Indian J Dermatol. 2009 Oct-Dec; 54(4): 303309.

doi: 10.4103/0019-5154.57602
PMCID: PMC2807702

TOPICAL TREATMENT OF MELASMA

Debabrata Bandyopadhyay
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Abstract
Melasma is a common hypermelanotic disorder affecting the face that is associated with
considerable psychological impacts. The management of melasma is challenging and requires a
long-term treatment plan. In addition to avoidance of aggravating factors like oral pills and
ultraviolet exposure, topical therapy has remained the mainstay of treatment. Multiple options for
topical treatment are available, of which hydroquinone (HQ) is the most commonly prescribed
agent. Besides HQ, other topical agents for which varying degrees of evidence for clinical
efficacy exist include azelaic acid, kojic acid, retinoids, topical steroids, glycolic acid, mequinol,
and arbutin. Topical medications modify various stages of melanogenesis, the most common
mode of action being inhibition of the enzyme, tyrosinase. Combination therapy is the preferred
mode of treatment for the synergism and reduction of untoward effects. The most popular
combination consists of HQ, a topical steroid, and retinoic acid. Prolonged HQ usage may lead to
untoward effects like depigmentation and exogenous ochronosis. The search for safer
alternatives has given rise to the development of many newer agents, several of them from
natural sources. Well-designed controlled clinical trials are needed to clarify their role in the
routine management of melasma.

Keywords: Melasma, newer agents, topical treatment

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Introduction
Melasma (from the Greek word, melas meaning black) is a common, acquired, circumscribed
hypermelanosis of sun-exposed skin. It presents as symmetric, hyperpigmented macules having
irregular, serrated, and geographic borders. The most common locations are the cheeks, upper
lips, the chin, and the forehead, but other sun-exposed areas may also occasionally be involved.
The term, chloasma (from the Greek word, chloazein meaning to be green) is often used to
describe melasma developing during pregnancy; however, as the pigmentation never appears to
be green, the term, melasma should be preferred.

Although melasma may affect any race, it is much more common in constitutionally darker skin
types (skin types IV to VI) than in lighter skin types, and it may be more common in light brown
skins, especially in people of East Asian, Southeast Asian, and Hispanic origin who live in areas
of the world with intense solar ultraviolet exposure. Melasma is the most common pigmentary
disorder among Indians.[1]. It is much more common in women during their reproductive years
but about 10% of the cases do occur in men. The clinical and histological features of melasma in
men are the same as those of melasma in women.[2]

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Pathophysiology of Melasma
The pathophysiology of melasma remains elusive, but multiple factors have been implicated. The
role of female hormonal activity has been suggested by the increased frequency of occurrence of
melasma in pregnancy and in those on oral contraceptive pills, estrogen replacement therapy, and
estrogen treatment for prostatic cancer. The mechanism of induction of melasma by estrogen
may be related to the presence of estrogen receptors on the melanocytes that stimulate the cells to
produce more melanin. Genetic factors are indicated by familial occurrence of melasma and its
increased incidence in people of Asian and Hispanic origins. Other factors implicated in the
etiopathogenesis of melasma are photosensitizing and anticonvulsant medications, mild ovarian
or thyroid dysfunction, and certain cosmetics. One of the most important factors in the
development of melasma is ultraviolet exposure from sunlight or other sources. Exacerbation of
melasma is universally seen after prolonged sunexposure but the pigmentation fades after periods
of avoidance of sunexposure. Whatever the mechanisms, melasma results in an increased
deposition of melanin in the epidermis, in the dermis within melanophages, or both. The number
of melanocytes in the lesions has been variably reported to be normal[3] or increased.[4] The
melanosomes within the melanocytes and keratinocytes have been reported to be increased in
size.[3,4]

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Types of Melasma
The lesions range in color from light brown to dark brownish-black and affect the regions of the
face in different patterns. Three clinical patterns of distribution of the pigmentation may be
recognized: Centrofacial, malar, and mandibular.[5]

The centrofacial pattern is the most common and involves the cheeks, nose, forehead, upper lip,
and chin. The malar pattern involves the cheeks and nose. The ramus of the mandible is
involved in the mandibular pattern. Melasma does not involve the mucous membrane.
With the help of Wood's lamp examination, melasma may be classified into four histological
types according to the depth of pigment deposition[6]. The epidermal type is the most common
in which the pigmentation appears more intense under Wood's lamp examination. Melanin is
distributed throughout the epidermis; topical treatment may work best in this type of melasma. In
the dermal type, the pigmentation is not intensified with Wood's light. The pigmentation is due to
plenty of melanophages in the dermis. In the mixed type, Wood's light intensifies pigmentation in
some areas while other areas remain unchanged. The pigmentation is due to increased epidermal
melanin as well as dermal melanophages. Wood's lamp examination is of no benefit in very dark
individuals, and this type is classified as indeterminate. This classification may partly work in
lighter skin types but not in brown or black skin types.[7] Moreover, there may not be good
correlation between the findings of Wood's lamp examination and histological depth of
pigmentation.[7]

Depending on the natural history of the lesions, melasma may also be classified into transient
and persistent types.[7] The transient type disappears within one year of cessation of hormonal
stimuli like pregnancy or oral contraceptive pills. The persistent type continues to be present
more than one year after the hormonal stimulus is removed and is caused by the action of UV
rays and other factors, highlighting the role of sun-avoidance in the management of melasma.

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Topical Treatment
By causing cosmetic disfigurement of the face, melasma is frequently associated with a
significant emotional effect. There is no universally effective specific therapy for the disease
existing agents have varying degrees of effectiveness, and the condition, more often than not,
relapses.[8] Most cases are treated with topical agents, used alone, or in combinations. Other
modalities of treatment utilized in the management of this hypermelanotic disorder are chemical
peels and physical therapies in the form of various lasers or intense pulse light sources. All
patients with melasma should be counseled about the natural course of the disease and the
necessity for adherence to a long-term treatment plan. Careful history about the possible
precipitating or aggravating factors must be taken with special attention to the intake of oral
contraceptives or other hormonal preparations, phototoxic and anti-seizure medications, and the
usage of cosmetics. Discontinuation of oral pills and avoidance of scented cosmetics is advised.
Recurrence of melasma occurs on exposure to sunlight and other sources of ultraviolet rays.
Photoprotective measures like the avoidance of direct sun-exposure and the regular use of a
broad-spectrum sunscreen are always advised, although clinical studies on their role are lacking.
Treatment with demelanizing agents must be continued for several months before significant
clinical benefits become noticeable. Topical agents are much more effective in the epidermal
type of melasma.[9]

Hydroquinone

Hydroquinone (HQ), also known as dihydroxybenzene, is a hydroxyphenolic compound that is

structurally similar to precursors of melanin. It inhibits the conversion of DOPA to melanin by
inhibition of the enzyme, tyrosinase. HQ affects not only the formation, melanization, and
degradation of melanosomes, but it also affects the membranous structures of melanocytes and
eventually causes necrosis of whole melanocytes.[10] HQ is an oxidizing agent that can oxidize
in tubes or bottles, turning the color of formulations from white to brown. Products that have
undergone this color change are ineffective and should be discarded.[11]

HQ is the most frequently prescribed depigmenting agent worldwide and it has remained the
gold standard for the treatment of melasma, particularly of the epidermal type. HQ preparations
are commonly used in the treatment of melasma at concentrations varying from 2 to 5% applied
once daily. Variably good yet reversible results are obtained in most of the patients treated with
HQ. The depigmenting effects of the HQ treatment become evident after 5-7 weeks. Treatment
should be continued for at least three months, up to one year.[9] HQ is also formulated in
combination with other agents like sunscreens, topical steroids, retinoids, and glycolic acids for
added benefits.

Adverse reactions of HQ are related to its dose and the duration of treatment. Irritation is the
most common complication; other adverse effects include erythema, stinging, colloid milium,
irritant and allergic contact dermatitis, nail discoloration, transient hypochromia, and paradoxical
postinflammatory hypermelanosis.[9,12] The so-called confetti-like depigmentation or guttate
hypomelanosis is characterized by mottled depigmented spots that develop on the macules of
melasma. This is observed in association with the use of HQ at concentrations higher than 2%.
Exogenous ochronosis[13,14] a blue-black pigmentation of the treated areas, has been mainly
reported in darker skin from prolonged use of a strong concentration, but has also been reported
in whites after short- or long-term use of 2% HQ preparations.[15] The etiology of
hydroquinone-induced hyperpigmentation in exogenous ochronosis remains speculative;
improvement occurs very slowly after avoidance of the offending agent.[16] The monobenzy
lether of HQ should never be used in the treatment of melasma as it can produce a permanent
loss of melanocytes, causing a disfiguring confetti-like leukoderma.

Regulatory agencies in Japan, Europe, and most recently the USA, have raised questions about
the safety of HQ[17] and it has been banned in cosmetic preparations in many countries. This has
encouraged research into alternative agents for the topical management of melasma.

Azelaic acid

Azelaic acid is a naturally occurring, nonphenolic, saturated, nine-carbon dicarboxylic acid that
competitively inhibits tyrosinase. Azelaic acid was initially developed as a topical anti-acne
agent but because of its effect on tyrosinase, it has also been used to treat hyperpigmentary
disorders like melasma. Its mechanisms of action include the inhibition of DNA synthesis and
mitochondrial enzymes, thereby inducing direct cytotoxic effects toward the melanocyte.[18]
Topical azelaic acid has no depigmentation effect on normally pigmented skin; this specificity
may be attributed to its selective effects on abnormal melanocytes.[19] It can be used for
postinflammatory hyperpigmentation in acne. Free radicals are believed to contribute to
hyperpigmentation, and azelaic acid acts by reducing free radical production.[20]

A double-blind randomized study has shown that a 20% concentration of azelaic acid was
equivalent to 4% hydroquinone in the treatment of melasma, but without its side effects.[21]
Another controlled study has found azelaic acid to be superior to 2% hydroquinone.[22] A
combination of azelaic acid with 0.05% tretinoin or 15-20% glycolic acid may produce earlier,
more pronounced skin lightening. Adverse effects of azelaic acid include pruritus, mild
erythema, and burning.[23]

Kojic acid

Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyrone) is a naturally occurring, hydrophilic fungal

product derived from certain species of Acetobacter, Aspergillus, and Penicillium.[19] It acts by
inhibiting the production of free tyrosinase; it is also a potent antioxidant.[24] It is generally
univalent to other therapies but may be more irritating. Kojic (KA) acid is used at concentrations
ranging from 1 to 4%. In one double-blind study, KA 2% combined with HQ 2% was shown to
be superior to glycolic acid (GA) 10% and HQ 2%[25] Another double-blind study compared
GA 5% with either HQ 4% or KA 4% for three months. Both combinations proved equally
effective with a reduction of pigmentation in 52% of the patients.[26] KA may be effective if a
patient has difficulty tolerating other first-line therapies. It may cause contact dermatitis and
erythema.[27]

Retinoids

Retinoids, such as tretinoin, were first used in combination with HQ as penetration enhancers,
but were later recognized to have their own effect on melanogenesis.[28] Retinoids affect
multiple steps in the melanization pathway. Tretinoin promotes the rapid loss of pigment through
epidermopoiesis and increased epidermal turnover decreases the contact time between
keratinocytes and melanocytes.[8] Retinoic acid (RA) suppresses UVB-induced pigmentation by
reducing tyrosinase activity. The acid acts at a posttranscriptional level on tyrosinase and
tyrosinase-related protein.[12] Compared with phenolic compounds like HQ, RA takes a much
longer time to act; clinically significant lightening becomes.evident after 24 weeks.

Tretinoin monotherapy has produced a good therapeutic response in clinical trials[29,30] but
better results are obtained in combination with other agents like HQ and corticosteroids. The
most common side effects include erythema, burning, stinging, dryness, and scaling. The
inflammation may cause hyperpigmentation, particularly in people with dark skin.[28] Patients
must be advised to use sunscreens during treatment with retinoic acid. Adapalene, a naphthoic
acid derivative with retinoid activity, was found to be equally efficacious in a randomized trial in
Indian patients but with significantly less untoward effects than tretinoin.[31]

Topical steroids

Reversible hypopigmentation of normal skin is a well-known untoward effect of prolonged

potent steroid application. The mechanism of the skin-lightening effect of topical corticosteroids
is ill-understood. Melanocytes respond to a wide variety of chemical mediators. The inhibitory
effects of corticosteroids on the synthesis of mediators like prostaglandin and leukotriene may
partly explain their effects on melanogenesis.[28] Potent or superpotent steroids, when used
alone, have been associated with good therapeutic responses,[32,33] but monotherapy is not
recommended due to their frequent untoward effects.
Topical steroids are used in combination products for their synergistic effects and for the
reduction of irritation from other products like tretinoin. Various combinations with HQ and
retinoic acid have given good cosmetic results in clinical trials.[34] Adverse effects of topical
steroids include irritation, rosacea-like dermatosis, atrophy, telangiectasia, and hypertrichosis.

Glycolic acid

Glycolic acid is an alpha-hydroxy acid that is usually combined with other agents at a
concentration of 5-10% for its skin-lightening property. The mechanism of its effect might be
due to epidermal remodeling and accelerated desquamation, which would result in quick pigment
dispersion on pigmentary lesions. It also directly reduces melanin formation in melanocytes by
tyrosinase inhibition.[35]

A randomized controlled trial has demonstrated that a formulation containing 10% glycolic acid
and 4% HQ had good clinical efficacy in treating melasma in a group of Hispanic patients.
Irritation was a common side effect which resolved with the temporary cessation of application
and application of moisturizers.[36]

Mequinol

Mequinol (4-hydroxyanisole, hydroquinone monomethyl ether) is a derivative of HQ. Its

mechanism of action is unclear; however, being a substrate of tyrosinase, it may act as a
competitive inhibitor of the formation of melanin precursors[11]. It is currently marketed in the
USA at a concentration of 2% in combination with 0.01% tretinoin as a penetration enhancer. In
a randomized, parallel-group, double-masked study involving 216 subjects, a mequinol 2%/
tretinoin 0.01% solution was found to be highly effective and well-tolerated treatment for solar
lentigines and related hyperpigmented lesions, being superior to HQ 3% for lesions on the
forearm and of similar efficacy for lesions on the face.[37] The results of a trial with a case series
of male patients with melasma has shown that four out of five patients achieved complete
clearance at 12 weeks, and one patient showed moderate improvement. Side effects were
minimal and consisted of stinging in one patient. All patients maintained results at the 16-weeks'
follow-up visit.[38]

An open-label study was conducted to determine the rate of adverse events of topical
mequinol/tretinoin, twice daily application for up to 24 weeks with concomitant sunscreen in the
treatment of solar lentigines and related hyperpigmented lesions. The untoward effects of this
topical combination were in the form of erythema, burning/stinging/tingling, desquamation,
pruritus, skin irritation, halo hypopigmentation, and hypopigmentation. The authors concluded
that when used with sunscreen of SPF 25 or greater, the combination was safe and well tolerated
and did not produce any unexpected or unusual adverse events.[39] Controlled clinical trials with
large numbers of patients are needed to clarify the role of this promising new agent in the routine
management of melasma.

Arbutin
Arbutin, the beta-D-glucopyranoside derivative of hydroquinone, is a naturally occurring plant
product which has been used successfully in the treatment of hyperpigmentary disorders. The
glycosidic bond is hydrolyzed in vivo leading to the controlled release of hydroquinone.[12]
Arbutin acts by the inhibition of tyrosinase, thereby decreasing melanin formation. The normal
skin microflora may also hydrolyze arbutin; the hydrolyzed hydroquinone shows more potent
free-radical scavenging activity and tyrosinase inhibition than arbutin.[40]

The action of arbutin is dose-dependent and less toxic than hydroquinone. Deoxyarbutin is a
recently developed derivative of arbutin that has been produced by removing the hydroxyl
groups from the molecule. This produces reversible skin-lightening by direct inhibition of
tyrosinase.[41] Although good controlled clinical trials are lacking, initial in vitro and in vivo
experimental studies have demonstrated that it could be a safe and effective treatment for
hypermelanotic disorders.[42,43]

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Other New and Experimental Agents

A number of agents, both synthetic and those derived from natural sources like plants, have been
investigated for their potential role in reducing melanin pigmentation. Although experimental
evidence suggests their possible benefits, dependable controlled clinical trials are mostly lacking.
Some of the compounds are formulated in combination products and marketed by
pharmaceutical companies; many are available as ingredients of over-the-counter preparations.

N-acetyl-4-S-cysteaminylphenol

NCAP is a phenolic agent which acts as an alternative substrate for tyrosinase, thus inhibiting the
enzyme's activity. It has been reported to be more stable and causes less irritation than
hydroquinone. In a study of 12 patients with melasma, using 4% NCAP, 66% of patients showed
marked improvement and 8% showed a complete resolution of melasma lesions. With daily
topical application, clinical changes were evident after 2-4 weeks.[44]

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Alpha-tocopheryl Ferulate
The compound of alpha-tocopherol and ferulic acid, also an antioxidant connected with an ester
bond, alpha-tocopheryl ferulate (alpha-TF), can absorb ultraviolet (UV) radiation and thus
maintain tocopherol in a stable state. In experimental studies, this agent was found to have
significant effect in the retardation of melanogenesis, possibly by inhibiting tyrosine hydroxylase
activity in an indirect manner.[45,46]

Ascorbic acid
Ascorbic acid has antioxidant properties and affects melanogenesis by reducing dopaquinone to
DOPA and preventing free-radical production and absorption of ultraviolet radiation.[12]
Comparing the efficacy of 5% ascorbic acid and 4% hydroquinone in 16 patients with melasma
in a double-blind clinical trial, the authors concluded that although hydroquinone showed a better
response, ascorbic acid may play a role in the therapy of melasma as it is almost devoid of side
effects and it could be used alone or in combination therapy.[47] In an open-label trial, 25% L-
ascorbic acid formulated with a penetration enhancer, was found to have a significant effect in
the treatment of melasma.[48] Ascorbic acid, however, is highly unstable in aqueous solution and
stable esters like magnesium ascorbyl-2-phosphate (MAP) have been synthesized. MAP has a
protective effect against UVB radiation[49] and it inhibits melanogenesis in vitro and in vivo.
Experiments demonstrated that MAP cream was absorbed into the epidermis and that 1.6%
remained 48 hours after application. The lightening effect was significant in 19 of 34 patients
with melasma or senile freckles and in 3 of 25 patients with normal skin.[50]

Niacinamide

Niacinamide (nicotinamide), the biologically active amide form of niacin (vitamin B 3), can
reduce pigmentation by reversibly preventing the transfer of melanosomes from melanocytes to
the keratinocytes.[51] It has no effect on tyrosinase activity. In clinical studies, niacinamide
significantly decreased hyperpigmentation and increased skin lightness compared with vehicle
alone after four weeks of use.[52]

Liquorice derivatives

Liquorice is the root of the perennial herb Glycyrrhiza glabra. Glabridin is an oil-soluble
derivative of liquorice extract. Glabridin has been shown to have tyrosinase inhibitory as well as
anti-inflammatory properties in experimental studies.[53] A clinical trial with Liquiritin, another
liquorice derivative, has also shown benefit in treating melasma.[54]

Flavonoids[12]

Flavonoids are naturally occurring polyphenolic compounds that have well-known anti-
inflammatory, antioxidant, antiviral, and anticarcinogenic properties. Many plant-derived
flavonoid compounds have hypopigmentary effects and their roles are still under investigation.
These include catechin conjugated with gallic acid (from green tea leaves), ellagic acid (from
green tea, strawberry, eucalyptus etc), and aloesin (from aloe tree).

Other agents known to affect melanin pigmentation and sometimes used in formulations are N-
acetyl glucosamine, thiotic acid (alpha-lipoic acid), gentisic acid, soybean extract, and paper
mulberry extract.

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Combination Treatment
Melanogenesis is a complex, multi-stage process in which precursor molecules are acted upon by
the enzyme tyrosinase to produce the complex biopolymer named melanin in specific organelles
called melanosomes. Melanized melanosomes are then transferred from melanocytes to the
keratinocytes, eventually producing the visually apparent skin color. Various topical agents act
on different stages of this process, thus providing a rationale for combinations of agents for
better therapeutic effect. In addition to having a synergistic effect, a particular drug may abrogate
untoward effects of another drug formulated in the same vehicle. For example, topical steroids
may reduce the irritant effects of HQ or retinoids. On the other hand, retinoids may prevent
steroid-induced cutaneous atrophy. Combinations of hypomelanotic agents with sunscreens are
also available in the market.

Various combinations of different topical agents have been studied and many are marketed by
pharmaceutical companies. Hydroquinone is generally the main component of formulations. It is
combined with drugs like glycolic acid, azelaic acid, kojic acid, retinoic acid, or corticosteroids.
In addition, arbitrary mixtures of various other demelanizing agents are marketed although
efficacy and safety have not been established by controlled clinical trials for most of them.

However, the most extensively studied and widely used combination is the so-called triple
combination, a formulation containing HQ, retinoic acid, and corticosteroids. First proposed by
Kligman and Willis,[55] the original combination utilized 5% HQ, 0.1% tretinoin, and 0.1%
dexamethasone and was found to be effective in the treatment of melasma, ephelides, and
postinflammatory hyperpigmentation. Concerned about the irritant potential of this combination
for its high tretinoin concentration, modifications of the theme have been tried (HQ 4%, tretinoin
0.05%, and fluocinolone acetonide 0.01%) and have been found to be highly effective in long-
term clinical studies.[34] It has been suggested that first-line therapy for melasma should consist
of effective topical therapies, mainly in the form of triple combinations, and only when triple
combinations are unavailable or when patients have hypersensitivity to them, should dual
ingredients or single agents be considered.[34]

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Treatment During Pregnancy[23]

Melasma is more resistant to treatment during pregnancy because of the persistent hormonal
trigger for development of the disease. For this reason, treatment for melasma is routinely
deferred until after delivery. Moreover, treatment may be unnecessary because melasma in
pregnancy may be a transient affair; removal of the hormonal trigger after parturition may result
in significant improvement.

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Conclusion
Management of melasma can be challenging and requires long-term treatment with topical
agents. The results are often unsatisfactory and topical agents may sometimes cause significant
adverse reactions. Hydroquinone has remained the gold standard of topical treatment but
concerns regarding its side effects remain. A triple combination of hydroquinone, retinoic acid,
and corticosteroids has been suggested to be the first-line topical treatment for this pigmentary
disorder. Many new agents that inhibit melanogenesis have been developed. Although in vivo
and in vitro experimental studies have suggested their potential role in the management of
melasma, controlled clinical trials are mostly lacking and are urgently needed in the future.

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Footnotes
Source of Support: Nil

Conflict of Interest: Nil.

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