oils degradation 0.05% BV and 2% LA BM and 2% LA
e.g., safflower versus vehicle caused significant
Divided into 3 groups improvement
of 20 each, vehicle in melasma as
(Group A), 2% LM compared to
mixed with 0.05% BV vehicle or LM
(Group B), or 2% LM with BA
mixed with 0.05% BV
and 2% LA (Group C)
on the face every
night
Silymarin Plant Silybium Inhibits Elfar and El- Comparative TXA injection versus 60 female Topical silymarin Minimal II–II C
marinum melanogenesis Maghraby, study silymarin versus patients showed moderate adverse effects
2015[58] 50% GA peels benefit in
Divided into 3 groups melasma, parity
of 20 patients each: with GA peel,
group A (intradermal superior to
TXA injection), Group intradermal TXA
B (topical silymarin
cream) and group C
(GA peeling 50%)
5% methemazole Oral antithyroid Peroxidase Malek Case report 5% methimazole on 8 weeks Two Significant Minimal III C
drug inhibitor et al., 2013[59] melasma HQ-resistant improvement of adverse effects
melasma melasma
patients
Pidobenzone Phenolic Zanieri et al.[60] Case series 4% pidobenzone gel 16 weeks Significant Minimal II–III C
compound benefit in adverse effects
melasma

Contd...
Table 9: Contd...
evidence
Rucinol 4-n-butylresorcinol Inhibition of Khemis Double-blind, 0.3% rucinol versus 12 weeks 32 patients Lower Mild stinging, I B
tyrosinase and et al., 2007[61] split-face RCT vehicle pigmentation burning,
TRP-1 score on the erythema,
rucinol-treated peeling,
side benefits were dryness,
maintained for deesquamation
another 12 weeks
Huh Double-blind, 0.1% 8 weeks 23 patients Significantly No adverse
et al., 2010[62] split-face RCT liposome-encapsulated lower effects
rucinol versus vehicle pigmentation reported
scores with
the liposome
encapsulated
rucinol
Licorice extract Glycyrrhiza glabra, Tyrosinase Costa Mono-blind Emblica, licorice, and 60 days 56 patients Moderate Side effects I B
glabridin inhibition and et al., 2010[63] RCT belides 7% versus improvement in like burning
anti-inflammatory 2% HQ melasma. Rity and increase
Divided into two between both of the number
groups of 28 patients: groups of previous

Group A, cream with acne lesions
Emblica, licorice, and in 2 patients;
belides 7% used twice but lesser than
a day; Group B, HQ those with HQ
cream 2% used at
night
N-Acetyl-4-S- Phenolic agent Tyrosinase Jimbow, Case series N-acetyl- 6 months 12 patients Significant Recurrence of II–III C
cysteaminylphenol inhibition 1991[64] 4-S-cysteaminylphenol benefit in pigmentation
on melasma melasma in a patient

after
withdrawal of
drug
Acneiform
eruptions in
one patient
463
Contd...
compared to routine topical treatment. One group
AA: Azelaic acid, TRP-1: Tyrosinase-related protein-1, SF: Split face, O: Open, RCT: Randomised controlled trial, HQ: Hydroquinone, GA: Glycolic acid, BV: Betamethasone valerate, UV: Ultra violet,
evidence
Level of Quality
received oral TA 250 mg twice a day for 3 months
of
-
along with routine topical measures, whereas the other
evidence
group received routine topical treatment alone.[67] The
adverse effects evidence
melasma
No
in
combination treatment group showed statistically
significant decrease in mean MASI from baseline to
8 and 12 weeks. The authors concluded that oral
Side effect
TA provides rapid and sustained improvement in the
NAG: N-acetyl glucosamine, ODA: Octadienedioic acid, LA: Linoleic acid, LP: Lignin Peroxidase, PPARs: Peroxisome proliferator-activated receptors, LM: Lincomycin
Minimal
treatment of melasma.
Overall recommendation: as per available evidence, oral
and co-treatment
TA may be used alone or as an adjuvant to conventional
arbutin-43.5%,
compared with
Pigmentation
Aloesin-34%,
suppression :
topical drugs. It can also be used when other topical

treatments fail. However, there are limited studies with
- 63.3%,
Result
small sample size and variable dosage and duration.

Larger RCTs are required to evaluate the efficacy and
long-term follow-up as well as serious AE.
Treatmentduration Number of
Other oral drugs

patients
Procyanidin
There is only one RCT that has evaluated the efficacy
of oral procyanidin in melasma. In this double-blind,
placebo-controlled trial conducted by Handog EB et al.,
in 60 Filipino women with epidermal melasma, the
15 days
safety and efficacy of oral procyanidin plus Vitamin A, C,

E were compared with placebo.[75] The patients received
Table 9: Contd...
either the drug or placebo twice daily with meals for

divided into 4 groups:
applied 4 times a day

on volar forearm and
8 weeks. Results were evaluated using mexameter, MASI

irradiated (210 mJ)
Treatment model
Subjects were UV
arbutin-treated,
and aloesin and
aloesin-treated,
and global evaluation by the patient. The procyanidin

Vehicle control,
arbutin-treated
group showed a significant improvement in pigmentation

with minimal AEs.
However, this study had the limitation that procyanidin
was not evaluated as monotherapy and thus, the benefit
achieved cannot be ascribed to procyanidin alone.
Evidence level-B
Type
RCT
Oral polypodium leucotomos extract

et al., 2002[65]
One double-blinded RCT was done with oral polypodium

References
leucotomos extract (240-mg thrice a day) for 12 weeks

among 40 hispanic patients with moderate to severe
Choi
melasma.[76] There was an improvement in MASI

and melasma-related quality-of-life, but it was not
statistically significant.
Mechanism
Tyrosinase
chromone derived inhibition
Evidence level B
Recommendation: there is lack of evidence to recommend
this drug in melisma.
C-glycosylated
from aloe vera

Derived from
Pycnogenol
Pycnogenol is an extract of the bark of Pinus pinaster, a
French pine tree. It has antioxidant properties, increases
the endogenous antioxidant enzyme system and also
protects against UV radiation. Its efficacy in melasma
was evaluated in a single clinical trial conducted by Ni
et al. in 30 women with melasma who took one tablet
Aloesin
of Pycnogenol (25 mg) with meals three times daily

Drug
for 30 days.[77] MASI and pigmentary intensity index

Table 10: Summary of clinical trials with tranexemic acid

References Study type Patients Treatment Duration Method of Results Adverse effect
given assessment
Lee Retrospective 561 Asian Oral TA 4 months 89.7% improved AE in 7.1%
et al., 2016[68] analysis patients 10% no improvement Relapse rate
27.2%
Tan Retrospective 25 patients, Oral TA 250 Mean MASI, PGA Mean improvement: -
et al., 2016[69] analysis mixed race mg BD+pre- period of 69% at 3 months
Melasma existing treatment: 72% had relapse of
refractory combination 3.7 ± 0.33 melasma within 2
to topical topical months months of stopping TA
agents treatment Follow up: despite continuance of
(not 6 months topical agents
specified)
Padhi and O, RCT 40 Indian Group A: 8 weeks MASI Group A: significant
Pradhan, 2015[66] patients (20 TCC only Follow up - and faster
each group) Group B: 6 months improvement,
Oral TA 250 maintained for 6
mg BD + months
TCC
Na et al., 2013[70] O, NR, 25 Korean Oral TA 250 8 weeks Mexameter, MI and erythema
uncontrolled females mg TDS histopathology index decreased
and IHC significantly
(CD31 Ab, Histology: Reduction
anti-tryptase of epidermal
Ab) pigmentation, vessel
no and mast cell
counts
Shin RCT 48 Korean Group 1: 8 weeks Modified Score decreased
et al., 2013[71] female Laser+oral MASI, clinical significantly in
patients TA improvement both groups,
Group 2: scale better response in
Laser (2 combination group
sessions of
low fluence
Q-switched
NdYAG
laser)
Karn RCT 260 Group 3 months MASI Statistically
et al., 2012[67] Nepalese A: 130 significant decrease
patients patients, in mean MASI from
(130 in HQ + oral baseline to 8 and 12
each group) TA 250 mg weeks in Group A
BD
Group B: HQ
Cho Retrospective 51 Korean Group A: 4 months MASI Significantly better No AE
et al., 2013[72] analysis females Oral TA + response in Group A
IPL + laser
(Q-switched
NdYAG)
Group B:
IPL + Laser
Contd...

Table 10: Contd...

References Study type Patients Treatment Duration Method of Results Adverse effect
given assessment
Li et al., 2014[73] O, NR, 35 Chinese 250 mg oral 16 weeks 5 point scoring Significant GI AE: 12.5%
uncontrolled patients (32 TA TDS Follow up system improvement seen in patients
completed - nil 100% patients at 16 Menstrual AE - 2
study) weeks patients
Drowsines : 1
patient
Wu O, NR, 74 Chinese Oral TA 250 6 months PGA and Improvement GI discomfort:
et al., 2012[74] uncontrolled females mg BD Follow up: self-assessment excellent: 10.8% 5.4%
6 months Good: 54% Hypomenorrhoea:
Fair: 31.1% 8.1%
Poor: 4.1% Recurrence: 9.5%
6 month follow up:
Recurrence in 9.5% of
patients
O: Open, DB: Double blind, SB: Single blind, RCT: Randomised controlled trial, NR: Nonrandomized, TA: Tranexanemic acid,
HQ: Hydroquinone, MASI: Melanin Area and Severity Index, PGA: Physicians’ global assessment, IHC: Immunohistochemistry,
GI: Gastrointestinal, IPL: Intense pulsed dye laser, AE: Adverse effects, TCC: Triple-combination cream, MI: Melanin Index
Figure 1: Treatment algorithm for melasma in India, by a Consensus meeting of SPF(South Asian Pigmentary Disorders forum) with Pigmentary Disorders Society(PDS)
decreased after treatment. Several other symptoms such Conclusions

as fatigue, constipation, pains in the body, and anxiety Medical management of melasma with topical skin
were also improved, and no AE was seen. lightening therapy still remains the mainstay of therapy
It cannot be recommended in melasma until further and should always be used as first-line agents. HQ,
studies are available. triple combination therapy, other agents and upcoming
oral therapies will be used in combination in the
Glutathione future. The SPF with the Pigmentary Disorders Society
No available study in melasma suggests an easy to follow an algorithm, Figure 1,

where peels and lasers form second- and third-line 10. Vázquez M, Sánchez JL. The effcacy of a broad-spectrum
therapies respectively. sunscreen in the treatment of melasma. A randomized double
blinded controlled trial. Cutis 1983;32:95-6.
Acknowlegment 11. Haddad AL, Matos LF, Brunstein F, Ferreira LM, Silva A,
The Consensus Meeting of a group South Asian Pigmentary Costa D Jr., et al. A clinical, prospective, randomized,
double-blind trial comparing skin whitening complex with
Disorders Forum with Pigmentary Disorders Society was
hydroquinone vs. Placebo in the treatment of melasma. Int J
made possible by an educational grant by Galderma, India. Dermatol 2003;42:153-6.
Financial support and sponsorship 12. Monteiro RC, Kishore BN, Bhat RM, Sukumar D, Martis J,
Ganesh HK, et al. A comparative study of the efficacy of 4%
Nil. hydroquinone vs. 0.75% kojic acid cream in the treatment of
facial melasma. Indian J Dermatol 2013;58:157.
Conflicts of interest
13. Farshi S. Comparative study of therapeutic effects of 20%
There are no conflicts of interest. azelaic acid and hydroquinone 4% cream in the treatment of
melasma. J Cosmet Dermatol 2011;10:282-7.
What is new? 14. Baliña LM, Graupe K. The treatment of melasma 20%
azelaic acid versus 4% hydroquinone cream. Int J Dermatol
leads the list in treatment of melasma, a careful watch for side effects of topical
corticosteroids must be done.Mometasone or fluticasone containing creams
1991;30:893-5.
should be totally discouraged. 15. Piquero Martín J, Rothe de Arocha J, Beniamini Loker D.
Double-blind clinical study of the treatment of melasma with
be used for maintaining lightening of melasma. azelaic acid versus hydroquinone. Med Cutan Ibero Lat Am
1988;16:511-4.
more promising.
16. Verallo-Rowell VM, Verallo V, Graupe K, Lopez-Villafuerte L,
need more follow up for side effects. Garcia-Lopez M. Double-blind comparison of azelaic acid
and hydroquinone in the treatment of melasma. Acta Derm
Venereol Suppl (Stockh) 1989;143:58-61.
17. Espinal-Perez LE, Moncada B, Castanedo-Cazares JP.
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IJD® SYMPOSIUM
Chemical Peels in Melasma: A Review with Consensus Recommendations by

Indian Pigmentary Expert Group
Rashmi Sarkar, Shehnaz Arsiwala1, Neha Dubey2, Sidharth Sonthalia3, Anupam Das4, Latika Arya5, Narendra
Gokhale6, RG Torsekar7, VK Somani8, Imran Majid9, Kiran Godse10, G. Ravichandran11, Mohan Singh12, Sanjeev
Aurangabadkar13, T Salim14, Swapnil Shah15, Surabhi Sinha16
Abstract From the Dermatology, Maulana

Melasma is a notorious dermatosis, often resistant to treatment. Chemical peeling constitutes Azad Medical College and Lok Nayak
an acceptable option of management of melasma (of any type and duration). In this article, as Hospital, New Delhi, 1Consultant
Dermatologist, Saifee Hospital,
a group of experts from Pigmentary Disorders Society (PDS) in collaboration with South Asian
Prince Aly Khan Hospital, Mumbai,
Pigmentary Forum (SPF), we have tried to elaborate the various chemical peeling agents for 2
Consultant Dermatologist, Medanta
the treatment of melasma. Besides, we have reviewed the indications, mechanism of action, Hospital, Gurgaon, 3 Consultant
rationality and the detailed procedure of peeling. The evidence in favor of various peeling Dermatologist, Skinnocence: The
agents have been summarized as well. Skin Clinic, Gurgaon, Haryana,
4
Dermatology, KPC Medical College
KEY WORDS: Chemical peels, consensus, expert opinion, melasma and Hospital, Kolkata, West Bengal,
5
Consultant Dermatologist, L A Skin
and Aesthetic Clinic, New Delhi,
What was known? 6
Treatment of melasma is a multimodality approach. Chemical peels constitute the second-line of management in melasma, Sklinic Skin Clinic, Indore,
improving the epidermal component. However, peels are better avoided in dermal melasma, because of the chances of Madhya Pradesh, 7 Consultant
developing scars and post-inflammatory dyschromias. Proper patient selection, good counseling, priming of skin, and post Dermatologist, Fortis Hospital,
procedural use of topical therapies are essential to achieve the desired effects of peeling.
Mulund, Mumbai, 8 Consultant
Dermatologist,Skintrendz,
Himayat Nagar, Hyderabad,
Introduction 9
Dermatology, Govt Medical College,
Srinagar, Kashmir,
Melasma is a common chronic refractory acquired hyperpigmentation of the skin having 10
Dermatology, D Y Patil Hospital,
a serious impact on the quality of life and is challenging to treat. Treatment is often a Navi Mumbai,
multimodality approach. Due to the psychological and social stress attached to it, it is 11
Senior Consultant and Coordinator,
Dermatology, Apollo Hospitals,
important to counsel the patients adequately about disease chronicity, the importance
Chennai, 12 Consultant Dermatologist,
of photoprotection and role of hormones in disease persistence before embarking Mohan Skin Diseases Hospital,
on therapeutic correction, as improvement of whatever degree is often limited by Phagwara, Punjab, 13 Consultant
recurrences. Hence, melasma is a challenge to treat even by the best of interventions. Dermatologist, Skin and Laser
Clinic, Begumpet, Hyderabad,
Topical therapies are the mainstay of treatment for melasma and form the primary 14
Consultant Dermatologist, Cutis
mandatory step of single, dual, or triple combinations. Other interventions are often institute of Dermatology and
Aesthetic Sciences, Calicut, Kerala,
second- or third-line approach and constitute the adjunctive protocol. 15
Consultant Dermatologist, Solapur,
Chemical peels are a well-known modality of treatment and forms the second-line of Maharashtra, 16 Dermatologist
Specialist, Dr RML Hospital and
management in melasma and may be helpful in improvement of its epidermal component. PGIMS, New Delhi, India
The dermal component is handled by the ability of peel to induce phagocytosis of
stagnant melanin. However deep chemical peeling for a dermal component of melasma Address for correspondence:
is not recommended in skin types IV to VI since it can lead to scarring and severe Dr. Rashmi Sarkar,
dyschromias. Sequencing peels with a triple combination topically have shown a better Department of Dermatology,
Maualna Azad Medical
efficacy in moderate to severe melasma when measured by spectrometry. This article
[1]
College, New Delhi, India.
discusses available evidence and brings forward suggested treatment guidelines by E -mail: rashmisarkar@gmail.com
15 experts from Pigmentary Disorders Society (PDS) in
a collaborative discussion called South Asian Pigmentary
This is an open access article distributed under the terms of the Creative
Disorders Forum (SPF). Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows
others to remix, tweak, and build upon the work non-commercially, as long as the
Access this article online author is credited and the new creations are licensed under the identical terms.
Quick Response Code: For reprints contact: reprints@medknow.com
How to cite this article: Sarkar R, Arsiwala S, Dubey N, Sonthalia S,
Das A, Arya L, et al. Chemical peels in melasma: A review with consensus
recommendations by Indian pigmentary expert group. Indian J Dermatol
DOI: 10.4103/ijd.IJD_490_17 2017;62:470-6.
470 © 2017 Indian Journal of Dermatology | Published by Wolters Kluwer - Medknow

Sarkar, et al.: Chemical peels for melasma: Indian Consensus Recommendations
Rationale
Chemical peels have the capability of causing controlled
epidermal dyscohesion and subsequent regeneration.
The peeling agent causes superficial effects, i.e., enables
removal of epidermal melanin as well as melanin from the For example,
keratinocytes, halts melanosome transfer to keratinocytes,
hence being an indespensible modality in the treatment
of melasma. The type of chemical, its concentration,
number of coats applied and duration of application are Prepeel work up
the main factors which affect the efficacy and adverse
effects as well.[2] Accordingly, the results may be variable
with same or different agents in different patients and
can be repeated and rotated as and when needed for time taken, and expected outcome
optimal effects. Proper patient selection, good counseling,
priming of skin, and post peels use of topical therapies to
maintain the outcome and to prevent postinflammatory
hyperpigmentation (PIH) are essential. Literature evidence
reflects that clearance of melasma is better and faster
when chemical peels are combined with topical therapy.
Risk of PIH in skin of color looms large with medium and dermal nature of pigmentation
deep peels, and they need to be used with caution under
cover of vigilant priming and sun protection.
Indications
Sun Protection Factor
This is the absolute mandatory step in treating melasma.
A broad spectrum sunscreen with an inorganic filter of
Contraindications for peels in melasma Sun Protection Factor (SPF) 30 is necessary and should
be started at first consultation.
Priming
Priming in melasma is essential for at least 4[2-4] weeks
before the procedure. For 4% hydroquinone, at least 4
Basics before a peeling procedure weeks of priming is necessary. It not only ensures a
uniform penetration of the reagent but also reduces
the risk of complication. Hence, choosing the right and
specific priming agent is essential.[1-4]
Hydroquinone
medication, isotretinoin (medium depth peels), oral Hydroquinone (HQ) (2%–4%) is the gold standard for
contraceptives, immunosuppressives) priming. The depigmenting effects of HQ treatment become
evident after 5–7 weeks. Treatment should be continued
for at least 3 months as maintenance with peels.
Peels can be added after 4 weeks of HQ which should be
or deep chemical peel stopped 1 day before peels and resumed a day after for
superficial peels.
Retinoids
Retinoids as priming agents can be used alone or in
combination with kojic acid (KA), arbutin or glycolic
Evaluate for;
acid (GA). Tretinoin is the most commonly used retinoid
for the purpose. Ideally, it should be started 2-4 weeks
before the procedure and stopped a day prior.
system Adapalene and tazarotene can also be used for priming.
Adapalene has the advantage of less irritation than
infected, or wounded skin) tazarotene and tretinoin.
Glycolic acid preferred for sensitive skin, aqueous solution has higher
GA is the most widely used Alpha Hydroxy acids (AHA) for bioavailability of free acid and are preferred over gel
priming. Nearly 6%–12% GA is a good priming agent for based peels for cosmetic results.
peels in melasma and can be combined with tretinoin or Various studies in skin of color highlight the value of
HQ. It is started at least 2-6 weeks before peels and stopped GA peels. Some studies reported superior results when
a week before and reintroduced 2 days post procedure. GA concentration was as high as 50% with topical
Kojic acid therapies.[8] Few other studies emphasize the significance
KA is more effective in combination with other agents of its increased efficacy when 30%–40% GA peels are
when used twice a day for 1–2 months. Started 4 weeks combined with topical therapies such as topical 10%
before peels and stopped for a day before and reintroduced GA,[1] modified Kligman’s formula,[9] topical vitamin C,
1 day post peeling. Although it has a high sensitizing azelaic acid, and adapalene.[10]
potential KA is useful in patients who cannot tolerate
HQ. Level of Evidence-II-I
Priming agents when combined, add to the synergistic
Strength of recommendation-A
preparation of melasma skin before any form of interventions Lactic acid
are initiated. A dual or triple combination cream may Lactic acid (LA) is a small molecular weight AHA and have
be chosen with or without HQ. Retinoid in the triple proved beneficial when used as 92% strength at pH 3.5
combination may increase irritation potential of any peeling with double coats, which are applied for 10 min every
agent even in low strength and hence need to be withdrawn 3 weeks for epidermal melasma. It has been compared to
a week before peels. The disadvantage of retinoids is thinning Jessner’s peel and found to be safe and efficacious.[11]
of stratum corneum with resultant irritation and increased
photosensitivity in some patients. A good emollient should Level of Evidence-II-III
be added while priming with retinoids. One must also ensure Strength of recommendation-B
to defer a peel procedure when patients exhibit retinoid Mandelic acid
dermatitis. It should be initiated only when the dryness and Mandelic acid at 10%–50% applied weekly or biweekly
inflammation subsides.[5] is another peeling agent used in melasma. Its advantage
over other agents is its anti-inflammatory effect, thus
Peels Under Consideration for Melasma
causing less erythema and its synergistic effect with
The important category of peels being considered other peels and lasers.[4]
here are AHA peels (e.g., GA, mandelic acid) and Beta
Hydroxy acids (BHA) peels (e.g., salicylic acid (SA) and Phytic acid combination peels
combination peels like Jessner’s) and Tretinoin peels. Phytic acid is a large molecular weight AHA. It is used
[1,3,4,6,7,10,11,13,15,17-20] as a mild superficial peel and has antioxidant properties.
It is commercially available as a combination peel with
Important studies on peels in melasma are discussed
GA, LA and mandelic acid. It is used as self-neutralizing
in Table 1. GA and SA peels are useful in most cases
solution which can be left onto the skin. It can be used
of melasma. “Spot peeling” of discrete areas of
for sensitive skin. In melasma, it can be used twice a
hyperpigmentation may also be useful since it would
month for 4–5 sessions.[4,12]
reduce the contrast between the normal skin and
melanotic macules. It may also act as a test area when
Level of Evidence-III
higher strength peels such as 25% trichloroacetic
acid (TCA), Jessner’s solution or SA is used.[6] The levels Strength of recommendation-C
of evidence and strength of recommendations of various Beta hydroxy acid peels
peeling agents in the ethnic skin for melasma are Salicylic acid peel
described in Table 2 [Appendix 1 and 2].[5,7] SA peels in 20%–30% strength help in the elimination
of epidermal pigment in well-primed patients of
Alpha Hydroxy Acid Peels melasma. By its lipid solubility, it has a better
Glycolic acid peel keratolytic action and a smoother post peel texture.
This extremely hydrophilic reagent works by decreasing Grimes conducted five SA peels 20% and 30% in
keratinocyte cohesion at low concentration and by patients pretreated with HQ 4% and obtained moderate
epidermolysis at higher concentration. For melasma to significant improvement in 4 of 6 dark skinned
peeling, it is used in a concentration of 30%–70%. Two patients with melasma. Hyperpigmentation was
to three weeks apart weekly sessions are conducted observed more in patients who were on nonHQ priming
for a series of 4–6 sessions. Although gel based peel is agents.[13,14]

Table 1: Literature evidence of efficacy of peels in melasma

Author/year Peel agent Study group Methodology Outcome
Khunger, 2004[1] 70% GAP 1% tretinoin 10 Indian Split face study. Weekly peels Significant decrease in melasma
peel patients with applied. Patients evaluated at 6 and on both sides. Side effects were
melisma 12 weeks with MASI scoring minimal on both sides
Lim and Tham, 20%-70% GAP 10 Asian Peels done every 3 weeks for 8 Subjective better improvement on
1997[3] women with peels on one side of face. Cream peel side. No statistical significance
melisma containing 10% GA and 2%
hydroquinone applied on both sides
of face
Javaheri 50% GAP 25 Indian Peels done once per month for 3 Reduction in MASI scores seen
et al., 2001[4] women with months in 91% of patients. Epidermal
melasma Sunscreens and 10% GA lotion used responded better than mixed
with MASI for 2 weeks as prepeel
of 15
Grover and 10%-30% GAP 15 Indian Fortnightly superficial peel for 6 Good to fair response in melasma in
Reddu, 2003[8] patients of peels after priming for 2 weeks with >90% of patients
melasma and tretinoin Appreciable response seen on only
5 of PIH with 40% patients with PIH
skin Type
III-V
Kumari and 20%–35% GAP and 40 Indian Prepeel treatment with 12% GA or >70% improvement in MASI scores
Thappa, 2010[9] 10%-20% TCA patients with 0.1% Tretinoin. Peels were done in both groups. GAP has less adverse
a minimum every 15 days effects. TCA peel offers an advantage
MASI score of facial rejuvenation
of 10
Sarkar GAP with modified 40 Indian 20 patients received serial GAP and The group receiving GAP and topical
et al., 2002[10] Kligman’s regimen patients withmodified Kligman’s formula and the therapy had a statistically better
(hydroquinone 5%, melisma other 20 received only modified improvement
tretinoin 0.05%, Kligman’s formula
hydrocortisone acetate
1% in a cream base)
Sharquie 92% LA with pH 3.5 20 patients Peels were done every 3 weekly till 12 patients completed the study.
et al., 2005[11] with results or till a total of 6 sessions Marked response seen in all
melasma 12 patients
with Type IV
skin
GAP: Glycolic acid peel, MASI: Melasma Area and Severity Index, PIH: Postinflammatory hyperpigmentation, TCA: Trichloroacetic acid,
GA: Glycolic acid, LA: Lactic acid
Level of Evidence-II-III in the treatment of melasma reported that GA peel is

associated with fewer side effects than TCA and has the
Strength of recommendation-B
added advantage of facial rejuvenation.[9] Kalla reported
Trichloroacetic acid peel
degree of response was better with TCA but relapses
TCA peel work on the principle of causticity. In the were more common.[15] Topical ascorbic acid combined
lower strength of 15%, TCA can be used as a superficial
with 20% TCA peel in melasma improves the results
peel and at a higher strength of 35% it acts as a
and helps in maintaining the response to therapy[16]
medium depth peel. The sessions can be conducted at
and better when TCA is used along with modified
the monthly interval for about four sessions and can
Jessner’s peel.[17]
be done as 1–2 coats on melasma zone and a single
coat pan facially. It is a self-limiting peel and the end Level of Evidence-II-III
point is frosting, which acts as a guide to the depth of
peeling. Even with low strength formulation, one has Strength of recommendation-B
to be vigilant about the possibility of PIH, especially Jessner’s peel
in the skin of color. A single coat of TCA peel creates It is a combination of an AHA (LA) with a BHA (SA)
a superficial peel. Increasing number of coats can along with resorcinol, a phenol derivative. As a
make it medium depth. Frosting here acts as a guide superficial peeling agent it works well for all skin types.
to depth. A comparative study of TCA versus GA peels As a medium depth peel, it is used in combination with

other agents such as GA and TCA. In a study conducted Table 2: Levels of evidence and strength of
on melasma by Safoury et al., a combination of 15% recommendations for peels
TCA with modified Jessner’s was compared with only
Peeling agent Level of evidence Strength of
15% TCA, and the results were found to be better with recommendation
combination peels.[17] Phytic acid III C
LA II–iii B
Level of Evidence is II-III
GA II–i A
Strength of recommendation-B SA II–iii B
Retinoic acid peel (tretinoin) Jessner’s solution II–iii B
Tretinoin peels are useful in melasma, wherein 5%–10% Pyruvic acid III C
tretinoin is applied as a slow release peel and helps TCA II–iii B
to eliminate epidermal pigment, reduces photodamage, Levels of evidence and strength of recommendations for
and improve skin texture. It is beneficial as the various peeling agents in ethnic skin according to US
patients are already primed with topical tretinoin alone preventive services task force grades. SA: Salicylic acid,
or in triple combination therapy. Tretinoin peels versus LA: Lactic acid, TCA: Trichloroacetic acid, GA: Glycolic acid
GA peels in the treatment of melasma in dark-skinned
patients has been studied by Khunger et al. in Indian therapy, chemical peels have the capacity to bring
patients where tretinoin peel at 1% strength is applied about excellent cosmetic improvement. As a general
for 4 h once a week for 12 weeks and found to be of consideration, very superficial and superficial depth
equal efficacy.[1] peels are safer in Indian patients. There is a plethora of
Strength of recommendation-C information over the type of peel for various types of
Some authors have found good results in melasma after melasma. Through this article, we intend to set guidelines
peeling with retinol.[1] which will provide a quick referral aid in deciding on
the type of peel to be used in a particular patient. This
Different ethnicities in the Fitzpatrick skin type IV-VI will not only help in curating a stepwise approach for
may react variedly to the chemical agents used for the management of melasma but also increase the scope
peeling in melasma. of further developments in its management.
Practical Considerations Levels of evidence and strength of recommendations for
Good priming and strict sun protection ensures adequate various peeling agents in ethnic skin according to US
suppression of neomelanogenesis and reduces the risk of preventive services task force grades.[1,3,4,7,10,11,13,15,17-20]
PIH after peels Acknowlegment
Peels yield a good result in epidermal melasma of The Consensus Meeting of a group South Asian
<1 year duration. Peels are helpful to improve epidermal
Pigmentary Disorders Forum (SPF) with Pigmentary
pigmentation. Superficial chemical peels have no role
Disorders Society (PDS) was made possible by an
on the dermal pigment. Peels have to be combined with
educational grant by Galderma, India.
topical therapy and maintenance treatments with topical
agents is mandatory to prevent recurrence.[6] Financial support and sponsorship
Nil.
Postprocedure Care
To reduce the risk of complications and ensure quick Conflicts of interest
recovery of normal skin, optimum postprocedure care is There are no conflicts of interest.
essential. This is in accordance with the condition being What is new?
treated. -Priming should be done for peeling for at least 2-4 weeks.
-Peels are second line treatment for melasma and work well in combination with
other agents.
discomfort -Emollients can reduce irritation with topical priming agents.
-A single coat of peel with a second spot peel helps to decrease area of differences
between hyperpigmented and nonpigmented areas.
-Superficial combination and proprietary peels are better tolerated than
erythema and PIH, especially in darker skin types conventional peels even in sensitive skin.
maintenance peels. References

1. Khunger N, Sarkar R, Jain RK. Tretinoin peels versus glycolic
Conclusion acid peels in the treatment of melasma in dark-skinned
Although topical therapy forms the cornerstone of the patients. Dermatol Surg 2004;30:756-60.
treatment of melasma, as an adjuvant and maintenance 2. Resnik SS, Resnik BI. Complications of chemical peeling.

Dermatol Clin 1995;13:309-12. 2003;12 Suppl 2:43-50.

3. Lim JT, Tham SN. Glycolic acid peels in the treatment of 13. Grimes PE. The safety and efficacy of salicylic acid chemical
melasma among Asian women. Dermatol Surg 1997;23:177-9. peels in darker racial-ethnic groups. Dermatol Surg
4. Javaheri SM, Handa S, Kaur I, Kumar B. Safety and efficacy of 1999;25:18-22.
glycolic acid facial peel in Indian women with melasma. Int J 14. Ahn HH, Kim IH. Whitening effect of salicylic acid peels in
Dermatol 2001;40:354-7. Asian patients. Dermatol Surg 2006;32:372-5.
5. Arsiwala S. Chemical peels for melasma. In: Sarkar R, editor. 15. Kalla G, Garg A, Kachhawa D. Chemical peeling – Glycolic
Melasma a Monograph. 1st ed. New Delhi: Jaypee Brothers acid versus trichloroacetic acid in melasma. Indian J Dermatol
Medical Publishers; 2015. p. 54-62. Venereol Leprol 2001;67:82-4.
6. Roberts WE. Chemical peeling in ethnic/dark skin. Dermatol 16. Soliman MM, Ramadan SA, Bassiouny DA, Abdelmalek M.
Ther 2004;17:196-205. Combined trichloroacetic acid peel and topical ascorbic acid
7. Sarkar R, Bansal S, Garg VK. Chemical peels for melasma in versus trichloroacetic acid peel alone in the treatment of
dark-skinned patients. J Cutan Aesthet Surg 2012;5:247-53. melasma: A comparative study. J Cosmet Dermatol 2007;6:89-94.
8. Grover C, Reddu BS. The therapeutic value of glycolic acid 17. Safoury OS, Zaki NM, El Nabarawy EA, Farag EA. A study
peels in dermatology. Indian J Dermatol Venereol Leprol comparing chemical peeling using modified jessner’s solution
2003;69:148-50. and 15% trichloroacetic acid versus 15% trichloroacetic acid in
9. Kumari R, Thappa DM. Comparative study of trichloroacetic the treatment of melasma. Indian J Dermatol 2009;54:41-5.
acid versus glycolic acid chemical peels in the treatment of 18. Sharquie KE, Al-Tikreety MM, Al-Mashhadani SA. Lactic acid
melasma. Indian J Dermatol Venereol Leprol 2010;76:447. chemical peels as a new therapeutic modality in melasma in
10. Sarkar R, Kaur C, Bhalla M, Kanwar AJ. The combination of comparison to jessner’s solution chemical peels. Dermatol Surg
glycolic acid peels with a topical regimen in the treatment 2006;32:1429-36.
of melasma in dark-skinned patients: A comparative study. 19. Berardesca E, Cameli N, Primavera G, Carrera M. Clinical
Dermatol Surg 2002;28:828-32. and instrumental evaluation of skin improvement after
11. Sharquie KE, Al-Tikreety MM, Al-Mashhadani SA. Lactic acid treatment with a new 50% pyruvic acid peel. Dermatol Surg
as a new therapeutic peeling agent in melasma. Dermatol Surg 2006;32:526-31.
2005;31:149-54. 20. Sobhi RM, Sobhi AM. A single-blinded comparative study
12. Usuki A, Ohashi A, Sato H, Ochiai Y, Ichihashi M, Funasaka Y, between the use of glycolic acid 70% peel and the use of
et al. The inhibitory effect of glycolic acid and lactic acid topical nanosome vitamin C iontophoresis in the treatment of
on melanin synthesis in melanoma cells. Exp Dermatol melasma. J Cosmet Dermatol 2012;11:65-71.

Appendix 1: Levels of evidence and strength of recommendations at a glance

Level of evidence
Level Type of evidence
I Evidence obtained from at least one properly designed, randomized controlled trial
II–i Evidence obtained from well-designed controlled trials without randomization
II–ii Evidence obtained from well-designed cohort or case control analytical studies, preferably from more than one center or
research group
II–iii Evidence obtained from multiple-time series with or without the intervention; dramatic results in uncontrolled
experiments could also be regarded as this type of evidence
III Opinions of respected authorities based on clinical experience, descriptive studies or reports of expert committees
IV Evidence inadequate because of problems of methodology (e.g., sample size of length of comprehensiveness of follow-up
or conflicts in evidence)
Strength of recommendations
Grade Presence of evidence
A There is good evidence to support the use of the procedure
B There is fair evidence to support the use of the procedure
C There is poor evidence to support the use of procedure
D There is fair evidence to support the rejection of the use of the procedure
E There is good evidence to support the rejection of the use of the procedure
US preventive services task force levels of evidence for grading clinical trials
Appendix 2: Evidence based peels for melasma

GA - 10%–50% (C)
GA - 70% (B)
TCA - 10%–25% (C)
Jessener’s peel (SA + LA + resorcinol + ethanol) (C)
SA - 20%–30% (C)
Retinoic acid peel - 1%–5% (C)
KA - 2%–5% (C)
Pyruvic acid - 50% (C)
Combinations
GA (50%) + KA (10%) (C)
Retinol peel - 5% (C)
SA (20%) + GA (30%) (C)
SA: Salicylic acid, LA: Lactic acid, TCA: Trichloroacetic acid,
GA: Glycolic acid, KA: Kojic acid

[Downloaded free from http://www.ijdvl.com on Tuesday, October 6, 2020, IP: 182.68.216.144]
Review Article
Future therapies in melasma: What lies

ahead?
Rashmi Sarkar, Anuva Bansal, Pallavi Ailawadi
Department of Dermatology, Maulana Azad Medical College and Associated Lok Nayak Hospital, Delhi, India
Correspondence:
Abstract
Dr. Rashmi Sarkar,
Melasma is a common, acquired, symmetrical hypermelanosis. It negatively impacts the patient’s quality Department of Dermatology,
of life and responds poorly to treatment. Although earlier classified as epidermal and dermal, melasma is Maulana Azad Medical
now thought to be a complex interaction between epidermal melanocytes, keratinocytes, dermal fibroblasts, College, Bahadur Shah Zafar
mast cells, and vascular endothelial cells. Factors influencing melasma may include inflammation, reactive Marg, Delhi - 110 002, India.
oxygen species, ultraviolet radiation, genetic factors, and hormones. With a better understanding of the E-mail: rashmisarkar@gmail.com
pathogenesis of melasma and the realization that targeting melanin synthesis alone is not very effective,
treatments focussing on newly implicated factors have been developed. These include agents targeting
hyperactive melanocytes, melanosomal transfer to keratinocytes, defective skin barrier, the mast cells,
vasculature, and estrogen receptors as well as drugs with anti‑inflammatory and antioxidant activity. Many
of these newer agents are botanicals with multimodal mechanisms of action that offer a better safety
profile when compared with the conventional drugs. There has also been a focus on oral agents such as
tranexamic acid, flutamide, and ascorbic acid. It has been suggested that the “triple therapy of the future”
may be a combination of hydroquinone, an antiestrogen and a vascular endothelial growth factor inhibitor,
as the “ideal” skin‑lightening agent.
Key words: Future, melasma, pathogenesis, treatment
Introduction melanophages is heterogeneous, suggesting that all melasma

Melasma is a common, acquired, symmetrical hypermelanosis is “mixed” with the dermis often showing solar elastosis
that presents as light to dark brown macules on the face usually and increased vascularity as well.8,9 Thus, melasma is now
over the forehead and malar areas.1 Women with Fitzpatrick thought to be due to a complex interaction between epidermal
skin types III–V living in areas of increased ultraviolet (UV) melanocytes, keratinocytes, dermal fibroblasts, and vascular
light are frequently affected. Melasma is difficult to treat and endothelial cells, with hormonal and genetic factors and
negative impacts the quality of life.2-6 The most commonly exposure to UVR contributing to the variability, dynamicity
implicated etiological factors include genetic predisposition, and the unyielding nature of this process [Figure 1].9
exposure to UV radiation (UVR) and hormonal influences.7
The recognition that all melasma is “mixed” has suggested
Over the years the understanding of the pathophysiology of several potential targets for its treatment. Novel agents acting
melasma has undergone a paradigm shift. Melasma was earlier at various levels, from classically targeting the melanogenesis
classified on the basis of the localization of melanosomes as pathway, to acting on hyperactive melanocytes, reducing
epidermal, dermal, and mixed.1 However, in vivo reflectance
confocal microscopy has revealed that the distribution of This is an open access journal, and articles are distributed under the terms of
the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License,
Access this article online which allows others to remix, tweak, and build upon the work non-commercially,
as long as appropriate credit is given and the new creations are licensed under
Quick Response Code: Website: the identical terms.
www.ijdvl.com
For reprints contact: reprints@medknow.com
DOI:
10.4103/ijdvl.IJDVL_633_18 How to cite this article: Sarkar R, Bansal A, Ailawadi P. Future
therapies in melasma: What lies ahead? Indian J Dermatol Venereol
PMID: Leprol 2020;86:8-17.
***
Received: November, 2018. Accepted: April, 2019.
8 © 2019 Indian Journal of Dermatology, Venereology and Leprology | Published by Wolters Kluwer - Medknow
Sarkar, et al. Future therapy in melasma-What lies ahead?
inflammation and free radical production, and inhibiting Most conventional skin-lightening agents are inhibit
melanosomal transfer to keratinocytes have been developed. melanogenesis and its regulation. However, newer therapies
Some newer drugs may act by restoring the skin barrier or targeting other aspects of hyperpigmentation are now being
hormonal levels, while others target the dermal vasculature developed.
and mast cells.
Hyperactive Melanocytes
Melanogenesis and Its Regulation The genes involved in melanogenesis (tyrosinase, TYRP1,
Melanocytes residing in the skin produce melanin which is then TYRP2, and MITF) are upregulated in the lesional skin of
transferred to the adjoining keratinocytes.10,11 Melanogenesis patients with melasma, and lesional melanocytes show an
is influenced by genetic factors, age, ethnicity, UVR, and increased number of dendrites, mitochondria, golgi bodies,
drugs.7 Melanin is synthesized inside melanosomes through and rough endoplasmic reticulum. These findings suggest
a series of steps [Figure 2] catalyzed by tyrosinase, TYRP1, that heightened biological activity (rather than an increased
and TYRP2. The production of these enzymes is controlled number of cells) is responsible for the hyperpigmentation in
by micropthalmia-associated transcription factor (MITF).12,13 melasma.25,26 Thus, inhibiting the activity of melanocytes in
addition to reducing melanin synthesis may be more effective
The steps of this pathway are: in improving melasma.
• Conversion of tyrosine to DOPA; this upregulates
tyrosinase activity.14,15 Newer agents targeting melanogenesis and hyperactive
• Tyrosinase then transforms the DOPA to melanocytes
dopaquinone, which then undergoes spontaneous Conventional skin-lightening agents such as
conversion to 5,6 dihydoxyindole (DHI) and hydroquinone (HQ) and azelaic acid exert their effects
dihydroxyindole‑2‑carboxylic acid (DHICA).16,17 selectively in hyperactive melanocytes i.e. cells with
• Both DHI and DHICA are then converted to upregulated tyrosinase activity.27,28
eumelanin. The activation of TYRP-2 leads to the
formation of DHICA‑eumelanin associated with a Newer agents specifically targeting hyperactive
lighter skin phenotype.17,18 melanocytes
• Dopaquinone can also form pheomelanin in the Linoleic acid (topical)
presence of cysteine. A higher eumelanin: pheomelanin Linoleic acid selectively targets tyrosinase in hyperactive
ratio contributes to a darker skin phenotype, and TYRP1 melanocytes and decreases UVB‑induced pigmentation.29 In
and TYRP2 have been found to increase this ratio.16,19-21 a 6 week double-blind, randomized controlled trial (RCT), a
combination linoleic acid with lincomycin and betamethasone
Melanogenesis is regulated by the tyrosine kinase receptor valerate showed greater improvement than a combination of
KIT, its ligand SCF (stem cell factor), as well as MITF and the latter two or the vehicle alone.30
melanocortin-1 receptor (MC1R). The activation of MC1R
Ascorbic acid (topical)
induces a switch from the production of pheomelanin to
eumelanin.22-24 The SCF-KIT receptor tyrosine kinase Ascorbic acid decreases the oxidation of dopaquinone and
pathway activates MITF and regulates melanin production DHICA.31 In addition, it decreases tyrosinase activity,
through the induction of tyrosinase.22 reduces dermal damage, promotes collagen synthesis and
has an antioxidant and photoprotective effects, thus reducing
hyperpigmentation. 32 In a 16 week split-face study comparing
5% ascorbic acid (AsA) and 4% HQ cream improvement on
the HQ side was seen in 93% of 16 women as compared to
Figure 1 : Melasma – pathogenesis: A complex interaction among epidermal

and dermal entities Figure 2: Pathway of melanogenesis and the role of the DHI:DHICA ratio
Indian Journal of Dermatology, Venereology and Leprology | Volume 86 | Issue 1 | January-February 2020 9
62.5% on the AsA side (P < 0.05). Side effects (SEs) were Hydroxycoumarins (topical)
less frequent in AsA treated patients (6.2% vs 68.7%).32 Hydroxycoumarins are naturally occurring lactones that
inhibit tyrosinase and also have antioxidant activity.37
N-acetyl-4-S-cysteaminylphenol (topical) Umbelliferone (7‑hydroxycoumarin) has, in addition,
N-acetyl-4-S-cysteaminylphenol (NCAP) is effective in the anti‑inflammatory action.33
treatment of hyperpigmentation33 It is less irritant and more
stable than HQ.33,34 It inhibits tyrosinase in hyperactive Cinnamic acid (topical)
melanocytes, interferes with the thiol system decreasing Cinnamic acid is derived from ginseng. It inhibits
intracellular glutathione, and favors pheomelanin tyrosinase 33,42 and is more potent than HQ.43
synthesis. 34 NCAP 4% produced significant improvement in
66% of 12 patients with melasma with complete resolution Antisense oligonucleotides (topical)
in 8%.33,34 Antisense oligonucleotides act as skin-lightening agents
by downregulating the production of enzymes involved
Newer agents targeting melanogenesis in melanogenesis and decreasing the activity of DOPA
Arbutin and deoxyarbutin (topical) oxidase.37,44
Arbutin is a derivative of HQ. It inhibits tyrosinase and
DHICA, and prevents melanosomal maturation. Its effect is Role of Inflammation and Reactive Oxygen Species
dose-dependent and it has fewer SEs when compared with Reactive oxygen species (ROS) may be produced by
HQ.33,34 In an 8 week study of 54 patients with melasma several environmental factors including UVR. ROS can
2.51% arbutin was significantly more effective than placebo cause oxidative damage to the skin by interacting with
in improving melasma.35 Deoxyarbutin, a synthetic derivative cellular lipids, proteins, DNA, and carbohydrates.45,46
of arbutin, is also effective and safe.33 Excess ROS can activate tyrosinase and increase
melanin synthesis and melasma is associated with a
Aloesin (topical) disruption of the oxidant–antioxidant balance.33,47 Several
Aloesin is extracted from aloe vera. It competitively interleukins and cytokines can stimulate melanocyte
inhibits the conversion of tyrosine to DOPA and DOPA to proliferation, upregulate melanin production, and enhance
dopachrome.33 A dose-dependent skin-lightening effect was melanosome transfer.48,49 Thus, drugs with an antioxidant
noted when aloesin was applied four times daily for 15 days and anti‑inflammatory action are being investigated for their
on UV‑irradiated human forearm skin.36 potential as therapeutic agents in melasma [Figure 3].50
Rucinol (topical) Newer agents targeting ROS and inflammation

Rucinol (4-n-butylresorcinol) is a phenol derivative that Liquorice extract (topical)
inhibits tyrosinase and TYRP-137,38 In a randomized, Liquorice extract derived from the root of Glycyrrhiza glabra
double-blind, vehicle-controlled study 4-n-butylresorcinol inhibits melanin synthesis, causes melanin dispersion, and
0.1% cream was shown to be effective in 20 patients with decreases ROS production.33,37 It also has anti‑inflammatory
melasma.38 effects and can decrease UVB‑induced hyperpigmentation in
guinea pigs when used topically for 3 weeks.51
Flavonoids (topical)
Flavonoids are benzopyrene derivatives; they have Proanthocyanidin (oral)
anti‑inflammatory and antioxidant properties and are Proanthocyanidin extracted from grape seeds has significant
competitive inhibitors of tyrosinase.33,37 Hesperidin is a antioxidant action and has been shown to be beneficial in
flavonoid that protects against UVR‑induced free radical melasma in several studies.52,53 In a study of women with
damage.39 melasma, proanthocyanidin administered orally for 6 months
resulted in significant skin‑lightening in 10 of the 12
Epigallocatechin gallate and ellagic acid (topical) women (83%, P < 0.01).53
Epigallocatechin gallate is a phenolic compound
extracted from green tea.33,37 It inhibits
melanogenesis and also has significant anti‑inflammatory,
antioxidant, and anticancer properties.33 Ellagic acid is a
polyphenol derivative found in green tea, strawberries,
and pomegranate. It can inhibit tyrosinase and melanocyte
proliferation.40
Gentisic acid (topical)

Gentisic acid is a compound extracted from gentian roots. It
inhibits melanin synthesis.37,41 Figure 3: Role of drugs with antioxidant and anti‑inflammatory activity
10 Indian Journal of Dermatology, Venereology and Leprology | Volume 86 | Issue 1 | January-February 2020
Acidified amino acid peels (topical) Soymilk, soybean (topical)

Topical acidified amino acid peels with a pH similar to that Serine protease inhibitors (soy trypsin inhibitor (STI) and
of skin have significant antioxidant and tyrosinase inhibitory Bowman–Birk inhibitor (BBI)) found in soybeans have been
action and have fewer SEs as compared with glycolic shown to inhibit melanosome phagocytosis by keratinocytes
acid.37,54 via inhibition of PAR-2.48,57 In a double-blind, study of a
soy-containing moisturizer with a broad-spectrum sunscreen
Orchid extract (topical) in 68 patients, significant improvements in fine wrinkles and
Orchid extracts possess strong antioxidant activity. Orchid pigmentary changes were demonstrated after 3 months of usage.57
extract was as effective as 3% vitamin C in a study of
48 patients with melasma.33,37 The Defective Skin Barrier in Melasma
Impaired stratum corneum integrity has been demonstrated
Coffeeberry extract (topical) in melasma. A UVR‑induced, as well well as a de novo
Coffeeberry extract has antioxidant properties and it was found downregulation of several lipid metabolism genes (such as
to significantly reduce hyperpigmentation and photodamage peroxisome proliferator-activated receptor alpha) results in
impaired production of free fatty acids leading to a disrupted
in a 6-week study of 40 patients with melasma.33,37
epidermal barrier [Figure 4].58-62
Mulberry extract (topical) Newer agents targeting the defective barrier
Derived from the plant Mores alba, mulberry extract is Soy (topical)
a free radical scavenger and inhibits tyrosinase.33,47 The Topically applied, active soy moisturizer containing nondenatured
concentration producing 50% inhibition of tyrosinase activity serine protease inhibitors (STI and BBI) can decrease
is lower for mulberry extract than HQ and it markedly UVB‑induced pigmentation by restoring the skin barrier.57
improved the Melasma Area and Severity Index (MASI)
score in an RCT in 50 patients with melasma.47 The Vascular Component
Increased synthesis of proangiogenic factors such as vascular
Pycnogenol (oral) endothelial growth factor (VEGF) results in the proliferation
Derived from the bark of Pinus pinaster, this agent has of the dermal vessels. VEGF may increase melanin synthesis
significant antioxidant and anti‑inflammatory properties, through VEGF receptors located on melanocytes.63,64
and an oral formulation has been found to be beneficial in UVR‑induced release of plasminogen from dermal vessels
melasma.33,55 may also enhance melanogenesis.65
Other agents Newer agents targeting the vascular component

Polypodium leucomatous extracts act by inhibition of UV Tranexamic acid (oral)
induced ROS generation, including superoxide anions. AsA Tranexamic acid (TXA) inhibits the plasmin/plasminogen
and alpha tocopherol are strong anti‑inflammatory agents pathway. This results in interference in melanocyte
with a marked antioxidant mechanism.33 and keratinocyte interactions thus inhibiting melanin
synthesis [Figure 5].66 TXA also influences several other
dermal changes associated with melasma such as erythema
Melanosomal Transfer: Protease‑Activated
and reduces both epidermal and dermal pigmentation.67
Receptor 2 Several studies with oral TXA have demonstrated response
Melanosomes are transferred from epidermal melanocytes to rates of up to 89.7%, with visible lightening observed
neighboring keratinocytes as part of the epidermal-melanin at around 2 months.68-71 Padhi et al., observed faster
unit.48 Drugs inhibiting the keratinocyte protease‑activated improvement in melasma when a fluocinolone‑based triple
receptor 2 (PAR-2) inhibit melanosomal transfer and have combination cream was used along with TXA.72
been shown to be effective in melasma.33,48
Role of Histamine and the Mast Cells
Newer agents targeting melanosomal transfer An increased number of mast cells has been noted in
Niacinamide (topical) the lesional skin in melasma.73 UVR induces histamine
Niacinamide or vitamin B3, the active amide of niacin, synthesis and this in turn stimulates proliferation of
interferes with melanosomal transfer to the surrounding melanocytes through the H2 receptors. UVR also causes
keratinocytes by inhibiting PAR-2.33,46 mast cell tryptase activation leading to extracellular matrix
degradation and basement membrane disruption.74,75
Liquirtin (topical) Mast cells can produce VEGF, transforming growth
Liquirtin leads to a skin-lightening effect through dispersion factor-beta (TGF-β), and fibroblast growth factor‑2 all of
of melanin. A 20% liquiritin cream was shown to be effective which promote vascular proliferation thus contributing
in melasma.56 significantly to melasma.76,77
Figure 5: Role of vascular endothelium and mast cells – tranexamic acid

Figure 4: Role of a defective skin barrier in melisma inhibits the plasminogen pathway and decreases the activity of mast cells.
Zinc primarily affects mast cell degranulation
Despite the significant role of mast cells and histamine in
the pathogenesis of melasma, antihistamines have failed to melasma both 4% HQ cream or 1% flutamide cream were
demonstrate a significant benefit in the management of melasma. found to equally effective in treating melasma.88
Newer agents targeting mast cells Newer Agents with Unique Mechanisms: Potential
Tranexamic acid (oral) Targets of the future
TXAbeen shown to reduce the activity of mast cells. In a study of Curcumin (topical)
25 women with melasma, oral TXA tablets were administered Curcumin is a bioactive compound extracted from the rhizome
three times daily and a topical TXA agent was applied twice of Curcuma longa and its use is well established in traditional
daily for 8 weeks. On histopathological analysis, mast cells Chinese medicine for the treatment of various skin
were found to be decreased after treatment suggesting that diseases.89-91 It inhibits UVB‑induced production of ROS and
the effect on mast cells may underly the therapeutic effect of expression of matrix metalloproteinase in vitro by blocking
TXA in melasma.66 the activation of the UVB‑induced mitogen‑activated protein
kinase, nuclear factor-κB and AP-1 transcription factor signal
Zinc (topical) pathways.92 Curcumin gel has been found to be useful in the
Zinc reduces histamine secretion through inhibition of mast cell repair of photodamaged skin and the associated pigmentary
degranulation and is also an antioxidant. A significant reduction changes and solar elastosis.93
in melasma was seen in 14 patients using 10% topical zinc
sulfate after 3 months of therapy.78,79 In view of its anti‑inflammatory, free radical scavenging,
UV‑protective activities, curcumin in may serve as a novel
Role of the Estrogen Receptor skin-lightening agent of the future, both as a topical and an
Melasma is commonly seen among women in the oral preparation.
reproductive age group especially during pregnancy
or with oral contraceptive use.80,81 Estrogens Lignin peroxidase (topical)
upregulate the synthesis of enzymes involved in melanin Lignin peroxidase (LP), an enzyme derived from the fungus
production such as tyrosinase, TRP-1, TRP-2, and MITF, Phanerochaete chrysosporium. Since lignin is structurally
and also upregulate estrogen receptors in the lesional similar to melanin, lignin-degrading enzymes can be utilized
skin.82-86 to decolorize melanin.94,95 Lignin peroxidase is marketed as a
formulation containing the active enzyme component and its
Thus, drugs inhibiting the effect of estrogen such as activator (hydrogen peroxide) which causes the destruction
selective estrogen receptor modulators (eg., tamoxifen, of eumelanin. In 51 Asian patients, LP was found to be more
raloxifene) or aromatase inhibitors (eg., anastrozole, efficacious than HQ 2% with significant results seen as early
letrozole or exemestane) may be efficacious in the treatment as 7 days.96
of melasma.84,85 Furthermore, this research suggests that
the “triple therapy of the future” could include a HQ, an Platelet-rich plasma
antiestrogen, and a VEGF inhibitor.87 TGF-β1 released from α-granules in platelets has been
shown to cause significant inhibition of melanin synthesis
Newer agents targeting hormones through delayed extracellular signal-regulated kinase
Topical flutamide activation.97 PRP therapy may also cause improvement
Flutamide is an antiandrogenic agent that can in melasma by releasing platelet-derived growth factor,
influence alpha‑melanocyte‑stimulating hormone and which causes an increase in skin volume as a result of
cyclic adenosine monophosphate which are key regulators of angiogenesis and synthesis of collagen.98 A greater than
melanogenesis and in a randomized trial in 74 women with 80% reduction of melasma was seen in a 27-year-old
Table 1: Summary - newer drugs for melasma with level of evidence

Drug Mechanism of action Level of evidence Grade of recommendation
Newer agents targeting hyperactive melanocytes
Linoleic acid (topical) Tyrosinase inhibition29 2 #
Photoprotective29
NCAP (topical) Tyrosinase inhibition34 4 #
Favours pheomelanin synthesis34

Newer agents targeting melanogenesis
Arbutin (topical) Tyrosinase inhibition33 2 D
DHICA inhibition33
Prevents melanosomal maturation33
Aloesin (topical) Tyrosinase inhibition33 2 #
Rucinol (topical) Tyrosinase inhibition37,38 2 #
TYRP-1 inhibition37,38
Flavonoids (topical) Tyrosinase inhibition33,37 * #
Antioxidant action33,43
Anti‑inflammatory action33,37
Epigallocatechin (topical) Tyrosinase inhibition33 1 #
Anti‑inflammatory action
Antioxidants
Gentisic acid (topical) Melanin synthesis inhibition37 * #
Hydroxycoumarins (topical) Tyrosinase inhibition 33,37

* #
Anti‑inflammatory action33
Cinnamic acid (topical) Tyrosinase inhibition33 * #
Antisense oligonucleotides (topical) Dopa oxidase inhibition 37

* #
Newer agents targeting reactive oxygen species and inflammation

Liquorice extract (topical) Melanin dispersion33 2 #
Inhibits melanin synthesis33

Decreases free radical production33
Anti‑inflammatory effect33
Procyanidin (oral) Antioxidant action33 1 (in combination with #
vitamins A, C, E)
Acidified amino acid peels Tyrosinase inhibition37 * #
Antioxidant action37
Orchid extract (topical) Antioxidant action33 2 #
Coffee-berry extract (topical) Antioxidant action 33

1 #
Mulberry extract (topical) Tyrosinase inhibition 33

1 #
Free-radical scavenger33
Pycnogenol (oral) Antioxidant33 2 #
Anti‑inflammatory33
Newer agents targeting melanosomal transfer
Niacinamide (topical) PAR-2 inhibition33 2 B
Soymilk (topical) PAR-2 inhibition 47
2 #
Liquirtin (topical) Prevents melanin transfer 56

1 #
Melanin dispersion56
Newer agents targeting the defective barrier
Soymilk (topical) Restoration of the skin barrier62 2 #
Newer agents targeting the vascular component

Tranexamic acid (oral) Inhibits the plasmin/plasminogen pathway thus 1-4 A
disrupting the melanocyte and keratinocyte interaction66
Dermal changes associated with melasma such as
erythema67
Newer agents targeting mast cells
Tranexamic acid (oral) Reduces the activity of mast cells67 1-4 A
Zinc (topical) Inhibits mast cell degranulation78 2 #
Contd...
Table 1: Contd...
Drug Mechanism of action Level of evidence Grade of recommendation
Newer agents targeting the hormones
Topical flutamide Antiandrogenic 2 #
Decreases α‑MSH, cAMP89

*Adequate human clinical trials not available to suggest level of evidence, #There is not enough evidence to recommend the use in melisma. Grading of
recommendation as per OCEBM – levels of evidence (March 2009). Level of evidence as per OCEBM 2011 – 1: systematic review of randomized trials, 2:
randomized trial, 3: nonrandomized controlled cohort/follow-up study, 4: case series; case–control; or historically controlled studies. OCEBM: Oxford Centre for
Evidence-Based Medicine, DHICA: dihydroxyindole-2-carboxylic acid, PAR-2: protease-activated receptor-2, α-MSH: Alpha-melanocyte-stimulating hormone,
cAMP: cyclic adenosine monophosphate, NCAP: N-acetyl-4-S-cysteaminylphenol, TYRP:-Tyrosine related protein
Table 2: Classification of agents, based on level of evidence

Level of evidence
1 2 3 4
Epigallocatechin Linoleic acid - NCAP
Procyanidin Arbutin
(in combination with vitamins A, C, E) Aloesin
Coffee berry extract Rucinol
Mulberry extract Liquorice extract
Liquirtin Pycnogenol
Niacinamide Figure 6: Summary of the various new drugs and their mechanism
Soymilk of action. 1–7 represent the mechanisms of development of melasma:
Zinc 1 – hyperactive melanocytes and melanogenesis; 2 – melanosomal transfer
Fluatmide to keratinocytes; 3 – inflammation and reactive oxygen species; 4 – skin
NCAP: N-acetyl-4-S-cysteaminylphenol barrier; 5 – dermal vasculature; 6 – mast cells and histamine; 7 – estrogen
receptors. ER: estrogen receptors, NCAP: N-acetyl-4-S-cysteaminylphenol,
TXA: tranexamic acid
woman treated with three sessions of PRP with no
recurrence during follow-up.99
for development of newer therapies have now become
available.
Microneedling
Microneedling is commonly used for enhancing the drug
Melasma is no longer thought to be a static process but a
delivery of depigmenting agents in melasma. Microneedling
complex epidermal–dermal dynamic interaction with various
under topical anesthesia (two sessions, 1 month apart) along
cell types, inflammation, oxidative stress, and photodamage
with triple-combination cream applied at night was effective
all contributing significantly to this process. [Figure 6].
in reducing pigmentation in 22 patients with recalcitrant
facial melasma.100 This implies that the earlier approach of targeting epidermal
melanin alone is insufficient and newer drug classes that
Newer sunscreens target other aspects of the pathogenesis of melasma such
Visible light (VL) and infrared light (IR) have been shown to as hyperactive pendulous melanocytes, inflammation,
play an important role in hyperpigmentation, especially in the free radicals, melanosomal transfer, dermal vasculature,
darker skin types (III, IV, or V). VL may induce the production of hormone receptors, and the defective skin barrier may be
ROS leading to DNA damage. IR light provokes the activation effective [Tables 1and 2].
of the endothelin receptor B and the mitogen-activated protein
kinase which facilitate melanogenesis. Sunscreens containing There are few studies of this ever-expanding list of drugs
iron-oxide are effective against hyperpigmentation induced by for melasma and it is imperative to investigate the efficacy
VL. Other novel UV-VL sunscreens that allow absorption of and safety profile of these drugs in large scale trials. Despite
the radiation in the VL spectrum, and systemic antioxidants encouraging results in limited studies most have been inferior
such as vitamin A, C, and E, carotenoids and beta-carotene may to HQ and it is premature to recommend them as absolute
provide additive protection. Nonorganic and organic filters alternatives to conventional drugs. It is likely that these
that absorb or reflect IR are currently available and topical newer drugs may play a role only as add-on or second-line
antioxidants may be able to offer some protection against drugs or for as maintenance therapy.
IR‑related damage. However, their clinical efficacy still remains
to be determined.101,102 Acknowledgement
Jaypee Brothers Publishers: for Figures 1–5: Reproduced with
Conclusion permission from Bansal A, Ailawadi P, Sarkar R. Treatment
With improved understanding of the pathogenesis of of melasma. In: Sarkar R, editor. Melasma: A Monograph.
melasma, novel therapeutic targets with the potential 2nd ed. India: Jaypee Brothers Publishers; 2018.
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63. Kim EH, Kim YC, Lee ES, Kang HY. The vascular characteristics of human melanocytes by reverse transcriptase-competitive multiplex
melasma. J Dermatol Sci 2007;46:111‑6. PCR – Regulation by steroid hormones. J Invest Dermatol
64. Kim EJ, Park HY, Yaar M, Gilchrest BA. Modulation of vascular 1998;110:364-7.
endothelial growth factor receptors in melanocytes. Exp Dermatol 87. Cohen PR. Melasma treatment: A novel approach using a topical agent
2005;14:625-33. that contains an anti-estrogen and a vascular endothelial growth factor
65. Morelli JG, Norris DA. Influence of inflammatory mediators inhibitor. Med Hypotheses 2017;101:1-5.
and cytokines on human melanocyte function. J Invest Dermatol 88. Adalatkhah H, Sadeghi‑Bazargani H. The first clinical experience on efficacy
1993;100:191S-5S. of topical flutamide on melasma compared with topical hydroquinone:
66. Maeda K, Tomitab Y. Mechanism of the inhibitory effect of tranexamic A randomized clinical trial. Drug Des Devel Ther 2015;9:4219‑25.
acid on melanogenesis in cultured human melanocytes in the presence 89. Jagetia GC, Aggarwal BB. “Spicing up” of the immune system by
of keratinocyte-conditioned medium. J Health Sci 2007;53:389-96. curcumin. J Clin Immunol 2007;27:19-35.
67. Na JI, Choi SY, Yang SH, Choi HR, Kang HY, Park KC, et al. Effect 90. Ammon HP, Wahl MA. Pharmacology of Curcuma longa. Planta Med
of tranexamic acid on melasma: A clinical trial with histological 1991;57:1-7.
evaluation. J Eur Acad Dermatol Venereol 2013;27:1035‑9. 91. Tilak JC, Banerjee M, Mohan H, Devasagayam TP. Antioxidant
68. Tse TW, Hui E. Tranexamic acid: An important adjuvant in the availability of turmeric in relation to its medicinal and culinary uses.
treatment of melasma. J Cosmet Dermatol 2013;12:57‑66. Phytother Res 2004;18:798-804.
69. Cho HH, Choi M, Cho S, Lee JH. Role of oral tranexamic acid in 92. Hwang BM, Noh EM, Kim JS, Kim JM, You YO, Hwang JK, et al.
melasma patients treated with IPL and low fluence QS nd: YAG laser. Curcumin inhibits UVB‑induced matrix metalloproteinase‑1/3
J Dermatolog Treat 2013;24:292‑6. expression by suppressing the MAPK-p38/JNK pathways in human
dermal fibroblasts. Exp Dermatol 2013;22:371‑4. Arepally GM, et al. Platelet functions beyond hemostasis. J Thromb
93. Heng MC. Curcumin targeted signaling pathways: Basis for Haemost 2009;7:1759-66.
anti‑photoaging and anti‑carcinogenic therapy. Int J Dermatol 98. Kim DS, Park SH, Park KC. Transforming growth factor‑beta1
2010;49:608-22. decreases melanin synthesis via delayed extracellular signal-regulated
94. Woo SH, Cho JS, Lee BS, Kim EK. Decolorization of melanin by lignin kinase activation. Int J Biochem Cell Biol 2004;36:1482-91.
peroxidase from Phanerochaete chrysosporium. Biotechnol Bioprocess 99. Cayırlı M, Calışkan E, Açıkgöz G, Erbil AH, Ertürk G. Regression
Eng 2004;9:256-60. of melasma with platelet‑rich plasma treatment. Ann Dermatol
95. Ollikka P, Alhonmäki K, Leppänen VM, Glumoff T, Raijola T, 2014;26:401-2.
Suominen I, et al. Decolorization of azo, triphenyl methane, 100. Lima Ede A. Microneedling in facial recalcitrant melasma: Report of a
heterocyclic, and polymeric dyes by lignin peroxidase isoenzymes series of 22 cases. An Bras Dermatol 2015;90:919‑21.
from phanerochaete chrysosporium. Appl Environ Microbiol 101. Schalka S. New data on hyperpigmentation disorders. J Eur Acad
1993;59:4010-6. Dermatol Venereol 2017;31 Suppl 5:18‑21.
96. Mauricio T, Karmon Y, Khaiat A. A randomized and placebo-controlled 102. Teo WL, Gan E, Jinghan A, Chuah SY, Alain K, Goh CL et al. Double
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peroxidase cream vs. 2% hydroquinone cream. J Cosmet Dermatol dietary supplement rich in carotenoids as adjunct to topical lightening
2011;10:253-9. cream for the treatment of melasma: A pilot study. J Pigmentery Disord
97. Smyth SS, McEver RP, Weyrich AS, Morrell CN, Hoffman MR, 2015;2:164.
Announcement
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Erratum
Erratum: Future therapies in melasma: What lies ahead?

In the article titled “Future therapies in melasma: What lies ahead?”, published in pages 8-17, issue 1, vol. 86 of Indian Journal of Dermatology,
Venereology and Leprology[1], there are figure citations and legend mismatches:
• Fig 2: Legend -Drugs targeting hyperactive melanocytes, to be cited after ‘Newer agents targeting hyperactive melanocytes’ (Pg.9);
(Current Fig. 2 citation- to be removed)
• Fig 4- Legend ‘Drugs targeting melanosome transfer to keratinocytes. To be cited after the subheading: ‘Newer agents targeting
melanosomal transfer’ (Pg.11)
• Figure 5: Legend ‘Role of a defective skin barrier in melasma’; Figure 4 cited currently on page 11 to be cited as figure 5. (Current
Fig 5 citation – to be removed)
• Figure 6: Legend ‘Role of Endocrine factors in melasma’. Figure 6 to be cited on page 12 after ‘Newer agents targeting hormones’
(Current fig 6 citation in the conclusion – to be removed)
Reference
1. Sarkar R, Bansal A, Ailawadi P. Future therapies in melasma: What lies ahead? Indian J Dermatol Venereol Leprol 2020;86:8-17.
DOI: 10.4103/0378-6323.292501
608 © 2020 Indian Journal of Dermatology, Venereology and Leprology | Published by Wolters Kluwer - Medknow
Volume 7 | Issue 1 | January-June 2020
ISSN 2349 - 5847
In this issue:
• Editorial
COVID-19 and the dermatologist: fi nding calm in the chaos
• Review Articles
Novel corona virus infection: a dermatologist’s perspective
Tranexamic acid in melasma: a review
• Original Articles
A clinicoepidemological study of Lichen planus pigmentosus and its association with
metabolic syndrome and cutaneous manifestations in Indian population
A randomized controlled study to compare the effi cacy of methotrexate vs. oral
minipulse (betamethasone) along with NBUVB in patients with vitiligo vulgaris
“Pigmented irritant contact dermatitis” − an issue of concern due to dithranol
misuse in Andaman and Nicobar: an observational study
The Journal is indexed with DOAJ and Index Copernicus

Review Article
Tranexamic acid in melasma: a review

ABSTRACT
Tranexamic acid (TA), an anti-fibrinolytic agent, originally used for treating blood loss during surgery and various medical conditions, has
been found to show promising results in melasma. TA has been tried as oral therapy, topical formulations and even intradermally, with or
without adjuvants by various researchers in melasma but still there is no consensus on the optimum route, dose and timing of the treatment.
A systematic literature search of the PubMed electronic database was performed using the keywords ‘melasma’, ‘chloasma’ and
‘tranexamic acid’ in the title. The abstracts of the articles were screened and reviewed for relevance. The selected articles were read in detail
for inclusion and also the relevant references were traced. This review is an attempt to evaluate the role of TA by various routes in melasma
and offer suggestions for future directions of research.
Keywords: Chloasma, melasma, tranexamic acid
INTRODUCTION TA in melasma to establish the optimum dose and route of

administration for the best results.
Tranexamic acid (TA), a derivative of amino acid lysine, was
synthesized in 1962 by the Japanese researchers, Shosuke MATERIAL AND METHODS
and Okamoto. The antifibrinolytic activity of the trans-
isomer of TA was first described in 1964 and since then A systematic literature search of the PubMed electronic
it has been used in a variety of clinical settings and also to database was performed using the keywords ‘melasma’,
reduce blood loss during various surgeries.[1,2,3] The ‘chloasma’ and tranexamic acid in the title. A total of 54
theoretical concern about increased thromboembolic articles appeared, the abstracts of which were screened and
effects, though none have been reported, has resulted in reviewed by two of the authors independently for inclusion.
various guidelines not recommending its routine use. At In case of any conflict, the opinion of the third author was
present TA is recommended for use in emergency trauma sought. The articles included 26 studies on TA used in
surgery, cardiovascular surgery, elective oral surgery, hip melasma patients by various routes and used alone or in
and knee arthroplasty procedures, spinal surgery, heavy combination with other therapies.
menstrual bleeding and hereditary angioneurotic
oedema.[4,5]
AMRIT KAUR1, MALA BHALLA1, RASHMI SARKAR2

TA has recently been shown to be effective in treating 1
Department of Dermatology, Venereology and Leprosy,
melasma but the researchers have used various empirical
Government Medical College and Hospital, Chandigarh, India,
protocols, with and without adjuvants, which has made it 2
Department of Dermatology, Venereology and Leprosy, MAMC,
pretty difficult to understand and assign TA its place in the Delhi, India
vast armamentarium of melasma therapies. We have tried to
Correspondence to Dr. Mala Bhalla, Professor, Department of
review the basics of TA pharmacology as is already known
Dermatology, Venereology and Leprosy, Government Medical
from its previous non-dermatological uses in order to College and Hospital, Sector 32 B, Chandigarh, 160030, India.
understand its role in melasma. An attempt has also been E-mail: malabhalla@yahoo.co.in
made to include and interpret the various relevant studies of

Submission: 23 February 2020 Revision: 2 April 2020
Acceptance: 30 May 2020 Published: 10 July 2020
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10.4103/Pigmentinternational.
Pigmentinternational_9_20 How to cite this article: Kaur A, Bhalla M, Sarkar R. Tranexamic acid in melasma:
a review. Pigment Int 2020;7:12-25.
12 © 2020 Pigment International | Published by Wolters Kluwer - Medknow

Kaur, et al.: Tranexamic acid in melasma
The relevant references of the included articles were also

traced and included.
Tranexamic acid
The basic chemical structure is trans-4-
aminomethylcyclohexanecarboxylic acid (trans-AMCHA)
[Figure 1].[2] It inhibits the plasminogen activator by
reversibly blocking the lysine binding sites on both
plasminogen and plasmin, a molecule responsible for
degradation of fibrin which is a protein that forms the
framework of blood clots [Figure 2]. Thus, it prevents clot
breakdown and helps in stopping the bleeding while
exhibiting no effect on blood coagulation parameters like
platelet count, activated partial thromboplastin time and
prothrombin time. The coagulation, inflammation and
immunological pathways are known to be inter-related
with involvement of certain common factors and steps
which affect these responses. Plasmin is also known to
play a role in activation of complement, neutrophils and
monocytes and its inhibition thus may also have an anti-
inflammatory effect.[3,6]
Classically TA has been used orally at a dose of 0.5–1.5 g two

or three times daily and intravenously 0.5–1 g by slow
injection three times daily for controlling the blood loss
from major trauma, postpartum bleeding, surgery, tooth
removal, nose bleeds and menorrhagia.[4,5] It has also been
used as local intraarticular injections in arthroplasty
procedures and as 5% mouthwashes for oral procedures.[7]
Maximum plasma concentration of TA is attained within 3

hours of an oral dose. The presence of food in the
gastrointestinal tract has no effect on the
pharmacokinetics of the drug. The bioavailability of the
drug after oral administration is 34% and it is weakly Figure 1: Structure of Tranexamic acid
bound to plasma proteins (3%, which binds almost
exclusively to plasminogen). It crosses the blood-brain though the risk of thromboembolism was unclear but
barrier and the placenta, but excretion into breast milk is topical administration resulted in a ten-fold less plasma
minimal.[6] Over 95% of TA is eliminated unchanged in the concentration of TA with a potential reduction in adverse
urine so the dose should be adjusted in patients with renal effects.
impairment. In liver impairment, dose adjustment is not
needed as only a small amount of the drug is metabolized TA is regarded as pregnancy category B drug as no
through the liver. The total cumulative excretion after an mutagenic activity has been detected in in vitro and in
intravenous dose is approximately 90% after 24 hours.[4,5] vivo test systems. As it is only minimally excreted in
breast milk, breastfeeding may be continued, if
TA when used topically as mouthwashes (5% aqueous required.[3,6,7]
solution) in patients undergoing oral surgery showed
high drug concentrations (mean 200 mg/L) attained in The commonly reported side effects of TA are nausea,
saliva 30 minutes after mouth rinsing for 2 minutes while diarrhoea, vomiting and orthostatic hypotension. Rarely,
plasma concentrations remained below 2 mg/L. A Cochrane disturbances in colour vision, anaphylactic shock, skin
review by Ker et al.[7] also concluded that topical TA reduces reaction and acute renal cortical necrosis have also been
bleeding and need for blood transfusion in surgical patients, documented. No harmful foetal effects have been reported.
Pigment International | Volume 7 | Issue 1 | January-June 2020 13
Figure 2: Mechanism of action of Tranexamic acid in clotting system
TA has no effect on coagulation parameters and the overwhelming cosmetic impact for many patients leads to
theoretical thrombotic risk is very low. The risk may be tremendous emotional and psychosocial distress which
higher in patients of an older age group, those with pre- results in their seeking treatment. Despite the availability
existing morbidity, who are on other prothrombotic drugs of a wide variety of therapeutic options its treatment
(e.g., oral contraceptive pills), or have hereditary protein C remains challenging as pigmentation may fade but often
and protein S deficiency.[4,5] Theoretical risk may appear to recurs. All the therapeutic modalities aim at reducing the
be higher with the use of very high dose and long duration formation of melanin from melanocytes (topical agents) and
of TA but has not been reported. eliminating pre-existing melanin pigment (peeling and
laser). However, they inevitably may activate the
The conventional use of TA as an antifibrinolytic to decrease melanocytes by irritation, inflammation or by injuries to
blood loss during surgeries and menorrhagia is usually a keratinocyte that leads to recurrence or PIH. Various topical
short duration treatment of 4–7 days in a dosage of 2 to 4 g/ and physical therapies are thus, constantly being tried and
day but it has also been used long term for 8–34 months as evaluated both as stand-alone treatments as well as in
prophylactic therapy in hereditary angioedema. It has also different combinations.[13,14,15]
recently been found to be useful in melasma and post-
inflammatory hyperpigmentation.[9,10,11] The effect of TA in melasma was a serendipitous discovery
by Nijo Sadako[16] in 1979 when he used TA to treat a patient
Formulations available: Tablets: Only TA-500 mg, 250 mg; with chronic urticaria who also had melasma and observed
combination of 250 mg TA with proanthocyanadin that the melasma severity of the patient also reduced after
2-3 weeks. He then tried oral TA in a dose of 1.5 gram daily
Injections 100mg/ml along with vitamin B, C, E supplements for 5 months in 12
Topical creams (0.05g/50 ml) in combination with various patients of melasma who showed lightening of lesions
whitening agents like kojic acid, mulberry extract, arbutin, within 4 weeks of starting treatment in 11 patients.
vitamin E, etc.[4,5,8] Human keratinocytes are known to secrete urokinase
type plasminogen activator, which increases the activity
Tranexamic acid in melasma of melanocytes in vitro. Tranexamic acid is believed to
Melasma, also known as chloasma or mask of pregnancy, is a act in melasma by preventing the activation of
common, acquired, hyperpigmentary disorder usually melanocytes from ultraviolet (UV) light, hormones and
affecting females.[12] Though the exact pathomechanism injured keratinocyte through the inhibition of
of melasma is unknown many etiological factors have plasminogen activator system present in epidermal basal
been implicated in its causation as well as cells and keratinocytes. It also reduces melanocyte
aggravation.[2,3,4] Though asymptomatic, the tyrosinase activity by suppressing the production of
14 Pigment International | Volume 7 | Issue 1 | January-June 2020
prostaglandins and has an additional effect on the dermal After that studies of only topical tranexamic acid and in
blood vessels as it decreases the angiogenesis via inhibition combination with various lasers were conducted which did
of vascular endothelium growth factor (VEGF) [Figure 3]. By show response in melasma. Although topical TA is much
all these actions it not only improves the melasma, but may safer and free from systemic adverse effects of oral TA, still a
also reduce the likelihood of recurrence.[4,17,18] few studies have shown local side effects of itching, burning
and erythema which may hinder the long term use and also
Since the report by Sadako, TA has been tried by various lead to reduction in patient compliance.[4,19]
investigators in melasma in varying schedules and strengths
and even lower doses of tranexamic acid i.e. 500mg/day Intralesional injections are aimed at applying an adequate
have been reported to be effective.[5] amount of medication directly at the problematic area and
avoiding systemic effects. Furthermore, direct injection to
Despite the reports of its efficacy in melasma, there were the involved sites allows lower dosage of drugs to be used.
ethical concerns about using an antifibrinolytic drug for a TA has also been used as intradermal injections as well as
cosmetic condition. As it’s topical use was also seen to be with microneedling at varying intervals from weekly to
effective in both oral and other surgeries to control blood monthly treatments in melasma. Traditionally used as a
loss, this encouraged the researchers to evaluate the efficacy collagen induction therapy for facial scars and skin
of topical formulations and intradermal use of TA even in rejuvenation, microneedling is widely used as a
melasma. transdermal delivery system for therapeutic drugs and
vaccines. Microneedling delivery system offers a
Maeda et al.[1] were the first ones to study the effect of minimally invasive and painless method of transdermal
topical TA on skin pigmentation induced by UV exposure in drug administration but has even shown an
Weiser-Maples guinea pigs. Post-exposure applications improvement when used alone in a preliminary study on
of 2% and 3% solutions of topical TA to the exposed melasma.[17]
regions prevented the pigmentation process. The
histopathological examination after staining by the Physical therapies, like microneedling when used along with
Fontana-Masson method showed a significantly reduced conventional TA therapy may have an added effect as they
melanin content in the basal layer of UV-exposed also lead to improvement in the skin texture and results in
epidermis where 2% and 3% topical TA solutions had been better patient satisfaction. In melasma, TA has been used by
applied, compared with the vehicle control. various routes of administration (oral, topical, intralesional)
Figure 3: Mechanism of action of Tranexamic Acid in melasma

and in various dosages and concentrations and at different improvement in the mMASI (modified melasma area
time intervals.[20] severity index) or MASI(melasma area severity index) or
melanin index in the majority of the patients. Subjective
Most of the studies have been done on oral TA and fewer on satisfaction was usually greater and a significant lightening
topical and intralesional therapy but the results have been effect was usually seen by 2 months of therapy. Though in
encouraging. most of the studies oral TA was given for 12 weeks but it was
given safely in one study for 8 months and in another even
Oral tranexamic acid upto 2 years without any significant side effects.[28,29,30,31]
A total of 14 studies on oral TA were included for evaluation
but they had varying protocols with or without additional Recently the different routes of TA have also been evaluated
topical therapy, doses, treatment duration and outcomes vis a vis each other. Two studies compared oral TA 250 mg BD
[Table 1]. to intradermal TA injections every 4 weeks for a period of 12
weeks and found both routes to be effective (50 to 70 %
There were only two randomised controlled trials which are improvement)[20] but one concluded that oral therapy
considered to have the best level of evidence. One evaluated performed better than intradermal injections (57.5% vs
the role of only oral TA 250 mg B.D in melasma without any 43.5%).[32]
other therapy and showed 49% improvement as compared to
18% in the placebo group.[21] The other RCT compared oral Oral TA seems to be effective in melasma both as stand-
TA 250 mg B.D along with topical therapy with patients alone therapy and in combination with various topical
treated with only topical therapy and showed rapid and regimens as evidenced by the histological changes. The
sustained improvement in the combination therapy group.[5] usual effective dose of TA in melasma is lower than the
dose to reduce excessive bleeding. Though it usually takes
Two studies did a clinical and histopathological analysis. In at least 1 month to see a clinical response but it is advisable
refractory melasma, a higher dose of 500 mg BD was used and to continue for a minimum of 3 months before declaring it to
found to be effective. Biopsies done in these patients also be ineffective. Some authors have even suggested that the
showed evidence of decreased epidermal pigmentation and duration of the therapy may be more important than the
decreased Melan A staining on immunohistochemistry.[22] dose in the efficacy of treatment. Though there are no
Oral TA 500 mg TDS along with topical application of TA studies as yet describing the use of lower doses of TA i.e.
twice daily for 8 weeks showed decreased melanin index <500 mg/day but we have used doses as low as 250 mg and
scores and biopsies showed a decrease in epidermal even 125 mg daily and found them to be effective in
pigmentation, number of vessels and mast cells.[23] melasma [Figure 4]. The lower doses may also need to be
investigated further to elucidate their role in preventing
A single study evaluated the different dosages of oral TA recurrence or even as a maintenance dose at later stages.
(500 mg, 750 mg, 1000 mg and 1500 mg per day) and found
all the doses to be effective but lower doses than 500 mg Topical TA
have not been studied as yet for their effect.[24] Different strengths of topical TA have been used ranging for
2% to 5%. There are four studies on topical TA use and three
Triple combination creams and 4% hydroquinone creams are studies where topical TA has been used along with laser or
the usual standard therapy for melasma. Oral TA when used IPL procedures [Table 2].
with 4% hydroquinone gave favourable results as compared
to the patients using only 4% hydroquinone cream.[25] One In a clinico-histological study, 2% TA was used twice daily for
study which compared oral TA 250 mg BD along with 3% 12 weeks in mild melasma patients and 22 out of 23 patients
topical TA with oral TA with 20% Azaleic acid found both to showed improvement with lightening visible at 4 weeks.
be effective but a better response was noted in the group Fontana Masson stain showed a significant decrease in the
receiving both oral and topical TA.[26] melanin content in the epidermis. There was a decreased
number of CD31-positive vessels, decreased expression of
Patients treated with IPL or Q switched Nd yag lasers vascular endothelial growth factor and downregulation of
showed better results when oral TA was used along with Endothelin 1.[33]
the procedures.[27] Most of the studies used a dose of
250 mg B.D. added to the already ongoing topical therapy Rest of the studies had a split face design with the same
of melasma or laser procedures for a duration of 12 weeks patient acting as control. In one study 3% TA on one side was
and usually the results showed a greater than 50% compared to combination of 3% hydroquinone with 0.01 %
Table 1: Studies of oral tranexamic acid
S. Author & Study design No. of Dose Duration Any other Outcome measure results Side effects Follow Comments
No year patients therapy up
1 Del et al., Randomized, 44 Treatment group- 3 months Sunscreen mMASI score 49% reduction in Minimal side 3 Oral TA seems to
2018[21] placebo- 250mg mMASI score in the effects months be beneficial in
controlled, BDControl Group- TA group versus 18% patients with
double-blind placebo capsules in the placebo group. moderate to
study twice daily severe melasma
2. Tan et al., Retrospective 25 250 mg twice 3.7 ± 0.33 Combination MASI scorePhysician Mean improvement in - 6 Included patients
2017[5] study from daily months topical global MASI scores was months had melasma
August 2009 and therapy assessmentPhotography 69% refractory to
31 March 2011 topical treatment
which responded
to addition of
oral TA
3. Nagaraju Prospective 30 500mg BD Active treatment Sunscreen Modified MASI score & Clinical improvement Headache, 2 TA has an
et al., clinical immuno patients for 12 weeks with SPF histopathology and seen as early as 2 hypomenorrhea months inhibitory action
2018[22] histopathological of with 2 months above 30 immunohistochemistry weeks and maximal and weight gain on melanin
study refractor follow up improvement at end synthesis and
melasma of 4 months.Decrease melanocyte
in epidermal proliferation and
pigmentation and the result is
decrease in Melan A maintained in
staining on short term after
immunohistochemistry treatment
discontinuation
4. Na et al., Prospective clinic 25 500mg TDS 8 weeks Topical TA Melanin index (MI) and Significant decrease No serious - Histological
2013[23] histological study twice a day histopathology in mean lesional adverse events analysis showed
from Mar to July melanin index (MI) significant
2010 scores and reduction reduction of
of pigmentation on epidermal
histopathology. pigmentation,
vessel numbers
and mast cell
Pigment International | Volume 7 | Issue 1 | January-June 2020

counts.
5. Zhu et al., Randomised 45 Randomised to Initial 8 - MASI Melanin Photographic Mild stomach - Long term
2019[24] multi-centric patients receive TA at a weeksExtendable indexPhotography assessment showed upset, treatment with
prospective from 1 daily dose of to2 years that all 4 doses were decreased oral TA is safe
study from Oct centre 500 mg, 750 mg, effective but No menstruation. and well
2013 to Dec2016 and 27 1,000 mg, or significant differences tolerated.
from the 1,500 mg. in the MASI or Therapeutic
other melanin index effect may be
centre between the four related more to
doses. the treatment
duration than
dose.
6. MASI
(Continued )
17
18
Table 1 (Continued)
Lajevardi parallel-group, 100 Test group- 3 months HQ 4% At end of 6 months No additional 3 Relapse rate was
et al., assessor- and patients 250 mg TDS and treatment + 3 cream MASI score in the side effects months not significantly
2017[25] analyst-blinded, divided hydroquinone 4% months follow up intervention group were noted different (30% in
randomized into two cream (HQ) at was 1.8 points lower test vs 26% in
controlled trial groups nightControl than in the controls. control)
group- HQ 4% Patient satisfaction
cream at night was higher in test
group (82%vs 34%)
7. Malik et al., Prospective 100 All patients 6 months Group A- MASI Mean MASI score Oral TA seems to
2019[26] comparative patients received oral TA- topical 3% decreased perform better
study. divided 250 mg twice TAtwice significantly in both when combined
into 2 daily along with dailyGroup groups. Group A with topical TA
groups topical TA 3% in B-topical improved more than in comparison to
group A and 20 20% azelaic group B but the Azelaic acid
% azelaic acid in acid once difference was not
group B daily statistically significant
8. Cho et al., Retrospective, 51 Group A- oral TA 8 months IPL or low mMASI scores Group A showed Transient - Oral TA may
2013[27] comparative patients 500 mg daily fluence QS more reduction in headache improve efficacy
study divided with IPL or laser Nd:YAG laser Modified MASI score of laser or light
into 2 treatmentsGroup based therapies
groups B-only IPL or for melasma
laser
9 Khurana Prospective, 64 Group A- 3 months - Modified MASI Modified MASI score No major S/E 6- Oral TA showed
et al., randomized, divided localized scoresPhotographic improved in the oral month2 better efficacy
2019[32] comparative, into 2 microinjections assessment group by 57.5% as in the than intradermal
open-label study groups (4 mg/ml) of TA compared to 43.5% in oral TA in this study
of 32 monthlyGroup B- the intralesional group group but the effect of
each oral TA 250 mg and 3 in increasing the

BD the concentration or
injection frequency of
group injections needs

showed to be further
relapse assessed
10 Sharma Randomized, 100 Group A- Oral TA 12 weeks - MASI score Average reduction of Mild epigastric 24 Both oral and
et al., comparative patients 250 mg BDGroup MASI- 77.96 ± 9.39 discomfort, weeks2 intradermal
2017[20] study divided B- Intradermal in group A and hypomenorrhea, patients injections of TA
into 2 microinjections 79.00 ± 9.64 in group headache and of group seem to be
groups of TA of 4mg/ml B injection site A equally effective
of 50 at 4 weekly pain. relapsed in melasma
each intervals
11 Li Prospective, 35 500mg TDS 16 weeks Sunscreen MASI scorePhysician All patients had No serious - Oral TA appears
et al.,2014[28] open study in with SPF 30 assessmentPatient moderate to marked adverse effects to be an
2011-2012 assessment improvement effective and
(Continued )
Table 1 (Continued)
safe therapeutic
option.
12 Wu Prospective open 74 250 mg twice 6 months - Physician grading The improvement was Gastrointestinal 6 Recurrence was
et al.,2012[29] study daily excellent in10.8%,(8/ discomfort, months seen in 7
74)good in54%, (40/ hypomenorrhea patients at end
74)fair in 31.1%, (23/ of 6 months
74) and poor in 4.1%, follow up
(3/74).
13 Kam et al., Prospective, 260 Treatment group- 3 months Conventional MASI score Treatment group- - 3 Addition of oral
2012[30] randomized patients Oral TA 250mg topical Statistically significant months TA to
controlled trial divided BD along with therapies decrease in the mean conventional
into 2 conventional MASI from baseline topical therapies
groups topical to 8 and 12 may provide
therapiesControl weeksControl Group- rapid and
Group- decrease in mean sustained
conventional score was significant improvement
topical therapies at 8 weeks and
insignificant at 12
weeks
14 Lee et al., Retrospective 561 250 mg BD Median duration 551 −With Physician grading 89.7% patients- Transient in 40 Relapse TA seems to be
2016[31] study from of treatment-4 topical improved10.0%- no (7.1%) rate- a good therapy
January 2010 to months treatment or improvement0.4%- patients;1 had 27.2% for melasma and
June 2014 lasersAnd 10 worsenedAll the 10 deep vein can be used in
patients patients who received thrombosisbut combination with
received only only oral TA improved was other therapeutic
oral TA laterdiagnosed measures
with familial
protein S
deficiency

19
Figure 4: Photograph of female patient with centro-facial melasma at baseline (a, b, c) and after 12 weeks (d, e, f) of oral tranexamic acid 125 mg showing
80% decrease in pigmentation
dexamethasone on the other side which showed similar Topical TA also seems to be effective in melasma as seen by the
improvement.[34] Another study compared 5% liposomal TA histological changes but the optimum concentration for a
on one side with 4% hydroquinone on the other and found beneficial effect still needs to be established as the side
both to be effective with better results in the TA side though effects of erythema and irritation noted with increasing
not statistically significant.[35] Another study comparing 5% concentration may negate its lightening effect. Also, it seems
TA with its own vehicle found similar lightening on both thatregularapplicationoftopicalTAmaybemorebeneficialthan
sides with no difference but erythema was more on TA the episodic application during or after laser treatments as was
side.[36] alsoseenwiththeregularuseoforalTAwiththelasertreatments
which also helped in decreasing the post inflammatory
A split face study of low power CO2 fractional laser pigmentation which may happen with these procedures.
treatment every 4 to 6 weeks for five sessions over the
entire face along with either topical TA 3% applied after Intradermal TA
the laser treatment or intradermal TA given before the There are three studies in which intralesional TA injections
session on one side showed no statistically significant (4 mg/ml) were used, one where the solution was applied
difference between the sides.[37] Another split face study after microneedling and one comparing the intralesional
of IPL with topical TA applied immediately after the injections and microneedling [Table 3].
session on one side and vehicle on the other showed
that MASI decreased more on the topical TA side.[38] The open trial of weekly injections of TA for 12 weeks
Chung et al.[39] showed lightening of lesions in 85% of patients.[40] The other
two studies comparing TA to topical hydroquinone showed
Q switched Nd Yag laser treatment over the entire face with better results with TA.[41,42] In the split face study where
topical 3% TA applied on one side for 8 weeks showed more weekly microneedling was done on one side and sham
than 50% improvement in 80% patients. device applied on the other followed by application of
Table 2: Studies of topical tranexamic acid
S. Author & Study No. of Dose Duration Any other Outcome Results Side effects Additional comments
No year design patients therapy measure
1. Ebrahimi Double-blind 50 One half of face- topical 3% 12 Sun screen MASI score & No significant difference Erythema, skin Topical TA showed similar
et al., split-face TA emulsionOther half of weeks with SPF 30 patient between the two sides but side irritation, dryness, efficacy to combined
2014[34] trial face- combined solution of or more satisfaction effects of hydroquinone + scaling effect of hydroquinone
3% hydroquinone & 0.01% dexamethasone were and dexamethasone
dexamethasone twice a day significantly prominent as
compared with TA
2. Kim et al., Prospective 23 Topical 2% TA emulsion 12 Sun block Modified 22/23 showed improvement None reported Skin biopsies obtained
2016[33] study twice a day + face mask weeks MASI score & from 10 participants
with 2 % TA three times a chromameter showed decreased
week pigmentation, vascularity
and Endothelin 1.
3. Ayuthaya Double blind, 23 Topical 5% TA on one side 12 Sunscreen MASI,Melanin 18 patients showed a decrease Erythema was -
et al.[36], randomized, with only vehicle on other weeks and erythema in Melanin Index and MASI significant on the
2012 prospective side twice daily index score also decreased on both TA applied site as
split face physician and sides but no difference between compared to the
study patient global the sides. vehicle side
assessment
4. Banihashemi Split-face 23 5% topical liposomal TA on 12 week Sunscreen MASI mean MASI scores significantly No serious adverse Topical TA seems to be
et al., study one side and 4% reduced in both treated sides. events occurred as effective as 4%
2015[35] hydroquinone cream on the Though a greater decrease was with TA but hydroquinone
other side twice daily observed with 5% liposomal TA irritation occurred in
but it was not statistically three patients with
significant hydroquinone
5. Chung et al., Randomized, 15 Topical TA vs vehicle 12 IPL (4 Melanin index MI and mMASI decreased No serious side Topical TA also helped in
2016[38] split-face applied on randomly weeks monthly (MI) & significantly from baseline to 12 effects preventing rebound
study assigned side sessions) mMASI score weeks after the last IPL pigmentation after IPL
treatment on the topical TA side treatment
but not on the vehicle side

6. Tawfic et al., Randomized 30 One side randomly assigned 30 Fractional MASI score, Significant reduction of MASI Mild pain. Low power fractional CO2
2019[37] comparative to topicalTA solution after Weeks CO2 over the melanin index score over both sides but no laser is effective in

split-face the session immediately or entire face (MI), and difference between the two melasma but whether the
study intradermal microinjection of every4 to 6 erythema sides addition of TA adds to the
TA prior to the laser weeks for 5 index (EI) benefit needs further
session. sessions evaluation
7. Laothaworn Randomized, 25 Topical TA 3%vs vehicle 8 weeks QSNdYag mMASI Combination treatment showed No serious side -
et al., prospective, applied on randomly Laser1064- scores, significant decrease in the effects
2018[39] split-face, assigned side for 8 weeks nmat Mexameter mMASI score as compared to
controlled baseline and participant laser-alone.
trial at 4 weeks evaluation
over entire
face.
21
22
Table 3: Studies of intradermal tranexamic acid
S. Author and Study No. of Dose Duration Any other Outcome Results Side Follow Comments
No year design patients therapy measure effects up
1. Lee et al., Prospective 85 Weekly intradermal injections of 12 - MASI patient 8 patients rated good and Minimal - -
2006[40] open pilot 0.05 ml (4 mg/ml) TA weeks satisfaction score 65 rated fair and 12 rated
study poor results
2. Feng et al., Randomized, 180 Treatment group- intradermal TA 3 months Topical MASI Treatment group had None - Intradermal TA
2018[41] control trial patients and glutathione; monthly interval hydroquinone statistically significant reported adds to the
divided +topical hydroquinone every and better results than control effect of topical
into two nightControl group- topical glutathione group hydroquinone-
groups hydroquinone every night
3. Saki et al., Randomized, 37 TA (20mg/ml) intradermal injections 3 months Sunscreen Melanin and At one month TA was Acne, Pain 2 Intradermal TA
2018[42] split face monthly on one side and topical with SPF 50 erythema Index better than hydroquinone months may be more
study hydroquinone 2% on the other side but at 20 weeks there was beneficial than
OD no difference between the 2 % topical
two groups hydroquinone-
4. Budamakuntla Randomized, 60 (30 3 times at monthly intervals (0, 4 3 months - Modified MASI Microinjection group- Mild 3 The
et al., 2013[4] open label, +30) and 8 weeks) by 4mg/ml TAgroup score,Patient 35.72% improvement in the discomfort, months improvement
comparative 1- TA microinjections group 2- TA global MASI score.microneedling burning, was maintained
study microneedling assessment, group- 44.41% erythema at 3 months of
Physician global improvement follow up
assessment
5. Yang Xu et al., Randomized, 30 Test side of face- topical TA 0.5% 12 - Melanin Pretreatment with a No obvious - -
2017[43] self- along with functional microarray of weeks indexPatient functional microarray of adverse
controlled, microneedlesControl side of face- satisfaction score microneedles significantly reactions
split-face sham device plus topical TA4 increased the effectiveness were
study. weekly interval of topical TA observed

Figure 5: Photograph of male patient with malar melasma at baseline (a, b, c) and after 8 weeks (d, e, f) of tranexamic acid with microneedling on test side
(right side of face c & f) showing 70–80% decrease in pigmentation and microneedling with distilled water on control side (left side of face b & e) showing
20% decrease in pigmentation
0.5% TA over the entire face showed better results on the application of 10 % TA solution on one side and distilled
microneedling side which may have helped in the better water on the other side. The test side showed a much better
absorption of the TA.[43] improvement than the control side (65% improvement in
mean MASI vs 20%) [Figure 5].
A randomized, open label, comparative study of TA
microinjections and TA with microneedling in patients of Intradermal TA also seems to be effective in melasma both
melasma where treatments were done three times at as intralesional injections and with microneedling but
monthly intervals (0, 4 and 8 weeks) by 4mg/ml TA microneedling seems to have an edge because of its
showed better results in the microneedling group (44.41% independent skin rejuvenation properties.[44] The
improvement in the MASI score vs 35.72%).[5] studies have used various protocols of weekly to
monthly sessions so the optimum time interval still
In our split face study, 40 patients of melasma were treated needs to be established as well as the concentration to
by four sessions of two weekly microneedling followed by be used.

CONCLUSION 5. Tan AWM, Sen P, Chua SH, Goh BK. Oral tranexamic acid lightens
refractory melasma. Australas J Dermatol 2017;58:e105-8.
6. Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and
Melasma is a recurrent and refractory problem with a wide other indications. Drugs 1999;57:1005-32.
variety of both medical and procedural therapeutic options 7. Ker K, Edwards P, Perel P, Shakur H, Roberts I. Effect of tranexamic
available for its management. Appropriate and judicious use acid on surgical bleeding: systematic review and cumulative meta-
of medicines which are effective and can be used for longer analysis. BMJ 2012;344:e3054.
time is necessary to treat melasma without any side effects. 8. Zhang L, Tan WQ, Fang QQ, et al. Tranexamic acid for adults with
melasma: a systematic review and meta-analysis. Biomed Res Int
TA in all forms (oral, topical) have shown promising results
2018;2018:1683414. doi:10.1155/2018/1683414
over the past few years when used along with other 9. Sheu SL. Treatment of melasma using tranexamic acid: what’s known
therapies as well as when used as a stand-alone therapy. and what’s next. Cutis 2018;101:E7-E8
10. Christopher EM. Rooks textbook of dermatology. 9th ed. Wiley
TA has been tried at varying oral doses, varying topical Blackwell. p 43.6
11. Tant D. Tranexamic acid in chronic urticara. Br Med J 1979;1:266
concentrations and at varying time intervals intradermally
12. 12.Grimes P, Kelly AP, Torok H, Wills I. Community-based trial of a
and also with and without various adjuvants. Though almost triple-combination agent for the treatment of facial melasma. Cutis
all the studies show the beneficial effect of TA there is still 2006;77:177-84
no consensus on the optimum route, dose and timing of the 13. Sanchez NP, Pathak MA, Sato S, Fitzpatrick TB, Sanchez JL, Mihm
treatment with TA in melasma. For oral TA effectiveness the MC Jr. Melasma: a clinical, light microscopic, ultrastructural and
duration of therapy has been suggested to be more immunofluorescence study. J Am Acad Dermatol 1981;4:698-710.
14. Cayce KA, McMichael AJ, Feldman SR. Hyperpigmentation:an
important than the dose. Though lightening of
overview of the common afflictions. Dermatol Nursing
pigmentation is visible earlier, a minimum of 3 months 2004;16:401-16.
trial is recommended. Topical TA also seems to be more 15. Gilchrest BA, Fitzpatrick TB, Anderson RR, Parrish JA. Localization
effective with regular use rather than episodic use. When of melanin pigmentation in the skin with wood’s lamp. Br J Dermatol
used along with microneedling, the frequency of the 1977;96:245-8.
16. Sadako N. Treatment of melasma with tranexamic acid. The Clin Rep
treatment may depend on the size of the dermaroller
1979;13:3129-31 (in Japanese).
used i.e. the needle size with sessions at biweekly to 17. Singh A, Yadav S. Microneedling: advances and widening horizons.
monthly intervals while intradermal injections have even Indian Dermatol Online J 2016;7:244-54.
been given weekly. Further studies are required to elucidate 18. Grimes PE. Melasma. Etiologic and therapeutic considerations. Arch
not only the optimum formulation, concentration but also Dermatol 1995;131:1453-7
the role of maintenance doses/ sittings and even if there may 19. Kimbrough-Green CK, Griffiths CE, Finkel LJ, Hamilton TA,
Bulengo-Ransby SM, Ellis CN, et al. Topical retinoic acid
be some role of combination or sequential therapy with oral
(Tretinoin) for melasma in black patients: a vehicle controlled
and topical TA in the same patient. clinical trial. Arch Dermatol 1994;130:727-33.
20. Sharma R, Mahajan VK, Mehta KS, Chauhan PS, Rawat R, Shiny TN.
Therapeutic efficacy and safety of oral tranexamic acid and that of
Financial support and sponsorship tranexamic acid local infiltration with microinjections in patients with
Nil. melasma: a comparative study. Clin Exp Dermatol 2017;42:728-34.
21. Del Rosario E, Florez-Pollack S, Zapata L Jr, Hernandez K, Tovar-
Conflicts of interest Garza A, Rodrigues M, Hynan LS, Pandya AG. Randomized, placebo-
There are no conflicts of interest. controlled, double-blind study of oral tranexamic acid in the treatment
of moderate-to-severe melasma. J Am Acad of Dermatol 2018;78:
363-9.
References 22. Nagaraju D, Bhattacharjee R, Vinay K, Saikia UN, Parsad D, Kumaran
MS. Efficacy of oral tranexemic acid in refractory melasma: a clinico-
1. Maeda K, Naganuma M. Topical trans-4- immuno-histopathological study. Dermatol Ther 2018;31:e12704.
aminomethylcyclohexanecarboxylic acid prevents ultraviolet radiation 23. Na ji, Choi SY, Yang SH, Choi HR, Kang HY, Park KC. Effect of
induced pigmentation. J Photochem Photobiol 1998;47:136-41. tranexamic acid on melasma: a clinical trial with histological
2. Okamoto S, Okamoto U. Amino-Methyl-Cyclohexane-Carbolic Acid: evaluation. J Eur Acad Dermatol Venereol 2013;27:1035-9.
AMCHA. A new potent inhibitor of fibrinolysis. Keio J Med 24. Zhu CY, Li Y, Sun QN, Takada A, Kawada A. Analysis of the effect of
1962;11:105-15. different doses of oral tranexamic acid on melasma: a multicentre
3. Roberts I. Tranexamic Acid: a recipe for saving lives in traumatic prospective study. Eur J Dermatol 2019;29:55-58.
bleeding. Niger J Surg 2012;18:1. 25. Lajevardi V, Ghayoumi A, Abedini R, Hosseini H, Goodarzi A, Akbari
4. Budamakuntla L, Loganathan E, Suresh DH, Shanmugan S, Z, et al. Comparison of the therapeutic efficacy and safety of combined
Suryanarayan S, Dongar A, et al. A randomized, open-label, oral tranexamic acid and topical hydroquinone 4% treatment vs. topical
comparative study of tranexamic acid microinjections and hydroquinone 4% alone in melasma: a parallel-group, assessor- and
tranexamic acid with microneedling in patients with melasma. J analyst-blinded, randomized controlled trial with a short-term follow-
Cutan Aesthet Surg 2013;6:139-43. up. J Cosmet Dermatol 2017;16:235-42.

26. Malik F, Hanif MM, Mustafa G. Combination of oral Tranexamic Acid 36. Ayuthaya PKN, Nlumphradit N, Manosroi A, Nakakes A. Topical 5%
with Topical 3% Tranexamic Acid versus Oral Tranexamic Acid with tranexamic acid for the treatment of melasma in Asians: a double-blind
Topical 20% Azelaic Acid in the Treatment of Melasma. J Coll randomized controlled clinical trial. J of Cosmet and Laser Ther
Physicians Surg Pak 2019;29:502-4 2012;14:150-4.
27. Cho HH, Choi M, Cho S, Lee JH. Role of oral tranexamic acid in 37. Tawfic SO, Abdel Halim DM, Albarbary A, Abdelhady M. Assessment
melasma patients treated with IPL and low fluence QS Nd:YAG laser. J of combined fractional CO2 and tranexamic acid in melasma treatment.
Dermatolog Treat 2013;24:292-6. Lasers Surg Med 2019;51:27-33.
28. Li Y, Sun Q, He Z, Fu L, He C, Yan Y. Treatment of melasma with oral 38. Chung JY, Lee JH, Lee JH. Topical tranexamic acid as an adjuvant
administration of compound tranexamic acid: a preliminary clinical treatment in melasma: side-by-side comparison clinical study. J
trial. J Eur Acad Dermatol Venereol 2014;28:393-4. Dermatolog Treat 2016;27:373-7.
29. Wu S, Shi H, Wu H, Yan S, Guo J, Sun Y, et al. Treatment of melasma 39. Laothaworn V, Juntongjin P. Topical 3% tranexamic acid enhances the
with oral administration of tranexamic acid. Aesth Plast Surg efficacy of 1064-nm Q-switched neodymium-doped yttrium aluminum
2012;36:964-70. garnet laser in the treatment of melasma. J Cosmet Laser Ther
30. Karn D, Kc S, Amatya A, Razouria EA, Timalsina M. Oral tranexamic 2018;20:320-5.
acid for the treatment of melasma. Kathmandu Univ Med J (KUMJ) 40. Lee JH, Park JG, Lim SH, Kim JY, Ahn KY, Kim MY, et al. Localized
2012;10:40-3. intradermal microinjection of tranexamic acid for treatment of
31. Lee HC, Thng TGS, Goh CL. Oral tranexamic acid (tranexamic acid) in melasma in Asian patients: a preliminary clinical trial. Dermatol
the treatment of melasma: A retrospective analysis. J American Acad Surg 2006;32:626-31.
Dermatol 2016;75:385-92. 41. Feng C, Yan M. Clinical observation on tranexamic acid combined
32. Khurana VK, Misri RR, Agarwal S, Thole AV, Kumar S, et al. A with reduced glutathione for the treatment of chloasma. Pak J Pharm
randomized, open-label, comparative study of oral tranexamic acid and Sci 2018;31:2823-6.
tranexamic acid microinjections in patients with melasma. Indian J 42. Saki N, Darayesh M, Heiran A. Comparing the efficacy of topical
Dermatol Venereol Leprol 2019;85:39-43. hydroquinone 2% versus intradermal tranexamic acid microinjections
33. Kim SJ, Park JY, Shibata T, Fujiwara R, Kang HY. Efficacy and in treating melasma: a split-face controlled trial. J Dermatolog Treat
possible mechanisms of topical tranexamic acid in melasma. Clin Exp 2018;29:405-10.
Dermatol 2016;41:480-5. 43. Yang Xu, Ma R, Juliandri J, Wang X, Xu B, Wang D, et al. Efficacy of
34. Ebrahimi B, Naeini FF. Topical tranexamic acid as promising treatment functional microarray of microneedles combined with topical
for melasma. J Res Med Sci 2014;19:753-7. tranexamic acid for melasma: a randomized, self-controlled, split-
35. BanihashemiM,ZabolinejadN,JaafariMR,SalehiM,JabariA.Comparison face study. Medicine (Baltimore) 2017;96:e6897.
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hydroquinone on melasma. J Cosmet Dermatol 2015;14:174-7. series of 22 cases. An Bras Dermatol 2015;90:919-21.

MANAGEMENT OF MELASMA
Dr Rashmi Sarkar, Dr. Anuva Bansal
Based on the current evidence:
Sun Avoidance, Sunscreen Use, And Triple Combination regimen
is the most effective first-line treatment for melasma
1. Treat any triggering /contributing factor

2. Sun avoidance, physical barrier such as hats, full-sleeved clothing, umbrella
3. Sunscreens are a must-
Broad-spectrum sunscreen with SPF of at least 30, which covers UVA, (Minimum PA+++) UVB and Visible
Light is recommended in any melasma management strategy (Grade A recommendation)
Blend of inorganic (with iron oxide/zinc oxide) and organic sunscreens provides adequate protection and is
cosmetically acceptable.
Sunscreen to be applied liberally (teaspoon rule), every 2-3 hours and even when indoors, since infrared rays
contribute to its pathogenesis.
4. Topical agents are recommended as first line therapy
Text for melasma
Start with Fixed dose triple combination (FTC) (4% HQ + 0.05% Retinoic Acid (RA) + 0.01% Fluocinolone
Acetonide (FA)) cream – daily, once at night application for a maximum period of 8 weeks is recommended.
(Grade A recommendation).
Hydroquinone alone (2% to 4%) may be used as monotherapy (more effective than kojic acid, 20% azelaic
acid, and it can be continued for 3months (up to 1 year)
5. Maintain with any of the following topicals
Kojic Acid 2 % cream, Azelaic acid 20% cream, Arbutin cream, Ascorbic Acid or newer agents
FTC -twice weekly for up to 6 months (or 1year) (Grade of recommendation A
6. Chemical Peels
Several peels are available including glycolic acid (GA), tricholoracetic acid peel, tretinoin peel, salicyclic
acid peel, lactic acid peel, Jessner’s peel.
May be used as an add on therapy or as maintenance therapy and are associated with mild to moderate
response. (Grade of recommendation D).
GA peels act synergistically to enhance the effect of the topical regimen (Strength of Recommendation A)
The strength of the GA peel is gradually increased from 30–70%. After a test peel, serial GA peels are
applied 3–5 min every 2–3 weeks and then neutralized using water or 1% bicarbonate solution.
7. Oral Tranexamic acid leads to a mild to moderate improvement in melasma when used at a dose of 500–750
mg/day in a divided dose, for a maximum period of 6 months (Grade A recommendation).
8. A variety of lasers and light devices have been tried in melasma including pigment-specific lasers (Q-switched,
long-pulsed lasers, IPL), vascular lasers (pulsed dye, Copper bromide), fractional lasers and ablative lasers. Lasers
are not recommended as the first line treatment and may be used as an adjuvant therapy in recalcitrant cases
9. Platelet rich plasma therapy, microneedling, dermabrasion and microdermabrasion are various other newer
modalities with variable efficacy and success in melasma.
10. Several newer topical agents are available including aloesin, rucinol, flavonoids, epigallocatechin,
hydroxycoumarin, cinnamic acid, gentisic acid, liquorice extract, mulberry extract, niacinamide, soy-milk, liquirtin
etc. Although their efficacy in melasma has been seen in limited studies, most of these agents are considered to be
inferior to HQ and therefore are recommended as add-on therapy or as second-line drugs or as maintenance agents.

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IJD® SYMPOSIUM EDITORIAL

Treatment of Melasma: The Journey Ahead

© 2017 Indian Journal of Dermatology | Published by Wolters Kluwer - Medknow 447

448 Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

How to cite this article: Sarkar R, Ailawadi P. Treatment of melasma:

Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017 449

Lasers in Melasma: A Review with Consensus Recommendations by Indian

Abstract From the Department of

© 2017 Indian Journal of Dermatology | Published by Wolters Kluwer - Medknow 477

Q-switched Nd:YAG Laser

478 Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

a study which was conducted on Chinese patients, Vascular Laser

480 Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

What is new? treatment of low-fluence 1,064-nm Q-switched Nd:YAG laser

Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017 481

482 Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

Medical Management of Melasma: A Review with Consensus

Abstract From the Dermatology, Maulana

450 © 2017 Indian Journal of Dermatology | Published by Wolters Kluwer - Medknow

Methods testosterone in patients as compared to the control group,

Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017 451

Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

There are controversies regarding the safety of use

29% with with HQ

TCCs can be used as maintenance regimen for more than

daily/intermittent/tapering dose regimen. Adverse

long term is associated with more AE while intermittent

therapy was associated with higher relapse of melasma

presence of erythema was assessed in patients

8 weeks of the treatment regimen. Using narrowband

reflectance spectrophotometer, it was shown that

there was no difference between melanin levels in

the melasma lesions in patients following either

twice weekly or tapering regimen. [36] Adverse effects

borderline reduction in erythema with the tapering

Triple combinations using mid–potent

until recently. Despite the paucity of supporting evidence

physician’s prescription and over-the-counter drug. This

patients of melasma who had used a mometasone-based

TCC for at least 3 weeks over the past 1 year, it was

hypertrichosis (17/60), and acneiform eruption (11/60)

complained of worsening of pigmentation and the rest

claimed that their disease was the same as before and

454 Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017 455

Important points of HQ as monotherapy and in combination with other

456 Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017 457

Table 7: Summary of clinical trials with azelaic acid

Level and quality of evidence: C Level and quality of evidence IB

458 Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

Table 8: Summary of studies outlining the role of kojic acid in melasma

Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017 459

Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

Indian Journal of Dermatology | Volume 62 | Issue 6 | November - December 2017

on melasma melasma in a patient

compared to routine topical treatment. One group

adverse effects evidence

TA provides rapid and sustained improvement in the

topical drugs. It can also be used when other topical

small sample size and variable dosage and duration.

Other oral drugs