Melasma: Management

Authors:
Pearl E Grimes, MD
Valerie D Callender, MD, FAAD
Section Editor:
Robert P Dellavalle, MD, PhD, MSPH
Deputy Editor:
Rosamaria Corona, MD, DSc
Contributor Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: Nov 2020. | This topic last updated: Jul 30, 2020.

INTRODUCTION The management of melasma is often challenging,

with incomplete responses in many cases and frequent relapses [1,2]. A

combination of therapies targeting multiple pathogenic elements, such as
photodamage, inflammation, aberrant vascularity, and abnormal pigmentation,
generally provides the best clinical outcomes [3]. The available therapeutic
armamentarium includes a variety of agents that inhibit the biosynthesis of
melanin and increase epidermal turnover and chemical peels and lasers that
accelerate the removal of melanin, without influencing melanin synthesis or
melanosome transfer from melanocytes to keratinocytes [4-6].
This topic presents an overview of treatments for melasma that can be used as
part of a comprehensive management plan that should be individualized to each
patient [1-3,7-10]. The pathogenesis, clinical manifestation, and diagnosis of
melasma are discussed separately. Other congenital and acquired
hyperpigmentation disorders are also discussed separately.
●(See "Melasma: Epidemiology, pathogenesis, clinical presentation, and
diagnosis".)
●(See "Congenital and inherited hyperpigmentation disorders".)
●(See "Acquired hyperpigmentation disorders".)
●(See "Postinflammatory hyperpigmentation".)

PRETREATMENT EVALUATION Pretreatment evaluation of the

patient includes assessment of severity and duration of melasma, specific risk

and trigger factors, level of adherence to treatment, and willingness to adopt
strict photoprotection measures. Moreover, use and response to previous
treatments should also be assessed. As melasma is often influenced or
triggered by hormone therapies, clinicians should personalize recommendations
regarding the use of hormones, based on the unique needs of each patient [7].
(See "Melasma: Epidemiology, pathogenesis, clinical presentation, and
diagnosis", section on 'Risk and trigger factors'.)

PATIENT EDUCATION Patient education has a key role in the

management of melasma. Clinicians should educate patients about the risk

factors and triggers for melasma; the importance of daily use of a broadband
sunscreen that protects against ultraviolet, visible, and even infrared light; and
the importance of consistent use of maintenance therapy to minimize the risk of
recurrence [3,8,11]. (See 'Photoprotection' below.)

APPROACH TO TREATMENT There is no standard therapy for

melasma. Although several treatment guidelines and algorithms have been

proposed, they are, in most cases, based on expert consensus rather than on
evidence from robust, large, randomized studies [7,9,12]. In most cases, a
multimodality approach is required, incorporating photoprotection, skin
lighteners, exfoliants, antioxidants, and resurfacing procedures, based on the
patient's characteristics and clinical presentation [13]. Our approach to the
management of melasma is illustrated in the algorithm (algorithm 1).
Photoprotection — Strict photoprotection, including sun avoidance, sun-
protective clothing, and broad-spectrum sunscreens, is an essential component
of all treatment and prevention regimens for melasma [2,3,7,10,11]. We suggest
daily use of a broad-spectrum sunscreen with a sun protection factor (SPF) of
50 or higher. Sunscreen should be applied in an adequate amount in the
morning and reapplied every two to three hours while outdoors.
While studies document the role of visible light in darker-skinned patients with
melasma, there is a paucity of effective sunscreens blocking visible light [14].
Chemical and mineral (zinc oxide and titanium dioxide-based) broad-spectrum
sunscreens do not provide optimal protection from visible light. The most
efficacious visible light sunscreens contain iron oxide in concentrations above
3%. Of note, iron oxide is the major pigment used in colored topical products
and cosmetics. (See "Selection of sunscreen and sun-protective measures".)

Several studies support the use of ultraviolet (UV) and visible light protection in
the treatment and prevention of melasma:

●In a Moroccan study, 185 pregnant women in their first trimester (15
percent with a previous history of melasma and 6 percent with current
melasma) were asked to apply the sunscreen every two hours [15]. Skin
color stayed the same or became lighter in 79 percent of the women
throughout their pregnancy, and only five women (2.7 percent) developed
new-onset melasma. The authors previously reported that 53 percent of
pregnant women in the same geographical area developed melasma
during pregnancy. Eight of the 12 women with pre-existing melasma
improved.
●An eight-week, randomized trial assessed the efficacy of a broad-
spectrum sunscreen with an SPF ≥50 with or without iron oxide as a visible
light-absorbing pigment in 68 patients with melasma receiving
4% hydroquinone as a depigmenting treatment [16]. A greater improvement
in the Melasma Area and Severity Index (MASI) score and colorimetry
occurred in the group using the combination visible light and broad-
spectrum sunscreen formulation compared with the group using the broad-
spectrum sunscreen only.
●Another randomized study performed in the spring and summer compared
two identical sunscreen formulations, with the exception that one was tinted
 and contained iron oxide (UV plus visible light protection) and the other did
not (UV light protection only) [11]. Thirty-nine patients applied the cream
twice daily, with an additional application every 2 hours and 30 minutes
before exposure to sunlight. Maximal reduction in the MASI score occurred
in the group using the UV and visible light formulation.
Cosmetic camouflage — Cosmetic camouflage is a technique that uses
makeup to conceal skin lesions and normalize the appearance of the skin [17].
It can mitigate the psychosocial impact of melasma and improve the patient's
quality of life [3,18,19]. Anhydrous (water-proof) foundations that contain
titanium dioxide, zinc oxide, and iron oxide provide a dual benefit, as they act as
cosmetic concealers and sunscreen. Cosmetic camouflage can be used during
active treatment.
First-line therapies — Topical skin-lightening agents are the first-line therapy
for melasma (algorithm 1). (See 'Topical skin-lightening agents' below.)
For patients with mild melasma, we suggest hydroquinone 4% cream as first-
line therapy. Hydroquinone can be applied to the affected areas once or twice
daily for two to four months and up to six months, followed by maintenance
treatment for six months or longer. (See 'Hydroquinone' below
and 'Maintenance therapy and prevention of relapse' below.)
There is considerable variation among clinicians in their prescribing practices
for hydroquinone, regarding both the concentration used and the treatment
duration. In the authors' experience, hydroquinone can be safely and effectively
used beyond six months, if needed. In many cases, however, a rotational
treatment that cycles on and off hydroquinone and non-hydroquinone skin-
lightening agents seems to optimize outcomes. (See 'Non-hydroquinone
agents' below.)
Non-hydroquinone skin lighteners, such as azelaic acid, kojic acid, or
niacinamide, alone or in combinations, can be used as alternative first-line
therapies, particularly in patients who do not tolerate or have a demonstrated
allergy to hydroquinone. Of note, azelaic acid is one of a few agents that, if
needed, can be used in pregnant women. (See 'Azelaic acid' below.)
For patients with moderate to severe melasma, the fluocinolone, hydroquinone,
and tretinoin triple combination cream (TCC) is preferred to hydroquinone 4%
cream as initial treatment. The cream is applied nightly for two to four months.
The TCC is the only US Food and Drug Administration-approved melasma
treatment. (See 'Triple combination cream' below.)
Second-line therapies — Chemical peels and oral tranexamic acid are
second-line therapies for patients with melasma that does not respond to topical
therapies alone (algorithm 1). (See 'Chemical peels' below and 'Oral
agents' below.)
Superficial chemical peels commonly used for the treatment of melasma include
glycolic acid, other alpha-hydroxy acids, salicylic acid, Jessner's peel,
and trichloroacetic acid (table 1). Several sessions (approximately five to six)
administered at two- to four-week intervals can be used as an adjunct to regular
use of hydroquinone or non-hydroquinone lightening agents (table 2). Because
chemical peels temporarily remove epidermal melanin without affecting
melanogenesis or melanocytes, patients should be aware that any
improvements will probably be temporary. (See 'Chemical peels' below
and "Chemical peels: Procedures and complications".)
 Skin priming is essential to optimize outcomes with chemical peels.
Priming, or preparing the skin, involves the application of topical skin-
lightening agents, such as hydroquinone and tretinoin, prior to the peeling
procedure, with the aim of enhancing the effect of the chemical peel and
decreasing the risk of postinflammatory hyperpigmentation [20]. Priming
should be done for at least two to four weeks. Lightening agents can be
continued up to the time of peeling, whereas tretinoin should be
discontinued at least 7 to 10 days before the procedure. Tretinoin
significantly increases the depth of dermal penetration of the peeling agent,
which can lead to untoward complications. (See "Chemical peels:
Procedures and complications", section on 'Skin preparation'.)
Oral tranexamic acid, a hemostatic agent with antiplasmin activity, has shown
efficacy in the treatment of melasma at an average dose of 250 mg twice daily
[21-23]. However, relapses invariably occur upon discontinuing oral therapy.
Although the dose used in clinical studies for the treatment of melasma is
considerably lower than that used to treat hemorrhagic conditions (3500 mg
daily), general concerns linger regarding the safety profile, given tranexamic
acid's propensity to induce thromboembolic phenomena [10]. Therefore,
patients should be thoroughly screened for thrombotic risk factors before
starting oral tranexamic acid (table 3) [3,24]. (See "Overview of the causes of
venous thrombosis".)
Third-line therapies — Lasers and light therapies are third-line therapies for
melasma, appropriate for patients in whom topical treatments and often
chemical peels have failed to produce adequate improvement (algorithm 1) [6].
Importantly, lasers and light sources should be used with great care and caution
in darker-skinned individuals due to the risk of postinflammatory
hyperpigmentation. (See 'Lasers and light therapies' below.)
Patients should be informed that lasers and light therapies are not cures for
melasma. Indeed, approximately one-half of patients experience a recurrence
within three to six months of the end of treatment, irrespective of the device
used. Moreover, the recurrence may be associated with more intense
pigmentation, which may be recalcitrant to subsequent treatment. Thus,
clinicians should counsel patients about the importance of adhering to a
maintenance regimen to minimize the risk of recurrence following laser or light
therapy [6]. (See 'Maintenance therapy and prevention of relapse' below.)
Maintenance therapy and prevention of relapse — Routine approaches for
prevention of relapse involve the aggressive use of broad-spectrum and visible
light sunscreens as well as maintenance treatment with non-hydroquinone
lighteners, such as azelaic acid, kojic acid, niacinamide, and retinoids, all of
which are commonly used in the authors' practice (table 2 and algorithm 1).
Additionally, intermittent use of hydroquinone 4% cream or TCC twice weekly
can be incorporated in the maintenance regimen to maintain clearance.

Despite this approach with the available armamentarium of agents, however,

relapses are common. Relapses require resuming active treatment.

TOPICAL SKIN-LIGHTENING AGENTS A large number of

topical skin-lightening agents have been used for the treatment of melasma.
Many of them act as tyrosinase inhibitors or interfere with other steps in melanin
production and transfer (table 2). Novel agents that are also used as primary or
maintenance agents include combination hydroquinone-free preparations
and cysteamine [10]. (See 'Non-hydroquinone agents' below.)
Hydroquinone — Topical hydroquinone was first noted to lighten the skin in
1936 and was initially used to treat clinical hyperpigmentation in 1961 [2]. It
inhibits the conversion of tyrosine to melanin by competitively inhibiting
tyrosinase [25-27]. Inhibition of DNA and RNA synthesis by melanocytes and
increased melanosome degradation may also contribute to hydroquinone's
mechanism of action [3,5,28].
Numerous hydroquinone formulations are now available, either as monotherapy
or combined with other skin-lightening agents or exfoliants, such as glycolic acid
or tretinoin [2,29] (see 'Triple combination cream' below). Concentrations range
from 2% or less, in over-the-counter (OTC) formulations, to 4% or more,
available by prescription only [2]. Hydroquinone rapidly oxides, and tretinoin
may reduce hydroquinone oxidation [9,29].
Efficacy — A 2009 systematic review of 31 randomized and uncontrolled
studies assessing topical treatments, chemical peels, lasers, and other
therapies in Latin American patients with melasma concluded
that hydroquinone 4% monotherapy, triple combination cream (TCC;
hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetate 0.01%), and double
combinations (eg, 4% hydroquinone and 0.1% tretinoin) were the most
appropriate treatments for mild melasma, while TCC was the most appropriate
first-line treatment for moderate to severe melasma [7].
A 2010 systematic review of 20 randomized trials (2125 participants) examining
the efficacy of 23 treatments concluded that TCC was more effective at
lightening melasma compared with hydroquinone 4% alone or dual
combinations of hydroquinone and tretinoin or hydroquinone
and fluocinolone acetonide [30]. However, the included studies were generally
of poor quality and could not be pooled for analysis due to considerable
heterogeneity.
Adverse effects — Hydroquinone can lighten normal skin pigmentation.
However, pigment will return to normal upon discontinuation of the product [31].
Acute complications following hydroquinone application include irritation (the
most common reaction), allergic contact dermatitis, postinflammatory
hyperpigmentation, and hypopigmentation [2]. Patients may develop erythema
and peeling after using TCC [4]. The irritation (eg, itching, burning, and stinging
sensations) was generally mild [2].
Other chronic adverse events associated with hydroquinone include nail
discoloration, ocular side effects, and exogenous ochronosis. Nail discoloration
seems to be a result of oxidation and polymerization of byproducts due to
chronic hydroquinone use. Ocular complications are rare [26]. Exogenous
ochronosis typically presents as asymptomatic hyperpigmentation, erythema,
papules, papulonodules, and gray-blue colloid milia on sun-exposed skin and
often proves difficult to treat (picture 1 and picture 2 and picture 3) [7,26].
(See "Topical skin-lightening agents: Complications associated with misuse",
section on 'Hydroquinone'.)
Despite extensive use in the United States, hydroquinone-related
exogenous ochronosis is uncommon, especially compared with the number
of cases in Africa [32]. The routine use of sunscreens and the relative
 absence of resorcinol-containing and hydroethanolic formulations (which
may increase hydroquinone absorption) in developed countries may
account for these geographical differences [26]. Nevertheless,
hydroquinone is banned in some African and European countries [10].
There have been concerns about a possible link between hydroquinone and
malignancies. However, hydroquinone occurs naturally in some foods, including
coffee, tea, wheat, pears, and blueberries. No retrospective case series,
prospective study, or epidemiologic evaluation in the United States suggests a
causative link between hydroquinone and malignancies [29]. Another literature
review revealed no cases of skin cancer, internal malignancies, or hepatic
dysfunction related to topical hydroquinone use for skin lightening [10]. In
general, hydroquinone and TCC are well tolerated and supported by a long
history of use.
Contraindications — Hydroquinone is contraindicated in pregnant and
breastfeeding women and in patients with documented allergy.
Triple combination cream — The fluocinolone, hydroquinone, and tretinoin
cream, also called triple combination cream (TCC), is the only US Food and
Drug Administration-approved melasma treatment [33]. The various
components of the TCC have complementary effects that act synergistically to
produce the clinical benefits:
●Hydroquinone is a competitive tyrosinase inhibitor that inhibits the
conversion of tyrosine to melanin. (See 'Hydroquinone' above.)
●Topical retinoids (including tretinoin, adapalene, and tazarotene) improve
melasma by promoting turnover of keratinocytes [3]. Topical retinoids may
also inhibit tyrosinase as well by enhancing the penetration
of hydroquinone [2,29]. However, the onset of action when retinoids are
used as monotherapy is usually longer than hydroquinone, taking
approximately 24 weeks for significant lightening to emerge [34]. Tretinoin
is available in various doses (from 0.01 to 0.1%) and formulations (eg,
creams, gels, lotions, and solutions) but is not approved in the United
States as monotherapy for melasma [2].
●Topical corticosteroids may directly inhibit melanogenesis by reducing
production of inflammatory mediators, such as prostaglandins and
leukotrienes [2]. Few studies, however, have assessed the efficacy of
corticosteroids as monotherapy [2]. The topical corticosteroid in the TCC
also reduces irritation induced by the other two ingredients [9].
Efficacy — The efficacy of the TCC for the treatment of melasma has been
evaluated in randomized trials and in a systematic review [30,35,36]:
●In a randomized trial, 260 Asian women with moderate to severe melasma
were treated with the TCC or hydroquinone 4% cream [35]. At eight weeks
in the per protocol analysis, more participants in the TCC group than in the
hydroquinone group had a global severity score of "none" or "mild" (64
versus 39 percent). Similar results were obtained in the intention-to-treat
population (59 versus 36 percent). Adverse events were reported in 49
percent of patients in the TCC group and 14 percent of those in the
hydroquinone group and included erythema, irritation, desquamation, and
skin discomfort.
●In another study, 641 patients received the TCC or dual combination
creams (tretinoin 0.05% and hydroquinone 4%, tretinoin 0.05%
and fluocinolone acetonide 0.01%, hydroquinone 4% and fluocinolone
 acetonide 0.01%) twice daily for eight weeks [36]. In the TCC group, 26
percent had complete clearing of melasma compared with 9.5, 1.9, and 2.5
percent in each of the dual combination creams, respectively. Adverse
effects included erythema, desquamation, burning, dryness, and pruritus.
●A 2010 systematic review of 20 randomized trials (2125 participants)
examining the efficacy of 23 treatments concluded that the TCC was more
effective at lightening melasma compared with hydroquinone 4% alone or
dual combinations of hydroquinone and tretinoin or hydroquinone
and fluocinolone acetonide [30]. The included studies were heterogeneous
and generally of low quality.
Intermittent use of the TCC may be effective in preventing melasma relapse in
some patients [37,38]:
●In a randomized trial, 242 patients with moderate to severe melasma who
had no or mild melasma after eight weeks of daily TCC treatment were
assigned to a six-month maintenance treatment with the TCC in a twice-
weekly or tapering regimen (three times weekly for one month, two times
weekly for two months, and one time weekly for one month) [37]. At six
months, 54 and 53 percent of patients were relapse-free in the two groups,
respectively.
●In an open-label study by the author's group, 52 patients applied the TCC
daily for 12 weeks. Of these, 27 patients who were clear or almost clear at
12 weeks started maintenance therapy with the TCC twice weekly for an
additional 12 weeks, while 25 patients who were not clear or almost clear at
12 weeks continued daily treatment [38]. Of the 27 patients on
maintenance therapy, 21 relapsed and restarted daily treatment, and 6
remained on maintenance TCC throughout follow-up. At 24 weeks, 68
percent of patients in all groups combined were clear or had mild melasma.
Scores on a 10-point patient satisfaction score (where 10 was the best)
averaged approximately 9, and patients wanted to continue treatment [38].
Contraindications and adverse effects — The TCC is contraindicated in
pregnant and breastfeeding women. Adverse effects include skin irritation,
desquamation, and burning. Adverse effects of hydroquinone are discussed
above. (See 'Adverse effects' above.)
Non-hydroquinone agents
Azelaic acid — Azelaic acid inhibits tyrosinase and shows antiproliferative and
cytotoxic effects on several tumor cell lines in vitro [5,31]. In randomized trials,
azelaic acid 20% cream has been shown to be as effective as
4% hydroquinone cream but more effective than 2% hydroquinone cream
[39,40].
Skin lightening produced by azelaic acid typically takes one to two months to
develop [34]. Between 1 and 5 percent of patients treated with 20% azelaic acid
report pruritus, burning, stinging, and tingling. More rarely, patients experience
erythema, dryness, rash, peeling, irritation, and dermatitis [2].
Of note, azelaic acid is a US Food and Drug Administration category B agent
and, thus, one of the few ones that can be used for the treatment of melasma
during pregnancy, if needed (table 4).
Kojic acid — Kojic acid is derived from a species
of Aspergillus and Penicillium. It inhibits tyrosinase by chelating copper at the
enzyme's active site. Kojic acid is widely used in Asia and is available in several
OTC formulations at 2% in the United States, but when used as monotherapy, it
seems to be less effective than hydroquinone [3,7,29]. Patients who are
intolerant of hydroquinone may also consider kojic acid [8].
In a 12-week, split-face study, 40 Chinese women with melasma were treated
on one-half of the face with kojic acid 2% in a gel containing glycolic acid 10%
and hydroquinone 2% and on the other half with a comparable formula without
kojic acid [41]. Melasma improvement of ≥50 percent (based on reduction in
melasma area and degree of lightening) occurred in more sides treated with
kojic acid than in the control sides (60 versus 47.5 percent, respectively).
Several studies have reported that kojic acid is a sensitizer, and it has been
associated with mutagenicity and contact dermatitis [8,29].
Niacinamide — Niacinamide, also known as nicotinamide, is the physiologically
active form of niacin or vitamin B3 [42]. Niacinamide blocks the transfer of
melanosomes from melanocytes to keratinocytes. It has an anti-inflammatory
effect and increases the biosynthesis of ceramides, as well as other stratum
corneum lipids with enhanced epidermal permeability barrier function.
Several studies have documented the efficacy of niacinamide and niacinamide-
based formulations for treatment of melasma. In an eight-week, left-right,
randomized trial, 27 women with melasma were randomized to receive
niacinamide 4% cream on one side of the face and hydroquinone 4% on the
other [43]. The Melasma Area and Severity Index (MASI) score decreased by
70 percent from baseline in the sides treated with hydroquinone and by 62
percent in the sides treated with niacinamide. Moreover, good to excellent
improvement was reported in 44 percent of patients with niacinamide and 55
percent with hydroquinone 4%. Niacinamide reduced the mast cell infiltrate and
showed improvement in solar elastosis as well.
Rucinol — Rucinol is a resorcinol derivative that inhibits tyrosinase and
tyrosinase-related protein-1 (TRP-1), another enzyme in the melanin
biosynthetic pathway. The efficacy of rucinol was assessed in a randomized,
split-face trial of 32 women with melasma who applied 0.3% rucinol serum or
vehicle twice daily for 12 weeks, followed by open treatment of the full face for
an additional 12 weeks [44]. At 12 weeks, the mean MASI score was lower for
the rucinol-treated sides than for the sides treated with vehicle (6.2 versus 6.7,
respectively).
Cysteamine — Cysteamine is a naturally occurring antioxidant produced during
the coenzyme A metabolism cycle in all mammalian cells. The efficacy of
cysteamine hydrochloride cream for the treatment of melasma has been
documented in a few randomized trials [45-47]. In one trial that enrolled 50
patients treated with 5% cysteamine cream or placebo applied once daily for
four months, the MASI scores and colorimetric values were lower in the
cysteamine group than in the placebo group [46]. Side effects occurred in nearly
all patients in the cysteamine group but were mild and included erythema,
dryness, itching, burning, and irritation.
Undecylenoyl phenylalanine — Undecylenoyl phenylalanine is an antagonist
of alpha-melanocyte-stimulating hormone, beta-adrenergic receptors, and stem
cell receptors. In a randomized study, 40 women with melasma applied topical
undecylenoyl phenylalanine 2% or vehicle twice daily for 12 weeks; 37 patients
completed the study [48]. Seventeen of the 20 patients using undecylenoyl had
a partial response, with 11 showing a moderate improvement and 6 showing a
marked improvement. No patient showed a total response. Adverse effects
were mild and included erythema, itching, and burning at the application site.
Combination hydroquinone-free preparations — A combination
hydroquinone-free preparation containing a variety of topical skin-lightening
agents has been formulated to address the multiple pathways involved in the
induction of hyperpigmentation [49,50]. These pathways include melanocyte
activation, melanosome development, melanin synthesis, melanosome transfer,
and keratinocyte differentiation and desquamation. It is available online and
dispensed in clinicians' offices.
In a randomized trial of 43 patients with melasma or postinflammatory
hyperpigmentation, a facial serum containing tranexamic acid, tetrapeptides,
plankton extracts, niacinamide, phenylethyl resorcinol, and undecylenoyl
phenylalanine showed overall comparable efficacy to hydroquinone 4% [49]. In
another 12-week study assessing a different combination formulation, a facial
serum containing 3% tranexamic acid, 1% kojic acid, and 5% niacinamide
reduced the hyperpigmentation in 55 Brazilian women with mild to moderate
melasma (n = 48) or postinflammatory hyperpigmentation compared with
baseline.
Topical and intradermal tranexamic acid — Topical preparations
of tranexamic acid have been evaluated for the treatment of melasma in a few
studies [51-55]. A topical 5% solution of tranexamic acid was compared with
3% hydroquinone in a 12-week, randomized trial including 100 patients with
melasma [51]. Both treatments reduced the MASI score by 27 percent from
baseline. Mild erythema and irritation were reported in 19 of 50 patients in the
hydroquinone group and only in 3 of 50 in the tranexamic group.
Intralesional microinjection of tranexamic acid may improve local tolerability of
the drug, while resulting in a deeper and more even intradermal distribution of
the drug [56]. In an open study, 85 patients received weekly microinjections for
12 weeks. MASI scores significantly decreased from 13 at baseline to 9 at 8
weeks and 7.6 at 12 weeks [56]. Eight (9 percent) of 85 patients rated the
improvement as good (51 to 75 percent lightening) and 65 (76.5 percent) as fair
(26 to 50 percent lightening). The remainder regarded the improvement as poor.
All patients tolerated microinjections well [56].

ORAL AGENTS

Tranexamic acid — Oral tranexamic acid at the average dose of 250 mg twice

daily is a promising adjunctive treatment for patients with melasma who do not
respond to topical hydroquinone or triple combination cream alone [57].
(See 'Second-line therapies' above.)
Tranexamic acid, a hemostatic agent, is a synthetic derivative of lysine, which
inhibits plasminogen from binding to its receptors expressed by keratinocytes
[1,56]. This reduces ultraviolet (UV) light-induced plasmin activity and
concentrations of free arachidonic acids and lowers prostaglandin production,
tyrosinase activity in melanocytes, and the levels of melanocyte-stimulating
hormone [3,56]. Tranexamic acid may also reduce levels of vascular endothelial
growth factor (VEGF) and endothelin-1, chemical signals that promote
angiogenesis, which appears to contribute to melasma pathogenesis [3,58,59].
(See "Management of bleeding in patients receiving direct oral anticoagulants",
section on 'Antifibrinolytics and other pro-hemostatic therapies'.)
Several observational studies and randomized trials have documented the
efficacy of oral tranexamic acid for the treatment of melasma [21-23]:
●In a retrospective study of 561 melasma patients (91 percent female) from
Singapore treated with tranexamic acid 250 mg twice daily for an average
of four months, 90 percent of patients improved, 10 percent of patients
experienced no improvement, and two patients showed worsening [24].
The response rate was higher in patients without family history of melasma
compared with those with a family history (91 and 60 percent, respectively).
Clinical improvement was apparent within two months of starting
tranexamic acid, with a relapse rate of 27 percent. Moreover, 7 percent of
patients developed adverse events, which were generally transient. One
patient developed deep vein thrombosis and was later diagnosed with
familial protein S deficiency, which increases the propensity to develop
abnormal blood clots.
●In a single-center, randomized study, 44 Hispanic patients with moderate
to severe melasma were treated with 250 mg tranexamic acid twice daily or
placebo [21]. After three months, the modified Melasma Area and Severity
Index (MASI) scores declined by 49 and 18 percent in the tranexamic acid
and placebo groups, respectively. In patients with severe melasma, the
reductions were 51 and 19 percent, respectively. Three months after
treatment ended, the reductions were 26 and 19 percent with tranexamic
acid and placebo, respectively. No serious adverse events were seen in
either group.
Although tranexamic acid has an overall good safety profile, it should be
considered a second-line therapy. Adverse effects include abdominal bloating,
headache, tinnitus, menstrual irregularities, and, in rare cases, deep vein
thrombosis. Therefore, patients should be thoroughly screened for thrombotic
risk factors before starting oral tranexamic acid [3,24]. Relapses occur upon
discontinuing oral therapy.
Polypodium leucotomos — Extracts of Polypodium leucotomos, a fern native
to Central and South America, are attracting increasing attention as a possible
oral treatment for melasma and other pigmentary diseases [1,60-62]. P.
leucotomos promotes expression of the p53 suppressor gene, modulation of
inflammatory cytokines, and upregulation of endogenous antioxidant systems,
and it inhibits cyclooxygenase-2 (the inducible enzyme responsible for
prostaglandin production) triggered by UV radiation [10].
Clinical studies of oral P. leucotomos have produced mixed results. A small,
randomized trial including 33 Hispanic women with melasma compared 240 mg
oral P. leucotomos extract with placebo three times daily for 12 weeks with the
use of a sun protection factor (SPF) 55 sunscreen [61]. The melanin index (the
difference between pigmented and adjacent normal skin measured using
narrowband reflectance spectrophotometry) improved by approximately 29 and
14 percent in the P. leucotomos and placebo groups, respectively, between
baseline and week 12. MASI scores also significantly improved in both groups.
However, no statistically significant difference emerged between the groups on
either outcome.
P. leucotomos extract may hasten clinical improvements when added
to hydroquinone. A randomized study analyzed 33 Asian women receiving
treatment for melasma with 4% topical hydroquinone and an SPF 50+
sunscreen plus oral P. leucotomos extract or placebo for 12 weeks [25]. At 12
weeks, 31 and 6 percent of the P. leucotomos and placebo groups,
respectively, showed at least a 75 percent improvement in MASI scores. No
major adverse effects of treatments were reported.
Indeed, based on a review of the literature, doses of P. leucotomos extract
between 480 and 1200 mg daily do not seem to be associated with clinically
significant adverse events [1].
Glutathione — Glutathione, a tripeptide consisting of glutamate, cysteine, and
glycine, has multiple actions that combine to produce a skin-whitening effect. It
inhibits tyrosinase, is an endogenous antioxidant, reduces inflammation, and
can skew production from black or brown eumelanin to pheomelanin, which is
yellow-red [3,63]. Because the ratio between the two forms of melanin
determines skin color, an increase in pheomelanin lightens skin.
The effects of 500 mg glutathione lozenge taken orally once daily for eight
weeks was evaluated in an open study in 30 Filipino women [63]. Patients were
evaluated every two weeks. In sun-exposed skin, the melanin index significantly
and steadily decreased compared with baseline at all assessment times. Buccal
glutathione also decreased the melanin index compared with baseline in sun-
protected skin. Ninety percent of patients stated that buccal glutathione
produced a moderate skin-lightening effect, and the remainder reported a mild
effect. There were no serious adverse effects, although two participants
withdrew due to sore gums and the taste and consistency of the lozenge.
A topical glutathione 2% lotion was compared with vehicle alone in a
randomized, split-face study including 30 Filipino women (mean age 36) [64].
Patients applied the lotion twice daily for 10 weeks. At week 10, 67 percent of
the glutathione-treated sides exhibited skin whitening compared with 3 percent
of the vehicle-treated sides. Moreover, glutathione showed a rapid onset of
action, with 13 percent of treated sides exhibiting skin whitening at six weeks.
No adverse events related to the application of topical glutathione were
reported.

CHEMICAL PEELS Chemical peeling involves the topical application

of a wounding agent, wherein the desired outcome is a controlled regeneration

of the skin, depending on the depth of penetration of the specific agent used
(table 1 and figure 1).
Types of chemical peels — These agents remove definite skin layers (eg,
superficial, medium-depth, and deep), which triggers epidermal regeneration,
and are thus classified according to the histologic depth of peeling into
superficial very light, superficial light, medium-depth, and deep peels (table
1 and figure 1) [3,65]. The majority of clinicians using chemical peels for
melasma utilize superficial or medium-depth peels. These include glycolic acid,
other alpha-hydroxy acids, salicylic acid, Jessner's solution, and trichloroacetic
acid. (See "Chemical peels: Principles, peeling agents, and pretreatment
assessment" and "Chemical peels: Procedures and complications".)
Efficacy — Glycolic acid is the most extensively studied peeling agent for
melasma [3,66]:
●In a review of studies assessing the efficacy of chemical peels, including
glycolic acid, lactic acid, Jessner's solution, tretinoin, and salicylic acid, for
the treatment of melasma in dark-skinned patients, glycolic acid peeling
 was associated with a moderate response in approximately one-half of the
patients, with patients having the epidermal form of melasma showing the
best response [20].
●In a study of 40 Indian women with moderate to severe melasma, serial
30% and 40% glycolic acid peels plus daily use of hydroquinone 5% and
tretinoin were compared with the daily use of hydroquinone 5% and
tretinoin alone. Significantly greater improvement occurred in patients
treated with 30% and 40% glycolic acid peels plus daily use of the topical
lightening formulation compared with daily use of only the topical
formulation.
●In an eight-week, randomized study evaluating a 35% glycolic acid full-
face peel alone or in combination with a 10% or 20% trichloroacetic
acid spot peel in 30 patients with facial melasma, the mean reduction in the
Melasma Area and Severity Index (MASI) score from baseline was similar
in all groups [67]. One-third of patients in the trichloroacetic acid groups
experienced transient, postinflammatory hyperpigmentation.
●In a split-face study comparing the efficacy of a peeling solution that
included azelaic acid 20%, resorcinol 10%, and phytic acid 6% versus a
glycolic acid 50% in 42 women with skin type IV or less, both treatments
resulted in a 50 percent reduction of the baseline MASI score. However,
adverse effects, including protracted burning and dyspigmentation,
occurred in 32 and 36 percent of the sides treated with glycolic acid peel,
respectively, versus none of those treated with azelaic acid 20%, resorcinol
10%, and phytic acid 6% peel [68].
●The efficacy of a superficial peel containing glycolic acid and several other
alpha-hydroxy acids combined with activated vitamin C was evaluated in a
study including 21 women and 4 men aged 25 to 56 years with Fitzpatrick
skin types IV or V. Patients received four chemical peels at one- to two-
week intervals [65]. At eight weeks, improvement in pigmentation, pore
size, and skin evenness was noted, with 96 percent of patients reporting at
least fair improvement. No notable side effects or complications emerged.
Salicylic acid is a lipophilic, superficial peeling agent. The efficacy of 20% to
30% salicylic acid peeling has been documented by one of the authors and
others in the treatment of melasma [69,70]. However, in a split-face,
randomized study including 20 Latin American women with moderate to severe,
bilateral melasma treated on both sides with twice-daily 4% hydroquinone, the
addition of 20% to 30% salicylic acid peels every two weeks for four times on
one side was not more effective than hydroquinone alone in improving melasma
[71].
Adverse effects — Possible adverse effects of chemical peels include
infection, scarring (although this is rare during superficial peels), allergic
reactions, milia, acneiform eruptions, persistent erythema (more than three
weeks), and pigmentary changes [72]. Due to the risk of pigmentation and
scarring, deep and medium-depth chemical peels should be used with caution
in patients with darker skin tones [7,20,72].

LASERS AND LIGHT THERAPIES

Types of lasers/light sources — The principles dictating the use of lasers and
light sources in melasma are based on the theory of selective photothermolysis.
This concept proposes that the unique spectrum of light emitted by a specific
laser is absorbed selectively by a cell or tissue type. Pulses of light that are brief
and shorter than the thermal relaxation time of melanosomes are preferentially
absorbed by pigmented structures in tissue and can cause selective heating
and thermal damage to the pigmented structures [73-75]. Structures in the skin
differ in the wavelengths that they absorb and the resulting thermal damage.
This allows lasers to target specific chromophores, such as hair, tattoo ink, or
excessive melanin, with little collateral damage to the surrounding skin [6].
Moreover, different wavelengths of light penetrate the skin to varying depths,
allowing clinicians to target the particular depth of pigment in melasma (table 5)
(see "Laser and light therapy for cutaneous hyperpigmentation"):
●Nonablative fractional lasers – Epidermal pigmentation is most likely to
respond to a 1927 nm nonablative fractional laser. Dermal melasma may
be more sensitive to lasers emitting wavelengths of 1440, 1540, and 1550
nm [6]. Nonablative fractional lasers seem to be associated with the longest
delay in recurrence, followed by intense pulse light (IPL) and quality-
switched (QS) lasers, the last having the most rapid recurrence rate [6].
●Quality-switched neodymium-doped yttrium aluminum garnet (QS-
Nd:YAG) – The QS-Nd:YAG laser is the most commonly used laser for
melasma [76], despite a relatively rapid relapse rate [6]. QS-Nd:YAG lasers
use a wavelength of 1064 nm, which is better absorbed by melanin than
other skin structures. The QS-Nd:YAG laser also damages the upper
dermal vascular plexus, which is abnormal in melasma, and promotes
collagen formation in the surrounding dermis [76].
●Pulsed dye laser (PDL) – Angiogenesis contributes to melasma
pathogenesis [58,59,77]. The PDL is the gold standard for vascular lesions
and, therefore, can target the vascular component of melasma [77,78].
●Intense pulsed light (IPL) – IPL delivers a broad spectrum of
noncoherent light with a range of 500 to 1200 nm [76]. The clinician can
modulate various parameters, such as wavelength and the number,
duration, and delay of pulses, allowing for more accurate targeting of the
chromophore. Absorption of light by melanin results in thermolysis. This
forms melanin-containing "crusts" that migrate to the cornified layer of the
epidermis, from where they are shed. One study reported excellent results
(80 to 100 percent reduction in hyperpigmented areas and dark tones) with
IPL in 47 percent of 38 patients, good results (60 to 79 percent) in 29
percent, and moderate results (40 to 59 percent) in 13 percent [79]. IPL
targets all pigment in the skin and, therefore, may damage perilesional
normal skin. IPL is thus not recommended in patients with darker skin
tones (Fitzpatrick skin types IV through VI).
Efficacy — Over the years, many studies have evaluated the effect of different
laser protocols for melasma with varying results. However, most studies are
small, only a few are direct comparisons with other treatments, and, as laser
treatment is difficult to blind, laser studies are less robust than randomized,
controlled trials [2]. Moreover, the large heterogeneity of studies of laser
treatment for melasma makes drawing robust conclusions about relative
efficacy and tolerability difficult [6]:
 ●In a split-face, randomized study, 22 Asian patients received five weekly
treatments with a QS-Nd:YAG laser combined with 2% hydroquinone or
hydroquinone 2% alone [80]. On the laser-treated side, colorimetric relative
lightness improved by 93 percent and the mean Melasma Area and
Severity Index (MASI) score by 76 percent compared with 20 and 24
percent, respectively, on the control side. Three patients developed mottled
hypopigmentation, four experienced rebound hyperpigmentation, and
melasma recurred in all subjects.
●In a series of 40 patients from Korea who received 10 weekly treatments
with a QS-Nd:YAG laser, the mean modified MASI score decreased by 54
percent from baseline at 10 weeks. Thirty patients showed at least a fair
improvement, and only four subjects showed no benefit. Two patients
exhibited mottled hypopigmentation and rebound hyperpigmentation [81].
●The combination of microdermabrasion followed immediately by QS-
Nd:YAG was evaluated in 27 women with melasma that was refractory to
other treatments. Patients used sunscreen and topical hydroquinone with
either tretinoin or vitamin C. On average, patients received 2.6 treatments
at four-week intervals. Most patients showed more than 50 percent
clearance within a month of their first treatment. At 3 to 12 months after the
end of treatment, 81 percent of the patients showed more than 75 percent
clearance and 40 percent showed more than 95 percent clearance. Mild
post-treatment erythema after the microdermabrasion, which lasted 30 to
60 minutes, was the only adverse event observed [82].
Adverse effects — Worsening of hyperpigmentation or mottled
hypopigmentation may occur as a result of laser therapy. Patients should be
instructed to adopt rigorous sun-protective measures after treatment, including
sun avoidance and daily use of sunscreen. (See 'Photoprotection' above.)

SUMMARY AND RECOMMENDATIONS

The management of melasma is often challenging, with incomplete responses

in many cases and frequent relapses. Patient education about avoidance of
triggers and risk factors for melasma and the importance of strict sun protection
during and after treatment is key to successful management of melasma. Our
approach to the management of melasma is illustrated in the algorithm
(algorithm 1) (see 'Approach to treatment' above):
●Photoprotection, including sun avoidance, sun-protective clothing, and
broad-spectrum sunscreens, is an essential component of melasma
treatment. For all patients, we suggest daily use of a broad-spectrum
sunscreen with a sun protection factor (SPF) of 50 or higher. Formulations
containing iron oxide provide additional protection from visible light.
Sunscreen should be applied in adequate amounts in the morning and
reapplied every two to three hours while outdoors.
(See 'Photoprotection' above.)
●For patients with mild melasma, we suggest hydroquinone 4% cream as
first-line therapy rather than non-hydroquinone agents (Grade 2C).
Hydroquinone can be applied to the affected areas once or twice daily for
two to four months and up to six months. Other skin lighteners, such
as azelaic acid, kojic acid, or niacinamide, alone or in combinations (table
2), can be used as alternative first-line therapies, particularly in patients
who do not tolerate or have a demonstrated allergy to hydroquinone. For
patients with moderate to severe melasma, we suggest the fluocinolone,
hydroquinone, and tretinoin triple combination cream (TCC) rather than
hydroquinone 4% cream alone as initial treatment (Grade 2B). The cream
is applied nightly for two to four months. (See 'First-line therapies' above
and 'Hydroquinone' above and 'Triple combination cream' above.)
●Superficial chemical peels (glycolic acid, other alpha-hydroxy acids,
salicylic acid, Jessner's peel, and trichloroacetic acid) are a treatment
option for patients with melasma that does not respond to topical therapies
alone. Several peeling sessions (approximately five to six) at two- to four-
week intervals are generally required. Regular use of hydroquinone or non-
hydroquinone lightening agents should be continued between the peeling
sessions (table 2). (See 'Second-line therapies' above and 'Chemical
peels' above.)
●Lasers and light therapies are third-line therapies for melasma,
appropriate for patients in whom topical treatments and often chemical
peels have failed to produce adequate improvement (algorithm 1). They
should be used with great care and caution, particularly in patients with
darker skin to minimize the risk of postinflammatory hyperpigmentation.
(See 'Third-line therapies' above and 'Lasers and light therapies' above.)