Review of modern melasma treatment methods

Melasma is a common, difficult-to-treat pigmented skin disease characterized by a recurrent course. The article provides an overview of the etiology, pathogenesis and principles of melasma therapy. The multifactorial nature of the disease was noted, including genetic predisposition, exposure to ultraviolet and visible light, and hormonal factors. It is known that visible light, especially high-energy visible light with a wavelength of 400–500 nm (High Energy Visible Light, HEV rays, blue light), and long-wavelength UVA rays (370–400 nm) exacerbate the course of melasma. The importance of an integrated approach to treatment, including the elimination of trigger factors, pathogenetic therapy and mandatory photoprotection using modern broad-spectrum sunscreens, is emphasized. Special attention is paid to the need to inform patients about the chronic nature of melasma and the importance of prolonged therapy. The article considers a multi-level treatment regimen based on the use of topical drugs and peels as first-line therapy, with careful and balanced use of hardware methods at subsequent stages. The key principles of hyperpigmentation therapy are described, namely, inhibition of melanogenesis, reduction of melanosome transport and acceleration of melanin elimination processes. Given example of modern depigmenting topical treatment containing Thiamidol (Beiersdorf AG patent), which contribute to the improvement of mMASI (Modified Melasma Area and Severity Index) after 2 weeks of usage, and justified treatment with Thiamidol for monoand combination therapy of melasma. The proposed three-stage treatment regimen, adapted to the severity of the disease, makes it possible to optimize therapeutic tactics taking into account the individual characteristics of the patient.

1. Desai S, Chan L, Handog E, Djojoseputro L, Lim J, Ling R et al. Optimizing Melasma Management With Topical Tranexamic Acid: An Expert Consensus. J Drugs Dermatol. 2023;22(4):386–392. https://doi.org/10.36849/JDD.7104.

2. Moin A, Jabery Z, Fallah N. Prevalence and awareness of melasma during pregnancy. Int J Dermatol. 2006;45(3):285–288. https://doi.org/10.1111/j.1365-4632.2004.02470.x.

3. Taylor SC. Epidemiology of skin diseases in ethnic populations. Dermatol Clin. 2003;21(4):601–607. https://doi.org/10.1016/s0733-8635(03)00075-5.

4. Rathore SP, Gupta S, Gupta V. Pattern and prevalence of physiological cutaneous changes in pregnancy: a study of 2000 antenatal women. Indian J Dermatol Venereol Leprol. 2011;77(3):402. https://doi.org/10.4103/0378-6323.79741.

5. Mahajan VK, Patil A, Blicharz L, Kassir M, Konnikov N, Gold MH et al. Medical therapies for melasma. J Cosmet Dermatol. 2022;21(9):3707–3728. https://doi.org/10.1111/jocd.15242.

6. Lee AY. Recent progress in melasma pathogenesis. Pigment Cell Melanoma Res. 2015;28(6):648–660. https://doi.org/10.1111/pcmr.12404.

7. Holmo NF, Ramos GB, Salomão H, Werneck RI, Mira MT, Miot LDB et al. Complex segregation analysis of facial melasma in Brazil: evidence for a genetic susceptibility with a dominant pattern of segregation. Arch Dermatol Res. 2018;310(10):827–831. https://doi.org/10.1007/s00403-018-1861-5.

8. Kang HY, Suzuki I, Lee DJ, Ha J, Reiniche P, Aubert J et al. Transcriptional profiling shows altered expression of wnt pathway- and lipid metabolism-related genes as well as melanogenesis-related genes in melasma. J Invest Dermatol. 2011;131(8):1692–1700. https://doi.org/10.1038/jid.2011.109.

9. Ortonne JP, Arellano I, Berneburg M, Cestari T, Chan H, Grimes P et al. A global survey of the role of ultraviolet radiation and hormonal influences in the development of melasma. J Eur Acad Dermatol Venereol. 2009;23(11):1254–1262. https://doi.org/10.1111/j.1468-3083.2009.03295.x.

10. Hirobe T, Ishikawa A. l-tyrosine induces melanocyte differentiation in novel pink-eyed dilution castaneus mouse mutant showing age-related pigmentation. J Dermatol Sci. 2015;80(3):203–211. https://doi.org/10.1016/j.jdermsci.2015.10.002.

11. Mahmoud BH, Ruvolo E, Hexsel CL, Liu Y, Owen MR, Kollias N et al. Impact of long-wavelength UVA and visible light on melanocompetent skin. J Invest Dermatol. 2010;130(8):2092–2097. https://doi.org/10.1038/jid.2010.95.

12. Alcantara GP, Esposito ACC, Olivatti TOF, Yoshida MM, Miot HA. Evaluation of ex vivo melanogenic response to UVB, UVA, and visible light in facial melasma and unaffected adjacent skin. An Bras Dermatol. 2020;95(6):684–690. https://doi.org/10.1016/j.abd.2020.02.015.

13. Morgado-Carrasco D, Piquero-Casals J, Granger C, Trullàs C, Passeron T. Melasma: The need for tailored photoprotection to improve clinical outcomes. Photodermatol Photoimmunol Photomed. 2022;38(6):515–521. https://doi.org/10.1111/phpp.12783.

14. Tamega Ade A, Miot HA, Moço NP, Silva MG, Marques ME, Miot LD. Gene and protein expression of oestrogen-β and progesterone receptors in facial melasma and adjacent healthy skin in women. Int J Cosmet Sci. 2015;37(2):222–228. https://doi.org/10.1111/ics.12186.

15. Kim NH, Cheong KA, Lee TR, Lee AY. PDZK1 upregulation in estrogen-related hyperpigmentation in melasma. J Invest Dermatol. 2012;132(11):2622–2631. https://doi.org/10.1038/jid.2012.175.

16. Handog EB (ed.). Melasma and vitiligo in brown skin. Springer India; 2017. 377 p. Available at: https://link.springer.com/book/10.1007/978-81-322-3664-1.

17. Deshpande SS, Khatu SS, Pardeshi GS, Gokhale NR. Cross-sectional study of psychiatric morbidity in patients with melasma. Indian J Psychiatry. 2018;60(3): 324–328. https://doi.org/10.4103/psychiatry.IndianJPsychiatry_115_16.

18. Trivedi MK, Yang FC, Cho BK. A review of laser and light therapy in melasma. Int J Womens Dermatol. 2017;3(1):11–20. https://doi.org/10.1016/j.ijwd.2017.01.004

19. Rigel DS, Taylor SC, Lim HW, Alexis AF, Armstrong AW, Chiesa Fuxench ZC et al. Photoprotection for skin of all color: Consensus and clinical guidance from an expert panel. J Am Acad Dermatol. 2022;86(3 Suppl.):S1-S8. https://doi.org/10.1016/j.jaad.2021.12.019.

20. Sheth VM, Pandya AG. Melasma: a comprehensive update: part I. J Am Acad Dermatol. 2011;65(4):689–697. https://doi.org/10.1016/j.jaad.2010.12.046.

21. Philipp-Dormston WG. Melasma: A Step-by-Step Approach Towards a Multimodal Combination Therapy. Clin Cosmet Investig Dermatol. 2024;17:1203–1216. https://doi.org/10.2147/CCID.S372456.

22. Song H, Beckles A, Salian P, Porter ML. Sunscreen recommendations for patients with skin of color in the popular press and in the dermatology clinic. Int J Womens Dermatol. 2020;7(2):165–170. https://doi.org/10.1016/j.ijwd.2020.10.008

23. Grimes PE. Management of hyperpigmentation in darker racial ethnic groups. Semin Cutan Med Surg. 2009;28(2):77–85. https://doi.org/10.1016/j.sder.2009.04.001.

24. Levitt J. The safety of hydroquinone: a dermatologist’s response to the 2006 Federal Register. J Am Acad Dermatol. 2007;57(5):854–872. https://doi.org/10.1016/j.jaad.2007.02.020.

25. Nordlund JJ, Grimes PE, Ortonne JP. The safety of hydroquinone. J Eur Acad Dermatol Venereol. 2006;20(7):781–787. https://doi.org/10.1111/j.1468-3083.2006.01670.x.

26. Fleischer AB Jr, Schwartzel EH, Colby SI, Altman DJ. The combination of 2% 4-hydroxyanisole (Mequinol) and 0.01% tretinoin is effective in improving the appearance of solar lentigines and related hyperpigmented lesions in two double-blind multicenter clinical studies. J Am Acad Dermatol. 2000;42(3):459–467. https://doi.org/10.1016/s0190-9622(00)90219-6.

27. Draelos ZD. The combination of 2% 4-hydroxyanisole (mequinol) and 0.01% tretinoin effectively improves the appearance of solar lentigines in ethnic groups. J Cosmet Dermatol. 2006;5(3):239–244. https://doi.org/10.1111/j.1473-2165.2006.00260.x.

28. Jutley GS, Rajaratnam R, Halpern J, Salim A, Emmett C. Systematic review of randomized controlled trials on interventions for melasma: an abridged Cochrane review. J Am Acad Dermatol. 2014;70(2):369–373. https://doi.org/10.1016/j.jaad.2013.07.044.

29. Blume-Peytavi U, Fowler J, Kemény L, Draelos Z, Cook-Bolden F, Dirschka T et al. Long-term safety and efficacy of trifarotene 50 μg/g cream, a first-inclass RAR-γ selective topical retinoid, in patients with moderate facial and truncal acne. J Eur Acad Dermatol Venereol. 2020;34(1):166–173. https://doi.org/10.1111/jdv.15794.

30. Murphy MJ, Dow AA. Natural Cosmeceutical Ingredients for the Management of Hyperpigmentation in Hispanic and Latino Women. J Clin Aesthet Dermatol. 2021;14(8):52–56. Available at: https://pubmed.ncbi.nlm.nih.gov/34840659.

31. Navarrete-Solís J, Castanedo-Cázares JP, Torres-Álvarez B, Oros-Ovalle C, Fuentes-Ahumada C, González FJ et al. A Double-Blind, Randomized Clinical Trial of Niacinamide 4% versus Hydroquinone 4% in the Treatment of Melasma. Dermatol Res Pract. 2011;2011:379173. https://doi.org/10.1155/2011/379173.

32. González-Molina V, Martí-Pineda A, González N. Topical Treatments for Melasma and Their Mechanism of Action. J Clin Aesthet Dermatol. 2022;15(5):19–28. Available at: https://pubmed.ncbi.nlm.nih.gov/35642229.

33. Hayakawa R, Ueda H, Nozaki T, Izawa Y, Yokotake J, Yazaki K et al. Effects of combination treatment with vitamins E and C on chloasma and pigmented contact dermatitis. A double blind controlled clinical trial. Acta Vitaminol Enzymol. 1981;3(1):31–38. Available at: https://pubmed.ncbi.nlm.nih.gov/7027767.

34. Sarkar R, Bansal A, Ailawadi P. Future therapies in melasma: What lies ahead? Indian J Dermatol Venereol Leprol. 2020;86(1):8–17. https://doi.org/10.4103/ijdvl.IJDVL_633_18.

35. Arrowitz C, Schoelermann AM, Mann T, Jiang LI, Weber T, Kolbe L. Effective Tyrosinase Inhibition by Thiamidol Results in Significant Improvement of Mild to Moderate Melasma. J Invest Dermatol. 2019;139(8):1691–1698. e6. https://doi.org/10.1016/j.jid.2019.02.013.

36. Lima PB, Dias JAF, Cassiano DP, Esposito ACC, Miot LDB, Bagatin E, Miot HA. Efficacy and safety of topical isobutylamido thiazolyl resorcinol (Thiamidol) vs. 4% hydroquinone cream for facial melasma: an evaluator-blinded, randomized controlled trial. J Eur Acad Dermatol Venereol. 2021;35(9):1881–1887. https://doi.org/10.1111/jdv.17344.

37. Mann T, Gerwat W, Batzer J, Eggers K, Scherner C, Wenck H et al. Inhibition of Human Tyrosinase Requires Molecular Motifs Distinctively Different from Mushroom Tyrosinase. J Invest Dermatol. 2018;138(7):1601–1608. https://doi.org/10.1016/j.jid.2018.01.019.

38. Lee MH, Kim HJ, Ha DJ, Paik JH, Kim HY. Therapeutic effect of topical application of linoleic acid and lincomycin in combination with betamethasone valerate in melasma patients. J Korean Med Sci. 2002;17(4):518–523. https://doi.org/10.3346/jkms.2002.17.4.518.

39. Grimes PE, Bhawan J, Guevara IL, Colón LE, Johnson LA, Gottschalk RW, Pandya AG. Continuous therapy followed by a maintenance therapy regimen with a triple combination cream for melasma. J Am Acad Dermatol. 2010;62(6):962–967. https://doi.org/10.1016/j.jaad.2009.06.067.

40. Bertold C, Fontas E, Singh T, Gastaut N, Ruitort S, Wehrlen Pugliese S, Passeron T. Efficacy and safety of a novel triple combination cream compared to Kligman’s trio for melasma: A 24-week double-blind prospective randomized controlled trial. J Eur Acad Dermatol Venereol. 2023;37(12):2601–2607. https://doi.org/10.1111/jdv.19455.

41. Conforti C, Zalaudek I, Vezzoni R, Retrosi C, Fai A, Fadda S et al. Chemical peeling for acne and melasma: current knowledge and innovations. G Ital Dermatol Venereol. 2020;155(3):280–285. https://doi.org/10.23736/S0392-0488.19.06425-3.

42. Samargandy S, Raggio BS. Chemical Peels for Skin Resurfacing. In: StatPearls. Treasure Island (FL): StatPearls Publishing; 2023. Available at: https://pubmed.ncbi.nlm.nih.gov/31613532/

43. Alajmi A, Niaz G, Chen C, Lee K. A 15% Trichloroacetic Acid + 3% Glycolic Acid Chemical Peel Series Improves Appearance of Hand Lentigines: An Evaluator-Blinded, Split-Hand Prospective Trial. Dermatol Surg. 2024;50(5):467–470. https://doi.org/10.1097/DSS.0000000000004114.

44. Sharad J. Glycolic acid peel therapy – a current review. Clin Cosmet Investig Dermatol. 2013;6:281–288. https://doi.org/10.2147/CCID.S34029.

45. Sahu P, Dayal S. Most worthwhile superficial chemical peel for melasma of skin of color: Authors’ experience of glycolic, trichloroacetic acid, and lactic peel. Dermatol Ther. 2021;34(1):e14693. https://doi.org/10.1111/dth.14693.

46. Modi A, Parmar S, Marfatiya Y. Comparative Efficacy Of 35% Glycolic Acid Peel vs. Jessner Peel as an Adjuvant to Topical Triple Combination (2% Hydroquinone, 0.025% Tretinoin, 0.01% Fluocinolone Acetonide) Therapy in Melasma Females Cases. J Cosmet Sci. 2021;72(4):418–431. Available at: https://pubmed.ncbi.nlm.nih.gov/35262482.

47. Sumita JM, Leonardi GR, Bagatin E. Tretinoin peel: a critical view. An Bras Dermatol. 2017;92(3):363–366. https://doi.org/10.1590/abd1806-4841.201755325.

48. Sharquie KE, Al-Tikreety MM, Al-Mashhadani SA. Lactic acid as a new therapeutic peeling agent in melasma. Dermatol Surg. 2005;31(2):149–154. https://doi.org/10.1111/j.1524-4725.2005.31035.

49. Pazyar N, Raeispour M, Yaghoobi R, Seyedtabib M. Evaluation of the effectiveness of microneedling with tranexamic acid in comparison with microneedling with vitamin C in the treatment of melasma: A prospective and single-blind clinical trial. Health Sci Rep. 2023;6(10):e1636. https://doi.org/10.1002/hsr2.1636.

50. Feng X, Su H, Xie J. The efficacy and safety of microneedling with topical tranexamic acid for melasma treatment: A systematic review and meta-analysis. J Cosmet Dermatol. 2024;23(1):33–43. https://doi.org/10.1111/jocd.15965.

51. Calacattawi R, Alshahrani M, Aleid M, Aleid F, Basamih K, Alsugair G et al. Tranexamic acid as a therapeutic option for melasma management: meta-analysis and systematic review of randomized controlled trials. J Dermatolog Treat. 2024;35(1):2361106. https://doi.org/10.1080/09546634.2024.2361106.

52. Mumtaz M, Chandio TH, Shahzad MK, Hanif N, Anwar S, Rafique S. Comparing the Efficacy of Patelet-rich Plasma (PRP) versus Tranexamic Acid (4 mg/mL) as Intradermal Treatments of Melasma. J Coll Physicians Surg Pak. 2021;31(5):502–505. https://doi.org/10.29271/jcpsp.2021.05.502.

53. Balevi A, Ustuner P, Özdemir M. Salicylic acid peeling combined with vitamin C mesotherapy versus salicylic acid peeling alone in the treatment of mixed type melasma: A comparative study. J Cosmet Laser Ther. 2017;19(5):294–299. https://doi.org/10.1080/14764172.2017.1314501.

54. Iraji F, Nasimi M, Asilian A, Faghihi G, Mozafarpoor S, Hafezi H. Efficacy of mesotherapy with tranexamic acid and ascorbic acid with and without glutathione in treatment of melasma: A split face comparative trial. J Cosmet Dermatol. 2019;18(5):1416–1421. https://doi.org/10.1111/jocd.12874.

55. Duncan DI. Microneedling with Biologicals: Advantages and Limitations. Facial Plast Surg Clin North Am. 2018;26(4):447–454. https://doi.org/10.1016/j.fsc.2018.06.006.

56. Chang PY, Chin LC, Kimura K, Nakahata Y. Human placental extract activates a wide array of gene expressions related to skin functions. Sci Rep. 2022;12(1):11031. https://doi.org/10.1038/s41598-022-15270-y.

57. Nagae M, Nishio T, Ohnuki K, Shimizu K. Effects of oral administration of equine placental extract supplement on the facial skin of healthy adult women: A randomized, double-blind, placebo-controlled study. Health Sci Rep. 2022;5(2):e522. https://doi.org/10.1002/hsr2.522.

58. Sarkar C, Singh SK, Mandal SK, Saha B, Bera R, Ratha J et al. Human placental protein/peptides stimulate melanin synthesis by enhancing tyrosinase gene expression. Mol Cell Biochem. 2006;285(1-2):133–142. https://doi.org/10.1007/s11010-005-9069-3.

59. Maeda K. Timeline of the Development of Skin-Lightening Active Ingredients in Japan. Molecules. 2022;27(15):4774. https://doi.org/10.3390/molecules27154774.

60. Shimokawa Y, Kamisasanuki S, Tashiro M. Treatment of facial dysmelanosis with cosmetics containing Placen A. Nishinihon J Dermatol. 1982;44:1027–1029. (In Japan.).

61. Colomina MJ, Contreras L, Guilabert P, Koo M, Ndez E, Sabate A. Clinical use of tranexamic acid: evidences and controversies. Braz J Anesthesiol. 2022;72(6):795–812. https://doi.org/10.1016/j.bjane.2021.08.022.

62. Tse TW, Hui E. Tranexamic acid: an important adjuvant in the treatment of melasma. J Cosmet Dermatol. 2013;12(1):57–66. https://doi.org/10.1111/jocd.12026.

63. Kim HJ, Moon SH, Cho SH, Lee JD, Kim HS. Efficacy and Safety of Tranexamic Acid in Melasma: A Meta-analysis and Systematic Review. Acta Derm Venereol. 2017;97(7):776–781. https://doi.org/10.2340/00015555-2668.

64. Perper M, Eber AE, Fayne R, Verne SH, Magno RJ, Cervantes J et al. Tranexamic Acid in the Treatment of Melasma: A Review of the Literature. Am J Clin Dermatol. 2017;18(3):373–381. https://doi.org/10.1007/s40257-017-0263-3.

65. Lee YS, Lee YJ, Lee JM, Han TY, Lee JH, Choi JE. The Low-Fluence Q-Switched Nd:YAG Laser Treatment for Melasma: A Systematic Review. Medicina (Kaunas). 2022;58(7):936. https://doi.org/10.3390/medicina58070936.

66. Li JY, Geddes ER, Robinson DM, Friedman PM. A review of melasma treatment focusing on laser and light devices. Semin Cutan Med Surg. 2016;35(4):223–232. https://doi.org/10.12788/j.sder.2016.060.

67. Yi J, Hong T, Zeng H, Li P, Li P, Wang S et al. A Meta-analysis-Based Assessment of Intense Pulsed Light for Treatment of Melasma. Aesthetic Plast Surg. 2020;44(3):947–952. https://doi.org/10.1007/s00266-020-01637-x.

68. Li YH, Chen JZ, Wei HC, Wu Y, Liu M, Xu YY et al. Efficacy and safety of intense pulsed light in treatment of melasma in Chinese patients. Dermatol Surg. 2008;34(5):693–701. https://doi.org/10.1111/j.1524-4725.2008.34130.x.

69. Mun JY, Jeong SY, Kim JH, Han SS, Kim IH. A low fluence Q-switched Nd:YAG laser modifies the 3D structure of melanocyte and ultrastructure of melanosome by subcellular-selective photothermolysis. J Electron Microsc (Tokyo). 2011;60(1):11–18. https://doi.org/10.1093/jmicro/dfq068.

70. Kim JE, Chang SE, Yeo UC, Haw S, Kim IH. Histopathological study of the treatment of melasma lesions using a low-fluence Q-switched 1064-nm neodymium:yttrium-aluminium-garnet laser. Clin Exp Dermatol. 2013;38(2):167–171. https://doi.org/10.1111/j.1365-2230.2012.04473.x.

71. Sarkar R, Aurangabadkar S, Salim T, Das A, Shah S, Majid I et al. Lasers in Melasma: A Review with Consensus Recommendations by Indian Pigmentary Expert Group. Indian J Dermatol. 2017;62(6):585–590. https://doi.org/10.4103/ijd.IJD_488_17.

72. Choi YJ, Nam JH, Kim JY, Min JH, Park KY, Ko EJ et al. Efficacy and safety of a novel picosecond laser using combination of 1 064 and 595 nm on patients with melasma: A prospective, randomized, multicenter, splitface, 2% hydroquinone cream-controlled clinical trial. Lasers Surg Med. 2017;49(10):899–907. https://doi.org/10.1002/lsm.22735.

73. Han HJ, Kim JC, Park YJ, Kang HY. Targeting the dermis for melasma maintenance treatment. Sci Rep. 2024;14(1):949. https://doi.org/10.1038/s41598-023-51133-w.