Doi:10.1016/j.jaad.2005.12.039

Marta Rendon, MD,a Mark Berneburg, MD,b Ivonne Arellano, MD,c and Mauro Picardo, MDd ¨bingen, Germany; Mexico City, Mexico; and Rome, Italy Treatment of melasma involves the use of a range of topical depigmenting agents and physical therapies.
Varying degrees of success have been achieved with these therapies. The Pigmentary Disorders Academy(PDA) undertook to evaluate the clinical efficacy of the different treatments of melasma in order to generatea consensus statement on its management. Clinical papers published during the past 20 years wereidentified through MEDLINE searches and methodology and outcome assessed according to guidelinesadapted from the US Preventive Services Task Force (USPSTF). The consensus of the group was that first-line therapy for melasma should consist of effective topical therapies, mainly fixed triple combinations.
Where patients have either sensitivity to the ingredients or a triple combination therapy is unavailable,other compounds with dual ingredients (hydroquinone plus glycolic acid) or single agents (4% hydro-quinone, 0.1% retinoic acid, or 20% azelaic acid) may be considered as an alternative. In patients who failedto respond to therapy, options for second-line therapy include peels either alone or in combination withtopical therapy. Some patients will require therapy to maintain remission status and a combination oftopical therapies should be considered. Lasers should rarely be used in the treatment of melasma and,if applied, skin type should be taken into account. ( J Am Acad Dermatol 2006;54:S272-81.) Melasma is a pigmentary disorder of the Abbreviationsused: face involving the cheeks, forehead, andcommonly the upper lip. This condition is more common in women, accounting for 90% of all cases. It appears in all racial types, but occurs more frequently in those persons with Fitzpatrick skin types IV to VI who live in areas of high ultraviolet radiation; sun exposure deepens these hyperpig-mented areas. Treatment of melasma involves theuse of topical hypopigmenting agents, such as One aim of the Pigmentary Disorders Academy hydroquinone (HQ), tretinoin (RA), kojic acid, and was to estimate the clinical efficacy of the different azelaic acid. Physical therapies, such as chemical treatments of melasma in order to generate a con- peels (glycolic acid [GA], trichloroacetic acid [TCA]), sensus statement on its management. A MEDLINE laser therapy and dermabrasion, similar to that used search was conducted on therapeutic options for in other hyperpigmentary disorders, have also been melasma. Clinical studies (excluding case studies) evaluated with varying degrees of success.
that have been published over the past 20 years werereviewed and the data classified according to specificcriteria (see below). Subsequent treatment recom-mendations were generated on the basis of this From the Dermatology and Aesthetic Center, Boca Ratona; the published clinical evidence and expert opinion.
Department of Dermatology, Phototherapy, Lasermedicine,PDT, Eberhard Karls University, Tu¨bingenb; the Department ofDermatology, Mexico General Hospital, Mexico Cityc; and the Department of Cutaneous Physiopathology of the San Gallicano Dermatological Institute, Rome.d HQ inhibits the conversion of dopa to melanin by Supported by Galderma International.
inhibiting the activity of tyrosinase. Other proposed Disclosure: All authors are members of the Pigmentary Disorders Academy (PDA) and receive honoraria from Galderma for their mechanisms of action are inhibition of DNA and RNA synthesis, degradation of melanosomes, and Reprint requests: Marta Rendon, MD, Medical Director, The destruction of melanocytesHQ can cause perma- Dermatology and Aesthetic Center, Suite 3C, 880 NW 13th St, nent depigmentation when used at high concentra- tions for a long period of time. It is commonly used 0190-9622/$32.00ª 2006 by the American Academy of Dermatology, Inc.
at concentrations ranging from 2% to 5%, the higher concentrations trading off greater efficacy with greater skin irritation. Adverse effects of HQ include on a scale from 5, completely cleared (100%), to 1, irritant dermatitis, contact dermatitis, postinflamma- worsening; hyperpigmentation darker than that of tory pigmentation, ochronosis, and nail bleaching.
baseline melasma. Secondary success was defined as an improvement score between 3 and 5. Overall therapy for melasma, two representative placebo- evaluation by the patient at week 8 involved a scale controlled studies plus one comparative study have from 1, excellent, to 4, poor. At baseline, more than been chosen for inclusion in this review. Ennes, 98% of all patients had moderate (grade 2) or severe Paschoalick, and Mota De Avelar Alchornereported (grade 3) melasma. At weeks 4, 6 and 8, melasma on the use of HQ 4% in a double-blind, placebo- severity scores were significantly lower in the triple controlled trial involving 48 patients with melasma therapy groups than in the hydroquinone group on the face. HQ or placebo was applied twice daily (P \ .003). Primary success was achieved for 35% for 12 weeks; both contained a sunscreen with a sun of patients (21/60) and for 5.1% of patients (3/59) protection factor of 30. Evaluation of efficacy was in the triple therapy and HQ groups, respectively based on clinical observations and photographic (P = .0001). Secondary success was achieved for evaluations. Total improvement was defined as 73% (44/60) and 49% (29/59) of patients treated with complete disappearance of the spot; partial improve- triple therapy and HQ, respectively (P = .007). The ment as partial disappearance, and failure as no proportion of patients who considered that the change or worsening. Results indicated total im- treatment was ‘‘excellent’’ was greater for triple provement of melasma in 38% of patients treated therapy (50%) than for HQ (34%). There were no with HQ as well as partial improvement and no significant differences between the two treatment treatment failures in 57% of patients; 5% of patients groups for the incidence of the reported adverse discontinued therapy. In the placebo group, 8% of patients had total improvement, 58% had partialimprovement, but 17% were classified as treatment failures. Both therapies were well tolerated, with no Tretinoin. Tretinoin (retinoic acid [RA] or vita- serious adverse events reported. In a more recent min A acid) is thought to have an inhibitory effect on placebo-controlled study, HQ 4% was compared tyrosinase by inhibiting the enzyme’s transcription, with a skin whitening complex consisting of a as well as on dopachrome conversion factor, with mixture of uva ursi extract (a competitive inhibitor a resulting interruption of melanin synthesRA of tyrosinase that provokes chemical decoloration of reduces hyperpigmentation through the induction melanin), biofermented Aspergillus (chelates copper of desquamation. Concentrations ranging from ion needed for tyrosinase activity), grapefruit extract 0.05% to 0.1% have been used and the associated (exfoliative action), and rice extract (hydrating func- side effects are erythema and peeling in the area of tion) in 30 patients over a 3-month Treat- application; postinflammatory hyperpigmentation ment evaluation consisted of patient questionnaires and two independent observers. According to the RA 0.1% has been used to treat melasma in 30 observer evaluations, HQ use resulted in a 77% black patients, with results indicating that the average improvement with a 25% side-effect rate, primarily Melasma Area and Severity Index (MASI) score of the pruritus, compared with a 67% improvement and tretinoin-treated group decreased by 32% from base- 0% side effects with the skin-whitening complex.
line compared with a 10% decrease in the vehicle A comparative study has recently been completed control group.Histological examination of treated involving 4% HQ and the triple fixed combination skin revealed a significant decrease in epidermal therapy HQ 4%, RA 0.05%, and fluocinolone aceto- pigmentation in the RA group compared with the nide (FA) 0.01% (see belowA total of 120 patients control group (). Side effects were limited to a were randomized to one of the two treatment arms mild retinoid dermatitis in 67% of RA-treated patients.
and treatment was applied for 8 weeks. Efficacy Another randomized controlled study of 0.1% RA assessments involved the investigator’s static evalu- once daily in 38 Caucasian women indicated that 13 ation of melasma severity at each visit using a scale of 19 tretinoin-treated patients (68%) were clinically from 0, indicating melasma lesions that were very rated as improved or much improved, compared with similar to the surrounding normal skin or with 1 of 19 patients (5%) in the vehicle group (P = .0006).
minimal residual hyperpigmentation, to 3, severe Significant improvement first occurred after 24 weeks (markedly darker than the surrounding normal skin).
of tretinoin treatment. Colorimetry (an objective Primary success was defined as a melasma severity measure of skin color) demonstrated a 0.9 unit score of 0 at week 8. Evaluation of overall improve- lightening of tretinoin-treated melasma and a 0.3 ment was conducted by the investigator at each visit unit darkening with vehicle (P = .01); these results Table I. Melasma in black skin: Histologic results after 40 weeks of topical 0.1% tretinoinversus vehicle thera *All measurements represent mean 6 standard error and, except for epidermal thickness, are based on a semiquantative scale of 0 (none)through 4 (maximum). Percentages were determined before rounding off the means. (From Kimbrough-Green CK, Griffiths CE, Finkel LJ.
Arch Dermatol 1994;130:727-33, page 730, Copyright ª 1994, American Medical Association. All rights reserved.)yRepresents significance of change from baseline in tretinoin versus vehicle groups.
zFor each patient specimen, measurements from the top of granular layer to epidermal basement membrane at 5 interrete sites wereaveraged.
correlated with clinical lightening. Histologically, inhibition of mitochondrial oxidoreductase activity epidermal pigment was reduced by 36% following and DNA syntIt is also a weak competitive tretinoin treatment, compared with a 50% increase inhibitor of tyrosinase in vitro. Azelaic acid is avail- with vehicle (P = .002). Reduction in epidermal able as a cream at a concentration of 15% to 20%. A pigment also correlated with clinical lightening.
20% azelaic acidebased cream has been used to treat Moderate cutaneous side effects of erythema and 39 patients for 6 months with two applications per desquamation occurred in 88% of tretinoin-treated day. A reduction in melasma intensity was obtained and in 29% of vehicle-treated patients.
in 37 patients. A mean reduction in pigmentation of Isotretinoin. Isotretinoin 0.05% has been stud- 51.3% was reported. The overall judgment of physi- ied in 30 Thai patients with moderate to severe cian and patient were excellent or good in 79% melasma. Patients were randomized to treatment and 85%, respectively.A randomized, double- with isotretinoin plus sunscreen or vehicle plus blind comparative study in 155 patients of Indo- Malay-Hispanic origin found that 20% azelaic acid MASI and Melasma Area and Melanin Index scores was superior to HQ Over a period of 24 weeks, of treated patients decreased by 68.2% and 47%, 73% of the azelaic acid patients compared with 19% of respectively, compared with decreases of 60% and the HQ patients had good to excellent overall results, 34% for controls; although these differences were as measured by the reduction of the pigmentary clinically important, they were not statistically sig- intensity of melasma and lesion size (P \.001). In a nificant. Side effects were limited to mild transient double-blind study by Balina and Graupeinvolving retinoid dermatitis in 27% of patients.
329 women, 20% azelaic acid was shown to be as Adapalene. Adapalene is a naphthoic acid de- effective as HQ 4%, without the latter’s undesirable rivative with potent retinoid activity; it controls cell side-effects. In the azelaic acidetreated patients, 65% proliferation and differentiation and has signifi- of outcomes were graded as good or excellent cant anti-inflammatory actiA randomized trial compared with 72.5% of those of HQ-treated pa- of 0.1% adapalene versus 0.05% tretinoin for 14 tients. Azelaic acid 20% plus tretinoin 0.05% or 0.1% weeks in 30 Indian patients indicated a 41% and 37% has been shown to be more effective in enhancing reduction in MASI scores with adapalene and treti- the skin lightening effects of azelaic acid alone. In noin, respectively (not significant).Side effects an open-label randomized study of 50 patients, 24 were significantly more frequent with tretinoin than weeks of treatment with azelaic acid 20% and azelaic with adapalene; 63% of patients treated with treti- acid 20% plus tretinoin 0.05% resulted in excellent noin suffered with pruritus, burning, dryness, ery- results in 5.3% and 34.8% of patients, respec thema and scaling compared with mild erythema and Sarkar, Bhalla, and Kanwarhave also studied a burning sensation in 8% and dryness in 13% of sequential therapy of the potent topical steroid clobetasol propionate and azelaic acid. ThirtyIndian patients with melasma had azelaic acid 20% applied to one half of the face twice daily for 24 Azelaic acid has antiproliferative and cytotoxic weeks and to the other half, clobetasol propionate effects on melanocytes, which are mediated via 0.05% for just 8 weeks followed by azelaic acid 20% for the remaining 16 weeks. Results showed no success rate assessed by using spectrophotomet difference at 24 weeks in the lightening produced by Included in this group were 6 patients who needed either treatment; 96.7% and 90% of patients had good a second course of treatment. Erythema and scaling to excellent responses with azelaic acid plus steroid were observed during treatment. RA 0.1% plus 3% and azelaic acid, respectively. Side effects of the HQ has been evaluated in 40 female Korean women treatments were mostly mild, transient, local itching in a 20-week open label study.Overall, 59% of and burning. Acneiform eruptions were observed in patients were rated as having excellent to good 5 patients receiving clobetasol propionate, but these improvement by physician and patient evaluations disappeared once the steroid treatment was discon- after therapy. The majority of patients (96%) noted tinued. Three patients withdrew from the trial be- mild to moderate reactions to tretinoin cream. The cause of atrophy and telangiectasia resulting from sensations of burning, itching, erythema, and scali- clobetasol propionate treatment, and 4 patients with- ness lessened with continued therapy.
drew because of burning, erythema, and itching dueto azelaic acid. The authors recommend that sequen- tial treatment only be carried out under the supervi- Another combination study compared 10% GA plus 4% HQ in a cream containing vitamins C and Eand sunscreen with a cream containing sunscreen alone.A total of 39 Hispanic women with Fitzpa- Vitamin C inhibits melanin formation as well trick skin types III-V and bilateral epidermal melasma as reducing oxidized melanin.Iontophoresis has were enrolled in this randomized, controlled 12- been used to increase the penetration of vitamin C week trial. Changes in pigmentation were measured into the skin. In a comparative study, 29 patients by means of a Mexameter (CK Electronic, Cologne, were treated with vitamin C iontophoresis to one Germany) (spectrophotometric skin coloration mea- side of the face and water placebo to the other twice sure of melanin and hemoglobin levels), the MASI, a week for 12 weeksLuminance (L) value was and a global evaluation by the patient and a blinded measured by using a colorimeter to obtain an objec- investigator. Results indicated a significant decrease tive parameter of the brightness of the pigmentation.
in the degree of pigmentation using the study cream A significant decrease in L value was reported on the compared with sunscreen alone; 75% versus 13% treated side of the face (from 4.8 at baseline to 2.78 of patients improved (P \.0001). Irritation was more after 12 weeks) compared with placebo (4.45 at common with the study cream, but this resolved on baseline to 3.87 at 12 weeks) (P \.01). Side effects in cessation of use and the application of moisturizers.
a small number of patients included a mild sense ofelectric shock, itching, erythema, burning sensation, Kojic acid, a compound derived form the fungus Aspergillus oryzae, has been shown to inhibit tyro- sinaseand has been studied in combination with Phenolic and catecholic compounds are potent other agents. GA 5% combined with either 4% HQ or depigmenting agents of the skin. A melanocytotoxic 4% kojic acid daily for 3 months has been compared agent, N-acetyl-4-S-cysteaminylphenol, was synthe- in a split-face design in 39 patients with melasm sized consisting of phenol, catechol, and sulfur.
Although none of the patients was completely A retrospective observation of 12 patients treated cleared, both combinations proved equally effective, with 4% N-acetyl-4-S-cysteaminylphenol, a tyrosin- with reduction of pigmentation in 51% of patients; ase substrate, showed a complete loss (8%), a marked dramatic results were noted in 28% of patients treated improvement (66%), or a moderate improvement with GA/kojic acid and in 21% treated with GA/HQ.
(25%) of melasma lesions.Visible changes in themelanin in the dermis were seen 2 to 4 weeks after daily topical application. This depigmentation was HQ has been studied in combination with other associated with a decrease in the number of func- agents to provide greater therapeutic success than tioning melanocytes and in the number of melano- HQ alone.The addition of tretinoin 0.05% to 0.1% prevents the oxidation of HQ, as well as improvingepidermal penetration, allowing pigment elimination and increasing keratinocyte proliferation. First pro- A study of 0.1% RA, HQ 5% plus lactic acid 7% posed in 1975, Kligman’s formula (KF; HQ 5%, or ascorbic acid 10% twice daily for 16 weeks in tretinoin 0.1%, and dexamethasone 0.1%) has been 10 Oriental patients with melasma indicated a 70% the most widely used combination therapy for decreasing cellular metabolism. Tretinoin has beenfound to abrogate the epidermal atrophy that canoccur with topical corticosteroids. Various modifica-tions to the original formula have subsequently beenstudied.
A triple fixed combination of HQ 4%, RA 0.05%, and FA 0.01% has been studied in 641 patients withmoderate to severe melasma and Fitzpatrick skintypes I to IVThe study compared the triplecombination with HQ/RA, FA/RA, and FA/HQ overa period of 8 weeks; sunscreen with a sun protec-tion factor of 30 was used in all patients. Completeclearing on or before day 56 was reported in 26.1%,9.5%, 1.9%, and 3.1% of patients on a regimen ofHQ/RA/FA, HQ/RA, FA/RA, and FA/HQ, respectively). Comparative results for percentages ofcleared/almost cleared lesions were 77%, 46.8%,27.3%, and 42.2%. Importantly, efficacy was consis-tent across all racial and ethnic groups. Adverseevents were mild to moderate; the most commonreactions observed with all treatment groups wereerythema, skin peeling, burning, and/or stingingsensation. No skin atrophy was reported.
Two long-term safety studies have been con- ducted on the triple fixed combination of HQ 4%,RA 0.05% and FA 0.01%.These were multicenter,long-term (1 year), open-label studies involving atotal of 797 patients with mild, moderate, or severemelasma. Of these, 569 patients had already com-pleted the 8-week study already discussed and 228were newly enrolled patients.The treatment wasused for an average of 6.8 months and the majority ofpatients received two or more courses; all patientsused a broad-spectrum sunscreen. A total of 96patients used the treatment for 360 days. It wasobserved that each time the patient was treated, ashorter period was required to achieve a benefit sothat by month 12, more patients had mild and clearedmelasma (94%) compared with any month on studydrug. In terms of safety, there was no significantincrease in severity or the incidence of adverseevents when compared with the 8-week controlled Fig 1. Appearance of melasma in patient at baseline clinical study and only 3 patients (1%) discontinued (A) and after 8 weeks of treatment (B) with a triple fixed the study because of treatment-related adverse combination of hydroquinone 4%, retinoic acid 0.05%, events. A total of 129 patients (57%) experienced at and fluocinolone acetonide 0.01%. (From Taylor SC, least one treatment-related adverse event. Most were Torok H, Jones T, Lowe N, Rich P, Tschen E, et al. Efficacy expected application site reactions, mild and tran- and safety of a new triple-combination agent for the treat- sient in nature, and did not require remedial therapy.
ment of facial melasma. Cutis 2003;72:67-72, page 71.
Two cases of skin atrophy were recorded in patients Copyright 2003, Quadrant HealthCom Inc. Reprinted withpermission.) who had been treated for 180 days (out of 797patients) at the end of the study, confirming the idea melasma worThe addition of corticosteroids of abrogating the epidermal atrophy that can occur to a combined therapy involving HQ caused a decrease in the irritative effects of the hypopigment- ing agents, as well as inhibiting melanin synthesis by patients with moderate to severe melasma and Fitzpatrick skin types I to VI involving the triple combination has been conducted in the United improvement in melasma at the end of the study involving 12 weeks of treatment with kojic acid 2% severity (MASI score) and the change in the MASI.
gel plus glycolic acid 10% and hydroquinone 2% Results showed that the triple fixed combination of HQ/TA/RA produced a highly significant reduction in MASI scores (P \.0001). The majority of patients had ‘‘complete to nearly complete’’ (75%-99%) im- provement in MASI score by weeks 4 and 8. Efficacy was consistent across racial and ethnic groups. It was interesting to note that 60% of patients reported anadverse event, which was mainly skin irritation.
GA, Glycolic acid 10%; HQ, hydroquinone 2%.
There was no report of skin atrophy in any patient; Reproduced from Lim JT. Treatment of melasma using kojic acid ina gel containing hydroquinone and glycolic acid. Dermatol Surg a few cases of telangiectasia were reported.
1999;25:282-4, page 283, with permission from Blackwell Publishing.
A modification to KF in which HQ level was reduced to 2% has been assessed in a comparativeclinical trial with GA 30% to 40% (chemical peel).Forty Indian patients with Fitzpatrick skin types III to IV with moderate to severe melasma were random- ized to treatment with the modified KF daily plus 6 Chemical peels can be used to treat melasma and serial GA treatments at 3-week intervals or to modi- include such agents as GA, TCA, Jessner’s solution fied KF alone. A significant decrease in the MASI score (lactic acid, salicylic acid, resorcinol, and ethanol), at 21 weeks compared with baseline was observed in salicylic acid, tretinoin, and kojic acid. GA peels at both groups. The group receiving GA showed a trend concentrations ranging from 10% to 70% are popular toward more rapid and greater improvements than and can be used in dark-skinned patients. A 91% the group only receiving the modified KF. At 12 weeks improvement in melasma (reduction in MASI score) there was a 46% reduction and at 21 weeks an 80% was found in a study involving 25 nonpregnant reduction in MASI in the combined therapy group.
women treated with 50% GA once per month for This compared with a 33% and 63% reduction with 3 consecutive months.Patients enrolled had a min- KF alone at 12 and 21 weeks, respectively. Adverse imum MASI score of 15 and those with epidermal- type melasma had a better response to therapy than Another modified KF consisting of HQ 5%, RA those with mixed-type melasma. In terms of side 0.1%, and hydrocortisone 1% has been studied in effects, one patient developed a mild degree of hyper- 25 Korean female patients with therapy-recalcitrant pigmentation, reported to be the most common facial melasmTherapy was applied twice per week for 4 months. The severity of melasma was GA 70% has been compared with Jessner’s solu- scored at baseline, 4 weeks, and 4 months after tion in a split-face design trial with 16 pa treatment using a modified version of the MASI.As Colorimetric analysis showed an average lightening early as 4 weeks after treatment, 12% of patients had of 3.14 6 3.1 on the GA-treated side and 2.96 6 4.84 a definite improvement of more than 50% in the on the Jessner solutionetreated side (no statistical modified MASI score, 20% of patients had a 30% significance). The only adverse events reported to 50% improvement, and 16% of patients had a 10% occurred on the GA-treated area, which consisted to 29% improvement. At 4 months 52% and 19% of of crusting, postinflammatory hyperpigmentation, patients had a 50% or a 30% to 50% improvement, and erythema. Follow-up of 5 patients at 16 months respectively; 29% showed no improvement.
indicated that patients who continued topical ther-apy maintained their improvement, whereas those who discontinued experienced relapse.
The addition of GA 20% to 30% to 4% HQ has include bearberry extract, paper mulberry plant been studied in 21 Hispanic women with bilateral extract, arbutin, licorice extract, melawhite (leuko- epidermal and mixed melasmPatients under- cyte extract), ascorbic acid, mercury, and indometh- went twice-daily full-face application of HQ plus acin. At present there are no controlled studies GA 20% to 30% to one side of the face only every investigating the efficacy of these compounds and 2 weeks and pigmentation was measured by means data are insufficient to make a conclusion about the of a mexameter (spectrophotometric skin coloration efficacy of these therapies for melasma.
measure of melanin and hemoglobin levels) and Evidence obtained from at least one properly designed, randomized control trial Evidence obtained from well designed controlled trials without randomization Evidence obtained from well designed cohort or case control analytic studies, preferably from more than one center Evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled experiments (such as the results of the introduction of penicillin in the 1940s) could also be regarded as this typeof evidence Opinions of respected authorities based on clinical experience, descriptive studies, or reports of expert committees Evidence inadequate owing to problems of methodology (eg, sample size, or length or comprehensiveness of From Stevens A, Raferty J, editors. Health care needs assessment. New York: Radcliffe Medical Press; 1997, page 304. Reproduced withpermission.
Concentrations of 1% to 5% RA have been evalu- ated in a skin peeling protocol in 15 women with There is good evidence to support the use of this melasma and photoaged skin with Fitzpatrick skin types I to IV.There was a clinical improvement There is fair evidence to support the use of this in skin texture and appearance after 5 sessions of treatment applied at 2- to 3-day intervals. Histological There is poor evidence to support the use of the examination before and after treatment revealed a There is fair evidence to support the rejection of the decrease in the corneal layer, an increase in the epidermal thickness, and a lengthening of the cristae There is good evidence to support the rejection of A chemical peel protocol involving GA 50% plus kojic acid 10% has been evaluated in 20 patients with From Stevens A, Raferty J, editors. Health care needs assessment.
diffuse melasma.Treatment was applied at 2-week New York: Radcliffe Medical Press; 1997, page 340. Reproducedwith permission.
intervals for 3 to 6 months. Complete regression wasobserved in 6 patients (30%), partial regression in 12 the MASI. Results indicated that both treatments (60%), and no regression in 2 (10%). In a compara- significantly reduced (P \ .001) skin pigmentation tive study of 40 Chinese women with epidermal compared with baseline; however, no difference was melasma, half of the face was treated with kojic acid 2% gel plus GA 10% and HQ 2% and the other half of The combination of 10% GA and 2% HQ has been the face with the same preparation but without the studied in 10 Asian women with moderate to severe kojic acid twice daily for 12 weeksOf the patients melasmCombination therapy was applied twice treated with combination therapy, clearing of me- daily to both sides of the face for 26 weeks and 20% lasma was reported in 60% compared with 47.5% GA peels to one side every 3 weeks (total of 8 peels).
Assessment by a dermatologist was made using the erythema, redness, stinging, and exfoliation, which Munsell color chart. Results indicated that with occurred on both sides of the face but resolved by GA/HQ plus GA peel therapy up to 33% lightening of melasma was found in 6 patients and up to 66%lightening in 4 patients. With the GA/HQ therapy alone, 8 patients had lightening classified as slight The use of a single laser type, the Q-switched (#33%) in 7 patients and moderate ( #66% lighten- ruby laser. has been reported to be ineffective in 11 patients with melasma refractory to other types of Salicylic acid 20% to 30% at 2-week intervals has been used in 25 dark-skinned patients (Fitzpatrick of their lesions, 3 had no change, and darker hyper- skin types V-VI), including 6 with melasma, with pigmentation occurred in 4 patients at 4 weeks.
good results.Five peelings were conducted in Histopathological examination of pigmented lesions patients previously treated with 4% HQ for 2 weeks immediately after laser application indicated that not and resulted in moderate to significant improvement all pigment-producing structures were affected by in 88% of patients. Minimal to mild side effects a single laser treatment. Better results have been shown with a combination of pulsed CO2 laser Table V. Level and quality of evidence for melasma therapies 5% HQ 1 0.1%-0.4% RA 1 7% lactic acid/10% ascorbic acid 4% HQ 1 0.05% RA 1 0.01% fluocinolone acetonide 2% HQ 1 0.05% RA 1 0.1% dexamethasone (modified Kligman) 2% HQ 1 0.05% RA 1 0.1% dexamethasone (modified Kligman) 1 30%-40% GA peel Laser therapy (1chemical peels and topical therapies) Q-switched alexandrite laser 1 15%-25% TCA peel 1 Jessner’s solution GA, Glycolic acid; HQ, hydroquinone; KA, kojic acid; KF, Kligman’s formula; RA, retinoic acid; TCA, trichloroacetic acid.
with Q-switched alexandrite laser.The principle areas. No adverse events were noted. The converse behind the treatment was that the CO2 laser would of this study has compared the combination of destroy abnormal melanocytes and the alexandrite Q-switched alexandrite laser plus CO2 laser with laser would remove any remaining pigment left in Q-switched alexandrite laser alone.This split-faced the dermis. Eight patients with dermal-type melasma design involved treating 6 Thai patients with one were pretreated with a 14-day course of tretinoin pass of each laser treatment as appropriate and 0.05%, HQ 4%, and hydrocortisone 1%, after which assessing outcome at 6 months. Results revealed they were treated with one pass of the CO2 laser and that combination therapy produced superior im- then 4 patients with one pass of the Q-switched provement in MASI than did monotherapy. Two alexandrite laser and the other 4 with no treatment.
patients developed severe postinflammatory hyper- Assessment was by photography and an objective pigmentation, but this was effectively treated with blinded investigator. At 24 weeks after laser therapy, bleaching agents. Transient hypopigmentation (one results showed that the combination therapy was patient) and contact dermatitis (one patient) were more effective in removing all hyperpigmentation Twenty-four patients with recalcitrant facial pig- the keratinocytes. Consequently, therapies that can mentary disorders, of whom 6 had melasma, were act at different stages of the melanogenesis process treated with the Q-switched alexandrite laser in can produce better clinical results than a single addition to 15% to 25% TCA with or without Jessner’s solution.Clinician assessment at 24 months was The consensus of the group was that first-line clear, excellent, or good in 67% of patients, and no therapy for melasma should consist of effective significant complications with this combination were topical therapies, mainly fixed triple combinations.
noted. Another study examined the use of erbiu- Where patients have either sensitivity to the ingredi- m:YAG laser (2.94 m) at 5.1 to 7.6 J/cm2 in 10 women ents or a triple combination therapy is unavailable, with melasma unresponsive to previous topical ther- other compounds with dual ingredients (HQ plus apy or chemical There was marked improve- GA) or single agents (4% HQ, 0.1% RA, or 20% azelaic ment of the melasma (MASI; melanin reflectance acid) may be considered as an alternative. In patients spectrometry measurements) immediately after laser for whom therapy has failed, options for second-line surgery. The baseline mean MASI score of 19.1 therapy include peels either alone or in combination decreased to 4.1 on postoperative days 7 to 10. The with topical therapy. Some patients will require mean score rose to a maximum of 22.1 at week 6 therapy to maintain remission status and a combina- and was 10.6 at month 6. Mean preoperative melanin tion of topical therapies should be considered. Lasers reflectance spectrometry measurement was 48.8, should rarely be used in the treatment of melasma which decreased to 41.2 at postoperative day 4 and and, if applied, skin type should be taken into finally settling at 43.6 at 6 months. Between 3 and 6 weeks postoperatively, all patients exhibited post- There are currently no guidelines for the man- agement of melasma and given the variations ofassessing treatments it is difficult to make effective comparisons between outcomes. The group there- Kunachak, Leelaudomlipi, and Wongwaisayawan fore recommends the development of treatment have reported a large-scale study on dermabrasion in guidelines for melasma which will establish a uni- 533 patients with facial melasma. Treatment involved form set of criteria in scoring systems and allow for local dermabrasion or full-faced dermabrasion with a critical appraisal of specific treatments.
16-mm diameter coarse grit diamond fraise with the We acknowledge the assistance of Dr Christine McKil- patient under local anesthesia; the skin was dermab- lop in the preparation of this document.
raded down to the level of the upper or mid dermis.
Of the 410 patients followed up for a mean of 5 years(range 1-9 years), 398 (97%) achieved persistent 1. Palumbo A, d’Ischia M, Misuraca G, Prota G. Mechanism of clearance of melasma. Partial recurrence occurred inhibition of melanogenesis by hydroquinone. Biochem Bio- in the other 3% of cases. Complications were en- countered in 3 cases (0.7%); two patients developed 2. Ennes SBP, Paschoalick RC, Mota De Avelar Alchorne M.
hypertrophic scars and one patient had permanent A double-blind, comparative, placebo-controlled study of the hypopigmentation. Pruritus was a common conse- efficacy and tolerability of 4% hydroquinone as a depigment-ing agent in melasma. J Dermatolog Treat 2000;11:173-9.
quence in the early postoperative phase. Milia devel- 3. Haddad AL, Matos LF, Brunstein F, Ferreira LM, Silva A, Costa D.
oped in most patients, although it was self-limiting.
A clinical, prospective, randomized, double-blind trial compar-ing skin whitening complex with hydroquinone vs. placebo in the treatment of melasma. Int J Dermatol 2003;42:153-6.
4. Ferreira Cestari T, Hassun K, Sittart A, de Lourdes Viegas M.
The PDA has reviewed the literature on treat- A comparison of triple combination cream and hydroquinone ment of melasma and categorized the clinical find- 4% cream for the treatment of moderate to severe facial ings for each treatment according to guidelines melasma [abstract P2605]. Presented as a poster at the 63rd adapted from the US Preventive Services Task Annual Meeting of the American Academy of Dermatology, 5. Romero C, Aberdam E, Larnier C, Ortonne JP. Retinoic acid categorization of each therapeutic option for me- as modulator of UVB-induced melanocyte differentiation.
Involvement of the melanogenic enzymes expression. J CellSci 1994;107:1095-103.
6. Kimbrough-Green CK, Griffiths CE, Finkel LJ, Hamilton TA, Bulengo-Ransby SM, Ellis CN, et al. Topical retinoic acid(tretinoin) for melasma in black patients. Arch Dermatol completely defined, and pigmentation is a complex process that includes tyrosinase activity, formation of 7. Griffiths CE, Finkel LJ, Ditre CM, Hamilton TA, Ellis CN, melanosomes, and their transfer and organization in Voorhees JJ. Topical tretinoin (retinoic acid) improves melasma. A vehicle-controlled, clinical trial. Br J Dermatol efficacious 12-month treatment for melasma. Cutis 2005;75: 8. Leenutaphong V, Nettakul A, Rattanasuwon P. Topical isotret- 28. Taylor SC, Torok H, Jones T. Lowe V. Long-term (12 month) inoin for melasma in Thai patients: a vehicle-controlled clinical safety and efficacy of triple combination agent (4% hydroqui- trial. J Med Assoc Thai 1999;82:868-75.
none 1 0.05% tretinoin 1 0.01% fluocinolone acetonide) in 9. Shroot B. Pharmacodynamics and pharmacokinetics of topical the treatment of patients with melasma of the face [abstract adapalene. J Am Acad Dermatol 1998;39(Suppl):S17-24.
P234]. Presented as a poster at the 63rd Annual Meeting 10. Dogra S, Kanwar AJ, Parasad D. Adapalene in the treatment of of the American Academy of Dermatology, New Orleans, La, melasma: a preliminary report. J Dermatol 2002;29:539-40.
11. Fitton A, Goa KL. Azelaic acid. A review of its pharmacological 29. Galderma International. Data on file. March 8, 2006.
properties and therapeutic efficacy in acne and hyperpigmen- 30. Sarkar R, Kaur C, Bhalla M, Kanwar AJ. The combination of tary skin disorders. Drugs 1991;41:780-98.
glycolic acid peels with a topical regimen in the treatment 12. Rigoni C, Toffolo P, Serri R, Caputo R. [Use of a cream based on of melasma in dark-skinned patients: a comparative study.
20% azelaic acid in the treatment of melasma]. G Ital Dermatol 31. Kang WH, Chun SC, Lee S. Intermittent therapy for melasma in 13. Verallo-Rowell VM, Verallo V, Graupe K, Lopez-Villafuerte L, Asian patients with combined topical agents (retinoic acid, Garcia-Lopez M. Double-blind comparison of azelaic acid and hydroquinone and hydrocortisone): clinical and histological hydroquinone in the treatment of melasma. Acta Derm Venereol Suppl (Stockh) 1989;143:58-61.
32. Javaheri SM, Handa S, Kaur I, Kumar B. Safety and efficacy of 14. Balina LM, Graupe K. The treatment of melasma. 20% azelaic glycolic acid facial peel in Indian women with melasma. Int J acid versus 4% hydroquinone cream. Int J Dermatol 1991;30: 33. Lawrence N, Cox SE, Brody HJ. Treatment of melasma with 15. Zaumseil R-P, Graupe K. Topical azelaic acid in the treatment Jessner’s solution versus glycolic acid: a comparison of clinical of melasma: pharmacological and clinical considerations. In: efficacy and evaluation of the predictive ability of Wood’s light Melasma e New approaches to therapy. London: Martin- examination. J Am Acad Dermatol 1997;36:589-93.
34. Hurley ME, Guevara IL, Gonzales RM, Pandya AG. Efficacy of 16. Sarkar R, Bhalla M, Kanwar AJ. A comparative study of 20% glycolic acid peels in the treatment of melasma. Arch azelaic acid cream monotherapy versus a sequential therapy in the treatment of melasma in dark-skinned patients.
35. Lim JTE, Tham SN. Glycolic acid peels in the treatment of melasma among Asian women. Dermatol Surg 1997;23: 17. Ros JR, Rodriguez-Lopez JN, Garcia-Canovas F. Effect of L-ascorbic acid on the monophenolase activity of tyrosinase.
36. Grimes PE. The safety and efficacy of salicylic acid chemical peels in darker racial-ethnic groups. Dermatol Surg 1999;25: 18. Huh C-H, Seo K-I, Park J-Y, Lim J-G, Eun H-C, Pak K-C.
A randomized, double-blind, placebo-controlled trail of vita- 37. Cuce´ LC, Bertino MC, Scattone LK, Birkenhauer MC. Tretinoin min C iontophoresis in melasma. Dermatology 2003;206: peeling. Dermatol Surg 2001;27:12-4.
38. Cotellessa C, Peris K, Onorati MT, Fargnoli MC, Chimenti S. The 19. Jimbow K. N-acetyl-4-S-cysteaminylphenol as a new type of use of chemical peelings in the treatment of different cuta- depigmenting agent for the melanoderma of patients with neous hyperpigmentations. Dermatol Surg 1999;25:450-4.
melasma. Arch Dermatol 1991;127:1528-34.
39. Kopera D, Hohenleutner U. Ruby laser treatment of melasma 20. Yoshimura K, Harii K, Aoyama T, Iga T. Experience with a and postinflammatory hyperpigmentation. Dermatol Surg 1995; strong bleaching treatment for skin hyperpigmentation in Orientals. Plast Reconstr Surg 2000;105:1097-108.
40. Nouri K, Bowes L, Chartier T, Romagosa R, Spencer J. Combi- 21. Kauh YC, Zachian TF. Melasma. Adv Exp Med Biol 1999;455: nation treatment of melasma with pulsed CO2 laser followed by Q-switched alexandrite laser: a pilot study. Dematol Surg 22. Guevara IL, Pandya AG. Safety and efficacy of 4% hydroqui- none combined with 10% glycolic acid, antioxidants, and 41. Angsuwarangsee S, Polnikorn N. Combined ultrapulse CO2 sunscreen in the treatment of melasma. Int J Dermatol 2003; laser and Q-switched alexandrite laser compared with Q-switched alexandrite laser alone for refractory melasma: 23. Lim JT. Treatment of melasma using kojic acid in a gel split-faced design. Dermatol Surg 2003;29:59-64.
containing hydroquinone and glycolic acid. Dermatol Surg 42. Lee G-Y, Kim H-J, Whang K-K. The effect of combination treatment of the recalcitrant pigmentary disorders with 24. Garcia A, Fulton JE. The combination of glycolic acid and pigmented laser and chemical peeling agent. Dermatol Surg hydroquinone or kojic acid for the treatment of melasma and related conditions. Dermatol Surg 1996;22:443-7.
43. Manaloto RM, Alster T. Erbium:YAG laser resurfacing for 25. Kligman AM, Willis I. A new formula for depigmenting human refractory melasma. Dermatol Surg 1999;25:121-3.
44. Kunachak S, Leelaudomlipi P, Wongwaisayawan S. Dermabra- 26. Taylor SC, Torok H, Jones T, Lowe N, Rich P, Tschen E, et al.
sion: a curative treatment for melasma. Aesthetic Plast Surg Efficacy and safety of a new triple-combination agent for the treatment of facial melasma. Cutis 2003;72:67-72.
45. Williams HC. Dermatology. In: Stevens A, Raferty J, editors.
27. Torok HM, Jones T, Rich P, Smith S, Tschen E. Hydroquinone Health care needs assessment. Second series. New York: 4%, tretinoin 0.05%, fluocinolone acetonide 0.01%: a safe and Radcliffe Medical Press; 1997. p. 340.

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