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International Journal of Dermatology

2004,

43

, 604–

607

© 2004

The International Society of Dermatology

604

Abstract

Background

Melasma is an acquired treatment-resistant hyperpigmentation of the skin.

Methods

Sixteen women with idiopathic melasma were included in our trial. After
randomization by another clinician, they were instructed to use, at night, 5% ascorbic acid
cream on one side of the face and 4% hydroquinone cream on the other side, for 16 weeks.
Sunscreen was applied daily throughout the period of observation. They were evaluated every
month by colorimetry, digital photography, and regular color slides. Subjective evaluation by
each patient was also taken into account.

Results

The best subjective improvement was observed on the hydroquinone side with 93%
good and excellent results, compared with 62.5% on the ascorbic acid side (

P

< 0.05); however,
colorimetric measures showed no statistical differences. Side-effects were present in 68.7%
(11/16) with hydroquinone vs. 6.2% (1/16) with ascorbic acid.

Conclusion

Although hydroquinone showed a better response, ascorbic acid may play a role
in the therapy of melasma as it is almost devoid of side-effects; it could be used alone or in
combination therapy.

Blackwell Publishing Ltd. Oxford, UK IJD International Journal of Dermatology 0011-9059 Blackwell Publishing Ltd, 2003 45

Clinical trial

Ascorbic acid vs 4%hydroquinone in melasma Espinal-Perez, Moncada González, and Castanedo-Cazares Pharmacology and therapeutics

A double-blind randomized trial of 5% ascorbic acid vs. 4%
hydroquinone in melasma

Liliana Elizabeth Espinal-Perez,

MD

, Benjamin Moncada,

MD

, and
Juan Pablo Castanedo-Cazares,

MD

From the Department of Dermatology,
Hospital Central, University of San Luis
Potosí, San Luis Potosí, Mexico

Correspondence


Benjamín Moncada,

MD


2395 Venustiano Carranza Ave
San Luis Potosí
Mexico 78210
E-mail: moncadab@uaslp.mx

Introduction

Melasma is an acquired, symmetric, irregular hypermelanosis
on sun-exposed areas of the face, commonly seen in Latin
American and Asian women, particularly those with IV–V skin
types.

1,2

The etiology is unknown, but the most important pre-
disposing factor is sun exposure.

3,4

Other possible factors include
pregnancy, contraceptives, race, genetic factors, and hormone
alterations.

5

The diagnosis is made on a clinical basis, and treat-
ment is difficult with frequent relapses.

6

Until now, hydroqui-
none has been considered as the gold standard of treatment with
moderate results in 80% of patients.

6

Other treatments include
tretinoin, kojic acid, and glycolic acid.

1,7–10

Recently, ascorbic
acid has played an important role in photodamage treatment.
Amongst other actions, it suppresses melanin synthesis through
its antioxidant effect or by the inhibition of tyrosinase.

11–18

The aim of this study was to evaluate the therapeutic effect
of topical 5%

l

-ascorbic acid vs. topical 4% hydroquinone in
patients with melasma.

Patients and Methods

Sixteen female patients from our outpatient clinic, with a pair of
bilaterally symmetric lesions of melasma, were enrolled in the study.
The age ranged from 23 to 43 years (mean, 36 years). Exclusion
criteria included pregnancy, miscarriage, recent delivery, or the
use of hormones in the last 12 months, as well as topical treatment
for the last 2 months. All subjects gave written informed consent
before entering the study, which was approved by the local ethical
committee (Institutional Review Board). Patients were randomly
assigned in a double-blind manner to receive, on the left or right
side of the face, 5%

L

-ascorbic acid (La Roche Possay, France) or
4% hydroquinone water–oil emulsion (Stieffel, Coral Gables, FL,
USA). All patients were initially evaluated and supervised every
4 weeks during a 16-week period. Digital photographic registration
(frontal, right, and left views) with an SLR Fuji FinepixS1pro digital
camera was taken. Melasma was classified as epidermal, dermal,
or mixed type by Wood’s light examination. The methods of
assessment involved the evaluation of indirect pigmentary
changes using a skin narrow-band colorimetric equipment
(DermaSpect, Cortex Technology, Hadsund, Denmark)

19

and
patient assessment (patients rated their final results in the
following categories of lightening: mild, less than 25%; moderate,
25 to < 50%; good, 50 to < 75%; excellent, > 75%). All side-effects
were registered. All patients were instructed to apply a sunscreen
cover (both UVA and UVB range) every 3 h each morning.

Results

Of the 16 patients included, eight were skin type IV and eight
were skin type V. The melasma duration time varied from
8 months to 23 years. Eight patients were classified with
© 2004

The International Society of Dermatology International Journal of Dermatology

2004,

43

, 604–

607

605

Espinal-Perez, Moncada, and Castanedo-Cazares

Ascorbic acid vs 4% hydroquinone in melasma

Clinical trial

epidermal type and eight with mixed type (Table 1). Fifteen
patients had a family history of melasma. One patient received
only 3 months of treatment because of irritation to hydroqui-
none, and another due to excellent response to treatment
(hydroquinone, 100%;

l

-ascorbic acid, 90%). The subjective
assessment by patients (Fig. 1) to

l

-ascorbic acid was excel-
lent in two patients, good in eight, moderate in four, and mild
in two (Fig. 2). The hydroquinone-treated side was rated as
excellent in eight patients, good in seven, moderate in one,
and mild in none (Fig. 3). The data showed statistical signifi-
cance for the hydroquinone side (Wilcoxon,

P

= 0.001).
Colorimetric assessment was calculated by obtaining the
melanin index difference (M



) between the targeted lesional
and perilesional areas (M



= lesional



perilesional). This
was performed initially and at the end of the study. In
addition, we obtained the difference between the basal M



and the final M



; if positive, this implied that there was less
melanin in the lesion, with final improvement of the hyperpig-
mentation; if it was negative, worsening of the lesion had
occurred (Fig. 4). These data were analyzed using the sequen-
tial analysis method of Armitage,

20

and no difference was
found between the two sides (

P

= 0.052). The lightening
effect of hydroquinone was evident as early as the first month
of treatment, whereas that of

l

-ascorbic acid was noted at the
third month. There were no differences between the epider-
mal and mixed melasma types. With regard to adverse effects,
there was irritation in one patient with

l

-ascorbic acid
(6.25%) vs. 11 with hydroquinone (68.75%).
Table 1 Features of melasma patients and subjective/colorimetric improvement with l-ascorbic acid and hydroquinone
No.
Age
(years) Type
Evolution
time
(years)
Subjective
improvement
L-ascorbic acid
Subjective
improvement
hydroquinone
Colorimetric
improvement
L-ascorbic acid
Colorimetric
improvement
hydroquinone
1 30 Mixed 9 Moderate Good 2 6.1
2 37 Epidermal 4 Good Good 6.4 8.6
3 41 Mixed 12 Mild Excellent − 0.7 2.2
4 30 Mixed 8 Good Excellent 1.9 0.5
5 38 Epidermal 5 Good Good 3.6 5.2
6 30 Mixed 20 Good Excellent 0.8 2.4
7 40 Mixed 9 Mild Good 7.7 2.1
8 37 Mixed 23 Moderate Good 2.9 0
9 35 Epidermal 6 Good Excellent 2.4 6
10 43 Epidermal 8 months Good Moderate − 0.7 0.2
11 40 Epidermal 3 Excellent Excellent 6.8 7
12 23 Epidermal 3 Good Excellent 1.9 3.1
13 37 Mixed 13 Moderate Good 2.5 3.9
14 34 Mixed 14 Good Excellent 2.6 6.8
15 34 Epidermal 8 months Excellent Excellent 4.7 7
16 29 Epidermal 1 Moderate Good 0.3 4.3
Positive numbers in colorimetric improvement columns imply clearance of hyperpigmentation, negative numbers imply worsening.
Figure 1 Subjective improvement in melasma patients with
ascorbic acid vs. hydroquinone
Figure 2 Left side treated with l-ascorbic acid: onset and
16 weeks later. These is a marked decrease in pigmentation
International Journal of Dermatology

2004,

43

, 604–

607

© 2004

The International Society of Dermatology

606 Clinical trial

Ascorbic acid vs 4% hydroquinone in melasma

Espinal-Perez, Moncada, and Castanedo-Cazares

Discussion

Melasma is a common hyperpigmentation disorder that par-
ticularly affects individuals living in tropical countries. Its
cause is not completely understood. Kang

et al

.

21

have sug-
gested that there are certain clones of melanocytes that, once
activated by the interaction of the skin with UV light under
the influence of female hormones and a genetic background,
induce melanocyte hyperfunction over damaged dermal skin.
For this reason, a drug that inhibits melanin synthesis is
needed for this disorder. In recent years, it has been shown
that

l

-ascorbic acid affects the monopherase activity of tyro-
sinase via its ability to reduce the enzymatically generated

o

-quinones,

18

thus reducing melanin synthesis. In addition,
ascorbic acid has a photoprotective effect, preventing the
absorption of ultraviolet radiation (both UVA and UVB);

16

it is
retained in the epidermis, which is an advantage over sunscreens
that are easily removed.

11

It has an antioxidant effect (one of
the effects first described on skin), preventing the production
of free radicals which trigger melanogenesis;

15

in addition, it
is a promoter of collagen synthesis,

12

reducing dermal damage
and leading to adequate keratinocyte differentiation.

13,14

It
also minimizes oxidized melanin, changing the pigmentation
from black to tan. Consequently, ascorbic acid may have an
important effect on hyperpigmentation, such as in melasma.
In our trial, it was observed that, with 5%

l

-ascorbic acid,
62.5% of patients showed good or excellent subjective results,
confirming the lightening effect suggested by Kameyama

et al

.

18

Colorimetric assessment showed no statistical difference
between the two treatments (

P

= 0.052), implying that the
melanin component decreased similarly in the two treatments;
however, the

P

value is borderline, and larger trials are needed.
Hydroquinone had the disadvantage of irritation in 68.7%
of patients, but

l

-ascorbic acid was well tolerated, and therefore
could be used for longer periods. It can be speculated that,
if 10% ascorbic acid were applied, we might obtain better
results due to its longer half life in skin; therefore, further
clinical studies using this concentration are warranted. The
evolution time of melasma did not affect the response to
treatment. The type of melasma was not a predictive factor
for improvement, as suggested previously,

9

and there is doubt
about the existence of a dermal type.

21

We can conclude that

l

-ascorbic acid has a beneficial effect
on melasma, with a minimum of adverse effects. For this rea-
son, it can be used for a longer period of time as part of the ini-
tial hyperpigmentation treatment and as a maintenance drug;
however, further trials are required to assess the combination
of this topical drug with others, in order to identify additive
effects in the search for better treatments for melasma.

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© 2004

The International Society of Dermatology International Journal of Dermatology

2004,

43

, 604–

607

607

Espinal-Perez, Moncada, and Castanedo-Cazares

Ascorbic acid vs 4% hydroquinone in melasma

Clinical trial

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