Melasma Treatment & Management

Melasma is notoriously difficult to treat. The pigment of melasma develops gradually, and resolution is also gradual. Resistant cases or recurrences of melasma occur often and are certain if strict avoidance of sunlight is not rigidly heeded. ^[19] All wavelengths of sunlight, including the visible spectrum, are capable of inducing melasma. The most commonly accepted treatment remains strict sun avoidance often in combination with a topical combination hydroquinine cream. Limiting exposure to exogenous estrogens can play a critical role as well in exposed patients. A chemical peel or laser treatment may help in about a third of cases, a third of cases remain the same, and another third show hyperpigmentation. ^[20]

Prophylactic management is often the most effective means of prevention. Avoidance of sun exposure and use of broad-spectrum, high-SPF sunscreens (50+) in combination with a physical blocking agent (if not included) can prevent or slow the development of melasma. In one study of 200 Moroccan women who applied SPF-50+ sunscreen daily during pregnancy, less than 3% developed melasma. Although the study did not include its own control arm, this is well below the established rates of development in pregnancy (15-50%). ^[21]

The role of oral contraceptives in the development of melasma has been clearly defined, especially in women without a family history of the condition. Therefore, discontinuation of these medications and avoidance of oral contraceptive pills in the future is recommended when possible in women who have onset of melasma after starting these drugs.

The mainstay of treatment for melasma remains topical depigmenting agents. Hydroquinone (HQ) is a classic and commonly used first-line agent, both alone and when combined with other agents. It is a hydroxyphenolic chemical that inhibits tyrosinase, the enzyme that converts L-tyrosine to L-DOPA and the rate-limiting step in the pathway of melanin synthesis. Additionally, cytotoxic metabolites may cause interference with melanocyte function and viability. HQ can be applied in cream form or as an alcohol-based solution.

Concentrations vary from a 2% concentration available in the United States without a prescription to a standard 4% concentration and even higher when compounded. Efficacy is directly linked to concentration, but the incidence of adverse effects also increases with concentration. All concentrations can lead to skin irritation, phototoxic reactions with secondary postinflammatory hyperpigmentation, and irreversible exogenous ochronosis (reported even with long-term use of 2% HQ). Special care must be taken not to prescribe the monobenzyl ether of HQ (Benoquin), which causes an irreversible localized and generalized vitiligolike leukoderma. Outside the United States, topical creams with concentrations as high as 8% are available over the counter. These agents are associated with much higher rates of exogenous ochronosis and should not be used.

In recent years, concerns have been raised about the potential carcinogenic properties of HQ. This is based on the observation that hepatic metabolism of this agent results in the production of benzene derivatives during hepatic metabolism. In the case of topical application of HQ, this does not appear to be a concern, as the vast majority of metabolism of topically applied HQ is metabolized in the vascular system and renally excreted. ^[22] This knowledge has led to concern that free-radical metabolites could induce acute or chronic kidney injury; however, no association has been demonstrated in the 50+ year history of HQ’s use as a topical solution. ^[23] To date, all concerns regarding HQ’s potential toxic effect are considered speculative.

The use of topical retinoids (trans-retinoic-acid) can be effective as monotherapy. These agents are derivatives of vitamin A and lead to increased keratinocyte turnover and decreased melanocyte activity. They also increase the permeability of the epidermis, allowing for better penetration of adjunct therapies. ^{[24, 25]} Care must be taken with these agents, however, as retinoids are known teratogens. It is essential to avoid prescribing systemic retinoid therapy to pregnant patients or patients attempting to become pregnant. Additionally, although there is no evidence that topical retinoids are associated with congenital malformations, pregnant patients should be counseled concerning the risks and benefits of treatment for a cosmetic condition. The response to treatment with topical retinoids is also less than that with HQ and can be slow, with improvement frequently taking 6 months or longer.

Owing to tretinoin’s ability to increase the effectiveness of other therapies, combinations of tretinoin with HQ, with or without a topical corticosteroid, have been promoted. ^[24] In fact, the only topical ointment currently approved by the US Food and Drug Administration (FDA) for the treatment of melasma is a triple-combination cream, a composite of hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01% (Tri-Luma). Comparative studies of the effectiveness of the triple-combination cream versus topical HQ suggest that the combination cream is faster and more effective at reducing melasma pigmentation, but it does carry a slightly increased risk of an adverse reaction. ^[26] A 2010 study found that the triple-combination cream is safe and effective when used intermittently or continuously for up to 24 weeks. ^[27]

The major adverse effect of tretinoin is mild skin irritation, especially when the more effective, higher concentrations are used. Temporary photosensitivity and paradoxical hyperpigmentation can also occur. Tretinoin is believed to work by increasing keratinocyte turnover, thus limiting the transfer of melanosomes to keratinocytes. Adapalene is a synthetic retinoid analog that may be an alternative to tretinoin. A study in Asian Indian patients compared adapalene 0.1% topical to 0.05% tretinoin. After 14 weeks, reduction in MASI scores were equivalent between the two therapies, while the adapalene group developed fewer adverse effects and reported better tolerance to the therapy. ^[28]

Azelaic acid, available as a 20% cream-based formulation, appears to be an effective alternative to 4% HQ and may be superior to 2% HQ in the treatment of melasma. ^{[29, 30]} The mechanism of action is similar to that of HQ, but, unlike HQ, azelaic acid seems to target only hyperactive melanocytes and thus will not lighten skin with normally functioning melanocytes. The primary adverse effect is skin irritation. No phototoxic or photoallergic reactions have been reported. One benefit of azelaic acid is that it may be used in pregnancy. Other depigmenting agents that have been studied in the treatment of melasma are 4-N -butylresorcinol, phenolic-thioether, 4-isopropylcatechol, kojic acid, and ascorbic acid. ^{[31, 32]}

In an attempt to search for a new treatment for melasma, Wu et al studied oral administration of tranexamic acid (TXA) in Chinese patients. TXA tablets were prescribed to 74 patients at a dosage of 250 mg twice daily for 6 months. At follow-up, more than half the patients (54%) showed good results. ^[33] A 2018 review article examining the use of TXA in melasma determined that it is a safe and efficacious treatment modality for refractory melasma and may be administered in low doses over short periods and still demonstrate effect. ^[34] It is easy to administer with few and mild adverse effects, including nasal and sinus discomfort, musculoskeletal and back pain, abdominal pain, and oligomenorrhea. The most important adverse event to consider is a potential for increased thromboembolic events in at-risk populations; although data analysis does not show an increased risk of thrombosis—and surveillance of patients treated with TXA for menorrhagia has not demonstrated any serious adverse events—patients should be screened for contraindications to the use of TXA and for risk factors for thromboembolic events prior to starting therapy.

The use of Polypodium leucotomos extract (PLE) has been evaluated in recent years as well. This is a South American fern extract that is available over the counter with a demonstrated effect on the cutaneous minimal erythematous dose of UV light. It is used for the prevention of many light-sensitive conditions. Several small double-blinded randomized controlled trials have demonstrated that the addition of PLE to a regimen of sun avoidance, sun protection, and use of hydroquinone may improve MASI and MELASQoL scores. ^{[35, 36]}

It has been suggested that taking an oral proanthocyanidin (a class of flavonols) along with a vitamin regimen may significantly reduce pigmentation. At this time, the mechanism for this treatment method is not fully understood. Significantly more study is necessary before this method of treatment could be deemed effective. One major benefit to this mode, however, is that the use of proanthocyanidin is a natural treatment method, and it is a safe alternative in patients who exhibit a moderate or severe adverse reaction to a topical treatment. ^[37]

Quick fixes with destructive modalities (eg, chemical peels, lasers) yield unpredictable results and are associated with a number of potential adverse effects, including epidermal necrosis, postinflammatory hyperpigmentation, and hypertrophic scars. ^{[38, 39]} As such, they are considered second-line therapies, to be used after management with topical medications has failed. The precise manner in which these modalities can be used has not been fully delineated. However, in some experienced hands, they have been anecdotally reported to be safe and effective and to produce results much quicker than topical medications.

Superficial skin peels maybe effective and safe, but they do carry some risk of adverse outcomes. These peels use glycolic or salicylic acid–based compounds and are thought to hasten turnover of hyperpigmented keratinocytes. They are often titrated up slowly, applied first on a monthly basis and with low concentration formulas (20%) and progressing to weekly applications with higher concentrations. Lightening agents are usually used in conjunction with superficial peels for best results. Skin peels do carry risk, however, and should only be used after a trial of therapy with at least one skin-lightening agent. Close monitoring for skin dyspigmentation must be a primary consideration, and therapy should be halted if alterations in the patient’s pigmentation in the surrounding skin are noted.

The efficacy of lasers for the treatment of melasma is unclear and is often associated with equivocal or undesired cosmetic results. Their use should be considered in cases of extensive disease that is refractory to alternative modalities. Q-switched ruby laser treatment has been demonstrated to show no benefit for melasma and actually worsens the condition, especially in those with darker skin phototypes (Fitzpatrick IV to VI). ^[20] Manaloto et al tested erbium:YAG laser therapy in 10 melasma patients with refractory melasma and found no improvement in skin pigmentation, with the adverse effect of postinflammatory hyperpigmentation by 3-6 weeks post procedure, despite administration of oral steroids. ^[40] Given the adverse effects and need to administer systemic corticosteroid therapy, the risks seem to clearly outweigh the benefits.

Fractional resurfacing is another option within laser therapy that does not cause full-thickness epidermal burns. As such, it has reduced levels of postprocedure inflammation and, theoretically, dyspigmentation. A small study by Rokshar and Fitzpatrick showed promising results in 10 patients treated with fractionated laser for 4-6 sessions spread 1-2 weeks apart. They found a 75-100% clearing of melasma, with only one case of postinflammatory dyspigmentation. ^[41] However, follow-up studies were unable to reproduce these results and recommended against fractional ablative laser as a routine treatment modality for patients with melasma. ^[42]

Another study compared topical treatment with triple topical therapy with nonablative fractional laser therapy. ^[43] Both treatments were somewhat beneficial. However, the study did not clearly identify patients who experienced flare ups after the laser therapy. Typically, reactive hyperpigmentation develops in around a third of the cases, especially in patients with dark complexions. Patients must be warned of the potential for a flare-up. Absolute light avoidance is necessary; thus, a good sunscreen must be used during the day, even when inside.

Regardless of the treatments used, all will fail if sunlight is not strictly avoided. Prudent measures to avoid sun exposure include hats and other forms of shade combined with the application of a broad-spectrum sunscreen at least daily. UV-B, UV-A, and visible light are all capable of stimulating melanogenesis. Sunscreens containing physical blockers, such as titanium dioxide and zinc oxide, are preferred over chemical blockers because of their broader protection. Makeups containing zinc oxide or titanium dioxide can serve the dual purpose of covering melasma lesions that patients believe are unsightly, while also serving as protective and preventative therapy. In addition, patients should be forewarned that resolution is gradual and may take many months.

The major complications stemming from treatment of melasma is inflammation-associated hyperpigmentation. For this reason, all treatments must be carefully weighed to consider the risk of generating increasing hyperpigmentation if too aggressive or destructive of a treatment modality is used. Prolonged exogenous use of bleaching agents can also result in hyperpigmentation if used to aggressively or at unsafe concentrations. Patients should be appropriately counseled about the risk of hyperpigmentation that may occur with many of the commonly used melasma treatments.