Melasma Management

Chemical Peels  

Chemical peels are recommended as an alternative therapy if topical agents and triple combination therapy are not effective. Examples of chemical peels are Glycolic acid, Lactic acid, Mandelic acid, Phytic acid, Resorcinol, Salicylic acid, Trichloroacetic acid, and Jessner’s solution (Lactic acid, Resorcinol and Salicylic acid in Ethyl alcohol). These improve the response rate of patients to topical therapy. This is performed by applying chemical agents to the skin to induce progressive exfoliation of the superficial layers of the skin.

Alpha Hydroxy Acid  

Alpha hydroxy acid inhibits tyrosinase activity, thereby reducing melanin production. Examples of alpha hydroxy acid are Glycolic acid and Lactic acid. These are also effective as adjunctive agents to topical treatments. Studies showed that lactic acid works well against epidermal melasma.  

Beta Hydroxy Acid (β-Hydroxy Acid)  

Beta hydroxy acid inhibits tyrosinase activity. An example of beta hydroxy acid is Salicylic acid. This has keratolytic and lipolytic potential. This is more effective when used in combination with topical treatments.  

Topical Corticosteroids  

Topical corticosteroids are used as part of the triple combination therapy if previous combinations were ineffective. An example of a topical corticosteroid is 0.01% Fluocinolone acetate. Clobetasol was found to rapidly clear melasma pigmentation but the mechanism of action is not fully understood and it is not recommended for prolonged use due to local side effects.  

Topical Depigmenting Agents  

Azelaic Acid (9-Carbonodicarboxilic Acid)  

Azelaic acid in 10, 15, 20 and 35% preparations are used to lessen pigmentation. This is a natural dicarboxylic acid that has antiproliferative and cytotoxic effects on melanocytes. This acts by several mechanisms including inhibition of tyrosinase, cell membrane-associated enzyme thioredoxin reductase, specific mitochondrial dehydrogenases and DNA synthesis. A reduction in melasma intensity by 50% may be seen after 1 to 2 months with continuous application for up to 8 months. Studies have shown that the efficacy of Azelaic acid for melasma is comparable to that of Hydroquinone. This may be used in combination with other agents. This is safe for use and generally well tolerated in pregnancy and while breastfeeding.  

Cysteamine (L-Cysteamine)  

Cysteamine is an aminothiol with antioxidant and depigmenting properties by inhibition of tyrosinase and peroxidase which inhibit melanogenesis. This is a well-tolerated, and effective alternative for mild to moderate melasma. Based on randomized clinical trials, the use of cysteamine lowered the MASI scores and reduced the skin colourimetry values.  

Hydroquinone







Hydroquinone has been used for the treatment of hyperpigmentation for many decades. This is a hydroxyphenolic compound that inhibits the conversion of dihydroxyphenylalanine (DOPA) to melanin by inhibition of tyrosinase. This also inhibits DNA and RNA synthesis, induces degradation of melanosomes and promotes destruction of melanocytes. Hydroquinone is commonly used at concentrations ranging from 2-5%, and higher concentrations provide greater efficacy but with greater skin irritation. Hydroquinone can cause permanent depigmentation when used at high concentrations for a long period of time. This may be used in combination with other agents.  

Kojic acid  

Kojic acid is a non-phenol depigmenting agent used as an alternative treatment for patients allergic to Hydroquinone. This is a tyrosinase inhibitor that chelates copper at the enzyme’s active site and has a high sensitizing potential.  

Mequinol  

Mequinol is a phenolic depigmenting agent used as an alternative treatment for Hydroquinone-intolerant patients. This competitively inhibits tyrosinase while sparing melanocytes. This is usually used for solar lentigines when given in combination with Tretinoin.  

Methimazole  

Methimazole is an oral agent commonly used to treat patients with hyperthyroidism. The topical form of Methimazole was found to possess depigmenting effects by inhibiting peroxidase and tyrosinase. A combination with a Q-switched Nd:YAG laser was found to produce better results.  

Niacinamide (Nicotinamide, Vitamin B3)  

Niacinamide is used as adjunctive therapy for melasma due to its skin lightening and brightening effects. This inhibits melanosome transfer after melanin synthesis by modulating the protease-activated receptor (PAR)-2. This is safe for use in pregnancy and while breastfeeding.  

Thiamidol (Isobutylamido thiazolyl resorcinol)  

Thiamidol is a potent tyrosinase inhibitor used as an alternative treatment for Hydroquinone. This helps prevent UVB-induced hyperpigmentation. Clinical trials showed improvement in pigmentation and reduced MASI scores.  

Topical Retinoids  

Topical retinoids inhibit tyrosinase activity, slow down melanin transfer, increase keratinocyte turnover rate and melanin dispersion and help enhance skin permeation through the stratum corneum layer. Examples of topical retinoids are Adapalene, Isotretinoin, Retinaldehyde, Retinol, and Tazarotene.







Tretinoin  

Tretinoin in 0.05-1% preparations are known to reduce pigmentation. This inhibits tyrosinase transcription as well as dopachrome conversion, thereby interrupting melanin synthesis. This stimulates keratinocyte turnover and desquamation resulting in decreased melanosome transfer. This is effective as monotherapy, but better results are seen when used in combination with other compounds. Tretinoin typically takes at least 2 months to see clinical improvement. This may also increase pigmentation secondary to irritation. Cream forms are generally less irritating than gels and solution.  

Adapalene  

Adapalene is an alternative treatment for Tretinoin-intolerant patients. Adapalene in 0.1% preparations are used for long-term melasma treatment. This modulates follicular epithelial cell differentiation by binding to specific nuclear retinoic acid receptor proteins. Studies show that Adapalene is equally efficacious compared to Tretinoin.  

Systemic Agents  

Glutathione  

Glutathione is a tripeptide consisting of glutamate, cysteine and glycine with skin-whitening properties. This possesses antioxidant and anti-inflammatory properties from tyrosinase inhibition and increased intracellular cysteine levels and N-acetylcysteine, shifting melanogenesis from eumelanin to pheomelanin.  

Polypodium leucotomos  

Polypodium leucotomos is a fern of the Polypodiaceae family native to Central and South America, which may be considered as a melasma treatment in combination with other depigmenting agents (eg Hydroquinone, sunscreen). This has antioxidant and photoprotective properties. Further studies are needed to prove the efficacy and cost of Polypodium leucatomos therapy.  

Pycnogenol (Procyanidin)  

Pycnogenol is a standardized extract obtained from the bark of the French maritime pine Pinus pinaster that possesses antityrosinase activity, and antioxidant and anti-inflammatory properties which in turn suppress melanin biosynthesis. Studies showed a reduction in the MASI in subjects within the test group given oral Pycnogenol.  

Tranexamic acid  

Tranexamic acid acts as a plasmin inhibitor that prevents UV-induced pigmentation. This also inhibits melanogenesis and prevents plasminogen binding to keratinocytes which in turn reduces prostaglandin and arachidonic acid production needed for melanogenesis. This is effective as an adjuvant therapy for refractory cases of melasma or as a second or third-line treatment. This may be given orally, subcutaneously, or topically. Topical formulation is often in combination with other agents. Studies showed that the use is comparable to the Hydroquinone-Dexamethasone treatment combination, reduced MASI, and fewer adverse effects.  

Other Therapies  

Ascorbic Acid (Vitamin C)  

Ascorbic acid is an alternative treatment to Hydroquinone that provides skin lightening with less adverse effects. This directly inhibits tyrosinase, thereby reducing melanin production in melanocytes.  

Arbutin







Arbutin is a derivative of Hydroquinone used as an alternative treatment to Hydroquinone. This inhibits tyrosinase, 5,6-hydroxyindole-2-carboxylic acid, and melanosome maturation.  

Other Agents  

Plant extracts (Licorice, Grape seed, Orchid, Aloe vera, Soybean, Coffeeberry, Green tea, marine algae), Indomethacin, Vitamin E, Rucinol, Gigawhite. Malassezin, Metformin and Melatonin are also being investigated for their ability to affect the development of pigmentation.  

Combination Therapies  

Combination therapies are employed to increase efficacy and reduce side effects. Fixed dose (0.1%) triple combination therapy with Hydroquinone, Retinoic acid and corticosteroids provides greater therapeutic success than monotherapy and the most widely used combination therapy. An addition of Tretinoin 0.05-0.1% prevents the oxidation of Hydroquinone, as well as improving epidermal penetration, allowing pigment elimination and increasing keratinocyte proliferation. An addition of corticosteroids to a combined therapy involving Hydroquinone decreases the irritative effects of the hypopigmenting agents, as well as inhibiting melanin synthesis by decreasing cellular metabolism. Dual combination therapy with Hydroquinone and Glycolic acid or single agent therapy with 4% Hydroquinone, 0.1% Tretinoin or 20% Azelaic acid is used in patients who develop sensitivity to triple combination therapy. Other combination therapies include Hydroquinone and Retinoic acid, Hydroquinone and Azelaic acid, Mequinol and Tretinoin and Hydroquinone, and Glycolic acid and/or Kojic acid.

Patient Education  

Patients are advised to avoid sunlight exposure and wear protective clothing when going outdoors. Melasma is oftentimes resolved after pregnancy or discontinuation of contraceptive pills.  

Sunscreens

The use of sunscreens that block UVA and UVB light is highly recommended. A broad-spectrum sunscreen with sun protection factor (SPF) >30 coverage is recommended.  

Camouflage Make-up  

Heavy coverage of camouflage makeup on lesions while blending with unaffected skin color may help.  

Physical Therapies  

Cryosurgery  

Cryosurgery may be an option because melanocytes are susceptible to freezing.  

Intense Pulsed Light (IPL)

Intense pulsed light may be used as adjuvant treatment to topical therapy. Epidermal types respond better to IPL than deeper pigmented lesions, which often respond poorly; thus, it is not recommended in patients with Fitzpatrick skin types IV-VI.  

Laser Therapy







Laser therapy is used as a second-line treatment in cases resistant to other therapies. Examples of laser therapy are low-fluency quality-switched (QS) Nd:YAG lasers, picosecond Nd:YAG lasers, and fractional lasers. A combination of QS + fractional carbon dioxide (CO2) and QS + IPL is recommended for all skin types. Positive results were seen with the use of a pulsed CO2 laser with a Q-switched alexandrite laser. The non-ablative fractional therapy (NAFL) combined with topical tyrosinase inhibitor pre- and post-operative appears to effect a longer lasting clinical response compared with IPL and QS lasers.  

Light Emitting Diode (LED)  

Red or infrared light may be used for pigmentation problems of melasma.  

Microneedling







Microneedling can be used to enhance the treatment outcome of topical agents (eg vitamin C, platelet-rich plasma, depigmentation serums). This stimulates wound repair and collagen and elastin synthesis. This is a safe procedure that encourages keratinocyte proliferation.  

Pulsed Dye Laser (PDL)  

Pulsed dye laser can target the vascular component of melasma. This decreases the stimulus to melanocytes and subsequently the recurrence of the spots. This is not recommended in patients with Fitzpatrick skin types ≥VI.