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REVIEW
Evidence-Based Treatment for Melasma: Expert
Opinion and a Review
Krupa Shankar •Kiran Godse •Sanjeev Aurangabadkar •Koushik Lahiri •Venkat Mysore •
Anil Ganjoo •Maya Vedamurty •Malavika Kohli •Jaishree Sharad •Ganesh Kadhe •
Pashmina Ahirrao •Varsha Narayanan •Salman Abdulrehman Motlekar
To view enhanced content go to www.dermtherapy-open.com
Received: July 7, 2014 / Published online: October 1, 2014
ÓThe Author(s) 2014. This article is published with open access at Springerlink.com
ABSTRACT
Introduction: Melasma is one of the most
common pigmentary disorders seen by
dermatologists and often occurs among
women with darker complexion (Fitzpatrick
skin type IV–VI). Even though melasma is a
widely recognized cause of significant cosmetic
disfigurement worldwide and in India, there is a
lack of systematic and clinically usable
treatment algorithms and guidelines for
melasma management. The present article
outlines the epidemiology of melasma, reviews
the various treatment options along with their
mode of action, underscores the diagnostic
dilemmas and quantification of illness, and
weighs the evidence of currently available
therapies.
Electronic supplementary material The online
version of this article (doi:10.1007/s13555-014-0064-z)
contains supplementary material, which is available to
authorized users.
K. Shankar (&)
Department of Dermatology, Skin Diagnosis Centre,
Mahabodhi Mallige Hospital, Manipal Hospital, 98,
HAL Airport Road, Bangalore 560017, Karnataka,
India
e-mail: dermakrupa@yahoo.com
K. Godse
Shree Skin Center and Pathology Lab, Nerul,
Navi Mumbai, India
S. Aurangabadkar
Skin and Laser Clinic, 1st Floor, Brij Tarang,
Green Lands, Begumpet, Hyderabad,
Andhra Pradesh, India
K. Lahiri
Mani Square, IT-7A, 7th Floor 164/1 Manickatala
Road, Kolkata, India
V. Mysore
Venkat Charmalaya Clinic, 3437, 1st G Cross,
7th Main, Subbanna Garden, Vijayanagar,
Bangalore, Karnataka, India
A. Ganjoo
Skin and Cosmetology Centre, 105/4 LSC Gujrawala
Town, Delhi (North), New Delhi 110009, India
M. Vedamurty
RSV Skin and Laser Centre, 9/5, Mahalingam,
2nd Cross Street, Mahalinghapuram, Chennai,
Tamil Nadu, India
M. Kohli
Skin Secrets, 306/403/408 Doctor House, 14 Peddar
Road, Mumbai 400 026, Maharashtra, India
J. Sharad
Skinfiniti Skin and Laser Clinic, Mira Belle, Above
Scandal Shoe Shop, Near National College, Linking
Road, Bandra (W), Mumbai, Maharashtra, India
G. Kadhe P. Ahirrao V. Narayanan
S. A. Motlekar
Department of Medical Affairs, Wockhardt Ltd.,
Wockhardt Towers, Bandra Kurla Complex,
Mumbai 400051, Maharashtra, India
Dermatol Ther (Heidelb) (2014) 4:165–186
DOI 10.1007/s13555-014-0064-z
Methods: A panel of eminent dermatologists
was created and their expert opinion was sought
to address lacunae in information to arrive at a
working algorithm for optimizing outcome in
Indian patients. A thorough literature search
from recognized medical databases preceded the
panel discussions. The discussions and
consensus from the panel discussions were
drafted and refined as evidence-based
treatment for melasma. The deployment of
this algorithm is expected to act as a basis for
guiding and refining therapy in the future.
Results: It is recommended that
photoprotection and modified Kligman’s
formula can be used as a first-line therapy for
up to 12 weeks. In most patients, maintenance
therapy will be necessary with non-
hydroquinone (HQ) products or fixed triple
combination intermittently, twice a week or
less often. Concomitant camouflage should be
offered to the patient at any stage during
therapy. Monthly follow-ups are
recommended to assess the compliance,
tolerance, and efficacy of therapy.
Conclusion: The key therapy recommended is
fluorinated steroid containing 2–4% HQ-based
triple combination for first line, with additional
selective peels if required in second line. Lasers
are a last resort.
Keywords: Dermatology; Efficacy;
Hydroquinone; Laser; Melasma; Peels;
Photoprotection; Prevalence; Retinoids; Safety;
Topical steroids; Treatment
INTRODUCTION
Melasma (from the Greek word melas, meaning
‘black’) is a common, acquired, circumscribed
hypermelanosis of the sun-exposed skin [1,2]. It
presents as symmetric, hyperpigmented
macules having irregular, serrated, and
geographic borders. The most common
locations are the cheeks, upper lips, the chin,
and the forehead, but other sun-exposed areas
may also be occasionally involved. Studies
indicate the possible role of several risk factors
such as genetics, sunlight, age, gender,
hormones, pregnancy, thyroid dysfunction,
cosmetics, and medications [1]. The objective
of the current study was to prepare a treatment
consensus and algorithm based on clinical
experience and review of the evidence from
available literature.
METHODS
A panel of eminent dermatologists with at least
10 years of clinical experience combined with
academic contribution and interest in the
subject of melasma was created and their
expert opinion was sought to address lacunae
in information to arrive at a working algorithm
for optimizing outcome in Indian patients.
The process was initiated with a literature
search with the keywords as dermatology,
hydroquinone, laser, melasma, peels,
photoprotection, prevalence, retinoids, safety,
topical steroids, and treatment. The databases
searched included MEDLINE, COCHRANE
LIBRARY, and SCIENCE DIRECT DATABASE.
Literature was searched mainly over the
period of the last 2 decades (1990 to August
2013) to include data and latest concepts in
melasma epidemiology and therapy. However, a
few publications from the 1980s and two from
the 1970s have also been included so that
valuable foundation concepts as well as
evolution of current therapies and past issues
with certain drugs are also included.
Articles pertaining to risk and predisposing
factors for melasma as well as articles on
166 Dermatol Ther (Heidelb) (2014) 4:165–186
melasma management, including clinical
assessment, investigations, drug therapies,
combinations, procedural therapies, and newer
emerging therapies, from peer reviewed journals
were included. Articles not adequately powered
or not randomized with poorly defined
methodology and articles with conflicting or
non-committal results were excluded.
A total of 115 publications until August 2013
were obtained by electronic database searches of
which 52 were randomized controlled trials (1
retrospective) and 42 were review articles (17
were reviews and discussions of specific drug/
combination or procedural treatment). The
remaining publications included eight articles
on prevalence data, five articles of case series, five
articles on investigations and histopathology,
and three articles on validating scoring and
grading systems. The literature search was
completed and then followed by three panel
discussion sessions, each in the form of a 1-day
residential focused program where clinical
experiences of each panelist were brought to
the table along with the study of the associated
literature and publications. All discussions,
suggestions, and panel consensus were recorded
by a medical writer who was present. In addition,
experienced persons from the field of
pharmaceuticals also contributed with respect
to the pharmacological aspects of the various
drug therapies. In between each of these sessions,
the outcome and consensus of the previous
session were drafted and shared with the panel
members for further refining. After all panel
discussion sessions were concluded, the final
draft of the panel consensus and algorithm was
prepared along with the summary of the
reviewed literature. This draft was finally refined
and accepted by the panelists to come up with a
clinically practical, relevant, and acceptable
treatment algorithm for melasma. The
deployment of this algorithm is expected to act
as a basis for guiding and refining therapy in the
future.
This article is based on previously conducted
studies and the expert opinion of the authors,
and does not involve any new studies of human
or animal subjects performed by any of the
authors.
RISK AND PREDISPOSING FACTORS
Melasma commonly occurs in women during
their reproductive years. Pregnancy and use of
oral contraceptives through estrogen mediated
melanocyte stimulation is apparent in the
pathogenesis of melasma [2–4]. Dark-haired
persons (Fitzpatrick skin types III–VI) are more
susceptible to melasma [5]. Several studies have
reported a high incidence of melasma in family
members suggesting its genetic predisposition
[3,6–11].
The ultraviolet (UV) component of sunlight
is the major triggering and aggravating factor in
melasma causing focal melanocyte hyperplasia
and increase in melanosomes [1,12,13].
The use of topical cosmetics and fragrances
as well as phototoxic drugs can also trigger or
aggravate melasma by sensitizing the skin and
inducing postinflammatory hyperpigmentation
(PIH). Melasma is considered as photocontact
dermatitis in a study conducted by Verallo-
Rowell [14].
Melasma is classified according to the depth
of melanin pigment into epidermal melasma
with mixed melasma (a combination of the
epidermal and dermal types) having a worse
prognosis [1].
PRINCIPLES OF THERAPY
The objectives of melasma therapy should be
protection from sunlight and
Dermatol Ther (Heidelb) (2014) 4:165–186 167
depigmentation. Pigment reduction is
achieved by using chemicals that interfere
with various steps of the melanogenesis
pathways via: (i) the retardation of
proliferations of melanocytes; (ii) the
inhibition of melanosome formation and
melanin synthesis; and (iii) the
enhancement of melanosome degradation
[15]. Table 1shows the classification of the
pigment-reducing agents based on their
mechanism of action [16–18].
First-line therapy usually consists of topical
compounds that affect the melanin synthesis
pathway, broad-spectrum photoprotection, and
camouflage. Chemical peels are often added in
second-line therapy. Laser and light therapies
represent potentially promising options for
patients who are refractory to other modalities,
but also carry a significant risk of worsening the
disease. A thorough understanding of the risks
and benefits of various therapeutic options is
crucial in selecting the best treatment.
Table 1 Classification of depigmenting agents and their mechanism of action [16–18]
Stage of
melanin
synthesis
Deposition Active molecules
Before melanin
synthesis
Tyrosinase transcription Tretinoin, c-2 ceramide
Tyrosinase glycosylation PaSSO
3
Ca
Inhibition of plasmin Tranexamic acid
During melanin
synthesis
Tyrosinase inhibition Hydroquinone, mequinol, azelaic acid, kojic acid, arbutin, deoxyarbutin,
licorice extract, rucinol, 2,5-dimethyl-4-hydroxy-3(2H)-furanone, N-
acetyl glucosamine, resveratrol, oxyresveratrol, ellagic acid, methyl
gentisate, 4-hydroxyanisole
Peroxidase inhibition Phenolic compounds
Reactive oxygen species
scavengers
Ascorbic acid, ascorbic acid palmitate, thiotic acid, hydrocumarins
After melanin
synthesis
Tyrosinase degradation Linoleic acid, a-linoleic acid
Inhibition of melanosome
transfer
Niacinamide, serine protease inhibitors, retinoids, lecithins,
neoglycoproteins, soybean trypsin inhibitor
Skin turnover acceleration Lactic acid, glycolic acid, linoleic acid, retinoic acid
Regulation of melanocyte
environment
Corticosteroids, glabiridin
Interaction with copper Kojic acid, ascorbic acid
Inhibition of melanosome
maturation
Arbutin and deoxyarbutin
Inhibition of protease
activated receptor 2
Soybean trypsin inhibitor
168 Dermatol Ther (Heidelb) (2014) 4:165–186
CLINICAL ASSESSMENT
OF MELASMA
Traditionally, Wood’s lamp examination is
done to identify the location of pigment, but
is limited to epidermal melasma and cannot be
used reliably in Fitzpatrick skin types V and VI
as dark-skin melanin pigmentation obscures the
detection of dermal melanin [19]. Melasma is
reliably graded on the basis of area and severity
parameters [i.e., melasma area and severity
index (MASI) score] [20,21].
PHARMACOLOGIC THERAPY
Sunscreens
Sunscreen use is vital throughout treatment and
post-treatment to prevent hyperpigmentation
and relapse of melasma. Broad-spectrum anti-
UV A and B sunscreens with physical blocking
agents like ZnO and TiO
2
(SPF[30) should be
used regularly to cover the affected areas.
Patients with Fitzpatrick IV to VI skin types
[22] are at a heightened risk from sun exposure
[23,24]. Indian patients avoid sunscreens due to
oily, sticky nature and heat from exothermic
reaction of chemicals. However, physical
sunscreens do not release heat.
Hydroquinone
Hydroquinone (HQ; dihydroxybenzene) is
structurally similar to precursors of melanin.
HQ inhibits the conversion of dopa to melanin
by blocking tyrosinase action [25] and inhibits
the formation, melanization, and degradation
of melanosomes. HQ also affects the
membranous structures of melanocytes and
eventually causes necrosis of whole
melanocytes [26].
HQ has been used to treat
hyperpigmentation for more than 50 years.
While controversy exists regarding the long-
term safety of HQ, its efficacy in treating
melasma, both alone and in combination with
other agents is well established [5]. HQ 2–4% is
prominently used as a mono-therapy or in a
combination cream. HQ preparations [5% are
not recommended due to irritation, except for
refractory cases [27,28]. Pigment lightening by
HQ becomes evident after 5–7 weeks of the
treatment. Treatment with HQ should be
continued for at least 3 months and up to
1year[29].
For patients on HQ therapy, regular medical
follow-up is essential: every 3 months for high
phototype skin (Fitzpatrick type V and VI)
patients and every 6 months for lighter skin
types. Common adverse events (AEs) are
erythema and burning. Other rare AEs are
ochronosis and confetti-like depigmentation.
Speckling or reticulation indicates ochronosis.
Histopathology shows short, stout, curvilinear,
ochre-colored fibers in the papillary dermis [30].
Tretinoin
Tretinoin, a retinoid (RA), inhibits transcription
of the key melanin synthesis enzyme tyrosinase
[16–18]. Tretinoin plays an important role in
the triple-combination cream (described later)
and is used as a chemical peel.
Corticosteroids
Topical corticosteroids are anti-inflammatory
molecules that exert an anti-metabolic effect
on melanocytes, resulting in a decreased
epidermal turnover and thus, may produce a
mild pigment-reducing effect [31].
Corticosteroids are an active component of the
triple-combination creams. Triple formulations
Dermatol Ther (Heidelb) (2014) 4:165–186 169
using different corticosteroids have shown
efficacy, for example, dexamethasone [32],
hydrocortisone 1% [33], mometasone [34,35],
and fluorinated steroids [22,36–41]. Researchers
found that fluorinated steroids were more
effective and safer than non-fluorinated
steroids, for example, 0.01% fluocinolone
acetonide and fluticasone [22].
Kojic Acid
Kojic acid can substitute for HQ if a patient is
intolerant to HQ. Kojic acid inhibits tyrosinase
by chelating copper at the enzyme’s active site.
It is available in 1–4% concentrations, and also
in combination with HQ. Caution is required in
its use as kojic acid is a known sensitizer [5].
Azelaic Acid
Azelaic acid (AA) is anti-proliferative and
selectively cytotoxic towards hyperactive
melanocytes, inhibiting tyrosinase and
mitochondrial oxidoreductase enzymes with
minimal effects on normally pigmented skin
[42]. In different trials, AA treatment was found
to be less or as equally efficacious as HQ [42,43]
and hence may be used in case of intolerance to
HQ.
Triple Combination
Based on the current evidence: sun avoidance,
sunscreen use, and triple combination regimen
is the most effective first-line treatment for
melasma. Combination creams are more
efficient bleaching agents than mono-
therapies. The combination of HQ, a RA, and a
topical steroid (5% HQ, 0.1% RA, and 0.1%
dexamethasone), or Kligman and Willis’
formula was developed to enhance the efficacy
of each individual ingredient, shortening the
duration of therapy and reducing the risk of AEs
[44,45]. Since then, some variation of this
formula is the most commonly used therapy for
melasma worldwide [32]. Tretinoin prevents the
oxidation of HQ and improves epidermal
penetration while the steroid reduces irritation
from the other two ingredients and suppresses
biosynthetic and secretory functions of
melanocytes, leading to an early response in
melasma. The synergistic action of the three
topical agents achieves significantly higher
depigmentation than either agent alone.
Improvement is seen in 8 weeks without any
significant AE [46].
In India, a cream-based combination of HQ,
tretinoin and mometasone has been extensively
used after its launch in 2004. Long-term use on
the face (generally[12 weeks) of
corticosteroids, particularly mid-potent ones
like mometasone can cause skin atrophy,
telangiectasias, and/or an acneiform eruption
[37]. Moreover, a relapse is common when
mometasone use is stopped [47]. The
combination treatment is supposed to be used
for a maximum of 4–8 weeks after which the
treatment should be stopped or the dose
gradually reduced, and finally replaced with
safer treatment modalities [48]. We found
mometasone-based combination with glycolic
acid (GA) peels caused AEs like
hyperpigmentation, irritation, and persistent
erythema in 2 out of 10 patients (20%) [34].
Triple-combination creams with mometasone
should be prescribed only after thorough
patient counseling with explanation of long-
term AEs.
Evidence-based studies have shown triple
combination of 4% HQ with 0.05% tretinoin
and 0.01% fluocinolone acetonide to be the
most efficacious and safe available topical
modality for the first-line treatment of
melasma [40,41]. It is the only ointment
170 Dermatol Ther (Heidelb) (2014) 4:165–186
currently approved by the US Food and Drug
Administration for the treatment of melasma.
The safety and efficacy of the combination was
initially demonstrated in 641 melasma patients
in a multicenter, investigator blinded,
randomized prospective trial [36,39–41].
Night use of the triple-combination cream as
compared to dual-combination creams
(HQ ?tretinoin, HQ ?fluocinolone, or
tretinoin ?fluocinolone) achieved complete or
near-complete clearance in 77% of patients.
Clinically significant improvement was noted
within 4–8 weeks [39]. The most common AEs
were mild local irritation, erythema, and skin
peeling. For the Indian skin, which is mostly of
Fitzpatrick type IV–VI, a reduced HQ
combination of 2% HQ ?0.05%
tretinoin ?0.01% fluocinolone acetonide
(HQ ?RA ?FA) was launched in 2010 [47].
Safety studies in Indian population need to be
established. A recent Cochrane review of 20
studies with a total of 2,125 participants with 23
different treatments concluded that triple-
combination cream was significantly more
effective than HQ alone (relative risk 1.58,
95% CI 1.26–1.97) or dual combination [38].
The fluocinolone-based triple cream is safe in
the treatment of moderate to severe melasma
for up to 24 weeks. The risk of skin atrophy after
6 months of treatment with fluocinolone
acetonide 0.01%, HQ 4%, and tretinoin 0.05%
cream is very low as shown by histological
examination [4].
In the expert opinion of the authors,
fluticasone seems more effective and safer
than mometasone and fluocinolone in the
triple combination due to less long-term
([12 weeks) steroidal AEs. Once-daily
application of fluticasone (0.05%) was as
efficacious as twice-daily application of
betamethasone (0.12%), with less skin atrophy
and an absence of systemic AE of
hypothalamic–pituitary–adrenal axis
suppression [37]. In another study, fluticasone
did not cause cortisol suppression or major skin
atophy, and was similar to mometasone furoate
in efficacy [49].
Dual Combination
The dual combinations are recommended if
triple combination is not available or if patients
are intolerant to it. Those available in India
include HQ and GA, HQ and Kojic acid, and
mequinol and tretinoin. Table 2gives an
overview of studies that provide evidence on
topical agents for treating melasma.
Adjunctive Therapies
These include a wide range of chemicals and
natural extracts have been tested against
melasma (Table 3). Tranexamic acid is the
most common adjunctive therapy to be used
and works by decreasing melanogenesis in
epidermal melanocytes and provides a rapid
and sustained lightening in melasma [50–53].
Other therapies include a substance called
‘antipollon’, a finely grained aluminum silicate
that possesses the ability to adsorb melanin.
Laboratory studies with different
concentrations have shown up to 86%
melanin adsorption with 0.8% antipollon.
However, clinical studies establishing its
efficacy are awaited (Antipollon-HT efficacy
testing Nikkol Chemicals, data on file).
Interventions
Intervention procedures are used in
combination with topical first-line therapy to
treat recalcitrant melasma when patient shows
poor or no response. Intervention techniques
include chemical peels, lasers, intense pulsed
Dermatol Ther (Heidelb) (2014) 4:165–186 171
Table 2 Evidences involving important topical treatment options
References Study
type
Treatment mode Patients,
n
Severity Treatment
duration
Results
Monteiro et al.
[77]
R, DB 4% HQ vs. placebo ?SPF 30 48 N/K 20 weeks 38% HQ/8.3% placebo, total improvement
Haddad [27] R, DB,
SF
4% HQ vs. placebo ?SPF 25 30 N/K 3 months 79% HQ/67% SWC improvement
Farshi [78] R, O 4% HQ vs. azelaic acid 20% 29 N/K 2 months After 2 months treatment, the MASI score was
6.2 ±3.6 with HQ and 3.8 ±2.8 with azelaic
acid
Espinal-Perez
et al. [79]
R, O,
SF
4% HQ vs. 5% ascorbic acid 16 N/K 16 weeks HQ side with 93% good and excellent results,
compared with 62.5% on the ascorbic acid side.
Side effects were present in 68.7% with HQ vs.
6.2% with ascorbic acid
Nanda et al.
[80]
R, O Priming with 2% HQ vs. 0.025% RA once
daily (night time) 2 weeks before starting
trichloroacetic acid peels (every 2 weeks
for 12 weeks)
50 N/K 6 months HQ is superior to RA as a priming agent in
maintaining the results achieved with peels and
in decreasing the incidence of post-peel reactive
hyperpigmentation
Balina and
Graupe [43]
R, DB,
MC
4% HQ vs. 20% azelaic acid 329 N/K 24 weeks 65%/73% good or excellent in azelaic/HQ
patients
Piquero Martı
´n
et al. [81],
Verallo-
Rowell et al.
[82]
R, DB
O
4% HQ vs. 20% azelaic acid 60 N/K 24 weeks Azelaic acid was not better than the HQ in the
treatment of melasma
Verallo-Rowell
et al. [82],
Lim [83]
R, DB 2% HQ vs. 20% azelaic acid 155 N/K 24 weeks 73% of the azelaic acid patients, compared with
19% of the HQ patients, had good to excellent
overall results
Lim [83],
Ferreira
Cestari et al.
[84]
R 2% KA, 2% HQ, 10% GA vs. 2% HQ,
10% GA
40 N/K 12 weeks 2% KA, 2% HQ, 10% GA improvement in 60%
vs. 47.5% with 2% HQ, 10% GA
Ferreira Cestari
et al. [84],
Grimes et al.
[85]
R, O 4% HQ, 0.05% RA, 0.01% FA (TC) vs.
4% HQ ?SPF 30
120 M/S 8 weeks [75% improvement, 73% TC/49% HQ
(P=0.007)
Taylor et al.
[39]
R, SB 4% HQ, 0.05% RA, 0.01% FA (TC) vs.
4% HQ, 0.05% RA or 0.05% RA, 0.01%
FA or 4% HQ, 0.01% FA ?SPF 3
641 M/S 8 weeks 77% TC; 47% HQ/RA; 27% FA/RA; 42% HQ/
FA, cleared/almost cleared
Torok [41]R,O,
MC
4% HQ, 0.05% RA, 0.01% FA
(TC) ?SPF 30
585 M/S 12 months By month 12: 80% cleared or nearly cleared by
physician assessment (of patients who remained
in the study)
Grimes et al.
[85]
MC,
O
4% HQ, 0.05% RA, 0.01% FA
(TC) ?SPF 30
1,290 M/S 8 weeks 75% cleared or almost cleared at 8 weeks by
physician assessment
Wu et al. [50] O TA 250 mg bid 74 N/K 6 months Excellent (10.8%, 8/74), good (54%, 40/74), fair
(31.1%, 23/74), and poor (4.1%, 3/74). Side
effects of TA such as gastrointestinal
discomfort (5.4%) and hypomenorrhea (8.1%)
were observed. Recurrence of melasma was
observed in seven cases (9.5%)
Kanechorn Na
Ayuthaya
et al. [51]
R, DB,
O,
SF
Topical TA 5% vs. placebo 23 N/K 12 weeks Results were not significant between the two
regimens
Lee et al. [52] O 0.05 mL TA (4 mg/mL) was injected
intradermally
100 N/K 12 weeks (9.4%) rated as good (51–75% lightening), 65
patients (76.5%) as fair (26–50% lightening),
and 12 patients (14.1%) as poor (0–25%
lightening)
DB double blind, FA fluocinolone acetate, GA glycolic acid, HQ hydroquinone, KA kojic acid, MASI Melasma Area Severity Index, M/S moderate/severe, MC
multicenter, N/K not known, Oopen, Rrandomized, RA tretinoin, SB single blind, SF split face, SPF sun protection factor, SWC skin whitening cream, TC triple
combination, TA tranexamic acid
172 Dermatol Ther (Heidelb) (2014) 4:165–186
light (IPL), cryosurgery, dermabrasion, and
micro-dermabrasion. They are not considered
as first-line therapy as they can cause PIH and
are often ineffective [54–56]. Chemical peels,
lasers, and IPL are described here as their use in
melasma is better studied in the Indian setting
to some extent.
Chemical Peels
Chemical peels used for treating melasma are
described in Table 4. There is a medium-quality
evidence to suggest that undergoing serial
chemical peels with GA, salicylic acid, or
trichloroacetic acid (TCA) is moderately
effective in the treatment of melasma (Table 5)
[22,53,57,58]. GA peels are used as an
adjunctive therapy in refractory cases of
epidermal melasma as they enhance the
efficacy of topical regimen [59]. There are
many studies comparing GA and other peels
for melasma in dark-skinned patients (Table 6)
[53].
Chemical peels cause controlled exfoliation,
followed by regeneration of epidermis and
dermis [60]. Superficial and medium-depth
peels have been employed with variable
success in the treatment of melasma. After a
superficial peel, epidermal regeneration can be
expected within 3–5 days and desquamation is
usually well accepted [61]. Because of the risk of
prolonged dyschromia, medium-depth and
deep peels should be avoided in patients with
dark skin. In the authors’ opinion, maintenance
sessions or repeat sessions may be necessary.
Patients should be well informed.
Lasers and Light Therapy
Lasers have a limited role in the treatment of
melasma. Though successful use of Q-switched
(QS) lasers [50], fractional lasers [57,62–66], IPL
[56], and combination lasers [67–69] has been
reported, response to treatment is unpredictable
and pigmentation frequently recurs. In
addition, PIH is common in Indian patients.
Hence, a maintenance schedule has to be
initiated and continued. For these reasons,
lasers are not routinely recommended as the
treatment of choice for melasma in Indian
patients. It may be used in selected resistant
cases, at the discretion of the treating physician,
after proper counseling. A test patch may be
performed prior to treating the lesion. QS laser
and low-fluence mode laser toning alone or in
combination with either fractional CO
2
laser or
IPL have shown reasonable success in treating
melasma of Asian patients (Table 7). A number
of studies have shown successful treatment of
melasma with fractional lasers [non-ablative Er
(Erbium): Glass 1,540/1,550 nm lasers], and
they are recommended in all skin types [57,
62–65].
Table 3 Adjunctive therapeutic agents for melasma [86]
Therapeutic agent
Tranexamic acid
Vitamin C
Vitamin E
Soybean extract
Topical liquiritin
Licorice extract
Gigawhite
Bearberry extract
Pepper mulberry extract
Arbutin
Indomethacin
Niacinamide
Nicotinic acid
4-Nbutylresorcinolmercury
Melawhite
Dermatol Ther (Heidelb) (2014) 4:165–186 173
ALGORITHM FOR INDIAN
MELASMA PATIENTS
India is a country of multiple ethnicity and
origin, covering a wide range of skin types.
Melasma is found more frequently in Fitzpatrick
type III–VI skin [48]. Based on Pigmentary
Disorders Academy (PDA) recommendations
for melasma treatment for dark-skin types and
a thorough review and grading of the literature
on evidence-based studies (listed in Table 8)[48,
61] an algorithm is proposed in Fig. 1to treat
Indian melasma patients. All treatments
included and their hierarchy in the algorithm
is based on the grading of the associated clinical
studies according to the US preventive services
Table 4 Treatment mode and regimen for chemical peels
Chemical
peel
Treatment mode and regimen Comments
GA 30–70%. Superficial peel. After a test peel, serial GA
peels are applied 3–5 min every 2–3 weeks. The peel
is then neutralized using water or 1% bicarbonate
solution [53,56,58–60,73,87,88]
–
LA 92%. Superficial peel. 2 coats of LA at pH 3.5 are
applied for 10 min every 3 weeks [87–89]
Safe and effective, gentle action
SA Superficial peel. 20–30% plus HQ at 2-week intervals Tendency of darker skins to dyschromias, even
superficial peels to be used with caution [62]. A new
derivative of SA with an additional fatty chain, the
lipohydroxy acid, has increased lipophilicity, a more
targeted mechanism of action and greater keratolytic
effect. It is yet to be demonstrated if the peel is
equally effective and safer than the conventional SA
peels in patients with melasma [54,55,59,60,89,
90]
TCA 10–30%. Superficial peel. Or 35–50% medium-depth
peel. Peels 1–2 months,[13 months. Peel washed
off upon frosting
May cause scarring and PIH in dark skin, to be used
with caution [53,58–60,90]
Tretinoin 1–5%. Superficial peel. Tretinoin at 1% strength is
applied for 4 h once a week, for 12 weeks [91,92]
–
MA Superficial peel. MA at 30–50% applied weekly or
biweekly and used as a face wash at 2%
Available in algae extract gel or lotion base at 2–10%
in isolation or in combination with vitamins C and
E. Less erythema and synergistic effect with laser [53,
93]
Phytic
acid
Applied once a week but can be repeated twice a week
for accelerated effect. 5–6 peel sessions are required
to achieve lightening
No neutralization required. Safe and effective for dark
skin. No irritation, burning, or scarring [53,58,94]
GA glycolic acid, HQ hydroquinone, MA mandelic acid, LA Lactic acid, PIH postinflammatory hyperpigmentation, SA
salicylic acid, TCA trichloroacetic acid
174 Dermatol Ther (Heidelb) (2014) 4:165–186
Table 6 Comparative studies with chemical peels for melasma in dark skin [53]
References Study
type
Treatment mode Patients,
n
Treatment
duration
Results
Kalla et al.
[89]
R, O 55–75% GA vs.
10–15% TCA
100 Every 15 days Response faster in TCA as compared
to GA, but side effects more in TCA
Khunger
et al. [90]
O, SF 1% tretinoin peel vs.
70% GA
10 Biweekly for
12 weeks
Decreased MASI, no difference
between the two sides
Sharquie
et al. [87,
88],
O, SF 92% pure lactic acid vs.
Jessner’s solution
30 Every 3 weeks with
maximum 5
sessions
Statistically significant improvement
on both sides
Safoury et al.
[97]
O, SF Modified
Jessner’s ?15%
TCA vs. 15% TCA
20 Every 10 days with
8 sessions
Better improvement with
combination peel
Kumari and
Thappa
[94]
R, O 20–35% GA vs.
10–20% TCA
40 Every 15 days for
12 weeks
About 75% improvement on both
sides
Sobhi and
Sobhi [96]
O, SF 70% GA vs. nanosome
vitamin C
14 6 sessions Better results on vitamin C side
GA glycolic acid peel, MASI melasma area severity index, Oopen, Rrandomized, SF split face, TCA trichloroacetic acid peel
Table 5 Levels of evidence and strength of recommendations for various peeling agents in ethnic skin
Classification Peeling agent Level of evidence Strength of
recommendation
References
Superficial peel Phytic acid Expert opinion C [53]
Lactic acid Uncontrolled trial B [87,88]
Glycolic acid Non-randomized
controlled study
A[55,58,59,72,89,90,
94–96]
Salicylic acid Uncontrolled trial B [54]
Jessner’s
solution
Uncontrolled trial B [97]
Superficial-medium
peel
Pyruvic acid Expert opinion C [98]
Medium-depth peel Trichloroacetic
acid
Uncontrolled trial B [96,97]
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 the procedure
Dermatol Ther (Heidelb) (2014) 4:165–186 175
task force levels of evidence for grading clinical
trials [70].
The key considerations in developing the
algorithm are: the Fitzpatrick skin types
susceptible to melasma in the Indian
population, the severity of melasma, the
sensitivity of patients to active ingredients of
medication, the patient treatment history, any
existing skin condition (besides melasma),
possible therapy-related AEs such as PIH,
exogenous ochronosis, blotchy
depigmentation, irritation, erythema; and the
probability of pigment recurrence after stopping
treatment, i.e., prognosis indicators. The darker
skin types tend to be highly sensitive to
treatment agents, for example, ochronosis on
HQ treatment, sensitization to KA, and skin
irritation reactions to peeling agents like GA. In
addition, darker skin types are more prone to
PIH post-treatment and have a greater chance of
relapse [71]. With these considerations in mind,
darker skin types, which are commoner among
Table 7 Treatment mode and regimen for laser therapy
Type of laser Mechanism Treatment mode Comments
QS Nd:YAG Laser
1,064 nm (low-
fluence mode laser
toning)
Photothermolysis of melanin in
melanosomes in the
melanocytes and
keratinocytes. Also
photoacoustic effect. Sub-
cellular selective
photothermolysis occurs in
the low-fluence mode.
Destroys melanin without cell
damage
10 sessions, once weekly End point is mild erythema,
with no whitening. A large
spot size (6 mm) should be
exposed to 1–2 passes with
minimal overlap. This
treatment is recommended in
all skin types. Priming with
triple-combination cream
prior to laser therapy is
recommended [91,96]. PIH
and blotched depigmentation
have been reported [91,99]
Combination of QS
Nd:YAG 1,064, with
the fractional CO
2
laser
Laser toning, using a large spot
size with very low fluence
giving multiple passes at
frequent intervals
10 sessions, every 2–3 weeks Promising treatment modality.
Concomitant and post-
therapy topical treatment to
maintain remission.
Maintenance sessions may be
needed in case of relapse
IPL Same as laser – Effective in treating refractory
melasma in Asian patients
[56,67]
Combination of IPL
with QS Nd:YAG
laser 1,064 nm (low-
fluence mode laser
toning)
Same as laser 1st session IPL for clearing
epidermal melasma followed
by 4–5 sessions of QS
Nd:YAG laser at 2-week
intervals
Rapid resolution of mixed-type
melasma with possible long-
term benefits [67–69]. This
treatment is recommended in
all skin types
IPL intense pulsed light, Nd:YAG neodymium-doped yttrium aluminum garnet, PIH postinflammatory hyperpigmentation,
QS Q switched
176 Dermatol Ther (Heidelb) (2014) 4:165–186
Table 8 Level and quality of evidence for melasma therapies
Therapy Level of
evidence
Quality of
evidence
References
Topical
2% HQ II–ii C [83]
4% HQ I B [27,43,78,85]
0.1% tretinoin (RA) I B [20,100]
0.05% RA I C [92]
0.05% Isotretinoin II–ii C [92,101]
4% N-acetyl-4-S-Cysteaminylphenol III C [101,102]
5% HQ ?0.1–0.4% RA ?7% LA/10% AC III C [102,103]
3% HQ ?0.1% RA III C [102,103]
2% HQ ?0.05% RA ?0.01% fluocinolone acetonide I A [38,39,41,74,85,
103,104]
2% HQ ?0.05% RA ?0.01% dexamethasone (modified KF) III C [55,86]
2% HQ ?0.05% RA ?0.01% dexamethasone (modified
KF ?30–40% GA peel)
III B [55,86]
5% HQ ?0.1% RA, and 1% hydrocortisone III C [32,33]
4% HQ ?5% GA II–ii B [104,105]
4% KA ?5% GA II–ii B [98,99]
2% KA ?2% HQ ?10% GA II–iii C [83,84]
2% HQ ?10% GA II–iii C [83,84]
4% HQ ?10% GA I B [105,106]
20% Azelaic acid I B [42,43]
20% Azelaic acid ?0.05% RA III C [106,107]
Vitamin C iontophoresis II–i C [107,108]
Adapalene II–ii B [99,100]
Chemical peels
10–50% GA II–ii/III C [53,59]
10% ?2% HQ ?20–70% GA II–ii C [56,58]
20–30% GA ?4% HQ II–i B [108,109]
70% GA II–i B [109,110]
Jessner’s solution II–i C [109,110]
20–30% Salicylic acid III C [54,55]
1–5% RA III C [108,111]
Dermatol Ther (Heidelb) (2014) 4:165–186 177
Indian people, are recommended longer
treatment periods, with lower concentrations
of those treatment agents that can induce PIH
or irritation, followed by longer maintenance
periods to prevent recurrence of pigmentation
and melasma. We have found that treatments
like laser therapy, although described for all
skin types in literature, are in fact not suitable
for Indian skin as PIH and relapse occurs
frequently once treatment is stopped in spite
of maintenance therapy. However, light therapy
does have some value in Indian patients.
In the opinion of the authors, broad-
spectrum sunscreen use during and post-
treatment is mandatory, along with protective
clothing and hats. Experts recommend the fixed
triple combination as the first-line therapy for
all melasma types and degrees of severity, and
dual combinations or single agents should be
considered only when it is unavailable or
patients have sensitivity to the ingredients
[48]. In such cases, we suggest dual-
combination therapy (e.g., HQ ?GA) or
monotherapy (e.g., 4% HQ, 0.1% retinoic acid,
or 20% AA). For moderate or severe melasma
which does not respond to first-line treatment,
options for second-line therapy include peels
either alone or in combination with topical
therapy.
In the opinion of the authors, some patients
will require therapy to maintain remission
status and a combination of topical therapies
should be considered. A minimum of four
sessions of a given peel are suggested before
changing to an alternative therapy. It is to be
noted that for Indian skin types, especially
Fitzpatrick types IV–VI, the concentration of
certain agents should be reduced; 5% HQ
should be avoided for Indian patients as PIH
and irritation are more likely at higher
Table 8 continued
Therapy Level of
evidence
Quality of
evidence
References
50% GA ?10% KA III C [109,112]
Laser therapy (?chemical peels ?topical therapies)
Q-switched ruby IV C [110,113]
Pulsed CO2 ?Q-switched alexandrite IV C [67,68]
Q-switched alexandrite laser IV C [69,70]
Q-switched alexandrite laser ?15–25% TCA peel ?Jessner’s
solution
III C [111,114]
Erbium: YAG III D [112,115]
Dermabrasion II–iii E [76,113]
In accordance with the US preventive services task force levels of evidence for grading clinical trials. Reproduced with
permission from [48]
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 the 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
AC ascorbic acid, GA glycolic acid, HQ hydroquinone, KA kojic acid, KF kligman’s formula, LA lactic acid, RA retinoic
acid, TCA trichloroacetic acid
178 Dermatol Ther (Heidelb) (2014) 4:165–186
concentrations. Because of the risk of prolonged
hyperpigmentation, medium-depth peels
like C35% TCA should be conducted with
caution in patients with dark-skin types; deep
peels should not be used in these patients.
Furthermore, chemical peels are generally used
to treat only the epidermal and mixed forms of
melasma, as an attempt to treat with deep peels
often leads to unwanted complications like
hypertrophic scarring and permanent
depigmentation. There are ample studies on
the effect of GA peels on ethnic skin [55]
(Table 9) and hence make for a recommended
choice of treatment. In most of these studies,
there was a moderate improvement achieved in
almost one-half of the patients [58,59,72,73].
Lasers should rarely be used in the treatment
of melasma and, if applied, it is important to
consider skin type. The mode-toning laser
treatment is generally recommended in all
skin types and its major advantage is that it
destroys melanin without cell damage. Both QS
low fluence and IPL are effective for recalcitrant
melasma, when patients are non-responsive to
other treatments, or when patients are
intolerant of other treatment medications. The
combination of IPL with QS laser gives a rapid
resolution of mixed-type melasma with possible
long-term benefits [67–69]. Fractional non-
ablative lasers can be considered only if all
other modalities fail. Ablative lasers should not
be considered.
Fig. 1 Algorithm for melasma treatment in India. HQ hydroquinone, MASI melasma area and severity index, SPF sun
protection factor
Dermatol Ther (Heidelb) (2014) 4:165–186 179
Patient consent and a photograph of the
condition must be obtained prior to therapy. As
important as actual therapy is proper patient
counseling, and an understanding of the
psychosocial impact on the patient and of his/
her condition leading to low quality of life [74,
75]. This is likely to lead to a better patient
compliance and an adherence to the regimen. It
has been reported in Indian patients that
overuse of certain treatment modalities such
as mometasone-based therapies leads to
undesirable fallouts [47,49].
The recommendation is to use an alternative
triple-combination cream, better suited for
Indian patients, i.e., 2% HQ, 0.05% tretinoin,
and 0.01% of the mild steroid fluocinolone
acetonide cream. Another option is to replace
the mometasone-based triple combination after
4–8 weeks, with a fluocinolone or a
hydrocortisone-based one for a further 3- to
6-month period. As discussed earlier, this cream
is safe and effective based on extensive clinical
studies. The gradual withdrawal of the
therapeutic agent is also a consideration and is
achieved by decreasing doses of the active
agent. The proposed algorithm for Indian
patients is presented in Fig. 1.
BAD PROGNOSIS INDICATORS
There are several conditions that determine the
outcome of treatment in melasma since its
Table 9 Studies of melasma therapy on ethnic skin [53]
References Number and ethnicity
of patients
Peel Topical therapy Response
Lim and Tham
[58]
10 Asian (women) 20–70%
GA
– Not statistically significant
Grimes [54] 6 (darker racial ethnic
groups in USA)
20–30%
SA
– Moderate improvement in 66% patients
Jawahari et al.
[59]
25 Indian 50% GA Sunscreen SPF 15,
10% GA
46.7% epidermal, 27.8% mixed, 0%
dermal
Grover and
Reddu [73]
15 Indian Serial GA
peels
– Good to fair improvement
Sharquie et al.
[87]
20 Iraqi 92% LA – Significant improvement in all 12
patients who completed study
Godse and
Sakhia [72]
20 Indian Serial GA
peels
Triple combination
and sunscreen
[50% improvement in half of patients
GA glycolic acid, LA lactic acid, SA salicylic acid
Table 10 Bad prognosis factors
Factors that govern negative treatment outcome
Phenotype III–VI: dark hair and/or dark skin
Genetic and familial predisposition [3,6,8–10]
Long-term melasma in spite of C2 years of treatment
History of procedural interventions
Treated by C2 physicians
Long-term self-treatment with steroids [46,47]
Ochronosis [76,114]
Mixed-type melasma [115]
180 Dermatol Ther (Heidelb) (2014) 4:165–186
etiology is multifactorial. Several factors predict
potential failure of treatment (listed in
Table 10). Moin et al. [3] found a statistically
significant relationship between melasma and
ethnicity, and phototype and grade of parity.
Exogenous ochronosis has also been reported to
be being misdiagnosed as a melisma treatment
failure [76]. However, these prognostic factors
lack sufficient scientific evidence.
CONCLUSION
Here, the Indian dermatologists panel has graded
the results of safety and efficacy of various
melasma therapies from clinical trials conducted
worldwide (Table 7) applying the quality and level
of evidence based on the US preventive services
taskforceonhealthcare(Table8). Focus on the
efficacy as well as AEs particular to the major skin
types of Indian population, using evidence from
clinical trials and physicians’ experience in the
clinic, has directed the selection process for each
recommended therapy. Using these guidelines, a
much needed algorithm specific to melasma in
India has been evolved and will assist physician’s
decision on melasma treatment, disease
management, and optimal outcome. We have
also brought to attention some practices in
treatment of melasma, for example, prolonged
use of mometasone-based triple combination and
prognosis indicators that have negative
connotations. The key therapy recommended is
fluorinated steroid containing 2–4% HQ-based
triple combination for first-line therapy, with
additional selective peels if required in second-
line therapy. Lasers are a last resort.
ACKNOWLEDGMENTS
All named authors meet the ICMJE criteria for
authorship for this manuscript, take
responsibility for the integrity of the work as a
whole, and have given final approval for the
version to be published. The authors
acknowledge the help provided by Medical
writer Ms Madhavi Muranjan for manuscript
writing and Knowledge Isotopes Ltd. for editing
and submission. Wockhardt Pvt. Ltd. funded
the medical writing assistance and article
processing charges for this article.
Conflict of interest. Krupa Shankar, Kiran
Godse, Sanjeev Aurangabadkar, Koushik Lahiri,
Venkat Mysore, Anil Ganjoo, Maya Vedamurty,
Malavika Kohli, Jaishree Sharad, Ganesh Kadhe,
Pashmina Ahirrao, Varsha Narayanan, and
Salman Abdulrehman Motlekar declare no
current conflict of interest.
Compliance with ethics guidelines. This
article is based on previously conducted
studies and the expert opinion of the authors,
and does not involve any new studies of human
or animal subjects performed by any of the
authors.
Open Access. This article is distributed
under the terms of the Creative Commons
Attribution Noncommercial License which
permits any noncommercial use, distribution,
and reproduction in any medium, provided the
original author(s) and the source are credited.
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