""For skin problems such as Melasma, use the proven and effective Niacinamide Cream, Click Here to Learn More!
Dermatology Research and Practice
Volume 2011 (2011), Article ID 379173, 5 pages
doi:10.1155/2011/379173
Clinical Study
A Double-Blind, Randomized Clinical
Trial of Niacinamide 4% versus Hydroquinone 4% in the
Treatment of Melasma
Josefina Navarrete-Solís,1
Juan Pablo Castanedo-Cázares,1
Bertha Torres-Álvarez,1,2
Cuauhtemoc Oros-Ovalle,3
Cornelia Fuentes-Ahumada,1
Francisco Javier González,4
Juan David Martínez-Ramírez,4
and Benjamin Moncada1
1Department
of Dermatology, Hospital Central, Universidad Autónoma
de San Luis Potosí, San Luis Potosí, Mexico
2Department
of Dermatology, Hospital Central “Dr. Ignacio Morones Prieto”, 2395 Venustiano Carranza Avenue, CP 78210, San Luis Potosí, SLP,
Mexico
3Department
of Pathology, Hospital Central, Universidad Autónoma
de San Luis Potosí, San Luis Potosí, SLP, Mexico
4Coordinación
para la Innovación y la Aplicación de la Ciencia y la Tecnología, Universidad Autónoma
de San Luis Potosí, San Luis Potosí, SLP, Mexico
Received
16 January 2011; Revised 16 May 2011; Accepted 8 June 2011
Academic
Editor: D. J. Tobin
Copyright
© 2011 Josefina Navarrete-Solís et al. This is an
open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited.
Abstract
Background. Multiple modalities have been used in the
treatment of melasma with variable success. Niacinamide has anti-inflammatory properties and is able to
decrease the transfer of melanosomes. Objective. To evaluate the
therapeutic effect of topical niacinamide versus
hydroquinone (HQ) in melasma patients. Patients and Methods. Twenty-seven melasma patients were randomized to receive for eight weeks
4% niacinamide cream on one side of the face, and 4%
HQ cream on the other. Sunscreen was applied along the observation period. They
were assessed by noninvasive techniques for the
evaluation of skin color, as well as subjective
scales and histological sections initially and after the treatment with niacinamide. Results. All
patients showed pigment improvement with both treatments. Colorimetric measures
did not show statistical differences between both sides. However, good to
excellent improvement was observed with niacinamide
in 44% of patients, compared to 55% with HQ. Niacinamide
reduced importantly the mast cell infiltrate and showed improvement of solar elastosis in melasma skin. Side
effects were present in 18% with niacinamide versus
29% with HQ. Conclusion. Niacinamide
induces a decrease in pigmentation, inflammatory infiltrate, and solar elastosis. Niacinamide is a safe
and effective therapeutic agent for this condition.
1. Introduction
Melasma
is defined as an acquired chronic hypermelanosis on
sun exposed areas being most frequently found in women with III-V phototypes of
Fitzpatrick. The etiology is not completely
elucidated; however, the ultraviolet sunlight exposure appears to be the most
significant factor [1].
The basis of the treatment is photoprotection.
Diverse modalities in drug therapy have been used such as hydroquinone (HQ),
which inhibits the tyrosinase enzyme activity. In
spite of its serious adverse effects and moderate results in 80% of patients,
HQ is considered the gold standard treatment in melasma
although usually relapses after suspension [2].
Niacinamide
studies have demonstrated a suppression of melanosome
transfer suggesting the reduction of cutaneous pigmentation [3],
but to date there has been no clinical report of this effect in melasma. There have been several reports regarding other
beneficial effects of topical niacinamide on the
skin, including prevention of photoimmunosuppression
and photocarcinogenesis [4],
anti-inflammatory effects in acne [5],
rosacea [6],
and psoriasis [7].
It also increases biosynthesis of ceramides, as well
as other stratum corneum lipids with enhanced
epidermal permeability barrier function [8].
Moreover, its antiaging effects have been
demonstrated in randomized trials [9].
The
guidelines to clinical trials in melasma have
suggested a correct diagnosis by using at least two subjective methods (besides
an objective method), a comparison with the therapeutic gold standard and an
evaluation of safety outcome [10].
The
aim of this work was to assess the efficacy and safety of niacinamide
4% versus HQ 4% in the treatment of melasma through
subjective and objective methods.
2. Patients and Methods
This
is a double-blind, left-right randomized clinical trial. The protocol was
reviewed and approved by the ethic committee in our hospital, and each subject
signed a written informed consent. The sample size was determined based on favorable response: 0.8 for HQ and at least 0.4 for niacinamide, with 95% IC, two tails, α
of 0.05 and β of 0.8.
We
included 27 women with melasma attending the
outpatient clinic of Dermatology Department at the Hospital Central “Dr. Ignacio Morones Prieto”, from March 2008 to February 2009.
Our
inclusion criteria were women at least 18 years old without any topical,
systemic, laser, and surgical treatment on face during the previous year. The
exclusion criteria were pregnant and nursing women, patients with history of
hypersensitivity to some of the components of the formulas of the study, and
coexistence of associate diseases and other pigmentation diseases.
A
history was taken from each patient, regarding age, gender, occupation, time of
onset, history of pregnancy, contraceptive pills, and sun exposure.
At
baseline, we obtained two 2 mm
biopsies in 27 patients, one biopsy from lesioned and
another one from facial not photoexposed skin; these
were stained with haematoxylin and eosin to determine the general histopathological features of the epidermis and dermis.
The
inflammatory infiltrate was counted manually by two independent blinded
observers, using a 0.5×0.5 mm
ocular grid and 100×
magnification. The cells were counted for the entire section, and the
results expressed as the number of cells per mm2.
The same procedure was employed to count melanocytes (Fontana Masson) and
metachromatic granules (Wright-Giemsa) in mast cells.
To count the epidermal melanin, we obtained a magnification of 40× to get a
scanning view of the epidermis. Images were obtained from the entire 2 mm
sample with a digital camera mounted on a microscope (Olympus CX 31) which was
connected to a personal computer (PC). The image signals taken by the PC were
evaluated using Image-Pro Plus Version 4.5 (Media Cybernetics,
Silver Spring, MA, USA). With the aim of discern possible abnormalities of
melanin in melasma patients as shown before [11],
or even being induced by the intervention, we perform a qualitative analysis by
Raman spectrophotometry (Horiba, Jobin-Yvon T64000. Edison, NJ, USA) before and at the conclusion of the study.
Patients
were randomized in a double-blind manner to receive one treatment on the left
and the other on the right side of the face. They received two containers labeled right or left with 4% niacinamide
(Nicomide-T cream 4%, DUSA Pharmaceuticals Inc.) or
4% HQ (Eldoquin cream 4%, Valeant Pharmaceutical).
All patients were instructed to apply the correct amount of both treatments and
to use a SPF 50+ broad spectrum sunscreen every 3 hours during day time.
Concomitant
use of other skin care products or systemic treatments was not allowed during
the study. Treatment was administered for the period of 8 weeks, with basal
evaluation and followup at 4 and 8 weeks. Assessments
included a skin pigment evaluation by a chromameter
(CR-300; Minolta, Osaka, Japan), melasma area and
severity index (MASI), physician global assessment (PGA) by an independent
observer, conventional photography, and infrared thermography (Flexcam S, Infrared solutions, USA) with photographic
register which mainly was used to detect irritation. All side-effects were
registered. The double-blinded study was opened at 8 weeks in order to take a 2
mm biopsy in the side treated with niacinamide.
For
statistical analysis, we used the Student 𝑡-test and 𝑋2, and a 𝑃 value of less than 0.05 was considered
significant.
3. Results
Twenty-seven
female patients with melasma were included, 12 (33%)
were of skin phototype IV, and 13 (48%) of type V. The pattern of melasma was centrofacial in 13
(50%), malar in 10 (37%), and mandibular in 4 (14%).
The
patients age ranged from 25 to 53 years (mean, 37 years). The duration of melasma varied from 4 to 8 years (mean, 6.5 years). Family
history of melasma was found in 19 (70%) patients.
The most frequent precipitating factor was the sun exposure followed by
pregnancy. Eight patients (29%) have used oral contraceptives.
3.1. Clinical Results
The
onset average MASI score for the HQ side was 4 (5% CI, 90.9–1.8) and 1.2 (95%
IC, 0.8–1.6) after eight weeks (𝑃<0.001). The initial MASI score for the niacinamide side was 3.7 (95% CI, 2.9–4.4) and 1.4 (95% CI,
3.3–4.7) at the end of the study (𝑃<0.001). The average decrease for HQ was 70% and
62% for niacinamide. This improvement was registered
using conventional photography (Figures 1 and
2)
with no perceptible differences between both sides.
Figure 1: Right side treated with niacinamide.
View at onset and 8 weeks later with an excellent decrease in pigmentation.
Figure 2: Left side treated with HQ: Onset and 8 weeks later
with an excellent improvement.
The
PGA rated the niacinamide side improvement as
excellent in three patients, good in nine, moderate in seven,
and mild in eight. The HQ-treated side was rated excellent in seven, good in
eight, moderate in six, and mild in six patients (Figure 3).
Data showed statistical significance for both treatments, HQ (𝑃=0.003), and niacinamide
(𝑃=0.005).
Figure 3: Physicians Global Assessment in melasma
patients with niacinamide versus HQ.
Colorimetric
assessment was performed initially and at the end of the study; we evaluated
the luminosity axis (L*) as well as the erythema axis (a*). The lightening
effect of HQ and niacinamide was apparent at 4 weeks
of treatment, whereas it was more evident at 8 weeks. Colorimetric measures
showed no statistical differences between both treatments (Table 1).
The erythema was more intense on the side treated with HQ than with niacinamide, but it was not statistically significative.
Infrared light thermography at environmental temperature of 21°C showed a
diminished temperature of 0.8°C in both sides after treatment. There was no
statistical difference between both treatments.
Table 1: Changes in MASI scores and colorimetric values for
4% HQ and 4% niacinamide-treated sides in 27 patients
with melasma. Mast cell counts and melanin expression
initially and after treatment with niacinamide in 11
patients.
3.2. Histopathology Results
The
biopsy samples were stained with haematoxylin and eosin for general histology,
Fontana Masson to evaluate melanin pigment, and Wright-Giemsa
for metachromatic granules in mast cells. At baseline, we found a moderate to
severe degree of rete ridge flattening and epidermal thinning in 23 (85%) melasma biopsies. Solar elastosis
was present in all melasma samples. Mild to moderate
perivascular lymphohistiocytic infiltrates were also
present in all of them and moderate presence of mast cells near elastotic areas in 11 (40%) patients. With Fontana-Masson
stained sections, the amount of melanin was increased in all epidermal layers
of melasma skin; we observed pigment basal cells
protruded into the dermis in 20 (74%) biopsies as informed before [12].
In the upper dermis, we found scattered melanin in 19 (70%) melasma
biopsies. The features in the biopsies of nonexposed
sun skin were close to normal skin.
After
8 weeks of treatment, the blind was opened in order to take a biopsy from the
side treated with niacinamide. We obtained 11 posttreatment biopsies for analysis. By means of digital
analysis of biopsies images, we could observe that the amount of epidermal
stained melanin was diminished significantly (𝑃<0.0007). The average inflammatory infiltrate of
mast cells was reduced from 22 to 16 cells/mm2
(𝑃=0.01).
Solar elastosis was also reduced, but no statistical
differences were present (Figure 4).
Figure 4: Epidermal pigmentation reduction. (a) Basal melasma skin biopsy, (b) skin biopsy posttreated
with niacinamide. (Fontana Masson, original
magnification 40x). Below is shown the measured
positive areas for melanin using a computer-assisted image analysis program.
3.3. Spectrophotometry
Raman
spectroscopy measurements showed that the molecular structure of melanin was
normal and remained unaltered after exposure to niacinamide
since the measurements showed the characteristic peaks of melanin previously
published [11, 12].
Patients with abnormal melanin could respond differently to treatment and
explain the variable success rate to HQ [11].
We wanted to show that these patients were homogeneous in this aspect.
3.4. Side Effects
Side
effects were present in the niacinamide side in 5
patients (18%), compared to 8 patients (29%) for the HQ side. The most frequent
side effects were erythema, pruritus, and burning. Most of them were mild for niacinamide and moderated for HQ. On the niacinamide side, erythema, pruritus, or burning was
present in 2 (7%) patients, and on the HQ side they were present in 5 (18%)
patients. All these were reduced through continuous treatment in both
modalities, as the a* colorimetric value did not show
significant changes for both treatments at the end of the study.
4. Discussion
Melasma
is a chronic and persistent hyperpigmentation, representing a therapeutic
challenge because of the high rate of relapses. This work showed that niacinamide 4% is an effective agent for the treatment of melasma, as assessed by objective methods and clinical
evaluation. Our results indicate that 4% niacinamide
was effective in approximate 40% of patients, showing outstanding clinical
results. In the posttreatment biopsies, we could
observe that the amount of epidermal melanin and inflammatory infiltrate was
diminished significantly, as well as solar elastosis
although it was not enough to get statistical difference. This insufficient antiaging effect could be related to the short time of the
study; therefore, further clinical studies using niacinamide
for longer periods are warranted in this condition. We observed that the
evolution time of melasma did not affect the response
to treatment. On the other hand, colorimetric assessment showed no statistical
difference between these two treatments (𝑃=0.78). However, the lightening effect of HQ was
evident as early as the first month of treatment, whereas with niacinamide was noted at second month. HQ had the
disadvantage of moderate adverse effects in 18% of patients, compared to milder
in 7% with niacinamide. Treatment with niacinamide showed no significant side effects and was well
tolerated; therefore, it could be used for longer periods, as part of the
initial hyperpigmentation treatment and as maintenance drug. However, further
trials are required to assess the combination of this topical drug with others
agents and assess its additive effects in the treatment of melasma.
The mechanism of action of niacinamide in melasma could be through the reduction of melanosomes transfer [3], photoprotection actions [4],
its anti-inflammatory properties [5],
and a direct or related antiaging effects such as
reduction of solar elastosis [9].
We previously have described prominent infiltrates of mast cells in the elastotic areas of melasma skin [1]
and evidence of damage to epidermal basal membrane, which could facilitate the
fall or the migration of active melanocytes and melanin into the dermis
allowing the constant hyperpigmentation in melasma [13].
Due to these findings, we wanted to prove an intervention capable of inducing
modifications to these atypical findings related in the pathogenesis of melasma, in addition to modify the increased pigmentation.
Therefore, we propose niacinamide as an effective,
integral, and safe therapeutic alternative in the melasma
treatment, since it not only reduces pigmentation and inflammation, but also
may reduce solar degenerative changes with minimal adverse events.
References
Copyright © 2011 - 2018. MelasmaCream.org. All rights reserved.