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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The following is a journal-based CME activity presented by the American
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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
Academy’s core curriculum, identified professional practice gaps, the
educational needs which underlie these gaps, and emerging clinical
research findings. Learners should reflect upon clinical and scientific
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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continuing medical education for physicians.
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This journal-based CME activity is recognized by the American Academy
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activity is for continuing education purposes only and is not meant to substitute for the independent
medical judgment of a healthcare provider relative to the diagnostic, management and treatment
options of a specific patient’s medical condition.
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
camouflage. 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 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. ( J Am Acad Dermatol 2011;65:699-714.)
Key Words: chemical peels; chloasma; hydroquinone; laser therapy; melasma; pigmentation.
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 financial 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 financial
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
relevant financial relationships. The editorial and education staff in-
volved with this journal-based CME activity have reported no relevant
financial relationships with commercial interest(s).
Resolution of Conflicts of Interest
In accordance with the ACCME Standards for Commercial Support of
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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 efficacy, side effect profiles, and risks and benefits; and
develop an individualized, evidence-based treatment plan for patients
with melasma.
Date of release: October 2011
Expiration date: October 2012
Ó 2010 by the American Academy of Dermatology, Inc.
doi:10.1016/j.jaad.2011.06.001
699
700 Sheth and Pandya J AM ACAD DERMATOL
OCTOBER 2011

Melasma has traditionally been treated with a com- melasma and in enhancing the efficacy of
bination of photoprotection, avoidance of trigger fac- other topical therapies once melasma has
tors, and topical depigmenting agents with varying developed
degrees of success. New pathways involved in pigment d Camouflage makeup can be an important

production are being studied as targets for topical component of melasma treatment
therapy. Of late, there has also been a significant
increase in the types of laser and light technologies Several studies have shown that light from both
available for the treatment of the ultraviolet (UV) and even the visible spectrum
disorders of hyperpigmenta- can induce pigmentary
tion. While multiple options CAPSULE SUMMARY changes in the skin, includ-
currently exist to help treat ing in Fitzpatrick skin photo-
2,3
melasma, some of these thera-
d Topical treatment of melasma includes types IV to VI. Immediate
pies have come under increas- hydroquinone, retinoids, chemical peels, pigment darkening caused
ing scrutiny, underscoring the and many other less well studied by the redistribution and ox-
need for more research into compounds. idation of preexisting mela-
the pathogenesis and treat- d The evidence for improvement with laser nin occurs after low-dose
ment of melasma. therapy is mixed with a significant ultraviolet A (UVA) exposure
potential for worsening. and usually fades after 2
TREATMENT OPTIONS hours.4 Persistent pigment
d Newer topical agents and laser darkening lasts up to 24
FOR MELASMA technologies represent promising
The treatment of me- hours and occurs after higher
options for therapy, especially in doses of UVA exposure.
lasma includes topical for- treatment-resistant patients.
mulations, chemical peels, Delayed tanning can occur
lasers, and light sources. from either UVA or UVB ex-
While no single therapy has proven to be of posure and is caused by melanin synthesis. To
benefit to all patients as the sole therapy, combi- investigate if broad-spectrum sun protection could
nations of modalities can be used to optimize be used to inhibit the onset of melasma, Lakhdar et al5
management in difficult cases. Levels of evidence enrolled 200 Moroccan women who were less than 3
for the trials presented below are provided for months pregnant and gave them a sunscreen with a
each treatment modality based on guidelines sun protection factor (SPF) of 501 and a UVA
adapted from the US Preventive Services Task protection factor of 28 (Anthelios; La Roche-Posay
1
Force on health care. In this system, a rating of L’Oreal, Clichy, France) to use every 2 hours during
I means that the evidence is obtained from at least the day, regardless of sun exposure.5 Five of the 185
one properly designed, randomized controlled women (2.7%) who completed the 12-month trial
trial, and a rating of A means there is good developed melasma during pregnancy. Notably, the
evidence to support the use of the procedure same investigators reported a 53% prevalence of
(Appendix). melasma with pregnancy in a similar population in
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 hydro-
Key points quinone.7 A double blind study examining the
d Ultraviolet and visible light can induce mel-
difference in efficacy between patients using a
anin formation hydroquinone-containing agent with either vehicle
d The regular use of broad spectrum sun-
or 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 hydro-
From the Departments of Dermatology at Brigham and Women’s 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.
Reprints not available from the authors. important in the pathogenesis of melasma.3
Correspondence to: Amit G. Pandya, MD, Department of With the currently available data, a broad-
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
0190-9622/$36.00
J AM ACAD DERMATOL Sheth and Pandya 701
VOLUME 65, NUMBER 4

patients with melasma and should be reapplied Table I. Agents under investigation to decrease
frequently. Patients should also be instructed to cutaneous hyperpigmentation
wear protective hats and clothing when outdoors Proposed mechanism of action Compound
and to practice sun avoidance when possible. While
Tyrosinase inhibition Hydroquinone
sunscreens alone for the treatment of melasma have
Mequinol
never been studied, their use is recommended based Azelaic acid
on clinical experience. Studies showing the impor- Arbutin and deoxyarbutin
tance of sunscreen use in melasma should be Licorice extract
performed in the future, which would ideally inves- Rucinol
tigate the minimum SPF and the action spectrum that Resveratrol
is relevant for melasma. 4-hydroxy-anisole
In addition, many patients find the use of camou- 2,5-dimethyl-4-hydroxy-
flage makeup to be an important component in the 3(2H )-furanone
treatment of their melasma. Several widely available N-acetyl glucosamine
Stimulation of keratinocyte Retinoids
brands include Dermablend (Vichy Laboratories,
turnover
Paris, France), Covermark/CM Beauty (CM Beauty,
Reduction in melanosome Retinoids, soybean trypsin
Northvale, NJ), and Cover FX (Cover FX Skin Care; transfer inhibitor
Toronto, Ontario, Canada). These brands come in a Interaction with copper Kojic acid
broad range of shades and offer heavy coverage to Ascorbic acid
help even out skin tone. Inhibition of melanosome Arbutin and deoxyarbutin
maturation
Topical treatments: The old and the new Inhibition of protease- Soybean trypsin inhibitor
activated receptor 2
Because melasma is a disorder of pigmentation,
Inhibition of plasmin Tranexamic acid
topical treatments are largely aimed at disrupting
Reduction of alpha Beta-carotene
the enzymatic processes of pigment production melanocyte-stimulating
within melanocytes. Tyrosinase is the rate-limiting hormoneeinduced
enzyme in the process of melanin production, melanin production
converting L-tyrosinase to L-3,4-dihydroxyphenyla-
lanine (L-DOPA), and is the major target for many
of the agents that have been developed for me-
lasma.8 L-DOPA is a required cofactor, and copper
is an important molecule that interacts at the alone and in combination with other agents is well
enzyme’s active site. Many compounds exhibit studied and well established. Hydroquinone is
multiple effects leading to a decrease in melaniza- thought to act by inhibition of tyrosinase, possibly
tion. The major agents in use and the predominant by binding to the enzyme or by interaction with
components they target are shown in Table I. copper molecules at the enzyme’s active site. This
leads to altered melanosome formation and in-
creased melanosome destruction,9 and perhaps
PHENOLIC COMPOUNDS
even the inhibition of DNA and RNA synthesis.10
Key points
The ability of hydroquinone to induce skin light-
d Hydroquinone, a tyrosinase inhibitor, has
ening in cats was first reported by Oettel11 in 1936.
been extensively researched and found to be
Not long afterward, hydroquinone became available
very effective in treating disorders of
as a topical agent in parts of the United States, where
hyperpigmentation
d While controversy exists regarding the use
it was noted to induce skin lightening in humans.12
Spencer13 performed one of the first studies using
of hydroquinone, a review of the literature
hydroquinone at concentrations of 2%, 3%, and 5%
indicates that hydroquinone is safe as a top-
applied twice daily for 3 months to the dorsal surface
ical agent for melasma
of the hands of white men with solar lentigines. The
Hydroquinone: The evidence and the
results revealed a dose-dependent decrease in pig-
controversy
mentation on clinical examination, with maximum
One of the earliest compounds used for the improvement after 2 months of treatment and re-
treatment of hyperpigmentation, hydroquinone lapse once treatment was stopped. Patients also were
(1,4 dihydroxybenzene) has been in use for more found to have a transient inflammatory reaction to
than 50 years. While controversy exists regarding the the medication, especially during the first 2 weeks of
long-term safety of hydroquinone, its efficacy both 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 hydro-
quinone, 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 dis-
coloration, have been linked to the use of hydroqui-
none, 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 concentra-
tions 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 in-
vestigational 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 pro-
posed FDA ruling exist, including a concern over
systemic absorption of the drug, reports of exoge-
nous ochronosis, and a concern for drug-induced
carcinogenesis. In the European Union, hydroqui-
none 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 prescrip-
tion medication.
One of the concerns regarding hydroquinone is
the potential for risks from the production of ben-
zene 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 develop-
ing 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 quan-
tities of this agent have not been found to have any
significantly 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 malig-
nancy and an exceedingly low risk of developing
ochronosis or other side effects in patients using
available prescription topical preparations of hydro-
quinone 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
J AM ACAD DERMATOL
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 me-
lasma. Therefore, a recommendation for melasma
cannot be made at this time.
RETINOIDS
Key points
d Tretinoin is an effective treatment for me-
lasma but often causes irritation and usually
requires months to show improvement as
monotherapy
d 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 mech-
anism 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 hyperpigmen-
tation. It is thought to inhibit tyrosinase transcription,
interrupt melanin synthesis,29 inhibit tyrosinase-
related 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 vehicle-
treated 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 efficacy, with an initial benefit 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 irri-
tation, tretinoin may not be very useful as mono-
therapy for melasma.
Sheth and Pandya 703
Topical 0.05% isotretinoin gel applied daily in
combination with SPF 28 sunscreen has been eval-
uated in the treatment of melasma in Thai patients;
however, this agent did not show increased efficacy
versus vehicle and sunscreen alone.32 Although
tazarotene has been reported to be useful for post-
inflammatory 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 adapalene-
treated 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 me-
lasma (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 first 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% dexameth-
asone. The authors found that 10% hydroquinone
was more efficacious but more irritating, 0.2% tret-
inoin was more irritating without being more effec-
tive, 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 top-
ical steroid component reduces irritation from the
other two ingredients and decreases cellular metab-
olism, 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 gener-
ally 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 formu-
lations has been 4% hydroquinone, 0.05% tretinoin,
and 0.01% fluocinolone acetonide. This combina-
tion was initially studied in a large number of
melasma patients in a multicenter, investigator-
blinded, 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 treti-
noin, hydroquinone plus fluocinolone, or tretinoin
plus fluocinolone.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 hydro-
quinone 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 maxi-
mum of 46.8% of patients achieving this same goal
on the dual-combination regimens. Of note, all
ratings were based on investigator’s subjective rat-
ings. 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 hyperpigmenta-
tion 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 triple-
combination 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% hydroquinone—again
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).
J AM ACAD DERMATOL
OCTOBER 2011
Another combination that has been tested is 0.05%
tretinoin, 0.05% triamcinolone acetonide, 6% hydro-
quinone, 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 efficacious, the cost of combination topicals
can sometimes be prohibitive. However, a recent
cost/benefit analysis of combination therapy versus
hydroquinone alone in melasma patients found that
the use of a triple-combination agent daily as com-
pared 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 triple-
combination therapy than for single agent treatment
with hydroquinone. This analysis took into account
the added cost of adverse events related to medica-
tion use and other therapies used subsequently in
patients who failed to clear on the evaluated treat-
ments (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 efficacious as the above agents
and require significantly 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 hyper-
pigmentation (see Table I). Some of the more com-
monly used agents that have undergone clinical trials
are presented below.
Azelaic acid. Azelaic acid is a 9-carbon dicar-
boxylic 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, possi-
bly 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
VOLUME 65, NUMBER 4
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 com-
pared to the control group. Of note, patients treated
with azelaic acid with dermal melasma were ex-
cluded from the analysis. In comparison to hydro-
quinone, 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 enzyme’s 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 prepa-
ration, 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 im-
provement in patients applying a gel that also
contained kojic acid (60%) versus a gel that con-
tained 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 dihydro-
chinindol-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 im-
provement on the vitamin Cetreated side, but there
was no long-term follow-up to determine the dura-
tion 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 adjunc-
tive treatment in patients who cannot tolerate
hydroquinone because of side effects (level of evi-
dence, I).
Arbutin/deoxyarbutin. Arbutin is a beta-D-
glucopyranoside 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 hy-
droquinone, and deoxyarbutin-induced skin light-
ening of solar lentigines was actually maintained
without the use of maintenance therapy, whereas
hydroquinone-induced skin lightening was not sus-
tained.53 It has been used in Japan at 3% concentra-
tions, 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 tyro-
sinase, especially the rate-limiting first step of oxi-
dation.42 The active ingredients are liquiritin (which
disperses melanin) and isoliquiritin (which contains
flavonoids). Licorice extract also has topical antiin-
flammatory 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 avoid-
ance 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 keratino-
cyte phagocytosis of melanosomes.55 In vitro and
animal studies show that activation of the PAR-2
pathway enhances melanosome ingestion by kerat-
inocytes, but direct keratinocyteemelanocyte con-
tact 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 base-
line and UVB-induced pigmentation in vitro.57 This
was caused in part to the inhibition of keratinocyte
phagocytosis of melanosomes. In a multiagent com-
parative trial in patients with solar lentigines, soy
extract was shown to have a modest effect in light-
ening 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 hydro-
quinone. Ascorbic acid may also be a useful adjunc-
tive topical therapy. Kojic acid may give modest
improvement for melasma, but it often causes irrita-
tion. Soy inhibition of the PAR-2 pathway provides a
novel approach to treating melasma, but clinical
trials are needed to better determine its efficacy.
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
d Glycolic acid peels should be used in con-
junction with a depigmenting agent for max-
imal benefit and to minimize the risk of
postinflammatory hyperpigmentation
d 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 mel-
anin, they can also cause irritation, which can lead to
postinflammatory hyperpigmentation. This side ef-
fect 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 pH-
independent manner. These agents have been
J AM ACAD DERMATOL
OCTOBER 2011
shown to decrease melanin formation in a dose-
dependent fashion using melanin assays in mouse
B16 and human melanoma cell lines.59
In clinical studies, glycolic acid peels have shown
modest benefit. 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 me-
lasma 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 modified Kligman-Willis formula
(5% hydroquinone 1 0.05% tretinoin 1 1% hydro-
cortisone 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 post-
inflammatory hyperpigmentation (level of evidence,
II-iii). A similar trial evaluated patients with epider-
mal melasma treated with azelaic acid plus adapa-
lene with half of the group additionally treated with
glycolic acid peels of increasing concentrations ev-
ery 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 hydro-
quinone 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 benefit in
patients with epidermal melasma, with MASI scores
decreasing by almost 57% in Fitzpatrick skin photo-
type 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).
J AM ACAD DERMATOL
VOLUME 65, NUMBER 4
Salicylic acid peels
Salicylic acid is a beta-hydroxy acid that has been
studied as a treatment for melasma and postinflam-
matory 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 improve-
ment was seen. Adverse effects were seen in four
patients and were mild, including transient hyper-
and hypopigmentation and temporary dryness or
crusting. No permanent pigmentary changes were
seen by the end of the study, but there was no long-
term 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 spectro-
photometry68 (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 stud-
ies 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 benefits 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 significant
benefit 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.
Sheth and Pandya 707
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 treat-
ments. 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 be-
tween trials of pre- and postpeel regimens and the
use of concomitant topical therapies and photo-
protection. 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 pre-
sented, the addition of chemical peels to depigment-
ing 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:yttrium-
aluminum-garnet lasers have been shown to
worsen melasma
d 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 hy-
perpigmentation in darker-skinned patients
d 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
d Intense pulsed light therapy may provide
modest benefit as an adjunctive therapy for
refractory patients
d 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 pig-
ment, 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 postin-
flammatory hyperpigmentation, which may be long-
lasting 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 first 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 post-
inflammatory hyperpigmentation refractory to other
treatments, the authors noted no improvement and,
in some cases, worsening with laser treatments
regardless of fluence.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 hyper-
pigmentation 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 epi-
dermal 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 conduc-
tion, 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% hydroqui-
none 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 trea-
ted 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 efficacy of the Q-switched alexan-
drite 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 con-
cluded 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 inflam-
mation 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 hyperpigmen-
tation. 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 hyperpigmen-
tation, and several patients had transient postproce-
dure 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 hyperpigmen-
tation; 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 en-
larged melanocytes on electron microscopy; how-
ever, there was no correlation between histologic
improvement and investigator-rated improvement.
Importantly, no postinflammatory hyperpigmenta-
tion 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 hyperpigmen-
tation, some authors suggest using lower fluences,
variable pulses, and pretreating all patients with
hydroquinone for up to 6 weeks before laser ther-
apy, especially in patients with a history of post-
inflammatory 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 signifi-
cantly as well. The most common side effects in-
cluded 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 hydro-
quinone 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 post-
inflammatory 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 wave-
lengths 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
710 Sheth and Pandya J AM ACAD DERMATOL
OCTOBER 2011

Table II. Managing melasma

Alternative agents
Primary agent (strength of recommendation) (strength of recommendation)
First-line Triple combination products containing hydroquinone, a Azelaic acid (A)
retinoid, and a fluorinated steroid once daily (A), OR
hydroquinone 4% twice daily for up to 6-month periods (A)
Adjunctive treatment Ascorbic acid (C) Kojic acid (B)
Second-line Glycolic acid peels every 4-6 wks starting at 30% and
increasing in concentration as tolerated (B)
Third-line Fractional laser therapy (C) 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 light-
ening of lesional skin after treatment, but the effects
appeared to wane slightly at the 1-month posttreat-
ment 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 posttreat-
ment, indicating some effect of the laser on vascu-
larity 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 gener-
alizability 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 postproce-
dure hyperpigmentation and a possible need for
maintenance therapy. IPL treatment may also pro-
vide modest benefit as an adjunctive treatment.
Copper bromide lasers may also be beneficial in a
select population of patients, but larger studies are
needed before this therapy can be widely recom-
mended. Given their cost and the need for multiple
treatments, laser and light therapies should be con-
sidered third-line treatments in severe refractory
patients who have not responded to topical prepa-
rations 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 com-
pounds 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, double-
blind 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-amino-
methylcyclohexanecarboxylic acid, is a plasmin in-
hibitor and lysine analog that has been shown to
prevent UV-induced pigmentation in guinea pigs.86
In keratinocytes, it prevents the binding of plasmin-
ogen to keratinocytes, which leads to less free
arachidonic acid and subsequent decreased produc-
tion 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 signif-
icant 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 hyper-
pigmentation. 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 mea-
surements 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-4-
hydroxy-3(2H)-furanone (DMHF). Using B16 mela-
noma 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 pub-
lished 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 thera-
peutic agents.
Trials in melasma are fraught with many limita-
tions, including a lack of standardization in metho-
dology, heterogeneity in the study population,
variability in sun protection and other concomitant
therapies, and severity of melasma, which can cause
difficulty 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 depig-
menting agents is not standardized. Ideally, future
trials for melasma therapies will incorporate the use
of randomization and controls—such as a split-face
design, the regular use of sun protection, and the use
of validated outcome measures, both subjective
and objective—to better determine response to
treatment. Based on the current evidence, broad-
spectrum UV and visible light protection and avoid-
ance 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.
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OCTOBER 2011

Appendix. US Preventive Services Task Force levels of evidence for grading clinical trials1
Level of evidence Quality of evidence
I Evidence obtained from at least one properly designed, randomized
controlled trial
II-i Evidence obtained from well designed controlled trials without
randomization
II-ii Evidence obtained from well designed cohort or case control analytical
studies, preferably from more than one center or research group
II-iii Evidence obtained from multiple time series with or without the
intervention; dramatic results in uncontrolled experiments could also be
regarded as this type of evidence
III Opinions of respected authorities based on clinical experience, descriptive
studies, or reports of expert committees
IV Evidence inadequate because of problems of methodology (eg, sample size
or length of comprehensiveness of follow-up or conflicts in evidence)
Strength of recommendations
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