Topical Treatments for Melasma: A Systematic Review of Randomized Controlled Trials

We performed a systematic review of topical treatments for melasma. Strong evidence-based recommendations include cysteamine, TC, and TXA as first-line treatments for melasma. Cysteamine has excellent efficacy, is reported to have anti-cancer properties, and has no known risk for thrombosis or ochronosis. TC therapies and TXA are effective for melasma but carry theoretical risks for ochronosis or thrombosis, respectively. Natural compounds are associated with low risk for AEs, but more research is needed to determine the efficacy, optimal formulation, and appropriate concentration of novel treatments.

For all topical agents, continued treatment and use of medications is necessary as pigmentation may recur following treatment cessation. Future large RCTs with control arms using standard-of-care treatments (ie, HQ or TC) are necessary to assess the relative risks and benefits of a novel agent. Current topical treatments mostly inhibit melanin formation and transfer, but do not target the vascular components of melasma, inflammation, or underlying disease etiology. We believe that synergetic combination approaches are likely to have greater efficacy than stand-alone treatments. Future mechanistic research on the underlying etiology of melasma may facilitate the development of targeted approaches.

Dr. Jagdeo had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Acquisition, analysis, and interpretation of data: EA and JN. Drafting of the manuscript: EA. Critical revision of the manuscript for important intellectual content: JN and JJ.

Dr. Jagdeo is a speaker for L’Oréal/Skinceuticals and a consultant for Scientis. Dr. Jagdeo is on the scientific advisory board for Sun Pharma/DUSA Pharmaceuticals, Inc. for the product Levulan® photodynamic therapy. No funding has been received for this article. The views expressed in this article are those of the authors and do not necessarily reflect the official policy or position of the U.S. Department of Veterans Affairs or the United States Government.

 

1. Kwon S-H, Hwang Y-J, Lee S-K, et al. Heterogeneous pathology of melasma and its clinical implications. Int J Mol Sci. 2016;17(6):824. 
2. Ogbechie-Godec OA, Elbuluk N. Melasma: an up-to-date comprehensive review. Derm Ther. 2017;7(3):305-318. 
3. Vázquez M, Maldonado H, Benmamán C, et al. Melasma in men. Int J Derm. 1988;27(1):25-27. 
4. Sheth VM, Pandya AG. Melasma: a comprehensive update: part I. J Am Acad Dermatol. 2011;65(4):689-697; quiz 698. 
5. Lee AY. Recent progress in melasma pathogenesis. Pigment Cell Melanoma Res. 2015;28(6):648-660. 
6. Passeron T. Melasma pathogenesis and influencing factors–an overview of the latest research. J Eur Acad Dermatol Venereol. 2013;27(s1):5-6. 
7. Jiang J, Akinseye O, Tovar-Garza A, et al. The effect of melasma on self-esteem: A pilot study. Int J Women Dermatol. 2018;4(1):38-42. 
8. Pawaskar MD, Parikh P, Markowski T, et al. Melasma and its impact on health-related quality of life in Hispanic women. J Dermatol Treat. 2007;18(1):5-9. 
9. Sheth VM, Pandya AG. Melasma: a comprehensive update: part II. J Am Acad Dermatol. 2011;65(4):699-714; quiz 715. 
10. Qaseem A, Snow V, Owens DK, et al. The development of clinical practice guidelines and guidance statements of the American College of Physicians: summary of methods. Ann Intern Med. 2010;153(3):194-199. 
11. Farshi S. Comparative study of therapeutic effects of 20% azelaic acid and hydroquinone 4% cream in the treatment of melasma. J Cosmet Dermatol. 2011;10(4):282-287. 
12. Mazurek K, Pierzchala E. Comparison of efficacy of products containing azelaic acid in melasma treatment. J Cosmet Dermatol. 2016;15(3):269-282. 
13. Farshi S, Mansouri P, Kasraee B. Efficacy of cysteamine cream in the treatment of epidermal melasma, evaluating by Dermacatch as a new measurement method: a randomized double blind placebo controlled study. J Dermatol Treat. 2018;29(2):182-189. 
14. Mansouri P, Farshi S, Hashemi Z, et al. 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):209-217. 
15. Fujisawa T, Rubin B, Suzuki A, et al. Cysteamine suppresses invasion, metastasis and prolongs survival by inhibiting matrix metalloproteinases in a mouse model of human pancreatic cancer. PloS One. 2012;7(4):e34437. 
16. Besouw M, Masereeuw R, van den Heuvel L, et al. Cysteamine: an old drug with new potential. Drug Discovery Today. 2013;18(15-16):785-792. 
17. Lyons A, Stoll J, Moy R. A randomized, double-blind, placebo-Controlled, split-face study of the efficacy of topical epidermal growth factor for the treatment of melasma. J Drugs Dermatol. 2018;17(9):970-973. 
18. Taghavi F, Banihashemi M, Zabolinejad N, et al. Comparison of therapeutic effects of conventional and liposomal form of 4% topical hydroquinone in patients with melasma. J Cosmet Dermatol. 2019;18(3):870-873. 
19. Draelos ZD. A split-face evaluation of a novel pigment-lightening agent compared with no treatment and hydroquinone. J Am Acad Dermatol. 2015;72(1):105-107. 
20. Alvin G, Catambay N, Vergara A, et al. A comparative study of the safety and efficacy of 75% mulberry (Morus alba) extract oil vs placebo as a topical treatment for melasma: a randomized, single-blind, placebo-controlled trial. J Drugs Dermatol. 2011;10(9):1025-1031. 
21. Hakozaki T, Minwalla L, Zhuang J, et al. The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol. 2002;147(1):20-31. 
22. Navarrete-Solis J, Castanedo-Cazares JP, Torres-Alvarez B, et al. A double-blind, randomized clinical trial of niacinamide 4% vs hydroquinone 4% in the treatment of melasma. Dermatol Res Pract. 2011;2011:379173. 
23. Mendoza CG, Singzon IA, Handog EB. A randomized, double-blind, placebo-controlled clinical trial on the efficacy and safety of 3% Rumex occidentalis cream vs 4% hydroquinone cream in the treatment of melasma among Filipinos. Int J Dermatol. 2014;53(11):1412-1416. 
24. Viyoch J, Tengamnuay I, Phetdee K, et al. Effects of trans-4-(aminomethyl) cyclohexanecarboxylic acid/potassium azeloyl diglycinate/niacinamide topical emulsion in Thai adults with melasma: a single-center, randomized, double-blind, controlled study. Curr Ther Res Clin Exp. 2010;71(6):345-359. 
25. Kanechorn Na Ayuthaya P, Niumphradit N, Manosroi A, et al. Topical 5% tranexamic acid for the treatment of melasma in Asians: a double-blind randomized controlled clinical trial. J Cosmet Laser Ther. 2012;14(3):150-154. 
26. Atefi N, Dalvand B, Ghassemi M, et al. Therapeutic effects of topical tranexamic acid in comparison with hydroquinone in treatment of women with melasma. Dermatol Ther. 2017;7(3):417-424. 
27. Banihashemi M, Zabolinejad N, Jaafari MR, et al. Comparison of therapeutic effects of liposomal Tranexamic Acid and conventional Hydroquinone on melasma. J Cosmet Dermatol. 2015;14(3):174-177. 
28. Ebrahimi B, Naeini FF. Topical tranexamic acid as a promising treatment for melasma. J Res Med Sci. 2014;19(8):753-757. 
29. Bala HR, Lee S, Wong C, et al. Oral tranexamic acid for the treatment of melasma: a review. Dermatol Surg. 2018;44(6):814-825. 
30. Gong Z, Lai W, Zhao G, et al. Efficacy and safety of fluocinolone acetonide, hydroquinone, and tretinoin cream in chinese patients with melasma: a randomized, double-blind, placebo-controlled, multicenter, parallel-group study. Clin Drug Investig. 2015;35(6):385-395. 
31. Astaneh R, Farboud E, Nazemi MJ. 4% hydroquinone vs 4% hydroquinone, 0.05% dexamethasone and 0.05% tretinoin in the treatment of melasma: a comparative study. Int J Dermatol. 2005;44(7):599-601. 
32. Ferreira Cestari T, Hassun K, Sittart A, et al. A comparison of triple combination cream and hydroquinone 4% cream for the treatment of moderate to severe facial melasma. J Cosmet Dermatol. 2007;6(1):36-39. 
33. Chan R, Park KC, Lee MH, 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%