New vehicles for topical drug delivery are being investigated. Ethosomes® and Transferomes® have been studied in vitro for topical drug delivery of compounds such as linoleic acid which are used to treat disorders of hyperpigmentation [22]. By using these drug delivery carriers for topical medications, there may be increased skin penetration past the stratum corneum, which may lead to improved local and systemic delivery, as well as higher clinical efficacy.

New conjugates of traditional melasma medications may also be on the horizon. Treatments that typically cause skin irritability, such as salicylic acid (SA) and HQ, have been combined into new formulations which have higher lipophilicity, less aqueous solubility, and lower crystallinity than each medication separately [23]. These new conjugates may improve skin absorption and skin tolerance.

Novel skin-lightening agents are also being developed, many of which have shown promising results. The number of studies done on these newer agents however is very limited, and therefore larger studies will be needed to truly determine their safety and efficacy. One of these agents, undecylenoyl phenylalanine, an antagonist to alpha-melanocyte-stimulating hormone and beta-adrenergic receptors, has been found to significantly lighten melasma with minimal side effects [24]. Given that hormones are thought to play a role in the pathogenesis of melasma, topical flutamide 1 %, an antiandrogenic agent previously used for hair loss, has been studied in an RCT and was found to be as effective as topical HQ 4 % in improving melasma by mexameter assessment and was superior to HQ when comparing MASI scores [25]. Cysteamine, an intrinsic antioxidant that protects against ionizing radiation and that can inhibit melanin synthesis, was used topically in melasma patients and in comparison to placebo was found to significantly reduce MASI scores at 2 and 4 months [26].

Natural ingredients have been gaining popularity in the treatment of pigmentary disorders including melasma. Topical lignin peroxidase, a purified active enzyme derived from the fermented fungus Phanerochaete chrysosporium, has been studied in a 9-week single-center, open-label, prospective study in 31 Chinese women and was found to improve melasma through decrease in skin pigmentation and improvement in skin luminance [27]. Rumex occidentalis, an Asian herb that inhibits tyrosinase activity and blocks melanin formation, was studied in a randomized double-blind placebo-controlled trial in which 45 subjects either received 3 % R. occidentalis cream or 4 % HQ cream, and both were found to be comparable in efficacy and safety [28]. Plant extracts containing catechins/polyphenols, which have inhibitory effects on tyrosinase, have resulted in a significant decrease in melanin levels when compared to placebo [29]. Another plant-derived ingredient, silymarin, derived from the milk thistle plant, contains silybin, a potent antioxidant with photoprotective properties and the ability to inhibit L-dopa oxidation activity of tyrosinase. When studied in 96 melasma patients, a significant improvement was seen in a dose-dependent manner along with prevention of UV-induced skin damage and no significant side effects [30]. Mulberry extract, which has flavonoids and antioxidant properties as well as tyrosinase inhibiting properties, was evaluated in a randomized, single-blind, placebo-controlled trial and was found to significantly improve MASI and quality of life scores [31]. Topical niacinamide (4 %), which has anti-inflammatory properties and can decrease melanosome transfer, has been studied against HQ 4 % in an 8-week, 27-subject study and was found to similarly improve pigmentation in melasma as HQ, but also had the added benefit of reducing mast cell infiltrate and solar elastosis [32].

Various skin-brightening ingredients are also being marketed into commercial products that are hydroquinone free. A topical cream with disodium glycerophosphate, L-leucine, phenylethyl resorcinol, and undecylenoyl phenylalanine was used to treat mild to moderate melasma twice daily for 12 weeks in 20 female patients and resulted in a significant reduction in melasma severity and appearance with high tolerability [33]. Methimazole, an antithyroid medication, was formulated into a 5 % topical cream and used once daily in two patients with HQ-resistant melasma and after 8 weeks led to significant melasma improvement with high tolerability and no significant side effects [34].

Various chemical peels, lasers, and lights continue to be studied as treatment modalities for improving melasma [35]. Chemical peels recently studied include glycolic acid (GA), salicylic acid (SA), Jessner’s, mandelic acid (MA), and trichloroacetic acid (TCA) [36, 37]. Chemical peels have also been used in combination with topical creams.

Lasers and lights recently studied include Q-switched (QS), ablative, and non-ablative lasers that are fractional and non-fractional, long pulsed ND:Yag, intense pulsed light (IPL), copper bromide, and pulse dye lasers (PDL) [38–42]. Q-switched lasers, including ND:Yag, ruby, and alexandrite lasers, are continuing to be studied at various settings in different skin types with varied success rates [43, 44]. Although some laser and light treatments have caused improvement in melasma, other studies have found worsening rebound melasma, postinflammatory hyperpigmentation (PIH), and/or hypopigmentation.

Ablative and non-ablative lasers including CO₂ and Erbium Yag in fractional and non-fractional forms have also shown promise in melasma treatment particularly in targeting dermal melasma [45, 46]. The use of ablative lasers, however, has been more limited due to the increased risk of PIH and difficulty in maintaining long-term results [47].

A new type of IPL, called fractionated IPL, has recently been studied as a weekly treatment for melasma in Asian women and, when compared to biweekly conventional IPL, was found to result in decreased MASI scores with no melasma rebound [48]. Another new type of IPL uses a pulse-in-pulse mode, which releases multiple fractionated subpulses in one pulse width [49]. When compared to traditional IPL, both significantly decreased MASI scores, with the former being preferred by patients due to decreased discomfort during and after treatments. Another light treatment similar to IPL called variable pulsed light is also being investigated. Unlike IPL, it disperses energy as a few small, rapid microflashes instead of one flash of light. It offers the advantage of decreased pain and better absorption into select layers of the skin with decreased amounts of heat entering neighboring tissues [50].

Lasers targeting the vascular component of melasma are also garnering interest. Two recent studies examining the use of copper bromide laser which has wavelengths of 578 nm and 511 nm targeting vascular lesions and pigmentation, respectively, have found the laser to not be efficacious in treating melasma and when compared to Kligman’s combination cream formula , the latter was found to be more effective [51, 52]. In contrast, another report of a woman treated with PDL and Kligman’s formula found that the PDL treatment prevented recurrence of melasma in treated areas [2].

Combination treatments for melasma continue to show promise in further improving melasma and helping those with refractory melasma. Traditional topical treatments are being studied in combination with other topical and procedural treatments and have been found to have various degrees of therapeutic efficacy.

QS ND:Yag 1064 nm laser has been studied in combination with several other treatments. When used with IPL, it has been found to be more effective, particularly for refractory melasma and then when each is used as a monotherapy [39, 53, 54]. When QS ND:Yag laser toning has been combined with vitamin C ultrasonic application, it has led to higher physician and patient assessments [55]. QS ND:Yag laser done after microdermabrasion and maintained with a topical regimen of tretinoin or vitamin C along with sunscreen has been shown to be efficacious in inducing melasma remission for up to 6 months with minimal risk and recovery time [56].

IPL and fractional erbium glass laser, each combined with TCC, have shown greater efficacy together than when each treatment is used alone [57, 58]. Another recent study found that patients treated with oral TA, IPL, and QS ND:Yag laser treatments compared to those who had the laser and light treatments without TA found that the patients in the former group had improved clinical efficacy without significant side effects [59]. This result was supported by another Korean study, which examined the use of oral TA in patients receiving low fluence (LF) 1064-nm QS ND:Yag and found that those in the combination group had overall greater clinical improvement than those who had the laser treatment alone [60].

Additional treatments being investigated for melasma include modes of transdermal drug delivery including skin needling, microneedling, iontophoresis, and radiofrequency. Skin needling has been found to enhance the penetration of topical products, and in a study combining skin needling with a depigmenting serum (containing rucinol and sophora-alpha), the combination resulted in significant improvement of the melasma in comparison to the use of the serum alone [61]. Iontophoresis can increase drug penetration of a compound into the skin in a controlled fashion by applying current through the tissue [62]. Vitamin C iontophoresis has been used successfully in the treatment of melasma and when used in a nanosome formulation has even been found to have better clinical results than 70 % GA [63]. It has also shown efficacy in melasma treatment when followed by a home maintenance regimen consisting of MA [39].

Platelet-rich plasma (PRP) has recently been studied in a single patient who underwent three treatments and had regression of her melasma with greater than 80 % reduction in epidermal pigmentation [64]. The mechanism of action is not fully understood but may involve the effects of TGF-β1 on inhibition of melanin synthesis along with an increase in skin volume.

Energy devices, such as monopolar radiofrequency, have also been combined with transdermal drug delivery of a product containing kojic acid 1 % and were found to decrease MASI scores, average melanin, and erythema with no significant side effects [65].