Melasma: A comprehensive update

Part II
Vaneeta M. Sheth, MD,a and Amit G. Pandya, MDb
Boston, Massachusetts, and Dallas, Texas
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1. Reading of the CME Information (delineated below)
2. Reading of the Source Article
3. Achievement of a 70% or higher on the online Case-based Post Test
4. Completion of the Journal CME Evaluation
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Statement of Need:
The American Academy of Dermatology bases its CME activities on the
Academys core curriculum, identied professional practice gaps, the
educational needs which underlie these gaps, and emerging clinical
research ndings. Learners should reect upon clinical and scientic
information presented in the article and determine the need for further
study.
Target Audience:
Dermatologists and others involved in the delivery of dermatologic care.
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The American Academy of Dermatology is accredited by the
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continuing medical education for physicians.
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CME activity for a maximum of 1 AMA PRA Category 1 Credits.
Physicians should claim only the credit commensurate with the extent of
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This journal-based CME activity is recognized by the American Academy
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options of a specic patients medical condition.

Disclosures
Editors
The editors involved with this CME activity and all content validation/
peer reviewers of this journal-based CME activity have reported no
relevant nancial relationships with commercial interest(s).
Authors
Dr. Pandya has been an investigator and consultant for Galderma
Laboratories within the last 5 years and has received grants and
honoraria for these services. Dr. Sheth reported no relevant nancial
relationships with commercial interest(s).
Planners
Matthew Zirwas, MD, served as a peer reviewer for this CME activity and
is a speaker and consultant for Coria Laboratories and has received
honoraria for these services. He is also a consultant for Onset
Therapeutics and has received honorarium for this service. The other
planners involved with this journal-based CME activity have reported no
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Learning Objectives
After completing this learning activity, participants should be able to list
the various treatment options available for melasma and describe their
respective efcacy, side effect proles, and risks and benets; and
develop an individualized, evidence-based treatment plan for patients
with melasma.
Date of release: October 2011
Expiration date: October 2012
2010 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2011.06.001

Several methods of treatment are available to patients with melasma. First-line therapy usually consists of
topical compounds that affect the pigment production pathway, broad-spectrum photoprotection, and
camouage. Second-line therapy often consists of the addition of chemical peels, although these must be
used cautiously in patients with darker skin. Laser and light therapies represent potentially promising
options for patients who are refractory to other modalities, but also carry a signicant risk of worsening the
disease. A thorough understanding of the risks and benets of various therapeutic options is crucial in
selecting the best treatment. ( J Am Acad Dermatol 2011;65:699-714.)
Key Words: chemical peels; chloasma; hydroquinone; laser therapy; melasma; pigmentation.

699

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700 Sheth and Pandya

OCTOBER 2011

Melasma has traditionally been treated with a commelasma and in enhancing the efficacy of
bination of photoprotection, avoidance of trigger facother topical therapies once melasma has
tors, and topical depigmenting agents with varying
developed
d Camouflage makeup can be an important
degrees of success. New pathways involved in pigment
production are being studied as targets for topical
component of melasma treatment
therapy. Of late, there has also been a signicant
Several studies have shown that light from both
increase in the types of laser and light technologies
the
ultraviolet (UV) and even the visible spectrum
available for the treatment of
can
induce
pigmentary
disorders of hyperpigmentachanges
in
the
skin,
includCAPSULE SUMMARY
tion. While multiple options
ing
in
Fitzpatrick
skin
photocurrently exist to help treat
2,3
Topical
treatment
of
melasma
includes
Immediate
types
IV
to
VI.
melasma, some of these therahydroquinone, retinoids, chemical peels,
pigment darkening caused
pies have come under increasand
many
other
less
well
studied
by the redistribution and oxing scrutiny, underscoring the
compounds.
idation of preexisting melaneed for more research into
nin occurs after low-dose
The evidence for improvement with laser
the pathogenesis and treatultraviolet A (UVA) exposure
therapy is mixed with a significant
ment of melasma.
and usually fades after 2
potential for worsening.
hours.4 Persistent pigment
TREATMENT OPTIONS
Newer topical agents and laser
darkening lasts up to 24
FOR MELASMA
technologies represent promising
hours and occurs after higher
The treatment of meoptions for therapy, especially in
doses of UVA exposure.
lasma includes topical fortreatment-resistant patients.
Delayed tanning can occur
mulations, chemical peels,
from either UVA or UVB exlasers, and light sources.
posure
and
is
caused
by melanin synthesis. To
While no single therapy has proven to be of
investigate
if
broad-spectrum
sun protection could
benet to all patients as the sole therapy, combibe
used
to
inhibit
the
onset
of
melasma,
Lakhdar et al5
nations of modalities can be used to optimize
enrolled 200 Moroccan women who were less than 3
management in difcult cases. Levels of evidence
months pregnant and gave them a sunscreen with a
for the trials presented below are provided for
sun protection factor (SPF) of 501 and a UVA
each treatment modality based on guidelines
protection factor of 28 (Anthelios; La Roche-Posay
adapted from the US Preventive Services Task
1
LOreal, Clichy, France) to use every 2 hours during
Force on health care. In this system, a rating of
the day, regardless of sun exposure.5 Five of the 185
I means that the evidence is obtained from at least
women (2.7%) who completed the 12-month trial
one properly designed, randomized controlled
developed melasma during pregnancy. Notably, the
trial, and a rating of A means there is good
same investigators reported a 53% prevalence of
evidence to support the use of the procedure
melasma with pregnancy in a similar population in
(Appendix).
an earlier study.6 Eight of 12 patients with preexisting
melasma improved with the sunscreen (level of
SUNSCREENS AND CAMOUFLAGE FOR
evidence, II-iii). Broad-spectrum sun protection has
MELASMA
also been shown to enhance the efficacy of hydroKey points
quinone.7 A double blind study examining the
d Ultraviolet and visible light can induce meldifference in efficacy between patients using a
anin formation
hydroquinone-containing agent with either vehicle
d The regular use of broad spectrum sunor broad-spectrum sun protection found that 96.2%
screen is effective both in preventing
of patients using concomitant sun protection showed
improvement versus 80.7% of patients using hydroFrom the Departments of Dermatology at Brigham and Womens
quinone alone (level of evidence, II-i). A recent study
Hospital,a Harvard Medical School, and the University of Texas
revealed that visible light can produce significant
Southwestern Medical Center,b Dallas.
pigmentation in normal skin, a finding that may be
Funding sources: None.
important in the pathogenesis of melasma.3
Reprints not available from the authors.
With the currently available data, a broadCorrespondence to: Amit G. Pandya, MD, Department of
Dermatology, The University of Texas Southwestern Medical
spectrum UVA- and UVB-protective sunscreen with
Center, 5323 Harry Hines Blvd, Dallas, TX 75390-9190. E-mail:
an SPF of at least 30 along with a physical block, such
amit.pandya@utsouthwestern.edu.
as titanium dioxide or zinc oxide, should be used by
d

0190-9622/$36.00

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Sheth and Pandya 701

VOLUME 65, NUMBER 4

patients with melasma and should be reapplied

frequently. Patients should also be instructed to
wear protective hats and clothing when outdoors
and to practice sun avoidance when possible. While
sunscreens alone for the treatment of melasma have
never been studied, their use is recommended based
on clinical experience. Studies showing the importance of sunscreen use in melasma should be
performed in the future, which would ideally investigate the minimum SPF and the action spectrum that
is relevant for melasma.
In addition, many patients nd the use of camouage makeup to be an important component in the
treatment of their melasma. Several widely available
brands include Dermablend (Vichy Laboratories,
Paris, France), Covermark/CM Beauty (CM Beauty,
Northvale, NJ), and Cover FX (Cover FX Skin Care;
Toronto, Ontario, Canada). These brands come in a
broad range of shades and offer heavy coverage to
help even out skin tone.
Topical treatments: The old and the new
Because melasma is a disorder of pigmentation,
topical treatments are largely aimed at disrupting
the enzymatic processes of pigment production
within melanocytes. Tyrosinase is the rate-limiting
enzyme in the process of melanin production,
converting L-tyrosinase to L-3,4-dihydroxyphenylalanine (L-DOPA), and is the major target for many
of the agents that have been developed for melasma.8 L-DOPA is a required cofactor, and copper
is an important molecule that interacts at the
enzymes active site. Many compounds exhibit
multiple effects leading to a decrease in melanization. The major agents in use and the predominant
components they target are shown in Table I.

PHENOLIC COMPOUNDS
Key points
Hydroquinone, a tyrosinase inhibitor, has
been extensively researched and found to be
very effective in treating disorders of
hyperpigmentation
d While controversy exists regarding the use
of hydroquinone, a review of the literature
indicates that hydroquinone is safe as a topical agent for melasma
Hydroquinone: The evidence and the
controversy
d

One of the earliest compounds used for the

treatment of hyperpigmentation, hydroquinone
(1,4 dihydroxybenzene) has been in use for more
than 50 years. While controversy exists regarding the
long-term safety of hydroquinone, its efcacy both

Table I. Agents under investigation to decrease

cutaneous hyperpigmentation
Proposed mechanism of action

Tyrosinase inhibition

Stimulation of keratinocyte
turnover
Reduction in melanosome
transfer
Interaction with copper
Inhibition of melanosome
maturation
Inhibition of proteaseactivated receptor 2
Inhibition of plasmin
Reduction of alpha
melanocyte-stimulating
hormoneeinduced
melanin production

Compound

Hydroquinone
Mequinol
Azelaic acid
Arbutin and deoxyarbutin
Licorice extract
Rucinol
Resveratrol
4-hydroxy-anisole
2,5-dimethyl-4-hydroxy3(2H )-furanone
N-acetyl glucosamine
Retinoids
Retinoids, soybean trypsin
inhibitor
Kojic acid
Ascorbic acid
Arbutin and deoxyarbutin
Soybean trypsin inhibitor
Tranexamic acid
Beta-carotene

alone and in combination with other agents is well

studied and well established. Hydroquinone is
thought to act by inhibition of tyrosinase, possibly
by binding to the enzyme or by interaction with
copper molecules at the enzymes active site. This
leads to altered melanosome formation and increased melanosome destruction,9 and perhaps
even the inhibition of DNA and RNA synthesis.10
The ability of hydroquinone to induce skin lightening in cats was rst reported by Oettel11 in 1936.
Not long afterward, hydroquinone became available
as a topical agent in parts of the United States, where
it was noted to induce skin lightening in humans.12
Spencer13 performed one of the first studies using
hydroquinone at concentrations of 2%, 3%, and 5%
applied twice daily for 3 months to the dorsal surface
of the hands of white men with solar lentigines. The
results revealed a dose-dependent decrease in pigmentation on clinical examination, with maximum
improvement after 2 months of treatment and relapse once treatment was stopped. Patients also were
found to have a transient inflammatory reaction to
the medication, especially during the first 2 weeks of
therapy. This last finding was confirmed in another

702 Sheth and Pandya

study where up to 25% of patients treated with

hydroquinone were found to develop an irritant
dermatitis.14 Currently, other agents added to hydroquinone, such as tretinoin and glycolic acid, are
responsible for most of the irritation from application
of these combination creams.15,16
Comparing 4% hydroquinone to placebo for
melasma, Ennes et al17 found that 38% of patients
treated with hydroquinone had a complete clinical
response versus only 8% in the placebo-treated group
(level of evidence II-i). In a nonrandomized trial, 4%
hydroquinone and broad-spectrum sunscreen was
also shown to be efficacious in the treatment of
melasma, with 89.5% of subjects showing a good to
excellent response18 (level of evidence II-iii).
Over the last several years, concern has been
growing over the use of topical hydroquinone
preparations. This apprehension exists in large part
because of perceived risks of therapy and a lack of
good clinical data to justify the approval of many
currently marketed preparations according to new
federal guidelines in the United States. Several
reports of exogenous ochronosis, a bluish-gray discoloration, have been linked to the use of hydroquinone, especially in South African blacks.19 In the
United States, the occurrence of ochronosis after use
of hydroquinone has been much less common.20
One likely explanation for this phenomenon is the
fact that hydroquinone can be obtained in higher
concentrations (up to 8%) in over the counter
formulations in some countries outside the United
States. This uncontrolled access to high concentrations of hydroquinone and overuse can increase the
risk of adverse events related to the medication. In
addition, these over the counter preparations may
contain various other ingredients, such as resorcinol,
mercury, lemon juice, potash, crushed camphor
balls, peroxides, and chlorates that may contribute
to the development of exogenous ochronosis.21
The US Food and Drug Administration (FDA)
originally proposed in 1982 that hydroquinone was
safe and effective enough to be sold over the counter
in concentrations of 1.5% to 2%.22 However, in 2006,
the FDA announced that it would be changing its
position, stating that currently marketed over the
counter preparations containing hydroquinone and
prescription products not originally studied as investigational drugs must be submitted with New
Drug Applications with the requisite clinical studies
or be withdrawn from the market.23 The FDA has not
yet moved to remove these products from the
marketplace while awaiting comments regarding
this ruling. The only preparation that this ruling
would not affect is a triple combination cream
(TriLuma; Galderma Pharmaceuticals, Fort Worth,

J AM ACAD DERMATOL

OCTOBER 2011

TX) that was brought to market as an investigational

drug approved by the FDA after the performance of
adequate clinical trials. Several reasons for this proposed FDA ruling exist, including a concern over
systemic absorption of the drug, reports of exogenous ochronosis, and a concern for drug-induced
carcinogenesis. In the European Union, hydroquinone has been banned from use as a cosmetic
ingredient since 2001 because of a concern over
side effects such as ochronosis and occupational
vitiligo24; however, it is still available as a prescription medication.
One of the concerns regarding hydroquinone is
the potential for risks from the production of benzene derivatives after hepatic metabolism.24 These
derivatives are proposed to cause bone marrow
toxicity and exert an antiapoptotic effect. However,
topically applied hydroquinone bypasses the liver
initially, and the major route of metabolism of
hydroquinone is via water soluble, renally excreted
molecules.24 Another concern is the risk of developing renal adenomas because of potentially toxic
metabolites, but topical hydroquinone has not
been shown to have renal toxicity. In addition, there
have been no reports to date of skin or internal organ
malignancies occurring in humans as a result of
topical hydroquinone application, despite being in
use since the middle of the 20th century.25
Hydroquinone is a compound that is commonly
found in many foods and beverages, including
berries, tea, coffee, red wine, wheat, and the skin
of pears. Workers involved in the manufacture of
hydroquinone and who are exposed to large quantities of this agent have not been found to have any
signicantly increased risk of premature death or
increased prevalence of malignancy compared to
controls.25 Hydroquinone has not been found to be
carcinogenic in the Ames test. In addition, oral and
systemic injections of hydroquinone in animals did
not lead to the formation of malignancies or cause
marrow toxicity.25
In a review of hydroquinone safety issues,
Nordlund et al25 maintained that there does not
appear to be more than a theoretical risk of malignancy and an exceedingly low risk of developing
ochronosis or other side effects in patients using
available prescription topical preparations of hydroquinone under the supervision of a physician.
Mequinol
Mequinol (4-hydroxyanisole) is a phenolic agent
that is thought to act as a competitive inhibitor of
tyrosinase without damaging melanocytes.26 This
compound has been approved for use in Europe
and the United States and is available in combination

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VOLUME 65, NUMBER 4

with topical retinoids. Although mequinol has been

used as a tyrosinase inhibitor for hyperpigmentation,
it has only been studied for lentigines,27 not melasma. Therefore, a recommendation for melasma
cannot be made at this time.

RETINOIDS
Key points
d

Tretinoin is an effective treatment for melasma but often causes irritation and usually
requires months to show improvement as
monotherapy
Adapalene may be an alternative retinoid in
patients who cannot tolerate tretinoin

Several topical retinoids have been used with

some success in the therapy of melasma. The mechanism of action is thought to involve stimulation of
keratinocyte turnover, decreasing melanosome
transfer and allowing greater penetration of other
active ingredients.28 Tretinoin has been commonly
used in the treatment of disorders of hyperpigmentation. It is thought to inhibit tyrosinase transcription,
interrupt melanin synthesis,29 inhibit tyrosinaserelated proteins 1 and 2 (TRP-1 and TRP-2), and
has been shown to decrease posttranscriptional
levels of tyrosinase and TRP-1 after UVB exposure.28
A randomized, vehicle-controlled study of 0.1%
tretinoin versus vehicle cream applied nightly to
the face of white women with melasma for 40 weeks
reported that 68% of tretinoin-treated patients were
rated as improved or much improved compared to
just 5% of vehicle-treated patients.30 All patients used
regular photoprotection. Importantly, it took 24
weeks to see significant improvement. Histology of
treated lesions confirmed an average 36% epidermal
pigment decrease in tretinoin-treated skin compared
to a 50% increase in epidermal pigment in vehicletreated skin. Dermal pigment was unaffected.
Surprisingly, colorimetry showed a much more
modest benefit from the use of the tretinoin cream.
The most common side effects were erythema and
desquamation, seen in 88% of treated subjects (level
of evidence, I).
A similar study in African American subjects with
melasma treated with 0.1% tretinoin cream nightly in
addition to the use of regular photoprotection
revealed similar efcacy, with an initial benet also
seen after 24 weeks of treatment.31 Erythema and
desquamation were observed in 67% of patients
treated with tretinoin cream (level of evidence, I).
Given the longer treatment time needed to see a
clinical benefit and the frequent occurrence of irritation, tretinoin may not be very useful as monotherapy for melasma.

Topical 0.05% isotretinoin gel applied daily in

combination with SPF 28 sunscreen has been evaluated in the treatment of melasma in Thai patients;
however, this agent did not show increased efcacy
versus vehicle and sunscreen alone.32 Although
tazarotene has been reported to be useful for postinflammatory hyperpigmentation,33 there have been
no published reports of its use in the treatment of
melasma.
Adapalene, a synthetic retinoid with less irritancy,
has been tested for the treatment of melasma.34
Adapalene 0.1% was compared to 0.05% tretinoin in
the treatment of melasma in Asian Indian patients,
and after 14 weeks, investigators noted a 37%
reduction in Melasma Area and Severity Index
(MASI) scores in the tretinoin-treated group and a
41% reduction in MASI scores in the adapalenetreated group. In addition, patients in the adapalene
group developed fewer side effects and found the
medication more tolerable for regular use. Although
the degree of improvement was modest, adapalene
may present a more tolerable and equally efficacious
retinoid for use in the long-term treatment of melasma (level of evidence, II-ii).

COMBINATION PRODUCTS
Key points
d

A combination of hydroquinone, a retinoid,

and a topical steroid appears to be highly
effective for the treatment of melasma

One of the rst combination topical therapies

developed for the treatment of hyperpigmentation
was the Kligman-Willis formula,35 consisting of 5%
hydroquinone, 0.1% tretinoin, and 0.1% dexamethasone. The authors found that 10% hydroquinone
was more efficacious but more irritating, 0.2% tretinoin was more irritating without being more effective, 0.05% tretinoin was less irritating but required a
longer treatment time to see beneficial effects, and
dexamethasone could be increased to 0.2% with
enhanced activity without much change in irritancy.
The researchers also found that fluorinated steroids
were more effective than nonfluorinated steroids.
The time to see benefit with twice daily usage was
approximately 3 weeks. One theory behind the
effectiveness of this combination of agents is that
tretinoin prevents the oxidation of hydroquinone
and improves epidermal penetration while the topical steroid component reduces irritation from the
other two ingredients and decreases cellular metabolism, which inhibits melanin synthesis.36
Since this discovery, other dual and triple agent
therapies have been studied. Dual combination
topicals tested include hydroquinone plus retinoic

704 Sheth and Pandya

acid37 and hydroquinone plus retinol.38 While both

studies showed moderate improvement with generally tolerable irritant effects, one other important
finding was that the concomitant use of regular
photoprotection of at least SPF 15 increased the
efficacy of topical therapy significantly (level of
evidence, II-iii).
One of the most successful combination formulations has been 4% hydroquinone, 0.05% tretinoin,
and 0.01% uocinolone acetonide. This combination was initially studied in a large number of
melasma patients in a multicenter, investigatorblinded, randomized prospective trial in which
nightly use of the triple combination cream was
compared to nightly use of dual-combination
creams containing either hydroquinone plus tretinoin, hydroquinone plus uocinolone, or tretinoin
plus uocinolone.25 All patients also used regular
photoprotection with an SPF 30 sunscreen. The
investigators found that after 8 weeks, 26.1% of
patients using the triple-combination treatment
achieved complete clearance versus 9.5% for hydroquinone plus tretinoin, 1.9% for tretinoin plus
fluocinolone, and 2.5% for hydroquinone plus
fluocinolone. In addition, 77% of patients on the
triple-combination agent achieved complete or
near-complete clearance as compared to a maximum of 46.8% of patients achieving this same goal
on the dual-combination regimens. Of note, all
ratings were based on investigators subjective ratings. The outcome measure of clear or almost clear
is a reasonable goal for patients; therefore, a result of
77% of patients achieving success supports the use
of this combination cream. Side effects of treatment
occurred in the majority of patients, and included
erythema, desquamation, burning, dryness, and
pruritus; however, the severity was rated as mild in
most patients. Because irritation may lead to the
development of postinflammatory hyperpigmentation in patients with darker skin types, a decrease in
frequency of application is a reasonable approach to
those who develop irritation (level of evidence, I).
More recently, a trial comparing this triplecombination product with 4% hydroquinone alone
was performed.39 The investigators found that in
addition to regular photoprotection, the daily use of
the triple-combination therapy led to 35% of subjects
achieving an investigator rating of clear for melasma
severity as compared to 5.1% of patients who were
treated with twice daily 4% hydroquinoneagain
confirming the superiority of this combination cream
over hydroquinone alone. It is important to note that
the investigators were not blinded, which may have
caused bias. In addition, no objective outcome
measures were used (level of evidence, II-ii).

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OCTOBER 2011

Another combination that has been tested is 0.05%

tretinoin, 0.05% triamcinolone acetonide, 6% hydroquinone, and 0.1% ascorbic acid used nightly with
daily photoprotection in an open-label study.40 With
this combination, three out of six Hispanic patients
with epidermal or mixed melasma had clinical
improvement.
While efcacious, the cost of combination topicals
can sometimes be prohibitive. However, a recent
cost/benet analysis of combination therapy versus
hydroquinone alone in melasma patients found that
the use of a triple-combination agent daily as compared to twice daily use of hydroquinone actually led
to a 30% greater rate of clearance with a lower cost in
the United States.41 In other countries, the cost to
achieve clearance was also lower for triplecombination therapy than for single agent treatment
with hydroquinone. This analysis took into account
the added cost of adverse events related to medication use and other therapies used subsequently in
patients who failed to clear on the evaluated treatments (level of evidence, I).
Summary
Topical therapy with a triple combination agent
appears to be the most clinically effective initial
therapy for patients with melasma. Hydroquinone
4% in conjunction with regular photoprotection,
although less effective, is a good alternative to a
triple combination agent. Retinoids as monotherapy
are unlikely to be as efcacious as the above agents
and require signicantly more time before results are
visible.
Other commonly used topical agents
In addition to the compounds just discussed, there
are several other agents that are available in topical
preparations for the treatment of cutaneous hyperpigmentation (see Table I). Some of the more commonly used agents that have undergone clinical trials
are presented below.
Azelaic acid. Azelaic acid is a 9-carbon dicarboxylic acid derived from Pityrosporum ovale that
acts as a weak reversible competitive inhibitor of
tyrosinase.42,43 This molecule may have cytotoxic
and antiproliferative effects on melanocytes, possibly by interfering with mitochondrial respiration and
DNA synthesis in abnormal melanocytes.44 Another
possible mechanism of action includes decreased
free radical formation. The most commonly reported
side effects of preparations containing azelaic acid
include pruritus, mild erythema, scaling, and
burning. It has been shown to be safe for use in
combination with retinoids.26 In a randomized
double-blind multicenter trial comparing 20% azelaic

J AM ACAD DERMATOL
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acid versus vehicle in patients with Fitzpatrick skin

types IV to VI with at least moderate melasma,
investigator ratings showed a significantly greater
improvement in the azelaic acidetreated group.45
Chromameter measurements of pigment intensity
showed small but statistically significant decreases
in pigment intensity in the treatment group compared to the control group. Of note, patients treated
with azelaic acid with dermal melasma were excluded from the analysis. In comparison to hydroquinone, 20% azelaic acid has been shown to have
greater efficacy than 2% hydroquinone in a 6-month
study46 and to be equally as efficacious as 4%
hydroquinone in a 24-week double blind trial47
(level of evidence, I).
Kojic acid. Kojic acid is a molecule produced by
Aspergilline oryzae and Penicillium spp.42 It acts as
a tyrosinase inhibitor that works by chelating copper
at the enzymes active site. This agent is usually
available over the counter in a 2% concentration. It is
important to keep in mind that kojic acid is a known
sensitizer.26 Studies examining the efficacy of kojic
acid in melasma have shown mixed results. In one
split-face trial comparing a glycolic acid/kojic acid
preparation to a glycolic acid/hydroquinone preparation, the authors found no statistically significant
difference between the two formulations in terms of
clinical efficacy, and the kojic acidecontaining
preparation was more irritating to patients.48
Another split-face trial examining a gel containing
glycolic acid and hydroquinone showed more improvement in patients applying a gel that also
contained kojic acid (60%) versus a gel that contained only glycolic acid and hydroquinone
(47.5%)49 (level of evidence, II-i).
Ascorbic acid. Ascorbic acid, otherwise known
as vitamin C, is thought to decrease pigment by
interacting with copper at the active site of tyrosinase
and by reducing dopaquinone by blocking dihydrochinindol-2-carboxyl acid oxidation.20,26 However,
this molecule is rapidly oxidized, highly unstable,
and does not work well alone; it is therefore usually
combined with licorice extracts and soy to increase
efficacy. In vitro studies have shown that vitamin C
can significantly inhibit mushroom tyrosinase.50
Using iontopheresis with vitamin C in a 12-week
randomized double-blind split-face study, Korean
women with melasma reported a noticeable improvement on the vitamin Cetreated side, but there
was no long-term follow-up to determine the duration of these effects. In another randomized trial,
patients who applied 4% hydroquinone cream to
one side of the face and 5% ascorbic acid cream to
the other noted greater subjective improvement in
the hydroquinone-treated side (93% vs. 62.5% on the

Sheth and Pandya 705

ascorbic acidetreated side).51 However, colorimetric

analysis showed no difference between treatments.
Ascorbic acid caused significantly less irritation than
hydroquinone; therefore, it may be a useful adjunctive treatment in patients who cannot tolerate
hydroquinone because of side effects (level of evidence, I).
Arbutin/deoxyarbutin. Arbutin is a beta-Dglucopyranoside derivative of hydroquinone that is
derived from Uva ursi folium (the bearberry plant)
and can also be found in cranberry and blueberry
leaves.26,52 Its mechanism of action is inhibition of
tyrosinase and 5,6-hydroxyindole-2-carboxylic acid
(DHICA) polymerase and inhibition of melanosome
maturation. The synthetic deoxyarbutin is a more
potent tyrosinase inhibitor and in guinea pig and
human tests has been shown to be more effective
more rapidly.53 Deoxyarbutin was shown to be as
effective in inhibiting mushroom tyrosinase as hydroquinone, and deoxyarbutin-induced skin lightening of solar lentigines was actually maintained
without the use of maintenance therapy, whereas
hydroquinone-induced skin lightening was not sustained.53 It has been used in Japan at 3% concentrations, but a higher concentration may cause
paradoxical hyperpigmentation.26 These agents
have not been reported in the the treatment of
melasma (level of evidence, II-i).
Licorice extract. Licorice extract inhibits tyrosinase, especially the rate-limiting rst step of oxidation.42 The active ingredients are liquiritin (which
disperses melanin) and isoliquiritin (which contains
flavonoids). Licorice extract also has topical antiinflammatory properties. A split-face trial treated 20
women with epidermal melasma diagnosed with a
Wood lamp examination with liquiritin cream to
one half of the face and vehicle cream to the other
side twice daily for 4 weeks along with sun avoidance or sunscreen. Sixteen of 20 patients had a
clinically graded excellent response (defined as no
difference between lesional and normal skin) on
the liquiritin-treated side.54 In contrast, only one
patient showed a moderate clinical response on the
control-treated side. Patients generally use 1 g per
day for 4 weeks before any benefit is seen26 (level
of evidence, II-i).
Soy. Soybean trypsin inhibitor reversibly inhibits
the protease-activated receptor-2 (PAR-2) pathway
that is needed for melanosome transfer by keratinocyte phagocytosis of melanosomes.55 In vitro and
animal studies show that activation of the PAR-2
pathway enhances melanosome ingestion by keratinocytes, but direct keratinocyteemelanocyte contact was required for this to occur.56 Inhibition of
this pathway caused a dose-dependent loss of

706 Sheth and Pandya

pigmentation by as early as 4 weeks at the highest

tested dose. Additional work on this pathway has
shown that soybean trypsin inhibitor (STI) and
BowmaneBirk inhibitor (BBI) can inhibit both baseline and UVB-induced pigmentation in vitro.57 This
was caused in part to the inhibition of keratinocyte
phagocytosis of melanosomes. In a multiagent comparative trial in patients with solar lentigines, soy
extract was shown to have a modest effect in lightening the lesions.58 However, no trials in melasma
patients have been published to date, making it
difficult to directly compare the efficacy of soy to
other well studied compounds.
Summary
Azelaic acid may represent a useful second-line
topical therapy in patients who do not tolerate or do
not have access to preparations containing hydroquinone. Ascorbic acid may also be a useful adjunctive topical therapy. Kojic acid may give modest
improvement for melasma, but it often causes irritation. Soy inhibition of the PAR-2 pathway provides a
novel approach to treating melasma, but clinical
trials are needed to better determine its efcacy.
Additional studies are needed to determine the role
of arbutin/deoxyarbutin and licorice extract in the
treatment of patients with melasma.

CHEMICAL PEELS
Key points
d

Glycolic acid may be the most efficacious

alpha hydroxyl peeling agent for melasma,
but it should be used cautiously
Glycolic acid peels should be used in conjunction with a depigmenting agent for maximal benefit and to minimize the risk of
postinflammatory hyperpigmentation
Salicylic acid peels appear to be of minimal
benefit in the treatment of melasma

Although chemical peels may improve disorders

of hyperpigmentation by removing unwanted melanin, they can also cause irritation, which can lead to
postinammatory hyperpigmentation. This side effect is especially common in patients with darker
skin types; therefore, peels or any other procedure
causing injury to the skin should be performed with
extreme caution in patients with melasma.
Alpha hydroxy acid peels
Glycolic and lactic acids are food-derived alpha
hydroxy acids often used in chemical peels for
disorders of hyperpigmentation. They are thought
to work by inhibiting tyrosinase activity in a pHindependent manner. These agents have been

J AM ACAD DERMATOL

OCTOBER 2011

shown to decrease melanin formation in a dosedependent fashion using melanin assays in mouse
B16 and human melanoma cell lines.59
In clinical studies, glycolic acid peels have shown
modest benet. A dose-response trial studying the
effect of varying concentrations of glycolic acid
peels for melasma showed that 52.5% glycolic acid
applied for 3 minutes led to clinical improvement,
whereas lower concentrations did not.60 Another
open study performed in Indian females with melasma treated with sun protection involved the use
of 10% glycolic acid lotion nightly for 2 weeks
followed by monthly 50% glycolic acid facial peels
for 3 months.61 The authors found that patients with
mixed or epidermal melasma showed a decrease in
MASI score by the end of the study (level of
evidence, II-iii).
Glycolic acid has also been examined as an
adjunct to other topical treatments. When used in
combination with a modied Kligman-Willis formula
(5% hydroquinone 1 0.05% tretinoin 1 1% hydrocortisone acetate), it was shown to decrease the
MASI score by 79.9%, but the topical formula
performed almost as well when used alone in this
study, showing a 63.1% decrease in MASI score.62
Side effects in this study included erythema and
desquamation, and two patients developed postinflammatory hyperpigmentation (level of evidence,
II-iii). A similar trial evaluated patients with epidermal melasma treated with azelaic acid plus adapalene with half of the group additionally treated with
glycolic acid peels of increasing concentrations every 2 weeks.63 The investigators found that the group
treated with peels in addition to topicals had an 83%
decrease in MASI scores as compared to a 69%
decrease in the group using topicals alone. Glycolic
acid has also been studied as an adjunct to hydroquinone in a split-face trial where the authors
found no additional benefit to chemical peeling in
terms of Mexameter readings, reduction in MASI
scores, or blinded physician global assessments.64
Pretreatment with hydroquinone 2% for 2 weeks
before performing a glycolic acid peel has been
shown to enhance improvement when compared to
peels alone.65
Based on the current evidence, glycolic acid peels
are best used judiciously and as adjunctive therapy in
refractory cases of epidermal melasma. The evidence
that they are effective is mixed.
Lactic acid peels have shown some benet in
patients with epidermal melasma, with MASI scores
decreasing by almost 57% in Fitzpatrick skin phototype IV patients with no relapse seen at the 6-month
follow-up visit in a trial that was not controlled or
split-faced in design66 (level of evidence, II-iii).

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Sheth and Pandya 707

VOLUME 65, NUMBER 4

Salicylic acid peels

Salicylic acid is a beta-hydroxy acid that has been
studied as a treatment for melasma and postinammatory hyperpigmentation resulting from acne. In a
small open study by Grimes,67 patients with
Fitzpatrick skin phototypes V and VI with melasma,
acne, postinflammatory hyperpigmentation, and oily
skin were pretreated with 4% hydroquinone for 2
weeks before undergoing salicylic acid peels every 2
weeks for a total of five treatments (two 20% and
three 30% peels), with the hydroquinone restarted 2
days after each peel. Clinical response as measured
by independent investigators revealed that four of
the six patients with melasma had moderate to
significant improvement. In the group as a whole,
it took an average of two peels before any improvement was seen. Adverse effects were seen in four
patients and were mild, including transient hyperand hypopigmentation and temporary dryness or
crusting. No permanent pigmentary changes were
seen by the end of the study, but there was no longterm follow-up (level of evidence, II-iii). Another
trial in Korean patients with acne and resulting
postinflammatory hyperpigmentation revealed that
treatment with 30% salicylic acid peels every 2 weeks
for 3 months showed no statistically significant
posttreatment benefit when measured by spectrophotometry68 (level of evidence, II-iii). Salicylic acid
therefore appears to provide minimal benefit when
used alone and, based on the above pilot studies, it is
difficult to discern if it adds any additional benefit to
the more traditional hydroquinone. Additional studies with this agent are warranted.
Summary
Glycolic acid peels in increasing concentrations
may be a useful adjunct to topical therapy, especially
if patients are pretreated with hydroquinone for 2
weeks before the procedure. However, given the risk
of postprocedure hyperpigmentation, a thorough
discussion of the risks and potential benets should
be undertaken with the patient before treatment.
Lactic acid peels have not been studied well enough
to recommend their use at this time. Salicylic acid
peels have not been shown to add any signicant
benet to topical therapy alone in melasma patients
and do not appear to be effective as monotherapy.
Other chemical peels. Other agents that have
been used for chemical peeling include 1% tretinoin,
Jessner solution (composed of salicylic acid, lactic
acid, resorcinol, and ethanol), and 10% to 50%
trichloroacetic acid (TCA) peels. Tretinoin69 and
Jessner solution70 peels have not been shown to be
any more efficacious than glycolic acid in clinical
studies, although tretinoin may be less irritating.

Jessner solution has also been tested against lactic

acid peels in a split-face nonrandomized blinded
trial71 in which no statistically significant difference
in MASI reduction was seen between the two treatments. TCA in varying concentrations led to a greater
than 50% improvement by clinical grading in 11 of 20
patients, but there was no comparison group.72 One
common confounding factor is the variation between trials of pre- and postpeel regimens and the
use of concomitant topical therapies and photoprotection. Also, in the Jessner solution trial,70 of the
five patients who returned for the 6-month follow-up
visit, only those who had continued topical therapy
sustained their results, while the rest of the subjects
had disease relapse. Until further evidence is presented, the addition of chemical peels to depigmenting agents may not add any long-term benefit in
patients with melasma (level of evidence, II-i).

LASER AND LIGHT THERAPIES

Key points
d

Q-switched ruby lasers and erbium:yttriumaluminum-garnet lasers have been shown to

worsen melasma
The combination of carbon dioxide laser
with Q-switched Alexandrite laser does not
appear to be beneficial for melasma and
carries a significant risk of worsening hyperpigmentation in darker-skinned patients
Fractional resurfacing is approved by the
FDA for the treatment of melasma and has
been shown to have some benefit; however,
additional controlled trials are needed to
evaluate its efficacy for melasma
Intense pulsed light therapy may provide
modest benefit as an adjunctive therapy for
refractory patients
Copper bromide lasers may be of benefit for
melasma, especially in patients with a visible
vascular component, but require further
study

The use of laser and light therapy for melasma is

based on several observations: (1) melanin has a
broad absorption spectrum, allowing a variety of
lasers and light sources to be used; (2) melanosomes
have a short thermal relaxation time, in the range of
50 to 500 nanoseconds; and (3) longer wavelengths
penetrate deeper to ostensibly target dermal pigment, but melanin absorption is better with shorter
wavelengths.73 This therapeutic modality is more
challenging because damage to surrounding tissue
and subsequent inflammation can lead to postinflammatory hyperpigmentation, which may be longlasting and even delayed in onset. Therefore, lasers

708 Sheth and Pandya

and light-based therapies should be used after other

modalities have been proven to be unsuccessful and
should be used with extreme caution in Fitzpatrick
skin phototypes IV to VI.
Some of the rst types of lasers studied for the
treatment of pigmented skin lesions were the
Q-switched lasers. In one trial studying the effects
of the Q-switched ruby laser for melasma and postinammatory hyperpigmentation refractory to other
treatments, the authors noted no improvement and,
in some cases, worsening with laser treatments
regardless of uence.74 Histologic sections of biopsy
specimens taken before and after treatment showed
extracellular melanin immediately after treatment.
Several months after the last treatment, epidermal
pigmentation was back to baseline levels and dermal
melanophages were focally increased. In a split-face
trial studying the effectiveness of the Q-switched
ruby laser versus a erbium:yttrium-aluminum-garnet
(erbium:YAG) laser for treating various pigmented
lesions, the investigators found that the three study
patients being treated for melasma were the only
participants who did not have improvement. In fact,
the melasma patients developed postinflammatory
hyperpigmentation and worsening as a result of
therapy.75 Given these results, the Q-switched lasers
are not a recommended form of therapy for patients
with melasma (level of evidence, II-iii).
Erbium:yttrium-aluminum-garnet
The erbium:YAG laser (Continuum Biomedical,
Dublin, CA) emits at 2940 nm and targets water as its
chromophore and is therefore useful for ablative
resurfacing. Manaloto et al76 tested the erbium:YAG
laser in 10 patients with Fitzpatrick skin phototypes II
to V who had refractory melasma. Using MASI scores
and spectrophotometry, the authors found that there
was improvement immediately after the procedure,
but all patients developed postinflammatory hyperpigmentation by 3 to 6 weeks follow-up despite the
use of oral steroids for 5 days postprocedure. While
the postinflammatory hyperpigmentation improved
with serial glycolic acid peels, this side effect appears
to outweigh any benefit from this procedure (level of
evidence, II-iii).
Carbon dioxide and Q-switched alexandrite
The pulsed CO2 laser also targets water as its
chromophore and can be helpful in removing epidermal pigmentation. The Q-switched alexandrite
laser emits at a longer wavelength than some other
Q-switched lasers (755 nm) and therefore penetrates
deeper into the skin. Some authors have evaluated
the combination of the CO2 laser, which can remove
epidermal pigment, followed by the Q-switched

J AM ACAD DERMATOL

OCTOBER 2011

alexandrite laser, which can penetrate even deeper

and remove dermal pigmentation. Theoretically, the
CO2 laser has minimal downward thermal conduction, thereby decreasing the risk of developing
postinflammatory hyperpigmentation. Nouri et al77
tested eight patients with Fitzpatrick skin phototypes
IV to VI with dermal melasma who were pretreated
with 14 days of 0.05% tretinoin cream, 4% hydroquinone cream, and 1% hydrocortisone cream twice
daily. Four patients were randomized to receive spot
treatment with one pass of the CO2 laser, followed by
a pass of the Q-switched alexandrite pigmented dye
laser. The other four patients received treatment with
one pass of the CO2 laser alone. Using blinded
subjective investigator evaluation as the primary
endpoint, the authors felt that the combination
therapy led to better resolution of the treated area
with less peripheral hyperpigmentation of the treated area. However, the sample size was small, as was
the area being treated, limiting the generalizability of
these results (level of evidence, IV).
In Thailand, researchers performed a split-face
trial studying the efcacy of the Q-switched alexandrite 755-nm laser (Accolade; Cynosure, Chelmsford,
United Kingdom) with or without one pass of the
Ultrapulse CO2 laser (Coherent, Palo Alto, CA).78 The
authors found that of the six females with Fitzpatrick
skin phototypes II to V with refractory melasma who
were treated, there was no statistically significant
difference between the two modalities at the end of
the study. Importantly, three patients with Fitzpatrick
skin phototypes IV to V had postinflammatory
hyperpigmentation on both sides at 2 to 4 weeks
lasting up to 3 months, and one patient had transient
hypopigmentation lasting 6 months. Given the risk
of postoperative dyspigmentation, the authors concluded that neither modality was safe enough to
recommend for routine use for melasma in the
Southeast Asian population (level of evidence, II-ii).
Fractional resurfacing
Fractional resurfacing is a newer technology that
creates microzones of thermal damage. It does not
cause full-thickness epidermal wounds, so recovery
is more rapid and, theoretically, the resulting inammation and dyspigmentation is less of a risk. This
laser is approved by the FDA for the treatment of
melasma, periorbital rhytides, pigmented lesions,
skin resurfacing, acne scars, and surgical scars.79
The microthermal zones of injury limit the area of
skin that is damaged with each treatment, which may
decrease the risk of postinflammatory hyperpigmentation. In addition, the transepidermal elimination of
these microthermal treatment zones after injury
could serve as an effective method of removing

J AM ACAD DERMATOL
VOLUME 65, NUMBER 4

dermal melanophages. One clinical trial evaluated 10

patients with Fitzpatrick skin phototypes III to V
treated with a fractionated laser (Fraxel; Reliant
Technologies, Palo Alto, CA) for four to six sessions
1 to 2 weeks apart.80 None of the patients were
pretreated with hydroquinone. The authors found
that six out of 10 patients had 75% to 100% clearing of
melasma based on clinical evaluation only, and the
nonresponders were all Hispanic patients. One
patient developed postinflammatory hyperpigmentation, and several patients had transient postprocedure erythema. The average pain score was 6.3 out of
10, 10 being equivalent to a bee sting, and all patients
went through the procedure with topical anesthesia
alone. This trial had a small sample size, and a
longer-term follow-up would be helpful in assessing
the risk of delayed postinflammatory hyperpigmentation; however, the results are promising, and
additional studies are warranted (level of evidence,
II-iii).
Another small trial looked at the histopathologic
effects of fractional laser technology on melasma.81
The authors treated 10 patients with epidermal
melasma who had Fitzpatrick skin phototypes III to
IV every 2 weeks for four sessions. Biopsy specimens
were obtained before treatment and 3 months after
the final treatment, and they were instructed to avoid
depigmenting agents but to use sunscreen. After
treatment, lesional skin showed a decrease in the
number of epidermal melanocytes and fewer enlarged melanocytes on electron microscopy; however, there was no correlation between histologic
improvement and investigator-rated improvement.
Importantly, no postinflammatory hyperpigmentation was seen 3 months after therapy was completed
(level of evidence, II-iii).
Summarizing the reports above, fractional laser
therapy is the only laser treatment for melasma that
has been approved by the FDA, and it has shown
promising results. Given the risk for hyperpigmentation, some authors suggest using lower uences,
variable pulses, and pretreating all patients with
hydroquinone for up to 6 weeks before laser therapy, especially in patients with a history of postinammatory hyperpigmentation.79
Intense pulsed light
Intense pulsed light (IPL), a nonlaser light source
that emits light with wavelengths between 515 and
1200 nm, has been studied alone and in comparison
with hydroquinone for the treatment of melasma. In
one study, 89 Asian females with predominantly
mixed melasma unresponsive to topical therapy and
chemical peels were treated with IPL every 3 weeks
for a total of four sessions.82 They were instructed to

Sheth and Pandya 709

wear broad-spectrum sun protection and avoid

bleaching creams. A spectrophotometer was used
to measure both the melanin index and erythema
index on the highest point of the cheekbones, and
MASI scores were calculated. Mean MASI scores
dropped significantly, from 15.2 to 5.2 after four
sessions and to 4.5 at the 3-month follow-up visit.
Epidermal melasma responded better than the
mixed type. The melanin index as measured by the
Mexameter dropped from a mean value of 140.8 to a
value of 119; the erythema index dropped significantly as well. The most common side effects included temporary erythema and edema, microcrust
sloughing after 7 to 10 days, and postinflammatory
hyperpigmentation in three patients (level of
evidence, II-iii).
The addition of IPL therapy to hydroquinone and
sun protection has also been investigated. A group of
Taiwanese women with Fitzpatrick skin phototypes
III to IV and mixed melasma by UV photography
were randomized to receive treatment with hydroquinone plus a broad-spectrum sunscreen or the
same regimen and four sessions of IPL given 4 weeks
apart.83 Using a spectrophotometer, the authors
calculated a relative melanin index (defined as the
difference between the melanin index of lesional
skin and the melanin index of normal skin). The
patients who received additional treatment with the
IPL had a 39.8% decrease in the relative melanin
index after four treatments (16 weeks). In the control
group receiving topical therapy alone, there was
only an 11.6% decrease in relative melanin index
after 16 weeks. At 24 weeks posttreatment, the
improvement on the IPL-treated side had fallen to a
mean of 24.2%, suggesting the need for maintenance
treatments. Side effects of the IPL included some
crusting lasting 1 to 2 weeks and transient postinflammatory hyperpigmentation in two patients
resolving with hydroquinone (level of evidence, I).
Overall, IPL appears to give modest improvement as
an adjunctive therapy in patients with melasma
refractory to topical therapy alone and may be useful
in patients who do not mind the 1- to 2-week
recovery time.
Copper bromide laser
Copper bromide lasers can produce two wavelengths of light that may be emitted separately or
together. The 511-nm green beam is used to treat
pigmentary lesions, while the 578-nm yellow beam is
used to treat vascular lasers. In a recent pilot study,
10 Korean women with mixed or epidermal melasma
were treated with a copper bromide laser emitting
both wavelengths simultaneously at 2-week intervals
for a total of 8 weeks.84 MASI scores decreased

J AM ACAD DERMATOL

710 Sheth and Pandya

OCTOBER 2011

Table II. Managing melasma

Primary agent (strength of recommendation)

First-line

Adjunctive treatment
Second-line
Third-line

Triple combination products containing hydroquinone, a

retinoid, and a fluorinated steroid once daily (A), OR
hydroquinone 4% twice daily for up to 6-month periods (A)
Ascorbic acid (C)
Glycolic acid peels every 4-6 wks starting at 30% and
increasing in concentration as tolerated (B)
Fractional laser therapy (C)

Alternative agents
(strength of recommendation)

Azelaic acid (A)

Kojic acid (B)

Intense pulsed light (B)

It is recommended that all patients use regular broad-spectrum photoprotection and practice sun avoidance.

modestly from an average of 12.3 pretreatment to 9.5

at the 1-month posttreatment follow-up. Using a
chromameter, the authors noted measurable lightening of lesional skin after treatment, but the effects
appeared to wane slightly at the 1-month posttreatment follow-up. The same findings were seen when
erythema was measured. Clinically, three patients
were noted to have recurrence at the 6-month
posttreatment follow-up. The histologic examination
of lesional skin before and 3 months after treatment
showed decreased levels of basal layer melanin and
fewer melanosomes in the epidermis after treatment,
suggesting some longer-term benefit. In addition,
CD34 staining for blood vessels showed a decrease
in the number and size of dermal vessels after
treatment. Staining for vascular endothelial growth
factor was also decreased in keratinocytes posttreatment, indicating some effect of the laser on vascularity within treated lesions. It is significant to note
that none of the 10 patients exhibited scarring or
dyspigmentation from treatment. Copper bromide
lasers therefore seem relatively safe and at least
moderately effective for melasma in Asian patients
(level of evidence, II-iii). Additional studies in other
patient populations will help determine the generalizability of these results. Split-face trials comparing
this modality to other lasers will also help determine
if the added capability of treating vascularity in
lesional skin is of benefit in the treatment of
melasma.
Summary
Fractional laser therapy appears to be the most
promising laser or light treatment for melasma;
however, there is still a long-term risk of postprocedure hyperpigmentation and a possible need for
maintenance therapy. IPL treatment may also provide modest benet as an adjunctive treatment.
Copper bromide lasers may also be benecial in a
select population of patients, but larger studies are
needed before this therapy can be widely recommended. Given their cost and the need for multiple

treatments, laser and light therapies should be considered third-line treatments in severe refractory
patients who have not responded to topical preparations or chemical peels and who are willing to
accept the risks of these procedures.

ON THE HORIZON
Because no panacea for melasma has yet been
found, investigators continue to search for novel
inhibitors of melanin synthesis. Several new compounds are being studied as possible treatments of
melasma. Rucinol, a derivative of resorcinol that
inhibits tyrosinase and TRP-1 in a dose-dependent
manner in B16 mouse melanoma cells, has been
shown in a vehicle-controlled, split-face, doubleblind randomized trial to have a modest effect on
epidermal and mixed melasma lesions in patients
with Fitzpatrick skin phototypes III to V.85
Interestingly, broad-spectrum sun protection alone
used on the control side also showed a significant
benefit (level of evidence, I).
Tranexamic acid, also known as trans-4-aminomethylcyclohexanecarboxylic acid, is a plasmin inhibitor and lysine analog that has been shown to
prevent UV-induced pigmentation in guinea pigs.86
In keratinocytes, it prevents the binding of plasminogen to keratinocytes, which leads to less free
arachidonic acid and subsequent decreased production of prostaglandins. This in turn leads to a
decrease in tyrosinase activity in melanocytes. Of
note, topical tranexamic acid can cause allergy or
irritation, so newer liposomal delivery systems have
been created to improve tolerability. Intradermal
tranexamic acid injections have been investigated in
100 patients with Fitzpatrick skin phototypes IV to VI
and mixed or dermal melasma.87 Investigators found
that changes in MASI were statistically significant
(mean MASI 13.22 at baseline compared to 7.57 after
12 weeks of weekly injections), but clinically significant improvement was not seen until 4 weeks of
treatment. No long-term follow-up was performed
(level of evidence, II-iii).

J AM ACAD DERMATOL
VOLUME 65, NUMBER 4

Beta-carotene is a structural analogue of vitamin

A that decreases melanin production and is under
investigation for use in treating disorders of hyperpigmentation. One such study evaluated a topical
beta-carotene lotion formulated in nanothalospheres
in addition to broad-spectrum sunscreen, barrage
oil, and wheat germ oil.88 This was applied
twice daily for 8 weeks in 31 patients with only one
mild case resolving, 10 out of 13 moderate cases
showing improvement, and 10 out of 12 severe cases
showing lightening. No controls or objective measurements were used in this analysis; it is difficult to
draw firm conclusions about this agent (level of
evidence, II-iii).
Another promising agent is 2,5-dimethyl-4hydroxy-3(2H)-furanone (DMHF). Using B16 melanoma cells, DMHF has been shown to decrease
alpha melanocyte-stimulating hormone (a-MSH)e
induced melanin content and tyrosinase activity
without being cytotoxic.89 Even more intriguing are
the findings that DMHF can inhibit production of
microphthalmia- associated transcription factor and
tyrosinase, reduce the production of TRP-1 (but not
TRP-2), and block a-MSHeinduced increases in
melanin in normal human melanocytes. No published clinical trials are available.
Future studies using gene analysis, proteomics,
and other technologies may unlock the mechanisms
of hyperpigmentation in melasma, which could lead
to more effective preventive strategies and therapeutic agents.
Trials in melasma are fraught with many limitations, including a lack of standardization in methodology, heterogeneity in the study population,
variability in sun protection and other concomitant
therapies, and severity of melasma, which can cause
difculty in selecting the appropriate therapy in the
clinical setting. There is also tremendous variation in
the use of controls, randomization, and blinding,
bringing into question the validity of the conclusions
of such studies. Endpoints in many trials are often
subjective, which is especially problematic when
investigators are unblinded. In addition, for studies
involving chemical peels, laser therapies, or light
therapies, the practice of pretreatment with depigmenting agents is not standardized. Ideally, future
trials for melasma therapies will incorporate the use
of randomization and controlssuch as a split-face
design, the regular use of sun protection, and the use
of validated outcome measures, both subjective
and objectiveto better determine response to
treatment. Based on the current evidence, broadspectrum UV and visible light protection and avoidance and topical depigmenting agents appear to be
the most useful therapies for melasma (Table II). It is

Sheth and Pandya 711

still unclear if chemical peels or laser and light sources

significantly improve these patients, but there have
been a few promising developments in the use of
procedures for melasma. Newer treatment modalities
on the horizon are a cause for optimism in the
management of this chronic and recalcitrant disorder.
REFERENCES
1. Morton CA, McKenna KE, Rhodes LE. Guidelines for topical
photodynamic therapy: update. Br J Dermatol 2008;159:
1245-66.
2. Pathak MA, Riley FC, Fitzpatrick TB. Melanogenesis in human
skin following exposure to long-wave ultraviolet and visible
light. J Invest Dermatol 1962;39:435-43.
3. Mahmoud BH, Hexsel CL, Owen MR, Liu Y, Kollias N, Lim HW,
et al. Impact of long wavelength UVA and visible light on
melanocompetent skin. Presented in poster form at the 2008
American Society for Laser Medicine and Surgery Meeting,
Kissimmee, FL, April 2-6, 2008.
4. Mahmoud BH, Hexsel CL, Hamzavi IH, Lim HW. Effects of
visible light on the skin. Photochem Photobiol 2008;84:450-62.
5. Lakhdar H, Zouhair K, Khadir K, Essari A, Richard A, Seite S,
et al. Evaluation of the effectiveness of broad-spectrum
sunscreen in the prevention of chloasma in pregnant women.
J Eur Acad Dermatol Venereol 2007;21:738-42.
6. Khadir K, Amal S, Hali F, Nejjam F, Lakhdar H. Les signes
dermatologiques physiologiques de la grossesse. Ann Dermatol Venereol 1999;126:15-9.
7. Vazquez M, Sanchez JL. The efficacy of a broad-spectrum
sunscreen in the treatment of melasma. Cutis 1983;32:92, 95-6.
8. Gupta AK, Gover MD, Nouri K, Taylor S. The treatment of
melasma: a review of clinical trials. J Am Acad Dermatol 2006;
55:1048-69.
9. Jimbow K, Obata H, Pathak M, Fitzpatrick TB. Mechanism of
depigmentation by hydroquinone. J Invest Dermatol 1974;62:
436-49.
10. Briganti S, Camera E, Picardo M. Chemical and instrumental
approaches to treat hyperpigmentation. Pigment Cell Res
2003;16:101-10.
11. Oettel H. Hydroquinone poisoning. Arch Exp Pathol Pharmacol
1956;183:319-62.
12. Fitzpatrick TB, Arndt KA, el-Mofty AM, Pathak MA. Hydroquinone and psoralens in the therapy of hypermelanosis and
vitiligo. Arch Dermatol 1966;93:589-600.
13. Spencer MC. Topical use of hydroquinone for depigmentation.
JAMA 1965;194:114-6.
14. Haddad AL, Matos LF, Brunstein F, Ferreira LM, Silva A,
Costa D Jr. A clinical, prospective, randomized, double-blind
trial comparing skin whitening complex with hydroquinone
vs. placebo in the treatment of melasma. Int J Dermatol
2003;42:153-6.
15. Taylor SC, Torok H, Jones T, Lowe N, Rich P, Tschen E, et al.
Efficacy and safety of a new triple-combination agent for the
treatment of facial melasma. Cutis 2003;72:67-72.
16. Guevara IL, Pandya AG. Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and
sunscreen in the treatment of melasma. Int J Dermatol 2003;
42:966-72.
17. Ennes SBP, Paschoalick RC, Mota de Avelar Alchorne M. A
double-blind, comparative, placebo-controlled study of the
efficacy and tolerability of 4% hydroquinone as a depigmenting agent in melasma. J Dermatol Treat 2000;11:173-9.
18. Amer M, Metwalli M. Topical hydroquinone in the treatment of
some hyperpigmentary disorders. Int J Dermatol 1998;37:449-50.

712 Sheth and Pandya

19. Kramer K, Lopez A, Stefanato C, Phillips TJ. Exogenous

ochronosis. J Am Acad Dermatol 2000;42:869-71.
20. Lawrence N. Exogenous ochronosis in the United States. J Am
Acad Dermatol 1988;18:1207-11.
21. Olumide YM, Akinkugbe AO, Altraide D, Mohammed T,
Ahamefule N, Ayanlowo S, et al. Complications of chronic
use of skin lightening cosmetics. Int J Dermatol 2008;47:
344-53.
22. US Department of Health and Human Services, Food and Drug
Administration. Skin bleaching drug products for
over-the-counter human use; proposed rule. 71 Federal Register 51146-5115521 (2006) (codified at 21 CFR x310).
23. Levitt J. The safety of hydroquinone: a dermatologists response to the 2006 Federal Register. J Am Acad Dermatol 2007;
57:854-72.
24. Westerhof W, Kooyers TJ. Hydroquinone and its analogues in
dermatologya potential health risk. J Cosmet Dermatol
2005;4:55-9.
25. Nordlund JJ, Grimes PE, Ortonne JP. The safety of hydroquinone. J Eur Acad Dermatol Venereol 2006;20:781-7.
26. Draelos ZD. Skin lightening preparations and the hydroquinone controversy. Dermatol Ther 2007;20:308-13.
27. Fleischer AB Jr, Schwartzel EH, Colby SI, Altman DJ. The
combination of 2% 4-hydroxyanisole (Mequinol) and 0.01%
tretinoin is effective in improving the appearance of solar
lentigines and related hyperpigmented lesions in two
double-blind multicenter clinical studies. J Am Acad Dermatol
2000;42:459-67.
28. Ortonne JP. Retinoid therapy of pigmented disorders. Dermatol Ther 2006;19:280-8.
29. Romero C, Aberdam E, Larnier C, Ortonne JP. Retinoic acid as
modulator of UVB-induced melanocyte differentiation. Involvement of the melanogenic enzymes expression. J Cell
Sci 1994;107:1095-103.
30. Griffiths CEM, Finkel LJ, Ditre CM, Hamilton TA, Ellis CN, Voorhees
JJ. Topical tretinoin (retinoic acid) improves melasma. A
vehicle-controlled, clinical trial. Br J Dermatol 1993;129:415-21.
31. Kimbrough-Green CK, Griffiths CEM, Finkel LJ, Hamilton TA,
Bulengo-Ransby SM, Ellis CN, et al. Topical retinoic acid
(tretinoin) for melasma in black patients. Arch Dermatol
1994;130:727-33.
32. Leenutaphong V, Nettakul A, Rattanasuwon P. Topical isotretinoin for melasma in Thai patients: a vehicle-controlled clinical
trial. J Med Assoc Thai 1999;82:868-75.
33. Grimes P, Callender V. Tazarotene cream for postinflammatory
hyperpigmentation and acne vulgaris in darker skin: a
double-blind, randomized, vehicle-controlled study. Cutis
2006;77:45-50.
34. Dogra S, Kanwar AJ, Parsad D. Adapalene in the treatment of
melasma: a preliminary report. J Dermatol 2002;29:539-40.
35. Kligman AM, Willis I. A new formula for depigmenting human
skin. Arch Dermatol 1975;111:40-8.
36. Lynde CB, Kraft JN, Lynde CW. Topical treatments for melasma
and postinflammatory hyperpigmentation. Skin Therapy Lett
2006;11:1-6.
37. Pathak MA, Fitzpatrick TB, Kraus EW. Usefulness of retinoic
acid in the treatment of melasma. J Am Acad Dermatol 1986;
15(4 pt 2):894-9.
38. Grimes PE. A microsponge formulation of hydroquinone 4%
and retinol 0.15% in the treatment of melasma and postinflammatory hyperpigmentation. Cutis 2004;74:362-8.
39. Cestari TF, Hassun K, Sittart A, de Lourdes Viegas M. A
comparison of triple combination cream and hydroquinone
4% cream for the treatment of moderate to severe facial
melasma. J Cosmet Dermatol 2007;6:36-9.

J AM ACAD DERMATOL

OCTOBER 2011

40. Guevara IL, Pandya AG. Melasma treated with hydroquinone,

tretinoin, and a fluorinated steroid. Int J Dermatol 2001;40:210-5.
41. Cestari T, Adjadj L, Hux M, Shimizu MR, Rives VP. Costeffectiveness of a fixed combination of hydroquinone/
tretinoin/fluocinolone cream compared with hydroquinone
alone in the treatment of melasma. J Drugs Dermatol 2007;6:
153-60.
42. Kim Y-J, Uyama H. Tyrosinase inhibitors from natural and
synthetic sources: structure, inhibition mechanism and perspective for the future. Cell Mol Life Sci 2005;62:1707-23.
43. Nazzaro-Porro M. Azelaic acid. J Am Acad Dermatol 1987;17:
1033-41.
44. Fitton A, Goa KL. Azelaic acid. A review of its pharmacological
properties and therapeutic efficacy in acne and hyperpigmentary skin disorders. Drugs 1991;41:780-98.
45. Lowe NJ, Rizk D, Grimes P, Billips M, Pincus S. Azelaic acid 20%
cream in the treatment of facial hyperpigmentation in
darker-skinned patients. Clin Ther 1998;20:945-59.
46. Verallo-Rowell VM, Verallo V, Graupe K, Lopez-Villafuerte L,
Garcia-Lopez M. Double-blind comparison of azelaic acid and
hydroquinone in the treatment of melasma. Acta Derm
Venereol Suppl (Stockh) 1989;143:58-61.
47. Bali~
na LM, Graupe K. The treatment of melasma. 20% azelaic
acid versus 4% hydroquinone cream. Int J Dermatol 1991;30:
893-5.
48. Garcia A, Fulton JE Jr. The combination of glycolic acid and
hydroquinone or kojic acid for the treatment of melasma and
related conditions. Dermatol Surg 1996;22:443-7.
49. Lim JT. Treatment of melasma using kojic acid in a gel
containing hydroquinone and glycolic acid. Dermatol Surg
1999;25:282-4.
50. Choi YK, Rho YK, Yoo KH, Lim YY, Li K, Kim BJ, et al. Effects of
vitamin C vs. multivitamin on melanogenesis: comparative
study in vitro and in vivo. Int J Dermatol 2010;49:218-26.
51. Espinal-Perez LE, Moncada B, Castanedo-Cazarez JP. A
double-blind randomized trial of 5% ascorbic acid vs. 4%
hydroquinone in melasma. Int J Dermatol 2004;43:604-7.
52. Picardo M, Carrera M. New and experimental treatments of
chloasma and other hypermelanoses. Dermatol Clin 2007;25:
353-62.
53. Boissy RE, Visscher M, deLong MA. DeoxyArbutin: a novel
reversible tyrosinase inhibitor with effective in vivo skin
lightening potency. Exp Dermatol 2005;14:601-8.
54. Amer M, Metwalli M. Topical liquiritin improves melasma. Int J
Dermatol 2000;39:299-301.
55. Rendon M, Berneburg M, Arellano I, Picardo M. Treatment of
melasma. J Am Acad Dermatol 2006;54(5 suppl):S272-81.
56. Seiberg M, Paine C, Sharlow E, Andrade-Gordon P, Costanzo
M, Eisinger M, et al. The protease-activated receptor 2 regulates pigmentation via keratinocyte-melanocyte interactions.
Exp Cell Res 2000;254:25-32.
57. Paine C, Sharlow E, Liebel F, Eisinger M, Shapiro S, Seiberg M.
An alternative approach to depigmentation by soybean
extracts via inhibition of the PAR-2 pathway. J Invest Dermatol
2001;116:587-95.
58. Hermanns JF, Petit L, Pierard-Franchimont C, Paquet P, Pierard
GE. Assessment of topical hypopigmenting agents on solar
lentigines of Asian women. Dermatology 2002;204:281-6.
59. Usuki A, Ohashi A, Sato H, Ochiai Y, Ichihashi M, Funasaka Y.
The inhibitory effect of glycolic acid and lactic acid on melanin
synthesis in melanoma cells. Exp Dermatol 2003;12(suppl 2):
43-50.
60. Gupta RR, Mahajan BB, Garg G. Chemical peelingevaluation
of glycolic acid in varying concentrations and time intervals.
Cosmetology 2001;67:28-9.

J AM ACAD DERMATOL

Sheth and Pandya 713

VOLUME 65, NUMBER 4

61. Javaheri SM, Handa S, Kaur I, Kumar B. Safety and efficacy of

glycolic acid facial peel in Indian women with melasma. Int J
Dermatol 2001;40:354-7.
62. Sarkar R, Kaur C, Bhalla M, Kanwar AJ. The combination of
glycolic acid peels with a topical regimen in the treatment of
melasma in dark-skinned patients: a comparative study.
Dermatol Surg 2002;28:828-32.
63. Erbil H, Sezer E, Tastan B, Arca E, Kurumlu Z. Efficacy and safety
of serial glycolic acid peels and a topical regimen in the
treatment of recalcitrant melasma. J Dermatol 2007;34:25-30.
64. Hurley ME, Guevara IL, Gonzales RM, Pandya AG. Efficacy of
glycolic acid peels in the treatment of melasma. Arch
Dermatol 2002;138:1578-82.
65. Garg VK, Sarkar R, Agarwal R. Comparative evaluation of
beneficiary effects of priming agents (2% hydroquinone and
0.025% retinoic acid) in the treatment of melasma with
glycolic acid peels. Dermatol Surg 2008;34:1032-9.
66. Sharquie KE, Al-Tikreety MM, Al-Mashhadani SA. Lactic acid as
a new therapeutic peeling agent in melasma. Dermatol Surg
2005;31:149-54.
67. Grimes PE. The safety and efficacy of salicylic acid chemical
peels in darker racial-ethnic groups. Dermatol Surg 1999;25:
18-22.
68. Hyo HA, Kim I-H. Whitening effect of salicylic acid peels in
Asian patients. Dermatol Surg 2006;32:372-5.
69. Khunger N, Sarkar R, Jain RK. Tretinoin peels versus glycolic
acid peels in the treatment of melasma in dark-skinned
patients. Dermatol Surg 2004;30:756-60.
70. Lawrence N, Cox SE, Brody HJ. Treatment of melasma with
Jessners solution versus glycolic acid: a comparison of clinical
efficacy and evaluation of the predictive ability of Woods light
examination. J Am Acad Dermatol 1997;36:589-93.
71. Sharquie KE, Al-Tikreety MM, Al-Mashhadani SA. Lactic acid
chemical peels as a new therapeutic modality in melasma in
comparison to Jessners solution chemical peels. Dermatol
Surg 2006;32:1429-36.
72. Chun EY, Lee JB, Lee KH. Focal trichloroacetic acid peel
method for benign pigmented lesions in dark-skinned patients. Dermatol Surg 2004;30:512-6.
73. Alster TS, Lupton JR. Laser therapy for cutaneous hyperpigmentation and pigmented lesions. Dermatol Ther 2001;14:
46-54.
74. Taylor CR, Anderson RR. Ineffective treatment of refractory
melasma and postinflammatory hyperpigmentation by
Q-switched ruby laser. J Dermatol Surg Oncol 1994;20:592-7.
75. Tse Y, Levine VJ, McClain SA, Ashinoff R. The removal of
cutaneous pigmented lesions with the Q-switched ruby laser
and the Q-switched neodymium: yttrium-aluminum-garnet

76.
77.

78.

79.

80.

81.

82.

83.

84.

85.

86.

87.

88.

89.

laser. A comparative study. J Dermatol Surg Oncol 1994;20:

795-800.
Manaloto RMP, Alster T. Erbium:YAG laser resurfacing for
refractory melasma. Dermatol Surg 1999;25:121-3.
Nouri K, Bowes L, Chartier T, Romagosa R, Spencer JM.
Combination treatment of melasma with pulsed CO2 laser
followed by Q-switched Alexandrite laser: a pilot study.
Dermatol Surg 1999;25:494-7.
Angsuwarangsee SA, Polnikorn N. Combined ultrapulse CO2
laser and Q-switched alexandrite laser compared with
Q-switched alexandrite laser alone for refractory melasma:
split-face design. Dermatol Surg 2003;29:59-64.
Rahman Z, Alam M, Dover JS. Fractional laser treatment for
pigmentation and texture improvement. Skin Therapy Lett
2006;11:7-11.
Rokhsar CK, Fitzpatrick RE. The treatment of melasma with
fractional photothermolysis: a pilot study. Dermatol Surg
2005;31:1645-50.
Goldberg DJ, Berlin AL, Phelps R. Histologic and ultrastructural
analysis of melasma after fractional resurfacing. Lasers Surg
Med 2008;40:134-8.
Li Y-H, Chen JZS, Wei H-C, Wu Y, Liu M, Xu YY, et al. Efficacy
and safety of intense pulsed light in treatment of melasma in
Chinese patients. Dermatol Surg 2008;34:693-701.
Wang CC, Hui CY, Sue YM, Wong WR, Hong HS. Intense pulsed
light for the treatment of refractory melasma in Asian persons.
Dermatol Surg 2004;30:1196-200.
Lee HI, Lim YY, Kim BJ, Kim MN, Min HJ, Hwang JH, et al.
Clinicopathologic efficacy of copper bromide plus/yellow laser
(578 nm with 511 nm) for treatment of melasma in Asian
patients. Dermatol Surg 2010;36:885-93.
Khemis A, Kaiafa A, Queille-Roussel C, Duteil L, Ortonne JP.
Evaluation of efficacy and safety of rucinol serum in patients
with melasma: a randomized controlled trial. Br J Dermatol
2007;156:997-1004.
Maeda K, Naganuma M. Topical trans-4-aminomethylcyclohexanecarboxylic acid prevents ultraviolet radiation induced
pigmentation. J Photochem Photobiol 1998;47:130-41.
Lee JH, Park JG, Lim SH, Kim JY, Ahn KY, Kim MY, et al.
Localized intradermal microinjection of tranexamic acid for
treatment of melasma in Asian patients: a preliminary clinical
trial. Dermatol Surg 2006;32:626-31.
Kar HK. Efficacy of beta-carotene topical application in melasma: an open clinical trial. Indian J Dermatol Venereol Leprol
2002;68:320-2.
Lee J, Jung E, Lee J, Huh S, Boo YC, Hyun CG, et al. Mechanisms
of melanogenesis inhibition by 2,5-dimethyl-4-hydroxy-3(2H )furanone. Br J Dermatol 2007;157:242-8.

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Appendix. US Preventive Services Task Force levels of evidence for grading clinical trials1
Level of evidence

I
II-i
II-ii
II-iii

III
IV
Strength of recommendations
A
B
C
D
E

Quality of evidence

Evidence obtained from at least one properly designed, randomized

controlled trial
Evidence obtained from well designed controlled trials without
randomization
Evidence obtained from well designed cohort or case control analytical
studies, preferably from more than one center or research group
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
Opinions of respected authorities based on clinical experience, descriptive
studies, or reports of expert committees
Evidence inadequate because of problems of methodology (eg, sample size
or length of comprehensiveness of follow-up or conflicts in evidence)
There is good evidence to support the use of the procedure
There is fair evidence to support the use of the procedure
There is poor evidence to support the use of the procedure
There is fair evidence to support the rejection of the use of the procedure
There is good evidence to support the rejection of the use of the procedure