Abstract
Melasma is a chronic, acquired disorder of focal hypermelanosis that carries significant psychosocial impact and is challenging for both the patient and the treating practitioner to manage in the medium to long term. Multiple treatments have been explored, often in combination given the many aetiological factors involved in its pathogenesis. Therapeutic discoveries to treat melasma are a focal topic in the literature and include a range of modalities, with recent developments including updates on visible light photoprotection, non-hydroquinone depigmenting agents, oral tranexamic acid, chemical peels, and laser and energy-based device therapy for melasma. It is increasingly important yet challenging to remain up-to-date on the arsenal of treatments available for melasma to find an efficacious and well-tolerated option for our patients.
Avoid common mistakes on your manuscript.
Efficacious and well-tolerated novel therapies for melasma continue to be explored as alternatives to traditional topical bleaching agents and triple combination creams. |
Trials for melasma treatments include a variety of modalities that may also work synergistically with existing treatments to enhance the delivery of therapeutic agents as well as target melasma lesions through multiple mechanisms of action. |
Despite the range of treatment options available, melasma remains a difficult disorder of hyperpigmentation to treat, with a high risk of recurrence. |
1 Introduction
Melasma is a chronic, acquired disorder of focal hypermelanosis [1]. It clinically presents as hyperpigmented patches over photo-exposed areas such as the face. It is more common in, but not exclusive to, women and people with darker skin tones, and can be associated with cumulative ultraviolet (UV) light exposure, pregnancy, heat exposure, contraceptive pill use, and familial predisposition [2].
Melasma carries a significant psychosocial impact and it is challenging for both the patient and the treating practitioner to manage in the medium to long term. Multiple treatments have been explored, often in combination, given its multifactorial pathogenesis.
This manuscript reviews the key literature behind existing treatments and provides an up-to-date synthesis of recent developments, including visible light (VL) photoprotection, non-hydroquinone depigmenting agents and the latest literature on oral tranexamic acid (TXA), chemical peels, and laser and energy-based device therapy for melasma.
A literature search was conducted on the PubMed and OvidMedline databases. OvidMedline was used to identify specific treatments, map terms to Medical Subject Headings (MeSH), and utilise Boolean operators. Papers were also obtained from citations of relevant literature. Twenty-one active or completed phase II, III, or IV trials were identified on ClinicalTrials.gov using the term ‘melasma’. Recent papers using standardised measurements such as the Melasma Area Severity Score (MASI) and Melasma Quality of Life (MelasQOL) score and colourimetry were preferentially included [3].
2 Photoprotection and Traditional Topical Treatments
2.1 Ultraviolet and Visible Light Photoprotection
Melasma has long been observed following UV light radiation, with sunscreen application used to treat melasma since the 1900s [4, 5].
In a prospective, single-arm study of 100 patients with melasma, a 3 mL thrice daily application of broad-spectrum sunscreen demonstrated a statistically significant reduction in mean MASI scores of 12.38 ± 14.7 to 9.15 ± 4.7 and mean Hindi MelasQOL scores of 47.2 ± 14 to 38.1 ± 14.2 after 12 weeks [6]; 7% reported burning and 3% reported erythema as minor adverse effects [6]. Meta-analyses reported adverse effects including erythema, peeling, itching, irritation, pruritis, dryness, burning, and oedema, and, less frequently, telangiectasia, contact allergy, hyperpigmentation, and acneiform lesions [7]. Sunscreen has not been found to significantly impact serum vitamin D concentrations [8].
A 12-month observational study in 200 pregnant women using sun protection factor (SPF) 50+ sunscreen found an incidence of melasma of 2.7%. Eight of 12 women with pre-existing melasma reported an improvement in their melasma with sunscreen use. This study was compared with a usual-condition study with the same investigators, geographical area, and time frame, which found 53% of participants develop melasma, suggesting that photoprotection can both treat and prevent melasma in pregnancy [9].
The composition of the sunscreen is also important, particularly in regard to VL protection (400–700 nm) and UVA [10]. Iron oxide is a commonly used VL-absorbing pigment used in tinted sunscreens [11]. A randomised controlled trial on 40 patients with melasma compared the use of a sunscreen formula without VL wavelength protection with the use of a tinted sunscreen formula with iron oxides during the spring and summer [12]. The median MASI score increased by 0.45 (interquartile range [IQR] 0.0–1.65) with VL wavelength protection compared with a 2.43 increase (IQR 0.45–3.68) without VL protection after 6 months [12]. Interestingly, a randomised controlled trial found that sunscreen formulations with different iron oxide concentrations demonstrated no statistically significant differences in the prevention of VL-induced pigmentation, but formulations containing iron oxide were better at preventing VL-induced pigmentation than sunscreens without iron oxide, even if the latter formulations contained titanium or zinc oxide [10].
A randomised controlled trial compared broad-spectrum sunscreen with iron oxide (UV-VL group) versus regular broad spectrum sunscreen (UV-only group) in 68 patients who also used 4% hydroquinone [11]. The trial reported a MASI reduction of 77.8% ± 11% in the UV-VL group versus 61.9% ± 16% in the UV-only group after 8 weeks [11]. Greater relative reduction in colourimetric values and melanin levels were also noted in the UV-VL group [11]. This trial supports the hypothesis that VL protection has a role in treating melasma and suggests that VL protection also enhances the effectiveness of hydroquinone in treating melasma [11].
2.2 Hydroquinone
Initially a rubber antioxidant in gloves, hydroquinone was discovered as a depigmenting agent in the 1930s, via the inhibition of tyrosine oxidation in the melanin biosynthesis pathway [4, 13]. Hydroquinone is applied as a topical cream in concentrations of 4–5% for melasma. It has been considered as the gold-standard treatment choice for melasma and has been used in many trials as the comparative arm to assess the efficacy and safety of novel agents [14,15,16].
Irritation is the most common adverse reaction to hydroquinone [17]. Paradoxically, hydroquinone has a rare but significant risk of exogenous ochronosis: pigmented non-inflammatory papulonodules caused by melanocyte migration into the papillary dermis and subsequent abnormal production of pigmented fibre bundles [18, 19]. This risk is greater in patients with skin of colour with over 6 months of continual product use, or from hydroquinone use without medical supervision [17,18,19,20]. There is a variability in prescribing practices of hydroquinone, although often it is used in a rotational manner, such as a 6-month on/off cycle to reduce the risk of adverse effects [21]. Many alternatives have been investigated that do not have the risk of exogenous ochronosis.
Combination treatments with hydroquinone have also been developed for melasma, including with sunscreen, retinoids, traditional and novel agents, chemical peels, or as triple combination therapy (TCC), discussed in their respective sections [11, 18, 22,23,24,25]. Importantly, sunscreen with VL protection further augments the depigmenting efficacy of hydroquinone, as described in the aforementioned study by Castanedo-Cazares et al. [11].
2.3 Retinoids
Retinoids target melasma via multiple mechanisms, including tyrosinase inhibition, acceleration of epidermal turnover and hence pigment loss, and interference with keratinocyte pigment granules and pigment transfer [26]. In a randomised vehicle-controlled trial of 38 women, 68% rated their melasma as improved or much improved with 0.1% tretinoin compared with 5% who reported improvement in the vehicle group after 40 weeks of use. The tretinoin group demonstrated a 0.9-unit lightening with colourimetry and 36% reduction in epidermal pigment versus 0.3-unit darkening and 50% increase in epidermal pigment in the vehicle group [27].
Retinoic acid can be irritating, especially on initial use. Adapalene is a retinoid derivative that is less irritating. In a randomised controlled trial of 30 women, 0.1% adapalene gel was non-inferior in efficacy to 0.05% tretinoin [28]. Adapalene gel demonstrated a comparable reduction of MASI score (41% vs. 37% at 14 weeks), with fewer adverse effects; 8% reported mild erythema or burning and 13% with dryness with adapalene compared with 63% with pruritus, burning, dryness, erythema, and scaling in the tretinoin group [28]. In contrast, a randomised vehicle-controlled trial found that 0.05% isotretinoin gel did not demonstrate a significant improvement in melasma versus vehicle [29].
Retinoic acid is commonly used with hydroquinone, and like sunscreen, can increase the effectiveness of hydroquinone in treating melasma [22, 23]. Concentrations vary to include 0.025–0.1% retinoic acid with 2–5% hydroquinone [22]. In a prospective, single-arm study of 20 patients, 4% hydroquinone with 0.025% tretinoin cream resulted in a significant (p < 0.001) MASI score reduction after 12 weeks of use [30].
Trifarotene is a novel retinoid used in acne, with a high selectivity for the retinoic acid receptor gamma. No studies could yet be identified that explore its use in melasma, however anti-pigmenting activity has been demonstrated in mouse models [31].
2.4 Triple Combination Therapy
TCC is one of the most popular combination therapies and has been considered a gold-standard treatment. It involves the addition of a mild potency steroid in combination with a retinoid and hydroquinone. Each component targets melasma lesions through a unique mechanism, while also working synergistically. For example, retinoids enhance epidermal penetration of hydroquinone and protect it from oxidation, and the steroid reduces skin irritation from both hydroquinone and the retinoid [32].
TCC can vary in the type of corticosteroid and in the concentration of hydroquinone and/or retinoid, such as 0.1% dexamethasone + 5% hydroquinone + 0.1% tretinoin (Kligman’s), 0.01% fluocinolone acetonide + 4% hydroquinone + 0.05% tretinoin (TriLuma; Hill Dermaceuticals, Inc., Sanford, FL, USA), or modified regimens such as 0.1% mometasone + 2% hydroquinone + 0.025% tretinoin.
Complete or near-complete clearance of melasma was achieved after 12 months of daily Tri-Luma application in a prospective, single-arm study of 228 patients, although 129 patients experienced transient application site reactions and 6 developed telangiectasia [24]. There was no skin atrophy [24]. In a randomised controlled trial of 34 women receiving two variations of TCC, Mexameter readings measured a mean decrease in melanin values from 360 to 300 and 352 to 291, respectively, for each formulation of TCC after 8 weeks, with 30 of the participants demonstrating a lightening of melasma lesions [33]. No skin atrophy was reported, only mild burning and stinging [33]. The trial followed 21 of these patients after treatment completion, and found an increase in pigmentation after 16 weeks, although after 40 weeks, melanin indices remained below pretreatment levels in most patients [33]. A prospective, single-arm study of 22 Middle Eastern patients found a sustained reduction in modified MASI (mMASI) scores, and improved skin lightness (L value) and pigmentation (E value) under Visio Face analysis after 8 weeks of daily TCC application [34].
A prospective, single-arm, multicentre study assessed the impact of TCC on the quality of life of 150 patients with moderate-to-severe melasma after 8 weeks and found both a significant reduction in severity (mean MASI reduction of 4.1 ± 3.7) and improvement in quality of life, as seen by a reduction in MelasQOL score of 44.4 ± 14.9 to 24.3 ± 15.5 [35]. The main adverse effects were telangiectasias and irritation [35].
A retrospective study of 60 patients with melasma found 31 (51.7%) required TCC for more than 3 months in the year preceding the study due to a relapse after the discontinuation of initial treatment [36]; 26 reported telangiectasia, 19 reported skin atrophy, 17 reported hypertrichosis, and 11 reported acneiform eruptions [36]. A correlation between adverse effects and duration of use approached 100% for over 3 months of continuous or recurrent TCC use [36]. However, when used in a maintenance regimen, TCC has demonstrated safety and efficacy in preventing melasma relapse; a randomised controlled trial of 242 patients with moderate to severe melasma tested a twice-weekly regimen versus a tapering regimen [37] and found the twice-weekly regimen was more effective for severe melasma, while the tapering regimen was more appropriate for moderate melasma, and both were well tolerated [37].
2.5 Older Skin Lightening Agents: Kojic Acid, Arbutin, Niacinamide, Ascorbic Acid, Azelaic Acid
Multiple substances have demonstrated efficacy in treating melasma over the years. A selection of treatments used as adjunctive therapies or for mild cases are summarised here.
Kojic acid has been a skin-lightening agent since the late 1980s that functions via tyrosinase inhibition and antioxidant effects [38, 39]. It is a popular over-the-counter ingredient for hyperpigmentation [39]. Arbutin is an effective treatment for hyperpigmentation through reversible inhibition of tyrosinase activity, used since 1989 for melasma [38]. Arbutin cream has reduced MASI scores in trials but can result in erythema and pruritis [40, 41]. Niacinamide is a form of vitamin B3 with antioxidant effects against cellular changes that trigger hyperpigmentation and inhibits melanosome transfer into keratinocytes. It is usually used in 4% or 5% concentrations and in combination with retinoids, sunscreen, or tyrosinase inhibitors [42,43,44,45]. Ascorbic acid (or vitamin C) is an excellent antioxidant for hyperpigmentation but struggles to penetrate the epidermis; a split-face trial of an ascorbic acid serum only showed improvement in 15% of patients with melasma [46]. The clinical response was more significant when ascorbic acid was combined with microneedling in the same trial [46].
These topical agents are often used in combination with other ingredients. For example, a prospective, single-arm study of 3% TXA, 1% kojic acid, and 5% niacinamide improved dyschromias, including melasma, after 12 weeks, evaluated by Mexameter readings and clinical grading [45]. A prospective, single-arm study in patients with a MASI score under 10.5 at baseline found that 4% niacinamide, 3% arbutin, 1% bisabolol, and 0.05% retinaldehyde reduced MASI scores and melasma surface area on medical imaging [42]. A randomised controlled trial of 4% hydroquinone + 3% ascorbic acid demonstrated equal effectiveness after 4 months to 5% cysteamine cream in terms of mMASI reduction and quality-of-life improvement, and produced a greater melanin index reduction [25].
Azelaic acid inhibits tyrosinase, has anti-inflammatory properties, and selectively targets overactive melanocytes [47.] Some papers suggest it has a similar efficacy to hydroquinone [48, 49]. An open-label comparative trial compared 20% azelaic acid cream twice daily with 4% hydroquinone in 29 patients with mild melasma [50] and found no significant difference in mean MASI scores after 1 month but a significant difference after 2 months, with a decrease of MASI from 7.6 ± 3.5 to 3.8 ± 2.8 with azelaic acid versus 7.2 ± 3.2 to 6.2 ± 3.6 with hydroquinone [50]. The azelaic acid group also noted less erythema and pruritis [50]. Azelaic acid represents a well-tolerated alternative to hydroquinone in mild melasma and has also demonstrated efficacy with oral TXA or chemical peels for more severe cases [51,52,53].
3 Novel Topical Treatments
3.1 Thiamidol
Thiamidol (isobutylamido thiazolyl resorcinol) is a potent reversible inhibitor of tyrosinase that may challenge hydroquinone as a treatment choice for melasma.
An exploratory split-face randomised controlled trial compared a 0.2% thiamidol-containing formulation with an untreated control, and with 2% hydroquinone [54]. In 39 patients, there was a significant decrease in mean mMASI on the thiamidol-treated side of 9.73 ± 4.45 to 6.44 ± 4.42, with no significant change on the control side after 12 weeks [54]. Twenty-eight patients participated in the comparison of thiamidol versus hydroquinone, which found a 2.84 ± 2.25 reduction in mMASI after 12 weeks on the thiamidol-treated side compared with a 1.52 ± 2.15 reduction on the hydroquinone-treated side [54]. Upon self-assessment, 96.4% of subjects reported an improvement in pigmentation on the thiamidol-treated side versus 57.1% on the hydroquinone-treated side [54]. Notably, 10% of subjects experienced a worsening of mMASI scores after 12 weeks, on the hydroquinone-treated side [54]. Image analysis of clinical photography demonstrated a statistically significant improvement of L*-values for the thiamidol-treated sides at all time frames; this was not statistically significant in the control or hydroquinone sides [54]. There were no adverse effects with thiamidol [54].
A randomised controlled trial of 50 women with melasma compared the efficacy of 0.2% thiamidol versus 4% hydroquinone over 90 days [55]. All patients received tinted SPF60 sunscreen [55]. There was a mean 43% (95% confidence interval [CI] 35–50%) reduction in mMASI scores in the 0.2% thiamidol group compared with a 33% (95% CI 23–42%) reduction in the 4% hydroquinone group. Two patients (8%) receiving thiamidol reported allergic contact dermatitis, but no serious adverse effects were noted [55]. Although this study did not find a significant difference in efficacy with thiamidol, it proposes thiamidol as a suitable and well-tolerated alternative to hydroquinone.
Forty-eight women with moderate-to-severe melasma completed a 24-week randomised controlled trial that compared thiamidol with a vehicle [56]. A mean MASI reduction of 4.2 ± 2.4 using thiamidol compared with 2.3 ± 1.7 using the vehicle was obtained [56]. The mean MASI score increased after treatment cessation but remained below baseline at 13- to 20-week follow-up [56]. At 24 weeks, MelasQOL scores decreased by 25.1 ± 16.1 with thiamidol compared with 17.5 ± 13.3 with the vehicle, suggesting a significant quality-of-life improvement (p < 0.001) in patients using thiamidol [56]. Akin to the other trials, thiamidol was very well tolerated [56].
In late 2023, a randomised controlled trial of 40 patients investigated the efficacy and safety of 0.1% thiamidol + 0.1% retinoic acid + 0.1% dexamethasone acetate compared with a traditional TCC formulation (5% hydroquinone + 0.1% retinoic acid + 0.1% dexamethasone acetate), applied daily for 12 weeks [57]. At week 12, the mean mMASI for the thiamidol combination group improved by 63% compared with 39% in the TCC group, but statistical significance was not achieved [57]. Greater MelasQoL improvement was also noted in the thiamidol combination group. A partial but limited relapse was noted in both groups 12 weeks after treatment cessation; patients were instructed to use sunscreen as maintenance therapy [57]. No major adverse events were reported, however irritation adverse effects were noted in 68.4% and 65% of the thiamidol combination and TCC groups, respectively [57].
3.2 Cysteamine
Cysteamine is an aminothiol with depigmenting properties, used after the discovery of formulations that reduce its sulphur-like odour. A cysteamine-containing cream is applied to the skin for 15 min to 2 h and then washed off. Its mechanism of action is not fully understood, however theories include an inhibition of tyrosinase and peroxidase, reduction in the rate conversion of tyrosine to dopaquinone, and upregulation of intracellular glutathione, which collectively inhibit melanogenesis and shift eumelanin to pheomelanin synthesis [58, 59].
A randomised placebo-controlled trial of 50 patients demonstrated statistically significant MASI score reductions after 4 months (7.2 ± 5.5 with cysteamine vs. 11.6 ± 7.9 with placebo), and a greater reduction in colourimetry scores: 26.2 ± 16 from 75.2 ± 37 with cysteamine, and 60.7 ± 27.3 from 68.9 ± 31 in the placebo group [60]. Another randomised, placebo-controlled trial of 40 patients found lower MASI scores and reduced skin colourimetry values with cysteamine [61].
A double-blinded, randomised controlled study divided 20 patients into a 5% cysteamine or 4% hydroquinone group [16]. After 16 weeks, the mean mMASI reduced by 21.3% (5.6 ± 2.7 from 7.1 ± 3.41) following cysteamine use compared with a reduction of 32% (6.3 ± 4.8 from 9.2 ± 5.7) following hydroquinone application [16]. The predominant adverse effect for both treatments was irritation, which was more common with cysteamine [16]. In a quasi-randomised, multicentre, evaluator-blinded comparative trial of 5% cysteamine versus 4% hydroquinone on 40 women, the cysteamine group had an inferior reduction in mMASI (24% vs. 41%) and a smaller decrease in MelasQOL scores, but similar levels of depigmentation with colourimetric assessment [58]. This study included different cysteamine application times, from <30 min to overnight facial contact time, despite recommendations to use the cream for up to 2 h [58]. Up to 20% of patients in the cysteamine group reported erythema and burning, similar to the hydroquinone group [58].
The shift in eumelanin to pheomelanin synthesis induced by cysteamine may pose a theoretical risk of melanoma-genesis. An increase in pheomelanin has been demonstrated to increase the rate of melanoma-genesis in mice induced to carry a high pheomelanin-to-eumelanin ratio, a change intended to mimic individuals with a red hair/fair skin phenotype [62]. However, reassuringly, no studies have been identified that suggest an increased risk of melanoma in humans using cysteamine.
Although cysteamine may be inferior in efficacy to hydroquinone, it can be a well-tolerated, effective alternative for mild-moderate melasma.
3.3 Tranexamic Acid: Topical and Intradermal Formulations
TXA is a lysine amino acid derivative that targets melasma through reversible inhibition of plasminogen to plasmin conversion. UV exposure activates the plasmin-keratinocyte-plasminogen activator system, from which plasmin increases intracellular release of arachidonic acid and α-melanocyte-stimulating hormone, resulting in melanogenesis [63]. New research has found an association between melasma and solar elastosis, an increase in mast cells and vascularisation in melasma lesions, and suggests that melasma carries a photoaging component [64, 65]. TXA also targets melasma by decreasing mast cells and angiogenesis [64].
Topical TXA has been trialled in formulations including gel, liposome, cream, and solution-based mediums of 2–10% concentrations, with varying efficacy [63]. A double-blind, split-face trial found 3% topical TXA has comparable efficacy with 3% hydroquinone + 0.01% dexamethasone, with fewer adverse effects [66]. In a prospective, single-arm study, topical 3% TXA demonstrated efficacy and tolerability in combination with 5% niacinamide and 1% kojic acid [45]. However, a randomised vehicle-controlled trial of 21 women with melasma found 5% TXA to show no difference in MASI or melanin index to its vehicle [67].
TXA has also been trialled with intradermal administration, laser-assisted delivery, and as an oral agent (laser and oral delivery is described in later sections) [68].
A randomised comparative trial of topical versus intradermal TXA in 60 women noted significantly better results in the intradermal group, with a mean MASI reduction of 39.1%, 62.7%, and 4.2% in a 4 mg/mL intradermal, 10 mg/mL intradermal, and 10% TXA cream, respectively [69].
A randomised, split-face study compared TXA mesoneedling with intradermal TXA microinjections in 27 women and found a respective reduction in mMASI of 1.28 with mesoneedling versus 0.89 with microinjection, a comparable but not statistically significant difference [70]. TXA mesoneedling resulted in better patient satisfaction but more erythema, scaling, and oedema than microinjection [70]. Another randomised, split-face trial found comparable efficacy and safety between microneedling + topical 4% TXA and 4% hydroquinone monotherapy, but acknowledged the frequent visits and financial burden that microneedling may require [71].
Consensus suggestion is that the efficacy of TXA is largely based on its ability to penetrate the skin and deliver the dose to the target site [63]. The TXA molecule itself is 157 daltons [72]. Molecules under 500 daltons are considered small enough to penetrate the epidermis, however papers have raised concerns that the water-soluble nature of TXA limits its transepidermal absorption [72].
3.4 Other Novel Agents and Techniques: Metformin, Resveratrol, Platelet-Rich Plasma, Microneedling
Metformin has demonstrated a downregulating effect on melanogenesis via the inhibition of cyclic 5′ adenosine monophosphate (cAMP)-related genes involved in melanogenesis [73]. In a randomised controlled trial, 40 patients received either 30% metformin cream or TCC (hydroquinone 2% + tretinoin 0.025% + fluocinolone acetonide 0.01%) for 8 weeks [73]. MASI scores decreased with both, with a 55.97 ± 16.77% versus 56.50 ± 19.44% reduction in the metformin and TCC groups, respectively [73]. Patient satisfaction was similar, and no patients reported irritation using metformin [73]. Another randomised controlled trial of 40 patients over 8 weeks found that 30% metformin lotion was almost as effective as TCC in the management of melasma [74]. Both studies did not achieve statistically significant differences in efficacy [73, 74].
Resveratrol inhibits tyrosinase directly and indirectly, regulates melanocyte function, and carries antioxidant and anti-inflammatory properties [75, 76]. It has been trialled in combination with 4-n-butylresorcinol, a compound related to thiamidol [75]. A prospective, single-arm study of liposome-encapsulated 4-n-butylresorcinol and resveratrol cream produced a significant improvement in melasma in 21 women, with a reduction in melanin index using Mexameter (from 201.08 ± 25.76 at week 0 to 182.83 ± 18.61 at week 4) [75]. Two patients reported mild irritation that resolved after 4 weeks [75].
Autologous platelet-rich plasma (PRP) has been tested as a novel treatment; platelet release of transforming growth factor-beta from alpha-granules inhibits melanin synthesis [77]. PRP is obtained from centrifugation of the patient’s blood, activated with calcium chloride, then administered by intradermal injection [77]. A prospective, single-arm trial of PRP in 23 patients found a significant decrease in MASI from 15.5 ± 8.4 to 9.5 ± 7.2, and an improvement in MELASQOL from 42 ± 14.8 to 16.6 ± 7.2 after three applications over 15-day intervals [78]. A split-face prospective trial found a higher mMASI reduction with 1 mL PRP intradermal injections (53.66 ± 11.27%) versus 4 mg TXA intradermal injections (45.65 ± 8.10%), administered monthly for 3 treatments [77]. The PRP side had less pain (7.5% vs. 62.5%) and erythema (32.5% vs. 55%) than TXA [77]. PRP with 4% hydroquinone has also demonstrated superiority to 4% hydroquinone alone; a reduction of 82% versus 69% in mMASI scores was achieved in 30 patients in a split-face comparative study [79],
Microneedling has been postulated to lighten recalcitrant melasma lesions via the stimulation of collagen and elastin to diminish the visibility of dermal pigment [80]. A pilot study of 20 patients reported a reduction in mMASI following 4 months of microneedling, and another pilot study of 6 patients reported a reduction in MASI scores following 2 months of microneedling with TCC [80, 81]. A systematic review of eight studies revealed only low-level evidence for use in melasma, with most studies assessing its efficacy alongside other topical therapies that should be considered confounding factors [82].
4 Oral Treatments
4.1 Oral Tranexamic Acid
Oral TXA has been investigated in recent trials from Korea, China, and Japan, with potentially more promise than topical and intradermal formulations in treating moderate-to-severe melasma [83, 84]. Oral TXA has been historically used in higher doses to manage excessive bleeding, and is a cheap and available medication.
A prospective, randomised, open-label study found a significant reduction in MASI with oral TXA compared with intralesional injections; 100% vs. 53% achieved MASI-50 following 250 mg twice-daily oral TXA versus monthly 4 mg/mL TXA microinjections over 3 months [85]. Other studies with the same dosing regimens have found oral and intradermal TXA to be equally efficacious [86, 87]. Adverse effects included headaches, gastrointestinal discomfort, hypomenorrhoea, and injection site pain (for intradermal TXA) [86, 88].
In an observational study, 42 patients received 325 mg TXA twice daily and were observed over an average of 12.7 months [88]; 73.8% reported an improvement in melasma, and of the 11 without improvement, 10 used TXA for under 1 month [88].
To identify an effective dose, a randomised, open-label trial compared 250 mg TXA twice daily with 500 mg TXA twice daily in 50 patients over 12 weeks, with 24 weeks follow-up. After 12 weeks, mean mMASI scores were reduced by 4.8 ± 2.2 versus 6.8 ± 3.4 in the 250 mg and 500 mg groups [89]. Efficacy was maintained after 12 weeks post-treatment [89], and no adverse effects were observed [89]. The study suggests that both doses were comparable and well-tolerated, with low rates of relapse [89].
Oral TXA has been combined with other therapies. 325 mg TXA twice daily with TCC cream has been compared with 325 mg TXA twice daily as monotherapy over 16 weeks [64]. The combination group found a reduction in mMASI at weeks 4, 8, and 16 of 50.04%, 65.45%, and 35.31% from baseline, respectively, noting a slight relapse over time [64]. The TXA monotherapy group found a 42.22%, 60.74%, and 76.85% reduction in mMASI from baseline at weeks 4, 8, and 16, respectively, noting a more sustained improvement [64]. The combination group had more marked decreases in melanin index at weeks 4 and 8, but a lower melanin index was noted in the TXA monotherapy group at week 16 [64]. MELASQOL scores were similar [64]. Only mild adverse effects were noted in either group [64]. A randomised controlled trial of 60 patients did not reach a statistically significant decrease in MASI scores when investigating oral TXA combined with TCC versus TCC alone, and another randomised controlled trial of 100 patients found synergistic effects using oral TXA combined with 4% hydroquinone but there was no improvement in relapse rates (30% vs. 26% for TXA with TCC vs. TCC) [90, 91]. This is in contrast to a study of 120 Indian patients with melasma that found a greater improvement in mMASI following 250 mg TXA twice daily with TCC versus TCC alone for 12 weeks of treatment; 65.6% versus 11.9% achieved mMASI-75, and a recurrence rate of 18.03% versus 64.4% was observed at Week 24 [92].
TXA 250 mg daily with liposomal 20% azelaic acid demonstrated a greater improvement than oral TXA combined with 4% hydroquinone and was also more tolerable [51], However, 250 mg TXA taken twice daily with topical 3% TXA applied twice daily achieved lower MASI scores (6.06 ± 5.06 from 33.7 ± 12) than 250 mg TXA taken twice daily with daily 20% azelaic acid (10.62 ± 7.43 from 34 ± 13) in a different study [52].
Oral TXA demonstrated a higher efficacy than PRP as monotherapy; a study of 60 patients found a 65.7 ± 24.6% MASI reduction with oral TXA versus a 54.6 ± 20.7% reduction with monthly PRP intradermal injections after 3 months of treatment [93].
4.2 Oral Polypodium l eucotomos
Polypodium leucotomos (PLE) is a tropical fern with potential evidence as a melasma therapy [94]. It is an antioxidant with photoprotective activity, prompting its use in sunscreens or for photosensitive conditions such as polymorphous light eruption [95].
Forty patients with melasma who were already using 4% hydroquinone cream and SPF50+ sunscreen were recruited and treated with 240 mg twice daily oral PLE or placebo [95]. The PLE group experienced a 49.4% reduction in mMASI at day 56 of treatment, compared with a reduction of 32.6% in the placebo group [95]. The findings were statistically significant; 31.3% in the PLE group achieved mMASI-75 compared with 6.3% in the placebo group, but this did not reach statistical significance due to the cohort size [95]. A greater response to treatment was also noted at day 28 in the PLE group, suggesting a faster clinical response [95]. MelasQOL improvement was comparable [95]. Two patients reported mild itching and stinging in the PLE group that was attributed to the hydroquinone cream [95].
A different trial recruited 40 women who either received 240 mg thrice daily oral PLE or placebo, alongside sunscreen for 12 weeks [96]. There was an improvement in melanin index of 28.8% versus 13.8% in the PLE group compared with the placebo group, which was not statistically significant [96]. The study was powered to detect a difference of 11.7 points in melanin index but only resulted in a difference of 5.1 points, and there was no significant intergroup difference in MASI and MelasQOL [96]. The study concluded that PLE does not provide enough improvement in melasma to justify its cost and use [96].
4.3 Pycnogenol
Pycnogenol is an extract from French maritime pine bark with anti-tyrosinase activity, antioxidant and anti-inflammatory properties, and targets the vascular component of melasma through inhibition of vascular endothelial growth factor [97]. A randomised controlled trial of 44 women received either 75 mg oral pycnogenol or placebo for 60 days [97]. Both groups also used a tinted sunscreen and TCC [97]. At 60 days, the mean (95% CI) reduction in mMASI scores was 49% (36–61%) with pycnogenol versus 34% (16–17%) with placebo, which was a statistically significant reduction (p = 0.040) [97]. A 30-day, prospective, single-arm trial in China of 30 women receiving 75 mg pycnogenol described a mean reduction of 25.8 mm2 in melasma area after 30 days and a reduction in pigment intensity [98]. A randomised, single-arm trial of 100 mg pycnogenol with sunscreen over 90 days showed a significant (p < 0.05) reduction in MASI and MELASQOL scores, and 94.4% of participants reported clinical improvement on self-evaluation [99]. Pycnogenol was well tolerated in all of the trials, although any literature on possible adverse effects to consider remains limited [97,98,99,100].
5 Chemical Peels
Chemical peels are an effective option for refractory melasma, acting via the elimination of pigment through exfoliation. Alpha-hydroxy acids, beta-hydroxy acids, combination peels, and combinations with topicals such as 20% azelaic acid, have been used for enhanced efficacy [53, 101, 102]. The peel is applied over the affected area for 2–10 min and then washed off.
To reduce the risk of post-inflammatory hyperpigmentation, consensus groups suggest first using a priming agent in the preceding weeks [103]. Studies have found 2% hydroquinone to be superior to either 0.025% tretinoin or no primer in improving chemical peel efficacy and reducing hyperpigmentation [104, 105]. The depth of action of the peel is associated with the severity of adverse effects, with superficial peels used for sensitive skin. Post-procedure care with sunscreen, emollients, and maintenance doses of peel ingredients or other topical treatments are encouraged and used in most studies [103].
Glycolic acid (GA) is an alpha-hydroxy acid used commonly for melasma [106]. Higher concentrations (35%, 50%, and 70%) provide greater efficacy, with a trial suggesting that 50% GA may be ideal [102]. Diminished returns and a greater risk of post-inflammatory pigmentation may occur at higher concentrations than this [102].
The efficacy and tolerability of different chemical peels has been trialled. Comparisons involving fortnightly treatments of 30% GA, 92% lactic acid (LA), and 15% trichloroacetic acid (TCA) were conducted in 30 patients over 12 weeks [107]. Peels were applied for up to 5 min. There was a statistically significant improvement in mean MASI with the GA and TCA peels compared with the LA peel, which was attributed to the deeper penetration of TCA and GA [107]. MelasQOL scores were lowest in the GA group, followed by TCA and then LA, although a statistical difference was only noted between GA and LA. GA targets deeper skin layers due to its small molecular size, while TCA peels cause coagulative necrosis of the epidermis and upper dermis, prompting tissue rejuvenation [106, 107]. Likely due to its superficial depth, LA was the best tolerated, with 90% of patients reporting good or excellent tolerance compared with 30% for GA and 20% for TCA [107]. However, equal efficacy was demonstrated in another study of 92% LA and 50% GA applied for 30 min, suggesting that the duration of application is a key factor [107, 108]. A different study found a comparable reduction in MASI scoring after 12 weeks (79% vs. 73%) in GA and TCA, but fewer adverse effects with GA peels [109].
Jessner’s solution (LA, salicylic acid, and resorcinol in 95% ethanol solution) has been compared with 92% LA in a split-face study of 30 patients with melasma resistant to previous therapies. Patients received two to five sessions. A 79.34% decrease in mean MASI was obtained with LA peels compared with 80.26% using Jessner’s solution, with a sustained response in both groups at 6-month follow-up. Excluding erythema and exfoliation in a few patients, both peels were well tolerated [110].
Tretinoin peeling is effective against melasma; a 1–5% twice-weekly application for 2.5 weeks saw similar histological responses to a daily topical tretinoin (Retin-A) applied for 4–6 months, noting the rapid effect of the peel [111]. One percent tretinoin peels demonstrated comparable efficacy with 70% GA with minimal adverse effects after 12 weeks, although this was in a pilot study of just 10 patients [112]. In 20 patients, a significant improvement in MASI, Mexameter readings, and digital photography was noted after four sessions of a 10% tretinoin mask applied every 3 weeks [113]. Improvement was maintained at 1-year follow-up [113].
A combination of peels may not have additive effects in treating melasma. There was no significant difference in MASI reduction in a study of 30 patients divided into 35% GA full face, 35% GA full face + 10% TCA spot peel, and 35% GA full face + 20% TCA spot-peel groups [114]. However, the group using only 35% GA demonstrated the least adverse effects [114]. A trial compared 35% GA versus 20% salicylic-10% mandelic acid versus phytic acid combination (phytic acid + GA + LA + mandelic acid) peels in 30 patients each [106]. Four percent hydroquinone and 0.05% tretinoin acid was used as a priming agent for 4 weeks prior [106]. A MASI reduction of 62.36%, 60.98%, and 44.71% in the GA, salicylic-mandelic acid, and phytic acid group was observed, respectively, after 12 weeks; significantly less improvement was noted with the phytic combination peel [106]. All patients developed erythema and skin peeling, although salicylic-mandelic acid produced less stinging, burning, and post-inflammatory hyperpigmentation [106]. In contrast, a split-face study including 27 patients compared TCA peels applied every 10 days with a single application of a combination peel of salicylic acid, LA, phytic acid, citric acid, and tocopheryl acetate [115]. Four percent hydroquinone was provided as daily treatment for both sides of the face. After 3 months, a reduction in mMASI of 62.8 ± 19.4% and 66.4 ± 23.4% in the combined and TCA sides was achieved, respectively [115]. Although the combination peel was not superior, it suggests that a single session of combined chemical peels may be a convenient alternative [115].
6 Laser Therapies
Laser or energy-based devices treat refractory melasma and include Q-switched neodymium-doped yttrium aluminium garnet (QS Nd:YAG), picosecond technology, intense pulsed light (IPL), radiofrequency, and combinations including medications with laser, microneedling with laser, and combinations of different lasers. Laser therapies are not a first-line treatment for melasma, but instead should be considered in patients who have not improved with medical management, after taking into consideration the financial commitment and high risk of recurrence upon discontinuation of therapy.
A variety of treatments exist in the literature, with recent research focusing on topics such as the picosecond laser, combination regimens, and novel wavelengths.
6.1 Low-Fluence QS Nd:YAG
The 1064 nm QS Nd:YAG laser targets dermal melanin and allows for minimal damage to the epidermis [116,117,118,119]. It is considered a gold-standard laser for melasma in Asia and is well tolerated [120].
A low-fluence offers selective photothermolysis of melanosomes without destruction of the cells themselves; protection of the melanosome-containing cells reduces the risk of vascularisation and activation of melanocytes from dermal inflammation, and hence dyspigmentation [120]. A comparative study of QS Nd:YAG at 1.5 J/cm2 for four passes versus 3 J/cm2 for two passes found equal therapeutic responses but less pain with lower fluence [117]. Compared with high fluence, greater clinical response and fewer adverse effects, including irritant and confetti hypopigmentation and post-inflammatory hyperpigmentation, have been demonstrated [121]. Low-fluence 1064 nm QS Nd:YAG has comparable efficacy with TCC therapy, Jessner peeling, low-fluence Q-switched alexandrite laser (755 nm), and superior efficacy to GA peeling [121,122,123,124].
However, a high risk of relapses remain [122, 125]. In a prospective, single-arm study, 58.8% of 34 patients relapsed after 1-year post treatment, and 100% relapsed in a different randomised controlled trial [122, 125]. Reactivation of melanocytic dendritic cells after treatment has been observed with reflectance confocal laser microscopy [116].
Mottled hypopigmentation or punctate leukoderma, and rebound hyperpigmentation are an additional complication, particularly with higher energy levels, prompting some authors to favour alternative treatments such as chemical peels [120, 121, 126]. A method shown to reduce mottled hypopigmentation and rebound hyperpigmentation includes low-fluence Nd:YAG laser with a micropulse, a technique known as dual-toning [118, 127]. Likewise, combining Q-switched Nd:YAG with a low-power fractional CO2 laser minimised the risk of punctate leukoderma in a randomised split-face study [128].
The literature suggests that combinations of lasers, such as 1064 nm Q-switched Nd:YAG with pulsed dye laser (PDL), IPL, and radiofrequency are superior to single laser therapy in efficacy and sustained effect [129,130,131]. However, meta-analyses acknowledge a higher incidence of adverse effects with combination therapy [129].
6.2 Picosecond Technology
Picosecond Nd:YAG 1064 nm has challenged QS Nd:YAG as a treatment option with fewer adverse effects. Its shorter pulse duration and stronger photomechanical effect breaks melanin into smaller granules with less perilesional thermal damage [132]. A trial of 20 patients receiving nine sessions of 1064 nm picosecond laser at 4- to 6-weekly intervals found an improvement in mMASI from 10.8 to 2.7 and 3.6 at 6 and 12 weeks, with no major adverse effects and no dyspigmentation [133].
Picosecond Nd:YAG and QS Nd:YAG have similar efficacy, however picosecond laser treatments resulted in less pain and acneiform eruption (0% vs. 31.3%) in a comparative trial using the same wavelengths [134]. A split-face trial compared 755 nm picosecond laser with 1064 nm QS-Nd:YAG laser in 12 patients and showed a faster (more improvement after the second session) and greater clearance rate of melasma at 3 months follow-up using picosecond laser, assessed using a 5-point visual analogue scale [135]. Picosecond alexandrite laser has demonstrated a comparable efficacy with TCC based off MASI score reductions and VISIA analysis in a randomised controlled trial over 20 weeks [136].
A diffractive lens array (DLA) with the 755 nm picosecond laser can redistribute energy into microbeams at a fixed spot and minimise collateral tissue damage. Results suggest it has a good efficacy with minimal adverse effects [136, 137]. However, a randomised split-face trial of 18 patients receiving 755 nm picosecond laser compared DLA versus full-beam and found no additional benefits of DLA in clearing pigmentation [138]. Research using a DLA is unique for 755 nm picosecond lasers, however microlens arrays have been used for the 1064 nm laser successfully for melasma [139].
Although picosecond laser has demonstrated marked MASI reduction, improvement in relative skin lightness using a colourimeter, as well as greater patient satisfaction, like other lasers, recurrence rates after treatment remain high [140].
6.3 Other Lasers
IPL and PDL are controversial in their efficacy for melasma and have a risk of relapse, post-inflammatory hyperpigmentation, and melasma exacerbation. A split-face trial compared both modalities and found they were effective in lightening melasma lesions, however post-inflammatory hyperpigmentation (PIH) was noted in 28.6% and 14.3% of the PDL and IPL groups, respectively [141]. Erythema, oedema, and pain were also greater with PDL [141]. A trial of 17 patients receiving IPL with 4% hydroquinone found an initial reduction in melanin index of 39.8%, but the mean relative melanin index increased from 39.8 at week 16 to 50.1 at week 36, and two patients developed PIH [142]. Other studies have found that the thermal stimulation of IPL can aggravate melasma, particularly in dark-skinned patients [143]. In a prospective study of 32 patients with skin phototypes IV and V, 12 patients improved but 10 demonstrated no improvement, 4 showed deterioration, and 6 ceased treatment due to PIH [144]. The literature that does advocate for IPL suggests a lower fluence to reduce the risk of adverse effects [145].
Light emitting diode (LED) use for melasma, particularly with red or infrared light, has low evidence but may contribute to melasma treatment [146,147,148]. Red light has been used to both increase and decrease skin pigmentation, depending on the indication [149]. Blue light seems to worsen hyperpigmentation in melasma [146]. Likewise, radiofrequency carries a risk of hyperpigmentation [150].
1410 nm fractional photothermolysis effectively reduces melanin index, MASI, and visual analogue scale scores significantly but can result in erythema, dryness, and PIH, especially with over 5% coverage [151]. The literature describes fractional photothermolysis as an option for recalcitrant melasma but emphasises caution when used in patients with darker skin types, with one paper finding transient PIH in 28% of participants with phototypes 3 or 4 [152, 153]. Contrarily, the 1927 nm thulium fractional laser had reduced MASI scores, with a sustained improvement and greater tolerance than lower wavelength fractional lasers [154,155,156].
Recent trials have explored the 675 nm wavelength (RedTouch laser from Deka M.E.L.A, Calenzano, Italy) due to its high affinity with melanin, minimal interaction with the vascular chromophore, and reduced inflammation post treatments [119, 157, 158]. Various trials on the 675 nm wavelength found a significant reduction in MASI scores, photographic evaluation of pigmentary and vascular components, and histopathology findings, alongside minimal adverse effects and low pain scores in skin phototypes II–V [119, 157, 158]. Of the 58 patients in the three trials referenced on this laser modality, no cases reported post-inflammatory hyperpigmentation with this laser [119, 157, 158].
6.4 Laser with Other Treatments
Lasers can improve the delivery of topical treatments to the target site, as well as work synergistically.
A split-face trial of 25 women over 3 months demonstrated a greater MASI reduction with fractional 2940 nm erbium-doped YAG laser-assisted delivery of kojic acid versus kojic acid alone [159]. Likewise, a comparative trial found QS Nd:YAG laser with topical TXA, niacinamide, and kojic acid improved hemi-MASI scores more than laser alone [43]. Combination therapy with topical 5% methimazole and Q-switched Nd:YAG laser worked better and faster than methimazole monotherapy [160].
Laser-assisted delivery of TXA has been widely explored. Combination therapy with broadband light and intradermal TXA produced a greater reduction in MASI scores and a greater improvement in brown spot and red zone rankings using VISIA skin analysis compared with both treatments alone and a control group of oral TXA [161]. In a split-face trial of picosecond alexandrite laser and topical TXA versus laser monotherapy, greater efficacy in terms of hemi-MASI improvement, as well as patient satisfaction ratings, was demonstrated with picosecond lasers and topical TXA used together [162]. However, the study found less redness and sensitivity with laser monotherapy and suggested a need for further optimisation to create an ideal combination regimen [162].
A comparative study found oral TXA with laser to be superior to oral TXA monotherapy in mMASI improvement and may also reduce laser-related complications [163]. Another study found that the addition of oral TXA to an existing regimen of erbium:YAG laser and topical 5% TXA further decreased mMASI scores from 41.8 to 64.7% [164].
A randomised comparative trial of 56 patients compared monthly QS Nd:YAG laser with topical 3% TXA versus monthly microneedling with topical 3% TXA over five sessions and found no significant difference in mMASI reduction and patient satisfaction but more pain and erythema in the microneedling group [68].
Other combinations have less clear synergistic benefits. Picosecond laser with topical hydroquinone did not provide additional reduction in mMASI scores but had greater risks of PIH [165]. A combination of fractional erbium:YAG with TCC had a greater MASI reduction than TCC alone but did not significantly improve patient global assessment scale scores between the two groups [166]. Erbium:YAG laser with topical hydroquinone was comparable with intradermal TXA and topical hydroquinone but had greater recurrence rates [167].
7 Discussion
The wide range of treatment options available can make choosing the most appropriate therapy difficult. This section aims to add perspective for the treating clinician on how to approach patients with melasma based on the literature described. A summary of the mechanism of action of each treatment has also been provided to conceptualise each treatment’s role in managing melasma (Table 1).
Strict photoprotection, including the use of iron-oxide tinted sunscreens and non-irritating, non-photosensitising cleansers and moisturisers should be strongly encouraged in all patients. Topical bleaching agents including hydroquinone and tretinoin should be offered as first-line treatments, while combination therapies such as TCC can be considered for moderate-to-severe cases or cases without response to first-line monotherapies.
Novel topical treatments such as thiamidol and cysteamine are an option for patients who are intolerant of or did not respond to first-line agents, those who have contraindications, or when patients move into maintenance phase therapy. Like hydroquinone, cysteamine can result in irritant adverse effects.
Oral TXA uniquely targets melasma via its vaso-modulating effects and can be used as second- or third-line therapy alongside topical treatments. Initial therapy could be continued for 12–16 weeks but studies proving safety for greater durations are currently lacking. Topical and intradermal TXA is not recommended given issues with efficacy, access, cost, and patient discomfort, respectively.
Chemical peels can lighten melasma but should be used as an adjunct to topical therapies to enhance their efficacy. Chemical peels with deeper penetration have greater efficacy, however superficial peels are less irritating and may be more appropriate for patients with sensitive skin and for those with skin of colour.
Laser and energy-based devices should be reserved for severe, non-responsive cases of melasma in patients who are psychologically affected by the condition. Due to the financial commitment required, risk of recurrence after treatment cessation, and the potential adverse effects, this should be carefully considered and embarked upon with experienced laser physicians. If laser is to be used, the evidence is in favour of use of low fluence QS Nd:YAG or picosecond technology.
Maintenance therapy often involves cycling off hydroquinone or oral TXA in favour of tretinoin or over-the-counter skin-lightening agents such as azelaic acid, kojic acid, arbutin, and niacinamide, particularly during time periods with less sun exposure. These agents can be used as monotherapy or in combination. There is also evidence supporting either a tapering or twice-weekly maintenance regimen with TCC use [37].
Despite the multiple treatments that have been trialled, it is important to highlight that melasma is a chronic and recurrent condition for which no cure has been found. Many treatments may lighten lesions, however realistic expectations should be set with each consultation. Treatments will likely continue to evolve for this very challenging disorder of hyperpigmentation.
8 Conclusion
The range of treatments for melasma reflects its complex and multifactorial pathogenesis. Therapeutic discoveries to treat melasma are a focal topic in the literature and include a range of modalities. It is increasingly important yet challenging to remain up-to-date on the arsenal of treatments available for melasma to find an efficacious and well-tolerated option for our patients.
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Michelle Rodrigues has provided paid lectures for Cynosure and La Roche Posay, as well as Medical Advisory for SkinCeuticals and L’Oreal Group. Christian Gan has no conflict of interest to declare that may be relevant to the contents of this article.
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CG was responsible for the literature search and writing of the review. MR was the senior author and was responsible for the editing and revision process, as well as overall supervision of the review.
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Gan, C., Rodrigues, M. An Update on New and Existing Treatments for the Management of Melasma. Am J Clin Dermatol (2024). https://doi.org/10.1007/s40257-024-00863-2
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DOI: https://doi.org/10.1007/s40257-024-00863-2