Exciting new developments in treatment mean there are now even more diverse options for the common disorder.
Melasma is an acquired disorder of facial hyperpigmentation commonly presenting in women and in those with skin of colour.
It is a chronic disorder that can have a significant impact on the quality of life of the individual affected, affecting emotional and psychological wellbeing. Despite advances in treatment, relapses can occur, and it therefore can present a considerable therapeutic challenge to the practitioner.
Successfully managing melasma requires a multimodal approach, underpinned by strict patient adherence to long-term photoprotection (sunscreen and sun avoidance). There is also a diverse range of topical therapies, chemical peels and light or laser therapies that have been trialled with varying evidence and efficacy. This article provides an overview of the existing therapies for melasma with the strongest evidence, and aims to update the reader about emerging treatments.
What is melasma?
Melasma is a chronic acquired pigmentary disorder of the face.1 It predominantly affects adult females and people with skin of colour.2
There are a few risk factors associated with the development of melasma, including pregnancy, exogenous hormonal therapies, exposure to ultraviolet (UV) radiation, heat and the visible light (VL) spectrum, vascular modulation, and genetic or familial predisposition.3, 4
How does melasma present clinically?
Melasma presents as hyperpigmented macules or patches on sun-exposed areas of the face.2 A Wood’s lamp may help to identify the specific layer of pigment deposition.2 Histopathological examination demonstrates increased melanin deposition in the epidermis and dermis, and features of photoageing.5
When considering a presentation of a facial pigmentary disorder, there are also a number of possible differential diagnoses to consider, including: post-inflammatory hyperpigmentation, dermal melanosis and medication-induced hyperpigmentation, to name a few.
The new mMASI scoring system
In melasma clinical research and trials, we use the Modified Melasma Area and Severity Index (mMASI) score as a validated measure of melasma severity and as an outcome measure to quantify changes in melasma during treatment.6 It is calculated by rating the darkness and percentage of involvement of four areas of the face (forehead, left malar, right malar and chin region).6 The mMASI removes the “homogeneity” factor used in the original MASI while maintaining accuracy and improving usability.
A GP’s guide to the management of melasma
An essential part in early counselling of a patient presenting with melasma is education and managing patient expectations. Melasma is unfortunately a recalcitrant condition that cannot be completely cured and recurs in every patient. The management of melasma is never via a monotherapy approach.
The chronicity and difficulty in treating melasma can often have a significant cosmetic, self-esteem and mental health impact in patients. It is therefore essential for the general practitioner to explore the emotional impact on the patient, with referral for additional counselling from allied health colleagues if required.7
As discussed above, the cornerstone of treating melasma is a patient’s adherence to maintaining strict year-round photoprotection; UV and VL exacerbates melasma and can induce relapses.8
This regimen includes physical coverage (wearing a broad-brimmed hat, 100% UV-blocking sunglasses, long-sleeved clothing), applying broad-spectrum tinted sunscreen, seeking shade, sun avoidance (especially during high-UV times from 10am to 3pm) and avoidance of artificial UV sources (such as tanning salons).1, 3, 8
Other cosmetic camouflage with commercially available make-up foundation and concealer is often used as an effective interim solution that many patients employ before seeing a clinician.
The current topical therapies for melasma target the melanin synthesis pathway. The common topical agents used by dermatologists include:
Hydroquinone (HQ) (1,4 dihydroxybenzene) used in a 2-5% stabilised emollient acts as an effective tyrosinase inhibitor. It has been the gold-standard first-line therapy for epidermal melasma for more than 50 years.1
Short-term adverse effects are commonly local, and dose and duration dependent. These include erythema, stinging, xerosis, irritant or allergic contact dermatitis, and transient halo hypochromia.1, 9
Long-term effects include milia, confetti-like depigmentation and, rarely, exogenous ochronosis (a black-blue pigmentation that develops secondary to depigmenting phenols).10 It is contraindicated in those who are pregnant or breastfeeding.
Topical retinoids are vitamin A derivative preparations that have been effectively used to treat a range of dermatological conditions including melasma. However, retinoids can be cutaneous irritants (causing erythema and desquamation) and are known teratogens (therefore are contraindicated in pregnancy).11, 12
Tretinoin is a potent topical retinoid that has been found to be effective in treating epidermal melasma (with a 32-37% improvement in MASI), especially used in combination therapy.11, 12
Adapalene, a synthetic retinoid, has also proved to be an effective formula for melasma (41% reduction in MASI) with less cutaneous irritation than tretinoin.12
Azelaic acid (AA) is a Pityrosporum ovale derivative and functions as a competitive tyrosinase inhibitor. It has more significant adverse effects than hydroquinone, especially at higher concentrations.10 It can be used safely in pregnancy and during lactation. It can be found over the counter and is best used at concentrations about 10%.
Other topical agents that have been trialled for melasma include 60% kojic acid (tyrosinase inhibitor), 25% ascorbic acid, 3% arbutin (or deoxyarbutin), niacinamide (vitamin B3), topical tranexamic acid, licorice extract (melanin dispersion, tyrosinase inhibitor), rucinol 0.3% serum (phenolic acid derivative tyrosinase inhibitor), dioic acid, linoleic acid 2% and methimazole. However, these are not routinely used as they either have demonstrated only limited efficacy, are unstable as monotherapy, or have more significant adverse effects than current treatments.1
Combination topical therapies
Hydroquinone and retinoids are often used in combination formulas to synergistically treat moderate to severe melasma. The Kligman-Willis formula (KF) (5% hydroquinone, 0.1% tretinoin, 0.1% dexamethasone) was one of the earliest therapies for certain forms of hyperpigmentation.
Multiple other formulas exist, but the most extensively researched combination is the triple combination cream (4% hydroquinone, 0.05% tretinoin and 0.01% fluocinolone acetonide), which has demonstrated superior efficacy compared with monotherapy13 or dual therapy14.
The triple combination cream can be applied nightly for eight weeks, with a maintenance twice-weekly application thereafter for a few months. Adverse effects include local reactions as aforementioned for the separate components and must be monitored carefully.
Emerging topical therapies
Cysteamine (an aminothiol) in a 5% cream is a potent depigmenting agent, applied once daily for 15 minutes. It is hypothesised to inhibit a number of enzymes and substrates in the melanin synthesis pathway, with a good safety profile.15 Previously, oxidised cysteamine emitted an odour that rendered it unsuitable for topical use. In 2010, the formulation of cysteamine was stabilised and deodorised for use, with clinical trials demonstrating that cysteamine was effective in treating epidermal melasma.16 However, recent research has suggested that certain concentrations of this ingredient can affect the eumelanin-to-phaeomelanin ratio, raising questions about long-term carcinogenic risk. 17 It is not commercially available in Australia.
Tranexamic acid (TXA) is an antifibrinolytic agent inhibiting plasmin traditionally used for menorrhagia and other bleeding diatheses.18 Tranexamic acid is proposed to also inhibit the UV-induced plasminogen/plasmin system.5
Improvement in moderate melasma has been demonstrated after three months of low-dose tranexamic acid but recurrences are noted in most cases.5 Possible side effects can include headaches, nausea, menstrual irregularity and back pain, as well as arterial and venous thromboses.18 Contraindications include smoking; use of the oral contraceptive pill; cardiovascular, respiratory or renal disease; previous thrombosis or concurrent use of prothrombotic medications.9 Long-term continuous therapy safety data is still lacking for this agent. This systemic treatment should be dermatologist initiated and monitored for this indication.
It is the belief of the authors that tranexamic acid should be avoided during the covid pandemic in those who have higher chances of contracting or suffering complications of covid. This is due to the pro-thrombotic events that have been reported in even young and otherwise healthy individuals who are infected with covid19, and in context of the rare but serious risk of thrombosis with the Vaxzevria (AstraZeneca®) vaccine. Given the mechanism of action, tranexamic acid should be avoided in these cases.
Chemical peels are a common adjunct to topical agents, and used to induce controlled exfoliation and subsequent regeneration of the epidermis and dermis. They have greatest efficacy in epidermal layer melasma.
Glycolic acid at concentrations of 20-70%, trichloroacetic acid (TCA) 10-20% peels have demonstrated good short-term efficacy in lighter skin but has a risk of post-inflammatory hyperpigmentation and scarring in skin of colour.20 Salicylic acid in concentrations of 20-30% concentrations and Jessner’s solution have also been reported for use with varying efficacy.21
Other trialled peels include lactic acid, phytic acid, pyruvic acid, tretinoin peels, combination salicylic acid and mandelic acid. However, there is limited evidence for efficacy.
Laser and light therapies
Laser and light therapies should ever be used only for refractory, severe melasma that has not responded to general measures, topical therapies and chemical peels, and combinations of these and should be used in the hands of experienced dermatologists. Like chemical peels, they should be used very cautiously in skin of colour because of the high risk of inducing paradoxical post-inflammatory hyperpigmentation, worsening melasma and scarring. Other adverse effects include mottled confetti-like hypopigmentation, irritation and recurrence post-treatment.22, 23
Different modalities have been trialled to treat melasma, with variable and limited evidence. These include intense pulsed light (IPL) (560 nm);22 broad band light (BBL); pulsed-dye laser (PDL) (585 nm); Q-switched (QS) ruby laser (694 nm); QS neodymium?doped yttrium–aluminium–garnet (Nd:YAG) laser (532 nm or 1064 nm);23 fractional thulium laser (1927 nm); erbium glass non?ablative fractional laser (NAFL) (1550 nm); and Erbium:YAG ablative laser (2940 nm). They also carry a greater risk of erythema, irritation, recurrent and post-inflammatory hyperpigmentation.
Picosecond Alexandrite Laser (755 nm), with its lower photothermic effect, minimises damage to surrounding tissue and therefore reduces adverse effects.24 Nevertheless, it may still cause post-inflammatory hyperpigmentation and rebound melasma is seen in almost all cases. While there are now picosecond 730nm 1064nm lasers available, more well-constructed studies with these devices are needed.
The management of melasma requires a multifaceted long-term approach. Initial consultation should confirm melasma, assess clinical severity and address risks or exacerbating factors where possible. The first principles of management – avoiding triggers and strict year-round photoprotection with tinted sunscreen – should be emphasised. Cosmetic camouflage can be an immediately effective temporary measure.
Mild melasma is often treated with sunscreen and a short course of daily hydroquinone 2-4% cream, the gold-standard topical depigmenting agent.
Inadequate response or moderate-to-severe cases of melasma can be treated with a short course of daily combination or triple combination cream.
Refractory cases be escalated to short courses of intermittent chemical peels or referred to a dermatologist who has expertise in this area. Any course of treatment needs to be carefully monitored and regularly assessed for both efficacy and adverse events.
Dr Neda So (MBBS(Hons), BMedSc(Hons), MPH&TM) is an Australian doctor training as a registrar in the fields of paediatrics and dermatology in Melbourne, Australia. She has worked with Dr Rodrigues on a number of research topics in the interest areas of paediatric dermatology, skin of colour and public health. She is passionate about child health and barriers to health care for culturally and linguistically diverse patients.
Dr Michelle Rodrigues (MBBS(Hons), FACD) is an Australian dermatologist globally renowned for her skill and expertise in pigmentary disorders and skin of colour (non-Caucasian skin) dermatology. She is the founder and director of Chroma Dermatology, is a senior consultant at the Royal Children’s Hospital and is an honorary senior lecturer at The University of Melbourne. Her numerous academic publications, authorship of textbook chapters and invited national and international lectures are testimony to her commitment to education in her areas of expertise.
- Rodrigues M, Pandya AG. Melasma: clinical diagnosis and management options. Australas J Dermatol. 2015;56(3):151-63.
- Grimes PE. Melasma. Etiologic and therapeutic considerations. Arch Dermatol. 1995;131(12):1453-7.
- Boukari F, Jourdan E, Fontas E, Montaudie H, Castela E, Lacour JP, et al. Prevention of melasma relapses with sunscreen combining protection against UV and short wavelengths of visible light: a prospective randomized comparative trial. J Am Acad Dermatol. 2015;72(1):189-90 e1.
- Sarkar R, Jagadeesan S, Basavapura Madegowda S, Verma S, Hassan I, Bhat Y, et al. Clinical and epidemiologic features of melasma: a multicentric cross-sectional study from India. Int J Dermatol. 2019;58(11):1305-10.
- Del Rosario E, Florez-Pollack S, Zapata L, Jr., Hernandez K, Tovar-Garza A, Rodrigues M, et al. Randomized, placebo-controlled, double-blind study of oral tranexamic acid in the treatment of moderate-to-severe melasma. J Am Acad Dermatol. 2018;78(2):363-9.
- Rodrigues M, Ayala-Cortes AS, Rodriguez-Arambula A, Hynan LS, Pandya AG. Interpretability of the Modified Melasma Area and Severity Index (mMASI). JAMA Dermatol. 2016;152(9):1051-2.
- Balkrishnan R, McMichael AJ, Camacho FT, Saltzberg F, Housman TS, Grummer S, et al. Development and validation of a health-related quality of life instrument for women with melasma. Br J Dermatol. 2003;149(3):572-7.
- Castanedo-Cazares JP, Hernandez-Blanco D, Carlos-Ortega B, Fuentes-Ahumada C, Torres-Alvarez B. Near-visible light and UV photoprotection in the treatment of melasma: a double-blind randomized trial. Photodermatol Photoimmunol Photomed. 2014;30(1):35-42.
- Shihab N, Prihartono J, Tovar-Garza A, Agustin T, Legiawati L, Pandya AG. Randomised, controlled, double-blind study of combination therapy of oral tranexamic acid and topical hydroquinone in the treatment of melasma. Australas J Dermatol. 2020;61(3):237-42.
- Balina LM, Graupe K. The treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream. Int J Dermatol. 1991;30(12):893-5.
- Griffiths CE, Finkel LJ, Ditre CM, Hamilton TA, Ellis CN, Voorhees JJ. Topical tretinoin (retinoic acid) improves melasma. A vehicle-controlled, clinical trial. Br J Dermatol. 1993;129(4):415-21.
- Dogra S, Kanwar AJ, Parsad D. Adapalene in the treatment of melasma: a preliminary report. J Dermatol. 2002;29(8):539-40.
- Chan R, Park KC, Lee MH, Lee ES, Chang SE, Leow YH, et al. A randomized controlled trial of the efficacy and safety of a fixed triple combination (fluocinolone acetonide 0.01%, hydroquinone 4%, tretinoin 0.05%) compared with hydroquinone 4% cream in Asian patients with moderate to severe melasma. Br J Dermatol. 2008;159(3):697-703.
- Taylor SC, Torok H, Jones T, Lowe N, Rich P, Tschen E, et al. Efficacy and safety of a new triple-combination agent for the treatment of facial melasma. Cutis. 2003;72(1):67-72.
- Karrabi M, David J, Sahebkar M. Clinical evaluation of efficacy, safety and tolerability of cysteamine 5% cream in comparison with modified Kligman’s formula in subjects with epidermal melasma: A randomized, double-blind clinical trial study. Skin Res Technol. 2020.
- Mansouri P, Farshi S, Hashemi Z, Kasraee B. Evaluation of the efficacy of cysteamine 5% cream in the treatment of epidermal melasma: a randomized double-blind placebo-controlled trial. Br J Dermatol. 2015;173(1):209-17.
- Lee HK, Ha JW, Hwang YJ, Boo YC. Identification of L-Cysteinamide as a Potent Inhibitor of Tyrosinase-Mediated Dopachrome Formation and Eumelanin Synthesis. Antioxidants. 2021;10(8):1202.
- Bala HR, Lee S, Wong C, Pandya AG, Rodrigues M. Oral Tranexamic Acid for the Treatment of Melasma: A Review. Dermatol Surg. 2018;44(6):814-25.
- Klok FA, Kruip M, van der Meer NJM, Arbous MS, Gommers D, Kant KM, et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res. 2020;191:148-50.
- Kumari R, Thappa DM. Comparative study of trichloroacetic acid versus glycolic acid chemical peels in the treatment of melasma. Indian J Dermatol Venereol Leprol. 2010;76(4):447.
- Sharquie KE, Al-Tikreety MM, Al-Mashhadani SA. Lactic Acid Chemical Peels as a New Therapeutic Modality in Melasma in Comparison to Jessner’s Solution Chemical Peels. Dermatologic Surgery. 2006;32(12):1429-36.
- Wang CC, Hui CY, Sue YM, Wong WR, Hong HS. Intense pulsed light for the treatment of refractory melasma in Asian persons. Dermatol Surg. 2004;30(9):1196-200.
- Wattanakrai P, Mornchan R, Eimpunth S. Low-fluence Q-switched neodymium-doped yttrium aluminum garnet (1,064 nm) laser for the treatment of facial melasma in Asians. Dermatol Surg. 2010;36(1):76-87.
- Lee MC, Lin YF, Hu S, Huang YL, Chang SL, Cheng CY, et al. A split-face study: comparison of picosecond alexandrite laser and Q-switched Nd:YAG laser in the treatment of melasma in Asians. Lasers Med Sci. 2018;33(8):1733-8.