Pharmacology and therapeutics, clinical trial Oxford, UK International IJD Blackwell 0011-9059 41 Science, Journal Ltdof Dermatology 2002 A clinical, prospective, randomized, double-blind trial comparing skin whitening complex with hydroquinone vs. placebo in the treatment of melasma Skin whitening Haddad et al. complex and hydroquinone in melasma treatment Alessandra Lima Haddad, MD, Luiz Fernando Matos, MD, Flavia Brunstein, Lydia Masako Ferreira, MD, PhD, Ademir Silva, and Divaldo Costa Jr From Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil UNIFESP-EPM Correspondence Alessandra Haddad, MD Rua Dr Alceu de Campos Rodrigues 229 cj. 711/ 712 São Paulo SP Brazil E-mail: [email protected] Abstract Objectives To compare, in a double-blind, randomized, prospective study, the clinical improvement of hyperpigmentation in 30 patients with melasma using hydroquinone or skin whitening complex topically on one side of the face vs. a placebo cream on the other. The study was performed during the period November 2000 to March 2001 at the Federal University of São Paulo, Escola Paulista de Medicina. Methods Thirty patients received three tubes of cream and were divided into two groups: group 1, one tube containing hydroquinone 4% cream and one tube containing placebo to be applied to opposite sides of the face at night, and standardized sunscreen [sun protection factor (SPF) 25] for daily use; group 2, one tube containing skin whitening complex 5% cream and one tube containing placebo to be applied to opposite sides of the face at night, and standardized sunscreen (SPF 25). All of the tubes had the same appearance and the creams had the same characteristics. The only person who knew what was being used by each patient on each side of the face was the pharmacist. A professional photographer took photographs before and after treatment, which lasted for 3 months. Clinical evaluation was performed by two independent observers and by the patients themselves. Statistical evaluation was by the chi-squared and kappa methods. Results Twenty-five patients completed the study, with an overall improvement of 72% in comparison with placebo. Group 1 (hydroquinone and placebo) presented an improvement of 76.9% with 25% side-effects, and group 2 (skin whitening complex and placebo) presented an improvement of 66.7% with 0% side-effects. Conclusions Both depigmentation agents were useful in the treatment of melasma. The hydroquinone group presented more collateral effects than the skin whitening complex group. Considering that the patients showed Fitzpatrick skin types IV to VI and the study was conducted in the summer, skin whitening complex seems to be an excellent choice for the treatment of melasma. Introduction Melasma is a frequent clinical condition, characterized by a slowly progressive symmetrical hypermelanosis with an irregular coloration, ranging from light brown to gray and dark brown, which affects patients of all races and both sexes, with a greater frequency in females (90%)1 due to pregnancy and the use of oral contraceptives. Although less frequent, other factors involved in the pathogenesis deserve to be mentioned, such as genetic influences, exposure to ultraviolet rays, cosmetics, phototoxic drugs, and anticonvulsants. Melasma can be classified clinically into: (i) epidermal: light brown color – melanin in the basal and suprabasal layer of the epidermis; (ii) dermal: grayish coloration – melanophages © 2003 The International Society of Dermatology loaded with melanin in the papillary dermis; (iii) mixed: dark brown (iv) indeterminate or not apparent; occurs in black-skinned patients in visible in daylight but is not visible under wood’s lamp examination. In all subtypes, there is a moderate increase in the number of melanocytes and also in the cellular activity.2 The management of melasma is a challenge, as there is no gold standard treatment and recurrences are common. The principles which govern therapy are based on the following strategies: (i) sunscreen use; (ii) inhibition of the exacerbated activity of melanocytes; (iii) removal of melanin; (iv) dispersion of melanin granules. Hydroquinone, a hydroxyphenol that blocks the synthesis of melanin by inhibiting the tyrosinase enzyme, is the International Journal of Dermatology 2003, 42, 153 – 156 153 154 Pharmacology and therapeutics, clinical trial Skin whitening complex and hydroquinone in melasma treatment depigmentation agent of choice, offering the best response. Its use is associated with several side-effects, however, such as irritant or allergic contact dermatitis, telangiectasis, epidermal atrophy, acneiform lesions,2 ochronosis after prolonged use, and systemic anaphylactic reactions in extreme cases. Fitzpatrick skin types V and VI are more susceptible to side-effects, and focal depigmentation may also occur, known as “confetti leukoderma,” due to the definitive destruction of melanocytes. The Brazilian population presents a high incidence of Fitzpatrick skin phototypes IV, V, and VI. Alternative therapies for the management of melasma are required in these groups, especially in cases with proven intolerance to topical hydroquinone. In addition, the treatment of melasma in pregnant women, where the use of hydroquinone is counterindicated, must be considered, as must the spring and summer seasons in a tropical country, which limit the use of more aggressive treatments. Skin whitening complex (SWC), a depigmenting complex developed in France, contains the following components: (i) extract of uva-ursi, which provokes chemical decoloration of melanin and competes with the tyrosinase enzyme; (ii) biofermented Aspergillus that chelates copper ion, which is essential for tyrosinase enzyme activity, reducing its activity in the formation of new melanin; (iii) grapefruit extract, rich in citric and malic acids, with an exfoliative action and consequent removal of pigmented cells in the epidermis; (iv) rice extract, rich in oligosaccharides, with a hydrating function. As a result of these components, the clarifying action extends to various levels in the melanin-forming chain. SWC has been proven to be efficacious in in vitro studies,2 and its use has been approved at concentrations between 2 and 5%. Objective This double-blind, randomized, prospective, clinical study aimed to evaluate the efficacy of SWC in the treatment of facial melasma compared with hydroquinone and placebo. Patients and methods Inclusion criteria Thirty patients were selected, aged between 38 and 56 years, with clinical complaints of melasma, presenting Fitzpatrick skin types III, IV and V, and with no previous treatment over a period of at least 6 months. All patients gave signed and informed consent prior to participation in the study. Exclusion criteria Exclusion criteria included active dermatologic diseases, known skin sensitivity to clarifying agents or sunscreens, recent treatment, pregnant or breast-feeding women, a history of endocrinopathies, or treatment with oral retinoids in the last year. International Journal of Dermatology 2003, 42, 153 – 156 Haddad et al. Ethical considerations The project was evaluated and approved by the Committee of Ethics and Medical Research of the Hospital São Paulo, Federal University of São Paulo, Escola Paulista de Medicina. Photographic documentation This was carried out painstakingly by a professional photographer in studio conditions with controlled luminosity. Three angles were standardized for photographing the face (front, left, and right profiles) for each patient, before and after treatment. Methodology The patients were divided at random into two groups by the pharmaceutical team responsible for preparing the formulas: group 1, patients receiving hydroquinone 4% (HQ) in a cream vehicle for the treatment of one side of the face and placebo for the other; group 2, patients receiving SWC 5% in a cream vehicle for the treatment of one side of the face and placebo for the other. Only the pharmacist knew the contents of the creams used to treat the face of each patient after randomization. After manipulation, according to the technical norms necessary for each active product, the patients received a set of three personalized 30-g tubes containing the manipulated creams, and identified as “right side of face,” “left side of face,” and “sunscreen.” The sets of creams were delivered to the medical team who undertook the monthly distribution to the patients throughout the 3-month study period. Guidance was provided regarding the application of the creams to specific sides of the face at night and of the standardized sunscreen [sun protection factor (SPF) 25] for use during the day, without association with any other topically used products. In the presence of any side-effects, the medical team was consulted to re-evaluate the treatment. After three consecutive months of treatment, the patients completed a questionnaire and were also evaluated by two independent observers regarding the improvement of melasma, comparing the treated side of the face with the side that had received placebo. Statistical evaluation Statistical analysis was performed using the chi-squared and kappa methods. Results Of the 30 enrolled patients, 25 completed the study, 12 from group 1 (HQ) and 13 from group 2 (SWC). The percentage of patients reporting clinical improvement (72%) agreed with the findings of the observers (Table 1). The opinions of observers 1 and 2 using the kappa test (κ > 0.40) were also considered to be concordant. © 2003 The International Society of Dermatology Haddad et al. Skin whitening complex and hydroquinone in melasma treatment Pharmacology and therapeutics, clinical trial Table 1 (a) Evaluation of correlation level between the observers’ opinions; (a) Observer 1 vs. observer 2 Observer 2 (b) Concordance level between the 2 observers by kappea method Observer 1 Both Right Left Ind Respectively Count % of total Count % of total Count % of total Count % of total Count % of total Both Right 1 4.0% 4.0% 10 40.0% Left Ind Total 4 16.0% 1 4.0% 2 8.0% 7 28.0% 1 4.0% 15 60.0% 7 28.0% 2 8.0% 25 100.0% 1 6 24.0% 1 4.0% 11 44.0% 6 24.0% (b) Symmetric measures Measure of agreement kappa N of valid cases Value Asymp. std. error* Approx. T† Approx. significance 0.566 25 0.126 4.509 0.000 *Not assuming the null hypothesis. †Using the asymptotic standard error assuming the null hypothesis. Table 2 Evaluation of improvement obtained with each active agent (no significant statistical differences) Group 1 Hydroquinone Group 2 Skin whitening complex Total No improvement Improvement Total Count % within group 3 23.1% 10 76.9% 13 100.0% Count % within group 4 33.3% 8 66.7% 12 100.0% Count % within group 7 28.0% 18 72.0% 25 100.0% P = 0.673 (Fisher’s exact test). LR = 1.154 (0.701–1.900), not significant. The two groups were evaluated separately. Group 1 (HQ vs. placebo) presented an improvement of 76.9% and group 2 (SWC vs. placebo) showed an improvement of 66.7%; however, according to Fisher’s test, this difference was not statistically significant (P = 0.673) (Table 2). The incidence of side-effects was greater among the patients in group 1, with 25% of patients reporting an itchy eruption, although this finding was not statistically significant in relation to group 2, in which there were no complaints of side-effects. There was a similarity between the two groups in terms of compliance to treatment (88% of the patients followed the treatment correctly) and satisfaction with treatment (84% classified the treatment as excellent or good and 16% as poor). © 2003 The International Society of Dermatology The patients’ satisfaction levels with treatment were 66.7% and 69.2%, respectively, in groups 1 and 2. When questioned about intolerance to the sunscreen, none of the patients (0%) complained. Discussion Due to its refractory and recurrent nature, melasma is difficult to treat. This is confirmed by the enormous variety of options for treatment, which range from the isolated use of retinoic acid, with a 68% improvement within 24 weeks,3 through combinations of the Kligman triad with 75% improvement,4 and including unsuccessful attempts with lasers, such as the Q-switched ruby equipment.5 In this context, the improvement International Journal of Dermatology 2003, 42, 153 – 156 155 156 Pharmacology and therapeutics, clinical trial Skin whitening complex and hydroquinone in melasma treatment of 66.7% obtained in this study using SWC 5% over such a short period (12 weeks) demonstrates that SWC is worth including in the therapeutic arsenal for the treatment of facial hyperchromia. This percentage is comparable to the 68% improvement obtained with the isolated use of topical retinoic acid, but without the 88% of moderate to mild side-effects reported.3 The results from group 1 (HQ vs. placebo) demonstrated an improvement of 76.9%, compatible with the findings of other authors,6,7 who described rates of improvement between 64 and 88% with other treatments. In the present study, there was no statistically significant difference between the improvement obtained in groups 1 and 2, indicating that the depigmenting action of SWC was similar to that of HQ, but without the 25% of side-effects that occurred amongst HQ users; this percentage of side-effects has been reported previously by other authors.1 Although HQ has been recognized as the most effective depigmenting agent8 in skin of phototypes IV and VI, it is rarely used as, in addition to irritant effects, it can trigger “confetti leukoderma” (a focal depigmentation of the skin) due to the definitive destruction of melanocytes.2 This occurs especially after prolonged use, making SWC an alternative for initial prescription in these patients, or for long-term maintenance of the results obtained initially by other methods. The study was painstaking in its standardization of the use of the principal active ingredients and vehicles, which were prepared by the same team of pharmacists and given by the doctors to the patients on a monthly basis; this guaranteed control over the use of the medication and over the ideal validity date of the products, in order not to adversely affect the final results. The results obtained in this study should encourage future investigations of: (i) the long-term use of SWC, including in the summer in tropical countries; (ii) the advantages arising from its association with exfoliants, such as retinoids and International Journal of Dermatology 2003, 42, 153 – 156 Haddad et al. alpha-hydroxy acids, with a potentially higher efficacy; (iii) its use during pregnancy. Conclusions Both methods used were equally effective in the treatment of facial melasma. The results obtained mean that a greater therapeutic arsenal is available for the treatment of melasma in patients with melanodermic skin phototypes, i.e. the majority of the Brazilian population. References 1 Pathak MA, Fitzpatrick TB, Paresh JA. Treatment of melasma with hydroquinone. J Invest Dermatol 1993; 76: 324 –329. 2 Morgan JE, Gilchrest B, Goldway R. Skin pigmentation. Plast Reconstr Surg 1975; 56 (6): 617. 3 Griffiths LJ, Finkel LJ, Ditre CM, et al. Topical tretinoin improves melasma. A vehicle controlled clinical trial. Br J Dermatol 1993; 129: 415 – 421. 4 Phiamphongsant T. Treatment of melasma: a review with personal experience. Int J Dermatol 1998; 37: 897 – 903. 5 Taylor CR, Anderson RR. Ineffective treatment of refractory melasma and post inflammatory hyperpigmentation by Q-switched ruby laser. J Dermatol Surg Oncol 1994; 20: 592 – 597. 6 Fitzpatrick TB, Arndt KA, Mofty AM, Pathak MA. Hydroquinone and psoralens in the therapy of hypermelanosis and vitiligo. Arch Dermatol 1966; 93: 589 – 600. 7 Sanchez IL, Vasquez MA. Hydroquinone solution in the treatment of melasma. Int J Dermatol 1982; 21: 55– 58. 8 Grimes EP. Etiologic and therapeutic considerations. Arch Dermatol 1995; 131: 1453 –1457. 9 Proserpio G, Premoli R. Tintarella di Luna – Agenti depigmentantie preparati schiarenti. Italian Cosmetic News 1999; XXII: 126 –129. © 2003 The International Society of Dermatology