REVIEW ARTICLE

Advances in the Treatment of Melasma: A Review of the

Recent Literature
KATHARINE L. BALL AREFIEV, MD,*

AND

BASIL M. HANTASH, MD, PHD

BACKGROUND Melasma is an acquired pigmentary disorder classically manifesting as symmetric hyperpigmented macules and patches on the face. It most commonly affects women of reproductive age with
darker skin tones but may also affect adolescents, older women, and men. Although its pathogenesis
remains unclear, known risk factors include ultraviolet radiation, hormonal variations of pregnancy, thyroid
disease, oral contraceptives, and antiseizure medications. Hydroquinone-containing topical agents are the
current standard for melasma treatment, but concern about side effects and long-term safety has spurred
efforts to develop alternative treatment options.
OBJECTIVES

To review recent advances in melasma treatment.

MATERIALS AND METHODS MEDLINE was searched from 2006 to the present for randomized controlled
trials (RCTs) of melasma treatments.
RESULTS Nineteen published RCTs were found covering interventions such as topical therapies, chemical
peels, and electromagnetic devices. The outcomes of the studies were summarized into tabular form for
easy reference and comparison.
CONCLUSIONS Although melasma is difficult to treat, novel therapeutic modalities have emerged. Further
RCT need to be performed to better assess the safety and efficacy of these novel treatment modalities,
especially for the long-term maintenance of melasma.
Dr. Hantash holds stock in and serves as the Vice Chairman of Envy Medical, Inc., manufacturer of Lumixyl
cream, a non-hydroquinone-based skin lightening cream.

elasma is an acquired pigmentary disorder

classically manifesting as hyperpigmented
macules and patches distributed symmetrically on
the face, neck, and rarely the upper limbs. Most
cases of melasma occur in women of reproductive
age with darker skin tones (Fitzpatrick skin type
IVVI), but people of all ages, races, and skin colors may be affected. 1 The majority of cases have
been associated with identifiable risk factors such
as ultraviolet (UV) radiation and hormonal influences including oral contraceptives and pregnancy;
hence other common names frequently used for
melasma are chloasma and mask of pregnancy.2,3
Other risk factors include antiseizure medications,
thyroid disease, phototoxic medications, and

genetic predisposition, although it may be

idiopathic, particularly in men.4
The Melasma Quality of Life Scale (MELASQOL)
has shown that this disorder may have a significant
effect on patient quality of life.5,6 This is
particularly true of facial lesions, which are the
primary manifestations of melasma.6 Facial
involvement negatively affects a patients social
life, recreation, and emotional well-being, often
resulting in psychological disturbances.7,8 Given
that the clinical assessment of severity by a
physician may differ from the patients perception
of severity, this condition may be insufficiently
diagnosed or treated.5,8,9

*Department of Dermatology, Stanford University Medical Center, Stanford, California; Elixir Institute of
Regenerative Medicine, San Jose, California
2012 by the American Society for Dermatologic Surgery, Inc.  Published by Wiley Periodicals, Inc. 
ISSN: 1076-0512  Dermatol Surg 2012;38:971984  DOI: 10.1111/j.1524-4725.2012.02435.x
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ADVANCES IN THE TREATMENT OF MELASMA

Epidemiology and Etiology

The exact prevalence of melasma is unknown, but
some small-scale studies have suggested a prevalence of 4% to 10% in Latin America, increasing
to 50% in pregnant women, and up to 10% of
men.3,10 Excess melanin in the skin, which may
occur because of melanocytosis (increased number
of melanocytes) or melanogenesis (excess production of melanin) cause the hyperpigmented macules.11 Clinical evidence of improvement in many
patients during the winter and histologic evidence
of solar elastosis in the macules and patches of
melasma supported the importance of ultraviolet
(UV) radiation in the pathogenesis of melasma.11,12
UV radiation increases levels of dermal stem cell
factor and alpha-melanocyte-stimulating hormone
in the skin, which may explain the melanocytosis
and melanogenesis, respectively.1319
Hormonal changes are also important etiologies.
Factors such as onset of melasma in pregnancy,
greater incidence seen in women taking oral contraceptive pills or hormone replacement therapy,
the histologic finding of high estrogen receptor
expression in affected skin, and the strong correlation between estradiol levels and melanogenesis
support this conclusion.3,2024 Endocrine organ
dysfunction, such as thyroid gland abnormalities,
and family history of melasma are also important
risk factors.2528 Cosmetic products and antiseizure
or photosensitive medications may play a role as
well.29,30
Clinicopathologic Findings and Diagnosis
The macules of melasma tend to occur in three distinct facial patterns: malar, centrofacial, and mandibular. Although they are usually symmetric, the
macules may also be ill-defined, with an irregular
border and varied brown to grey color pattern. In
addition, a rare variant has been shown to appear
on the arms.22,23 Three histologic patterns have
been identified based on the primary location of
pigment accumulation: epidermal, dermal, and

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DERMATOLOGIC SURGERY

mixed.11 The epidermal pattern shows extra melanin deposits in the basal and suprabasal epidermal
layers, whereas the dermal pattern shows many
melanin-laden macrophages in the superficial dermis, often surrounding perivascular spaces. Mixed
melasma shows a combination of the two patterns.
There is a strong correlation between histologic
subtype and the gross appearance of the macules.16
The diagnosis of melasma depends primarily on
the clinical findings of the history and physical
examination. Woods lamp examination helps distinguish the histologic subtypes, although this
method is less reliable for darker skin types.11 Epidermal melasma normally appears light brown and
shows enhanced color contrast with Woods lamp
examination. Dermal melasma often appears
slightly grey or bluish on gross examination
because of the Tyndall effect, and with Woods
lamp shows less color contrast. Categorization of
the type of melasma is useful because it may help
guide treatment options and patient expectations
since dermal melasma is generally less responsive
to therapy, especially topical modalities.3135

Materials and Methods

In April 2011, we searched MEDLINE (2006present) for published clinical studies related to the
treatment of melasma. Nineteen randomized
controlled studies were identified covering
interventions such as topical treatments, chemical
peels, light-based devices, and oral medication
(Tables 1 and 2).
Outcomes to assess the efficacy of therapies in the
studies were measured using subjective assessment
scales including the Melasma Area and Severity
Index (MASI), Physicians Global Assessment, Melasma Severity Scale, Pigmentation Score, and
objective measurements such as pigment density,
melanin index, and relative lightness index. The
MASI evaluates the severity of melasma in four
regions: forehead, right malar area, left malar area,
and chin, corresponding to 30%, 30%, 30%, and

BALL AREFIEV AND HANTASH

TABLE 1. Summary of Topical Treatments,

Chemical Peels, and Oral Therapy
Topical treatments
Hydroquinone (HQ) 2, 4%
Ellagic acid 1%
Rucinol 0.1, 0.3%
HQ 4%, retinoic acid 0.05%, fluocinolone
acetonide 0.01%
Arbutin 1%
Oligopeptide (decapeptide-12 0.01%)
Azelaic acid 20% twice a day plus adapalene 0.1%
HQ 2% and kojic acid
HQ 5%, retinoic acid 0.1%,
dexamethasone 0.1% (modified Kligmans)
HQ 4% or 5%, retinoic acid 0.05%,
triamcinolone acetonide 0.1%
Chemical peels
Trichloroacetic acid 20%
Jessners solution
Glycolic acid 2070%
Salicylic acid 2030%
Amino fruit acid 2060%
Oral therapy
Procyanidin and vitamins A, C, and E

10% of the total face, respectively. Based on the

three variables of darkness, homogeneity, and
percentage of area involved, a numerical value is
given. The Physicians Global Assessment is a
subjective measure of change in severity of pigmentation from baseline. It often involves reference to
digital photographs taken at baseline, before treatment. A 7-point scoring system is used: 0 = clear;
1 = almost clear; 2 = marked improvement;
3 = moderate improvement; 4 = slight improvement; 5 = no improvement; 6 = worse. The Melasma Severity Scale is a 4-point scoring system that

rates the severity of melasma as 0 = lesions almost

equivalent to surrounding normal skin or with
minimal residual pigmentation; 1 = mild, slightly
darker than surrounding normal skin; 2 = moderate, moderately darker than surrounding normal
skin; 3 = severe, markedly darker than surrounding
normal skin. The Pigmentation Score is a grading
scale indicating no pigmentation (0) to high-intensity pigmentation (10). Reflectance spectroscopy is
an objective measure of skin color. It measures the
intensity of reflected light of specific wavelengths
to determine values such as pigment density, melanin index, and relative lightness index.32 Most of
the studies required at least daily application of a
broad-spectrum sunblock, and this information is
included in the summary tables when available
(Tables 36).
Topical Therapies
Hydroquinone and combination formulas with a
corticosteroid and retinoic acid The most wellstudied hypopigmenting agent used to treat melasma is topical hydroquinone (HQ), which inhibits
the conversion of L-3,4-dihydroxyphenylalanine to
melanin by competitive inhibition of tyrosinasethe enzyme catalyzing the rate-limiting step in the
melanin biosynthetic pathway. Its mode of action
may also be based on inhibition of melanocyte formation or increase of melanocyte degradation and
inhibition of DNA and RNA synthesis within melanocytes.36 In the United States, a triple combination cream (TCC) consisting of 4% HQ, 0.01%
fluocinolone acetonide, and 0.05% tretinoin is

TABLE 2. Summary of Device-Based Therapies

Modality

Settings

Carbon dioxide fractional ablative resurfacing

Low-fluence quality-switched neodymium-doped
yttrium aluminum garnet

10,600 nm, 11.3 J/cm2, 350 ns, 1 pass57

1,064 nm, 7 mm, 57 ns, 1.62.0 J/cm2, 2 passes58
1,064 nm, 6 mm, 10 Hz, 3.03.8 J/cm2, passes until
immediate lightening of pigment or mild erythema
without petechiae59
1,550 nm, 15 mJ, level 57, 8 passes61
1,550 nm, 7 mJ, level 5 and 7, 8 passes60
560 nm cut-off filter, double-pulse technique,
3.03.5 ms, 1418 J/cm2 63

Nonablative fractional erbium glass

Intense pulsed light

38:7:JULY 2012

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974

DERMATOLOGIC SURGERY

R, DB,
C, SF

R, C

R, DB,
C, SF

R, C, SB

Khemis45

Cestari40

Hantash50

Chan41

A) HQ 4%,
retinoic acid 0.05%,
fluocinolone acetonide
0.01% QD
B) HQ 4%
BID, SPF 60

A) Oligopeptide
(decapeptide-12 0.01%)
BID
B) Vehicle BID

A) HQ 4%,
retinoic acid 0.05%,
fluocinolone acetonide
0.01% QD
B) HQ 4%
BID + SPF 30

A) Rucinol serum
0.3% BID
B) Vehicle BID + SPF 60

A) Liposome-encapsulated
4-n-butylresorcinol
(Rucinol) 0.1% cream BID
B) Vehicle BID + SPF
A) Arbutin 1% BID
B) Ellagic acid 1% BID
C) Plant extract, ellagic
acid 1% BID

Treatments Assessed

A) 129/121
B) 131/126

5/5

A) 60/60
B) 60/59

32/28

A) 10/10
B) 10/9
C) 10/10

23/23

No. Enrolled/No.
Completed

E, M, D

n/k

E, M

E, M

n/k

Type

Moderate
to severe

Moderate,
recalcitrant

Moderate,
severe

Moderate,
severe

n/k

n/k

Severity

IIV

IV

IIV

IIIV

IIIV

n/k

Fitzpatrick
Skin Type

8 weeks

16 weeks

8 weeks

12 weeks

6 months

8 weeks

Duration

Melanin index: 7.5% and

3.3% decrease for groups
A and B, respectively
(p = 0.04)
Pigment density: Decrease
statistically significant for
groups A and C and 8/9
in B (p = 0.05, p = 0.05,
p = 0.04)
Pigmentation score:
Statistically significantly
lower on side A than
side B (p = 0.03)
Melasma Severity Scale:
35% in group A and 5.1%
in group B obtained
melasma severity of 0
(lesions very similar to
surrounding normal skin
or with min residual
hyperpigmentation)
(p = 0.001)
Global Assessment Scale:
>50% improvement at
16 weeks on side A; side
B did not exceed 4%
improvement (p < 0.001)
Global Severity Score:
None or mild at week 8 in
64.2% of group A and
39.4% of group B
(p < 0.001)

Primary Outcome
Measurement and
Results

BID, twice a day; C, controlled; D, dermal; DB, double bind; E, epidermal; Hq, hydroquione; M, mixed; n/k, not known or not stated in study. QD, every day; R, randomized; SB,
single blind; SF, split face; SPF, sun protection factor.

R, DB,
C, SF

Ertam42

Huh

46

Author

Study
Type

TABLE 3. Topical Therapies

ADVANCES IN THE TREATMENT OF MELASMA

Study
Type

R, C

R, C, SF

R, C, SF

R, SB

Author

Azzam55

Erbil48

Kodali54

Ilknur51

Garg52

A) Serial GA
peels (2070%)
B) Serial amino fruit acid
peels (2060%) SPF 30
A) Serial GA
peels (2060%)
B) +retinoic acid 0.025%
QHS
C) +HQ 2%
QHS SPF

A) TCA
20% peels*
B) Jessners solution
peels*
C) HQ 2% and
kojic acid QHS SPF 45
A) Serial GA
peels (2070%), topical
azelaic acid 20% BID,
adapalene 0.1% QID
B) Azelaic acid 20% BID,
adapalene 0.1% QID
SPF 15
A) Serial SA
peels (2030%) plus
HQ 4% BID
B) HQ 4% BID
SPF 30

Treatments Assessed

TABLE 4. Chemical Peels

A) 20/15
B) 20/17
C) 20/18

31/24

20/18

A) 16/15
B) 12/10

A) 15/15
B) 15/15
C) 15/15

No. Enrolled/No.
Completed

E, M, D

E, M

Type

n/k

n/k

Moderate,
severe

Recalcitrant

n/k

Severity

IV/V

II/III/V

III/IV/V

n/k

III, IV

Fitzpatrick
Skin Type

6 months

6 months

8 weeks

20 weeks

68 weeks

Duration

Both sides improved from

the second week to the
eighth week (p < 0.001);
no statistically significant
difference between peeled
and unpeeled sides
Statistically significant
decrease from baseline
to 3 and 6 months for
both (p < 0.05)
All groups showed a
statistically significant
decrease at 6 months
(p < 0.001); Group C
showed greatest
improvement at 6 months
(p < 0.01)

83.08% and 69.34%

decrease for groups A
and B, respectively
(p = 0.001 and p = 0.005)

All groups significant

decrease (p < 0.001).
Lower in group A than C
(p = 0.01) and lower in B
than C (p < 0.001)

Melasma Area and

Severity Index Results

BALL AREFIEV AND HANTASH

38:7:JULY 2012

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DERMATOLOGIC SURGERY

Six peels, 1-week intervals.

Eight peels, 2-week intervals.

Four peels, 2-week intervals.

Twelve peels, 2-week intervals.

Nine peels, 2-week intervals 9 3 months then 4-week intervals 9 3 months.

**
Six peels, 2-week intervals.
BID, twice a day; C, controlled; D, dermal; DB, double bind; E, epidermal; GA, glycolic acid; HQ, hydroquinone; M, mixed; n/k, not known or not stated in study; QD, every day; QHS,
before bedtime; QID, four times per day; R, randomized; SA, salicylic acid; SB, single blind; SF, split face; SPF, sun protection factor; TCA, tricholoroacetic acid.

Both groups showed

statistically significant
decrease (p < 0.001)
12 weeks
III/IV/V
n/k
R, DB
Ejaz53

A) Jessners solution
peels**
B) SA 30%
peels** + SPF 60 Both
groups applied 0.05%
retinoic acid QHS for
2 weeks before first peel

A) 34/32
B) 26/25

Fitzpatrick
Skin Type
Study
Type
Author

TABLE 4. Continued

Treatments Assessed

No. Enrolled/No.
Completed

Type

Severity

Duration

Melasma Area and

Severity Index Results

ADVANCES IN THE TREATMENT OF MELASMA

usually the recommended initial treatment and is

currently the only HQ-containing drug that the
Food and Drug Administration (FDA) has
approved for the treatment of melasma.31,32,32
35,3739
However, concern about steroid-induced
facial atrophy has limited use of this TCC to no
more than twice daily for 6 months, disqualifying
it as a maintenance therapy for melasma.39
Cestari and Chan compared the efficacy of hydroquinone 4% monotherapy with that of TCC. Both
studies demonstrated statistically significantly
greater improvement in the TCC arm than with
HQ alone (p < 0.01) noting 35% and 5.1%,
respectively, obtained a melasma severity of 0, and
64.2% and 39.4%, respectively, achieved a severity
scale of none or mild at week 8.40,41 Because HQ
and TCC are considered to be first-line agents in
the treatment of melasma, they were used as the
comparison arm in many of the studies evaluating
peels and lasers.
Arbutin Arbutin is a naturally occurring beta-Dglucopyranoside derivative of HQ derived from the
extract of the bearberry plant and is felt to have
fewer adverse effects than HQ. In the study by Ertam, the 10 patients randomized to the 1% arbutin
group showed a significant decrease in melanin
(Z = 2.803; p = 0.05) over the 6-month study,
but no statistical difference between the treatment
arms.42
Ellagic acid Ellagic acid is an antioxidant found in
certain plants and fruit. It is also a substrate of
tyrosinase, suggesting a possible inhibitory effect
on the melanogenesis pathway.43 Ertam investigated the skin lightening effects of synthetic and
naturally derived 1% ellagic acid applied BID, and
showed that 8/9 and 10/10 participants, respectively, achieved a significant decrease in melanin
(Z = 2.075, p = 0.04 and Z = 2.803, p = 0.05,
respectively) over the 6-month study.42
Rucinol Tyrosinase-related protein-1 (TRP-1)
is another important enzyme in the melanin

Study
Type

R, C,
SF

R, C,
SF, CO

Author

Trelles57

Wattanakrai59

Jeong58

TABLE 5. Lasers

A) HQ 4%,
retinoic acid 0.05%,
fluocinolone acetonide
0.01% QHS
B) Low-fluence QS-Nd:
YAG + SPF 50

A) HQ 5%,
retinoic acid 0.1%,
dexamethasone 0.1%
TID 9 5 days, BID 9 5,
QD 9 5 (modified
Kligmans)
B) CO2 fractional ablative
resurfacing*
C) CO2 fractional ablative
resurfacing and topical*
+ SPF 30 A and C
also applied kojic acid,
glycolic acid,
HQ 2% QD
after 15-day course of
topical therapy or
68 days after laser
treatment
A) Low-fluence QS-Nd:
YAG, HQ 2%
QHS
B) HQ 2%
QHS + SPF 60

Treatments
Assessed

13/13

22/22

A) 10/10
B) 10/10
C) 10/10

No. Enrolled/No.
Completed

n/k

D, M

E, M

Type

n/k

Recalcitrant

Mild,
moderate,
severe

Severity

III, IV

IIIV

IIIV

Fitzpatrick
Skin Type

16 weeks

7 weeks

12 months

Duration

Relative Lightness Index:

Laser side achieved an
average 92.5%
improvement, compared
with 19.7% on the
control side (p < 0.001);
mottled
hypopigmentation
developed in three
patients
MASI: Statistically
significant reduction in
both groups (p < 0.05);
no significant adverse
effects

MASI: A statistically
significantly greater
decrease was observed
for Group C than Groups
A and B (p < 0.001); crusting
experienced after laser
treatment in Groups
B and C took 68 days to
resolve

Primary Outcome
Measurement and Results

BALL AREFIEV AND HANTASH

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DERMATOLOGIC SURGERY

R, C,
SF, SB

R, SB

Goldman63

Kroon60

A) HQ 5%,
retinoic acid 0.05%, TA
0.1% QHS
B) 1,550-nm erbium glass
nonablative fractional
laser** + SPF > 50

A) HQ 4%,
retinoic acid 0.05%,
fluocinolone acetonide
0.01% QHS, IPL
B) Placebo, IPL + SPF 45

A) HQ 4%,
retinoic acid 0.05%,
triamcinolone acetonide
0.1% QD
B) Nonablative 1,550-nm
fractional laser + SPF 50

Treatments
Assessed

A) 10/10
B) 10/10

56/56

29/29

No. Enrolled/No.
Completed

E, M, D

n/k

E, M

Type

Moderate,
severe

Moderate,
severe

n/k

Severity

IIV

IIIV

IIV

Fitzpatrick
Skin Type

8 weeks

10 weeks

15 weeks

Duration

Melanin index: Significant

increase in
hyperpigmentation on the
laser-treated side from
baseline (p < 0.05); no
significant change on
topical treatment side;
31% of Group B
developed
postinflammatory
hyperpigmentation
Physician Global
Assessment: Melasma
severity significantly less
in group A than B
(p = 0.002); skin irritation
greater in Group A
(p < 0.025)
Physician Global
Assessment: Both groups
showed significant
improvement (p < 0.01)
but no difference between
groups; 75% of group B
experienced sunburn-like
erythema lasting 13 days

Primary Outcome
Measurement and Results

One treatment.
Five treatments, 1-week intervals.

Eight treatments, 1-week intervals.

Four to five treatments, over 15 weeks.

Treatments at Weeks 2 and 6.

**
Four treatments, 2-week intervals.
BID, twice a day; C, controlled; CO, crossover; CO2, carbon dioxide; D, dermal; E, epidermal; HQ, hydroquinone; IPL, intense pulsed light; M, mixed; MASI, Melasma Area and
Severity Index. n/k, not known or not stated in study; Nd-YAG, neodymium-doped yttrium aluminum garnet; QD, every day; QHS, before bedtime; QS, quality switched; R, randomized; SB, single blind; SF, split face; SPF, sun protection factor; TID, three times per day.

R, C,
SB, SF

Study
Type

Wind61

Author

TABLE 5. Continued

ADVANCES IN THE TREATMENT OF MELASMA

biosynthetic pathway. Rucinol is a resorcinol derivative and has been shown to inhibit tyrosinase and
TRP-1.44 Khemis compared 0.3% rucinol serum
with vehicle twice a day for 12 weeks in a splitface trial of 32 patients and showed a statistically
significantly lower pigmentation score on the rucinol-treated side (p = 0.03).45 Huh tested a novel
0.1% liposome-encapsulated formula of rucinol in
a split-face study of 23 patients and demonstrated
a statistically significantly greater reduction in melanin index of the treatment side than of the vehicle-treated side after 8 weeks ( 7.5% vs 3.3%;
p = 0.04).46

Melanin index:
Decreased at Weeks
4 and 8 in the
treatment group
(p < 0.001); no statistical
change in placebo group

Azelaic acid Azelaic acid is a naturally occurring

dicarboxylic acid synthesized by the yeast Malassezia furfur and is associated with the hypopigmented macules seen in tinea versicolor. It weakly
inhibits tyrosinase and has shown cytotoxic and
antiproliferative effects in abnormal melanocytes.47
Erbil compared azelaic acid along with adapalene
with and without serial glycolic acid (GA) peels.48
At the end of the 20-week trial, the 10 participants
who completed therapy in the nonpeel arm
achieved a 69.4% decrease in MASI (p = 0.005).
BID, twice a day; C, controlled; DB, double bind; E, epidermal; R, randomized.

8 weeks
IIIV
Mild, moderate
A) Oral procyanidin
and vitamins A, C,
and E, BID
B) Oral placebo
BID + SPF 24
R, DB, C
Handog65

A) 30/27
B) 30/29

Duration
Severity
Treatments
Assessed
Study
Type
Author

TABLE 6. Other

No. Enrolled/No.
Completed

Type

Photo
Type

Primary Outcome
Measurement and Results

BALL AREFIEV AND HANTASH

Oligopeptides A recent advance is the emergence

of oligopeptides as a new class of tyrosinase inhibitors that may also be beneficial alternatives to
hydroquinone due to their more favorable cytotoxicity and efficacy profiles.49 In the study by Hantash, twice-daily topical application of an emulsion
containing 0.01% decapeptide-12 (Lumixyl
cream, Envy Medical, Inc., Westlake Village, CA)
in 5 patients showed a >50% clinical improvement
over a 16-week period with minimal side effects
(p < 0.001).50
Chemical Peels
Glycolic acid GA is an alpha hydroxy acid that
thins the stratum corneum, disperses melanin in
the epidermis, and improves the distribution of
other drugs in the skin, making it a useful adjunct
to other topical hypopigmenting agents. In the

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ADVANCES IN THE TREATMENT OF MELASMA

previously mentioned Erbil study, the treatment

arm that included 8 serial peels (2070%) at 2week intervals showed a decrease in the MASI of
83.1% (p = 0.001).48 Twelve serial glycolic acid
peels (2070%) at 2-week intervals also showed a
statistically significant decrease in MASI 3 and
6 months from baseline (p < 0.05) in the study by
Ilknur.51 Garg also examined serial GA peels (20
60%) alone and with adjuvant tretinoin 0.025% at
bedtime or HQ 2% at bedtime. After nine peels,
all 3 treatment arms showed a significant decrease
in MASI at 6 months (p < 0.001), but the group
receiving GA peels and 2% HQ achieved a statistically significantly greater improvement than the
others (p < 0.01).52

Amino fruit acid Unlike glycolic acid and despite

its name, amino fruit acids (AFAs) are not actual
fruit acids, although they may be synthesized from
fruit acids. They are carboxylated amino acids that
have been found to be potent antioxidants and
promising in treating photopigmentation. As previously mentioned, Ilknur compared serial GA peels
(2070%) with serial AFA peels (2060%) for a
total of 12 peels over 6 months in 31 patients with
epidermal melasma in a split-face trial.51 Both sides
showed a statistically significant decrease in MASI
3 and 6 months from baseline (p < 0.05). Although
there was no significant difference between the
sides, three patients developed vesicles, crusting, or
erosions on the GAtreated side.

Salicylic acid Salicylic acid (SA) is a beta hydroxy

acid with keratolytic and antiinflammatory properties. It was compared with Jessners solution in a
study by Ejaz for patients with epidermal melasma.53 SA 30% peels were performed at 2-week
intervals over 12 weeks and demonstrated a statistically significant decrease in MASI from baseline
(p < 0.001). Fifteen percent of participants developed excessive crusting, and one patient developed
pigmentation. After a 12-week follow-up, both
groups showed an increase in the MASI, but MASI
was still lower than baseline. Khodali compared
four serial SA (2030%) peels at 2-week intervals
with and without HQ 4% twice a day in a splitface study.54 Both sides improved significantly
(p < 0.001), but there was no statistically significant difference between the sides.

Jessners solution Jessners peel is a combination of

SA 14%, lactic acid 14%, and resorcinol 14% in
an alcohol base. Through its keratolytic activity, it
acts as a superficial chemical peeling agent. In the
previously mentioned studies by Ejaz and Azzam,
Jessners solution was compared with SA 30%
peels and TCA 20% peels, respectively.53,55
Although there was a statistically significant
decrease in MASI with Jessners in both studies
and equivalence to SA 30% peels, it was less effective than TCA 20%.

Trichloroacetic acid Trichloroacetic acid (TCA) is a

derivative of acetic acid and causes protein denaturation, with depth of necrosis proportional to concentration. Azzam compared six weekly TCA 20%
peels with Jessners solution peels and a topical regimen of HQ 2% and kojic acid at bedtime in 45
patients with epidermal and mixed melasma.55 All
groups demonstrated a statistically significant
decrease in MASI (p < 0.001) that was maintained
after 12 weeks of follow-up. The TCA peel group
showed the greatest decrease in MASI (p = 0.01).

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DERMATOLOGIC SURGERY

Device-Based Therapies
Carbon dioxide fractional ablative laser The carbon dioxide (CO2) laser is an ablative resurfacing
treatment that nonselectively destroys the epidermis. A fractionated approach decreases the amount
of epidermal injury and therefore results in fewer
side effects and less risk of dyspigmentation. It has
also been reported that the microscopic injury
zones induced by fractional treatments allow transport of necrotic epidermal debris including melanin
through a compromised dermoepidermal junction.56 Trelles treated 60 patients with epidermal
and mixed melasma with one fractional CO2 highpower, fixed-pulse-width, low-frequency setting
(10,600 nm, 11.3 J/cm2, 350 ns, 1 pass) with or
without a topical maintenance cream.57 Another

BALL AREFIEV AND HANTASH

30 patients were treated with modified Kligmans

formula (HQ 5%, retinoic acid 0.1%, dexamethasone 0.1%) plus a topical maintenance cream. The
combined laser and topical group showed the
greatest improvement, and results were maintained
at the 12-month assessment (p < 0.001). There
were no reported adverse events, but crusting took
6 to 8 days to resolve after laser treatment.
Quality-switched neodymium-doped yttrium
aluminum garnet laser The 1,064-nm qualityswitched neodymium-doped yttrium aluminum garnet (Nd:YAG) laser targets melanin and can be
used with low fluence, short pulse width, and tophat beam mode to minimize thermal damage and
thus reduce the risk of hypopigmenting the treatment area. Jeong used a Nd:YAG laser (1,064 nm,
7 mm, 57 ns, 1.62.0 J/cm2, 2 passes) to treat 13
patients in a split-face crossover trial with TCC.58
There was a statistically significant decrease in
MASI score for both sides (p < 0.05) but no statistically significant difference between them. Side
effects of mild pain and erythema were experienced
in the laser group. Wattanakrai treated 22 patients
with dermal and mixed melasma in a split-face
trial with a Nd:YAG laser (1,064 nm, 6 mm,
10 Hz, 3.03.8 J/cm2, passes performed until
immediate lightening of pigment or mild erythema
without petechiae) with and without HQ 2%.59
The laser side achieved an average 92.5% improvement, compared with 19.7% on the control side
(p < 0.001), although mottled hypopigmentation
developed in 3 patients, and during follow up, four
of the 22 patients developed rebound hyperpigmentation.
1,550 nm fractional nonablative laser One of the
most recent modalities being investigated for
melasma is a fractionated nonablative 1,550-nm
erbium glass laser. In an 8-week study by Kroon,
20 patients were randomized to 4 treatments with
a 1,550-nm erbium glass nonablative fractional
laser (1,550 nm, 7 mJ, level 5 and 7, 8 passes) or a
combination of hydroquinone 5%, retinoic acid
0.05%, triamcinolone acetonide 0.1%.60 Both

groups showed significant improvement (p < 0.01),

but there was no difference between the groups.
Seventy-five percent of the laser-treated group
experienced sunburn-like erythema lasting 1 to
3 days. In a different study, Wind compared a
1,550-nm nonablative fractional laser (1,550 nm,
15 mJ, level 57, 8 passes; 45 treatments over
15 weeks) with a combination of hydroquinone
4%, retinoic acid 0.05%, triamcinolone acetonide
0.1%, and in contrast to the study by Kroon, there
was a significant increase in hyperpigmentation
(31%) on the laser-treated side from baseline
(p < 0.05).61 The topical treatment side showed no
significant change.
Intense pulsed light Intense pulsed light (IPL)
produces a broad spectrum of wavelengths, but
cut-off filters can be applied to block wavelengths
shorter than the filter, providing a level of
selective photothermolysis.62 Goldman completed
a 10-week placebo-controlled split-face study of
56 patients with moderate to severe melasma treated with IPL (560-nm cut-off filter, double-pulse
technique, 3.03.5 ms, 1418 J/cm2) with and
without adjuvant TCC therapy.63 Melasma
severity was significantly less on the IPLTCC
side than on the IPLplacebo side (p = 0.002).
Skin irritation was greater in the former
(p < 0.025).
Other Therapies
Oral procyanidin and vitamins A, C, and
E Procyanidin is a polymer of flavonoids extracted
from the French maritime pine bark Pinus pinaster
but is also found in other plants and fruits. It has
antioxidant and antiinflammatory properties.64
Handog enrolled 60 patients with epidermal melasma in a double-blind placebo-controlled trial of
twice-a-day oral supplementation with procyanidin
and vitamins A, C, and E.65 The melanin index
had decreased at weeks 4 and 8 in the treatment
group (p < 0.001). There was no statistically significant change in the placebo group and no adverse
events.

38:7:JULY 2012

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ADVANCES IN THE TREATMENT OF MELASMA

Conclusion
Melasma is a disorder with significant psychological effects. The identification of some of the etiologic factors has provided some guidance for
preventative strategies such as strict photoprotection, but treating the condition remains difficult.
Although considered the standard, the use of HQbased topical agents has become controversial since
the U.S. FDA proposed banning over-the-counter
sales of HQ products in 2006. In addition to raising concern over case reports of exogenous ochronosis, the FDA expressed alarm over studies
performed in rodents indicating that HQ may be a
carcinogen.66 In response, arguments have been
made showing that the risk of ochronosis is low,
specifically in the 2% over-the-counter HQ formulations and when used properly under clinical surveillance.67,68 In December 2009, the Department
of Health and Human Services National Toxicology Program proposed 3 studies to investigate the
metabolism, reproductive toxicity, and carcinogenicity of HQ in rodents before the FDA finalizes its
decision.69 In light of this, the presence of novel,
safe, effective HQ-free skin lightening alternatives
is a critical addition to the armamentarium of dermatologists treating patients with melasma. We
reviewed 19 RCTs published since 2006 that
examined a variety of topical and device-based
treatments for melasma. The heterogeneity in
severity and type of melasma (when reported) and
the wide variety of interventions, treatment
protocols, and outcome measurements makes it
impossible to perform a reliable meta-analysis.
Additionally, most of the studies did not compare
or use HQ as the control; thus, we are unable to
rank any one treatment above another. This review
shows how novel compounds and laser technologies are evolving to meet the need to develop safe
and effective treatments for melasma. We expect
that, as further innovations are made and additional combination treatment protocols designed,
dermatologists will be better able to individualize
treatment to achieve greater efficacy while minimizing safety concerns.

982

DERMATOLOGIC SURGERY

References
1. Kauh YC, Zachian TF. Melasma. Adv Exp Med Biol
1999;455:4919.
2. Ortonne JP, Arellano I, Berneburg M, Cestari T, et al. A global
survey of the role of ultraviolet radiation and hormonal
influences in the development of melasma. J Eur Acad Dermatol
Venereol 2009;23:125462.
3. Moin A, Jabery Z, Fallah N. Prevalence and awareness of
melasma during pregnancy. Int J Dermatol 2006;45:2858.
4. Vazquez M, Maldonado H, Benmaman C, Sanchez JL.
Melasma in men. A clinical and histologic study. Int J Dermatol
1988;27:257.
5. Freitag FM, Cestari TF, Leopoldo LR, Paludo P, et al. Effect of
melasma on quality of life in a sample of women living in
southern Brazil. J Eur Acad Dermatol Venereol 2008;22:
65562.
6. Pandya A, Berneburg M, Ortonne JP, Picardo M. Guidelines for
clinical trials in melasma. Pigmentation Disorders Academy. Br
J Dermatol 2006;156(Suppl 1):218.
7. Pawaskar MD, Parikh P, Markowski T, McMichael AJ, et al.
Melasma and its impact on health-related quality of life in
Hispanic women. J Dermatol Treat 2007;18:59.
8. Balkrishnan R, McMichael AJ, Camacho FT, Saltzberg F, et al.
Development and validation of a health-related quality of life
instrument for women with melasma. Br J Dermatol
2003;149:5727.
9. Rendon MI. Utilizing combination therapy to optimize melasma
outcomes. J Drugs Dermatol 2004;5(Suppl):S2734.
10. Failmezger C. Incidence of skin disease in Cuzco, Peru. Int J
Dermatol 1992;31:5601.
11. Sanchez NP, Pathak MA, Sato S, Fitzpatrick TB, et al.
Melasma: a clinical, light microscopic, ultrastructural, and
immunofluorescence study. J Am Acad Dermatol 1981;4:698
710.
12. Kang WH, Yoon KH, Lee ES, Kim J, et al. Melasma:
histopathological characteristics in 56 Korean patients. Br J
Dermatol 2002;146:22837.
13. Kang HY, Hwang JS, Lee JY, Ahn JH, et al. The dermal stem
cell factor and c-kit are overexpressed in melasma. Br J
Dermatol 2006;154:10949.
14. Imokawa G. Autocrine and paracrine regulation of melanocytes
in human skin and in pigmentary disorders. Pigment Cell Res
2004;17:96110.
15. Barker D, Dixon K, Medrano EE, Smalara D, et al.
Comparison of the responses of human melanocytes with
different melanin contents to ultraviolet B irradiation. Cancer
Res 1995;55:40416.
16. Grimes PE, Yamada N, Bhawan J. Light microscopic,
immunohistochemical, and ultrastructural alterations in patients
with melasma. Am J Dermatopathol 2005;27:96101.
17. Schauer E, Trautinger F, Kock A, Schwarz A, et al.
Proopiomelanocortin-derived peptides are synthesized and
released by human keratinocytes. J Clin Invest 1994;93:
225862.

BALL AREFIEV AND HANTASH

18. Im S, Kim J, On WY, Kang WH. Increased expression of alphamelanocyte-stimulating hormone in the lesional skin of
melasma. Br J Dermatol 2002;146:1657.

37. Grimes P, Kelly AP, Torok H, Willis I. Community-based trial

of a triple-combination agent for the treatment of facial
melasma. Cutis 2006;77:17784.

19. Im S, Moro O, Peng F, Medrano EE, et al. Activation of the

cyclic AMP pathway by alpha-melanotropin mediates the
response of human melanocytes to ultraviolet B radiation.
Cancer Res 1998;58:4754.

38. Taylor SC, Torok H, Jones T, Lowe N, et al. Efficacy and

safety of a new triple-combination agent for the treatment of
facial melasma. Cutis 2003;72:6772.

20. Lieberman R, Moy L. Estrogen receptor expression in melasma:

results from facial skin of affected patients. J Drugs Dermatol
2008;7:4635.
21. Resnik S. Melasma induced by oral contraceptive drugs. JAMA
1967;199:6015.
22. Johnston GA, Sviland L, McLelland J. Melasma of the arms
associated with hormone replacement therapy. Br J Dermatol
1998;139:932.
23. Varma S, Roberts DL. Melasma of the arms associated with
hormone replacement therapy. Br J Dermatol 1999;141:
592.
24. McLeod SD, Ranson M, Mason RS. Effects of estrogens on
human melanocytes in vitro. J Steroid Biochem Mol Biol
1994;49:914.
25. Ranson M, Posen S, Mason RS. Human melanocytes as a target
tissue for hormones: in vitro studies with 1 alpha-25,
dihydroxyvitamin D3, alpha-melanocyte stimulating hormone,
and beta-estradiol. J Invest Dermatol 1988;91:5938.

39. Grimes PE, Bhawan J, Guevara IL, Colon LE, et al. Continuous
therapy followed by a maintenance therapy regimen with a
triple combination cream for melasma. J Am Acad Dermatol
2010;62:9627.
40. Ferreira Cestari T, Hassun K, Sittart A, de Lourdes Viegas M.
A comparison of triple combination cream and hydroquinone
4% cream for the treatment of moderate to severe facial
melasma. J Cosmet Dermatol 2007;6:369.
41. Chan R, Park KC, Lee MH, Lee ES, et al. A randomized
controlled trial of the efficacy and safety of a fixed triple
combination (fluocinolone acetonide 0.01%, hydroquinone 4%,
tretinoin 0.05%) compared with hydroquinone 4% cream in
Asian patients with moderate to severe melasma. Br J Dermatol
2008;159:697703.
42. Ertam I, Mutlu B, Unal I, Alper S, et al. Efficiency of ellagic
acid and arbutin in melasma: a randomized, prospective, openlabel study. J Dermatol 2008;35:5704.
43. Munoz-Munoz JL, Garcia-Molina F, Garcia-Molina M, Tudela
J, et al. Ellagic acid: characterization as substrate of polyphenol
oxidase. IUBMB Life 2009;61:1717.

26. Perez M, Sanchez JL, Aguilo F. Endocrinologic profile of

patients with idiopathic melasma. J Invest Dermatol
1983;81:5435.

44. Kim DS, Kim SY, Park SH, Choi YG, et al. Inhibitory effects of
4-n-butylresorcinol on tyrosinase activity and melanin synthesis.
Biol Pharm Bull 2005;28:22169.

27. Sialy R, Hassan I, Kaur I, Dash RJ. Melasma in men: a

hormonal profile. J Dermatol 2000;27:645.

45. Khemis A, Kaiafa A, Queille-Roussel C, Duteil L, et al.

Evaluation of efficacy and safety of rucinol serum in patients
with melasma: a randomized controlled trial. Br J Dermatol
2007;156:9971004.

28. Lutfi RJ, Fridmanis M, Misiunas AL, Pafume O, et al.

Association of melasma with thyroid autoimmunity and other
thyroidal abnormalities and their relationship to the origin of
the melasma. J Clin Endocrinol Metab 1985;61:2831.
29. Grimes PE. Melasma. Etiologic and therapeutic considerations.
Arch Dermatol 1995;131:14537.

46. Huh SY, Shin JW, Na JI, Huh CH, et al. Efficacy and safety of
liposome-encapsulated 4-n-butylresorcinol 0.1% cream for the
treatment of melasma: a randomized controlled split-face trial. J
Dermatol 2010;37:3115.

30. Victor FC, Gelber J, Rao B. Melasma: a review. J Cutan Med

Surg 2004;8:97102.

47. Nazzaro-Porro M, Passi S. Identification of tyrosinase inhibitors

in cultures of Pityrosporum. J Invest Dermatol 1978;71:2058.

31. Gupta AK, Gover MD, Nouri K, Taylor S. The treatment of

melasma: a review of clinical trials. J Am Acad Dermatol
2006;55:104865.

48. Erbil H, Sezer E, Tastan B, Arca E, et al. Efficacy and safety of

serial glycolic acid peels and a topical regimen in the treatment
of recalcitrant melasma. J Dermatol 2007;34:2530.

32. Rendon M, Berneburg M, Arellano I, Picardo M. Treatment of

melasma. J Am Acad Dermatol 2006;5(Suppl 2):S27281.

49. Abu Ubeid A, Zhao L, Wang Y, Hantash BM. Short-sequence

oligopeptides with inhibitory activity against mushroom and
human tyrosinase. J Invest Dermatol 2009;129:22429.

33. Cestari T, Arellano I, Hexsel D, Ortonne JP. Latin American

pigmentary disorders A. Melasma in Latin America: options for
therapy and treatment algorithm. J Eur Acad Dermatol
Venereol 2009;23:76072.
34. Rigopoulos D, Gregoriou S, Katsambas A. Hyperpigmentation
and melasma. J Cosmet Dermatol 2007;6:195202.
35. Rajaratnam R, Halpern J, Salim A, Emmett C. Interventions for
melasma. Cochrane Database Syst Rev 2010;7:003583.
36. Palumbo A, dIschia M, Misuraca G, Prota G. Mechanism of
inhibition of melanogenesis by hydroquinone. Biochim Biophys
Acta 1991;1073:8590.

50. Hantash BM, Jimenez F. A split-face, double-blind, randomized

and placebo-controlled pilot evaluation of a novel oligopeptide
for the treatment of recalcitrant melasma. J Drugs Dermatol
2009;8:7325.
51. Ilknur T, Bicak MU, Demirtasoglu M, Ozkan S. Glycolic acid
peels versus amino fruit acid peels in the treatment of melasma.
Dermatol Surg 2010;36:4905.
52. 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;34:10329; discussion 1340.

38:7:JULY 2012

983

ADVANCES IN THE TREATMENT OF MELASMA

53. Ejaz A, Raza N, Iftikhar N, Muzzafar F. Comparison of 30%

salicylic acid with Jessners solution for superficial chemical
peeling in epidermal melasma. J Coll Physicians Surg Pak
2008;18:2058.
54. Kodali S, Guevara IL, Carrigan CR, Daulat S, et al. A
prospective, randomized, split-face, controlled trial of salicylic
acid peels in the treatment of melasma in Latin American
women. J Am Acad Dermatol 2010;63:10305.
55. Azzam OA, Leheta TM, Nagui NA, Shaarawy E, et al.
Different therapeutic modalities for treatment of melasma. J
Cosmet Dermatol 2009;8:27581.

63. Goldman MP, Gold MH, Palm MD, Colon LE, et al.
Sequential treatment with triple combination cream and intense
pulsed light is more efficacious than sequential treatment with
an inactive (control) cream and intense pulsed light in patients
with moderate to severe melasma. Dermatol Surg 2011;37:224
33.
64. Ni Z, Mu Y, Gulati O. Treatment of melasma with Pycnogenol.
Phytother Res 2002;16:56771.

56. Hantash BM, Bedi VP, Sudireddy V, Struck SK, et al. Laserinduced transepidermal elimination of dermal content by
fractional photothermolysis. J Biomed Opt 2006;11:041115.

65. Handog EB, Galang DA, de Leon-Godinez MA, Chan GP. A

randomized, double-blind, placebo-controlled trial of oral
procyanidin with vitamins A, C, E for melasma among Filipino
women. Int J Dermatol 2009;48:896901.

57. Trelles MA, Velez M, Gold MH. The treatment of melasma

with topical creams alone, CO2 fractional ablative resurfacing
alone, or a combination of the two: a comparative study. J
Drugs Dermatol 2010;9:31522.

66. Department of Health and Human Services. Food and Drug

Administration. Skin bleaching drug products for over-thecounter human use; proposed rule. 71 Federal Register 51146
5115521 (2006) (codified at 21 CFR Part 310).

58. Jeong SY, Shin JB, Yeo UC, Kim WS, et al. Low-fluence Qswitched neodymium-doped yttrium aluminum garnet laser for
melasma with pre- or post-treatment triple combination cream.
Dermatol Surg 2010;36:90918.

67. Draelos ZD. Skin lightening preparations and the hydroquinone

controversy. Dermatol Ther 2007;20:30813.

59. Wattanakrai P, Mornchan R, Eimpunth S. Low-fluence Qswitched neodymium-doped yttrium aluminum garnet
(1,064 nm) laser for the treatment of facial melasma in Asians.
Dermatol Surg 2010;36:7687.
60. Kroon MW, Wind BS, Beek JF, van der Veen JP, et al.
Nonablative 1550-nm fractional laser therapy versus
triple topical therapy for the treatment of melasma: a
randomized controlled pilot study. J Am Acad Dermatol
2011;64:51623.
61. Wind BS, Kroon MW, Meesters AA, Beek JF, et al. Nonablative 1,550 nm fractional laser therapy versus triple topical
therapy for the treatment of melasma: a randomized controlled
split-face study. Lasers Surg Med 2010;42:60712.

984

62. Moreno Arias GA, Ferrando J. Intense pulsed light for

melanocytic lesions. Dermatol Surg 2001;27:397400.

DERMATOLOGIC SURGERY

68. Levitt J. The safety of hydroquinone: a dermatologists response

to the 2006 Federal Register. J Am Acad Dermatol 2007;57:854
72.
69. FDA. Hydroquinone studies under the national toxicology
program (NTP). 2011. Available from: http://www.fda.gov/
AboutFDA/CentersOffices/CDER/ucm203112.htm Accessed
August 20, 2011.

Address correspondence and reprint requests to: Basil M.

Hantash, MD, PhD, Elixir Institute of Regenerative
Medicine, 5941 Optical Court, San Jose, CA 95138, or
e-mail: basil@elixirinstitute.org