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JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY January 2023 • Volume 16 • Number 1
ORIGINAL RESEARCH
Melasma is an acquired, chronic, and symmetric
hyperpigmentation disorder.1 Melasma lesions are irregular
brown patches in three predominant facial patterns:
centrofacial, malar, and mandibular.2 The overall prevalence of melasma
in the general population was estimated between 1 to 50 percent based
on several studies.2 Ultraviolet sunlight exposure and female hormonal
activity are the two most important risk factors for developing melasma.3
Positive family history is another risk factor reported in 55 to 64 percent of
cases.4, 5
According to a study by Amatya et al,6 melasma is associated with
a signi cant impact on quality of life compared to other dermatologic
diseases. Adverse e ects of melasma on quality of life include cosmetic
dis guration and decreased self-esteem and self-con dence. Feeling
inferior to others is another negative e ect of melasma.7,8
Di erent options are available for melasma treatment, including topical
agents, oral medicine, microinjections, mesotherapy, lasers ablation, and
combination therapies.9-11 Topical hydroquinone (HQ) treatment is the
standard gold therapy with a high recurrence rate of melasma lesions.8,10
In contrast, tranexamic acid (TA) has recently been introduced as a novel
therapy for melasma, which is the only treatment option that can prevent
the activation of melanocytes by sunlight and hormonal activity.11,12 TA
is widely used in oral, topical, and intradermal solutions with di erent
dosages.13 A recently published meta-analysis showed that the dosage and
treatment time is positively associated with the melasma improvement;
however, recurrence is still a serious issue in planning the treatment.14 The
present study aimed to evaluate the e cacy of 100mg/mL intradermal TA
and compare its adverse e ects with topical 4% HQ standard treatment on
female patients presenting with melasma lesions.
METHODS
This prospective, double-blind, randomized controlled trial was
conducted according to the CONSORT statement and declarations of
Helsinki from July 2020 to June 2021. The sample size was estimated to
be 48 patients splitting into two groups by block randomization based on
OBJECTIVE: Melasma is an acquired and chronic hyperpigmentation disorder associated with a negative impact on patients’ quality of life. This
study compares the e cacy of 100mg/mL intradermal TA with 4% topical HQ on female patients presenting with melasma lesions.
METHODS: In this randomized double-blind controlled trial, 48 women with melasma were allocated into two groups, treated with either 100mg/
mL intradermal TA or topical 4% HQ. The MASI (Melasma Area and Severity Index) score was assessed by paired t-tests and repeated measured
ANOVAs. The Dynamic Physician General Assessment (PGA) was also performed by taking photographs with a digital camera. RESULTS: The
average MASI score for the HQ and TA groups was 7.7 (3.0 SD) and 5.9 (2.5 SD), respectively. In both groups, the MASI decreased signi cantly after
three months of treatment; however, the decrease was not signi cant between the two groups (P=0.1). All participants developed mild degrees of
burning pain in the injection site without serious adverse e ects. LIMITATIONS: First, we only used the MASI score to measure melasma degree.
Second, this is a single-center study with a small sample size. Third, the before-after photos were not taken with a high-quality camera.
CONCLUSION: The results of our study showed that both TA and continuous HQ signi cantly reduced the MASI score of patients without any
signi cant di erences and serious side e ects. Although many treatment modalities are available for melasma, this condition is still challenging for
dermatologists with a high recurrence rate after treatment. KEYWORDS: Melasma, hydroquinone, tranexamic acid, skincare, dermatology
by NADER PAZYAR, MD; MOTAHAREH BABAZADEH DEZFULY, MD; MARYAM HADIBARHAGHTALAB, MD, MPH;
SEYEDEH YASAMIN PARVAR; SEYEDEH NASRIN MOLAVI, MD; MOHAMMAD ALI MAPAR, MD; and MARYAM ZEINALI, MD
Dr. Pazyar is an Assistant Professor with the Department of Dermatology at Imam Khomeini Hospital at Ahvaz Jundishapur University of Medical Sciences in Ahvaz, Iran. Drs. Dezfuly and Molavi
are Assistants of Dermatology with the Department of Dermatology at Imam Khomeini Hospital at Ahvaz Jundishapur University of Medical Sciences in Ahvaz, Iran. Dr. Hadibarhaghtalab and
Ms. Parvar are with the Molecular Dermatology Research Center at Shiraz University of Medical Sciences in Shiraz, Iran. Ms. Pavar is additionally with the Student Research Committee at Shiraz
University of Medical Sciences in Shiraz, Iran. Drs. Mapar and Zeinali are with the Department of Dermatology at Ahvaz Jundishapur University of Medical Sciences in Ahvaz, Iran.
J Clin Aesthet Dermatol. 2023;16(1):35-40.
FUNDING: No funding was provided for this article
DISCLOSURES: The authors report no con icts of interest relevant to the content of this article.
CORRESPONDENCE: Seyedey Yasamin Parvar, Medical Intern; Email: sy.parvar@gmail.com
Intradermal Injection of 100mg Tranexamic Acid
Versus Topical 4% Hydroquinone for the Treatment
of Melasma: A Randomized, Controlled Trial
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JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY January 2023 • Volume 16 • Number 1
ORIGINAL RESEARCH
Pazyar et al’s study.15 According to the following
formula with a 95 percent con dence interval
and 80 percent power (α: 0.02, β: 0.04, S1: 9.4,
S2: 7.5, mean 1: 2.2, mean 2: 2.2):N=z1-2+z1-
β212+22d2
The study population included women
aged 18 to 50 years who were referred to
the dermatology clinic of Imam Khomeini
Hospital in Ahwaz, Iran, to treat symmetrical
melasma with Fitzpatrick II−V Skin Types.
Exclusion criteria were as follows: pregnant
or breastfeeding women, previous history of
melasma treatment in the past month, active
facial herpes simplex lesions, allergies to the
study drugs, any history of coagulation disorders
and thrombotic problems, facial warts, patients
on anticoagulants and anticonvulsants (e.g.,
phenytoin), or oral contraceptive therapy in the
past year.
After the approval by the ethics committee of
the university and the registry of clinical trials,
all patients signed informed consent and were
given the necessary information regarding the
controlled trial. Patients’ data, including age,
duration of Melasma and its patterns, family
history of melasma, Fitzpatrick Skin Type, and
history of previous treatments, were obtained.
Predisposing factors consisted of ultra-violate
light, pregnancy, oral contraceptive pills, etc.
Randomization was done by ipping a coin and
each side of the participant’s face was randomLy
treated with TA and hydroquinone to reduce the
selection bias.
Wood’s lamp examination was performed
at the beginning of the study to determine
the melasma types, including dermal,
epidermal, and mixed. In the rst group, 60
minutes after applying local anesthetic agents
(Lidocaine+Prilocaine) and dressing on their
face, 100mg/mL of TA (Tranexipm®; Caspian
Tamin Company, Iran), which is available in
vials of 500mg per 5mL solutions was injected
intradermally on the melasma lesions using
1cc insulin syringe. Intradermal injection of TA
was done every two weeks. One-centimeter
distances were measured with a ruler and
marked with an easy-cleaning marker to avoid
cosmetic dis gurement. Each spot was injected
at an angle of 5 to 15 degrees with 0.1mL
solution to form a wheal-like area on the skin.
Then, spots were cleaned 30 minutes after the
procedure using an alcohol pad. Ice compress
was used after the procedure.
In another group, HQ 4% was applied
topically every night. Both groups were
recommended to prevent excessive sun
exposure and use non pigmented sunscreen.
Patients underwent therapy for three months
and were followed up for another three months
post-treatment every four weeks at Weeks 4, 8,
12, and 24. Four patients in the HQ group and
ve in the TA group did not present for the nal
follow-up.
Assessments were performed during each
visit using the Melasma Area and Severity Index
(MASI) score. The patients’ face was divided into
four areas: forehead (30%), right malar (30%),
left malar (30%), and chin (10%). The melasma
severity was assessed by three variables: the
percentages of total area involved (A), darkness
(D), and the homogeneity of hyperpigmentation
(H). The forehead on each side accounted for 15
percent, 30 percent on the cheek, and 5 percent
on the chin. The MASI score was calculated
FIGURE 1. CONSORT ow chart of the clinical trial.
FIGURE 2. Improvement of melasma lesions in two patients before and after treatment with 100 mg/mL tranexamic acid
intradermally.
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JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY January 2023 • Volume 16 • Number 1
ORIGINAL RESEARCH
according to the below formula, and the score
for each side of the face ranged from 0 to 24.
MASI=0.15(A)(D+H) + 0.3(A)(D+H) + 0.05(A)
(D+H).
The Dynamic Physician General Assessment
(Dynamic PGA) was also performed by
taking photographs with a digital camera
(Samsung Galaxy S8) at the beginning and
the last visit. According to Dynamic PGA score,
0%−25% improvement was reported as poor
improvement, 26%−50% as fair improvement,
51%−75% as good improvement, and
76%−100% improvement in lightening was
reported as an excellent improvement.
Statistical analyses were done using the IBM
Statistical Package for Social Sciences (SPSS,
version 21; SPSS Inc., Chicago, IL, USA), and
the signi cance level of the P-value was set at
0.05. The Mean, standard deviation (SD), and
frequencies were used to describe the baseline
characteristics of the study population after
checking the normal distribution. Paired t-tests
and repeated measured ANOVAs were also used
to assess the MASI score. Dermatology residents
did all the assessments. The analyzers were
blinded.
RESULTS
Fifty-six female patients with melasma
were enrolled in the study (Figure 1). Eight
participants were excluded from the study:
Two patients left the trial due to using other
treatment modalities, one patient became
pregnant, three participants had trouble with
transportation, and the other two patients
developed ecchymosis and ochronosis.
Therefore, a total number of 48 participants
were allocated into two groups.
The patients’ mean age was 35.6 (5.7 SD)
years (range, 24-48), and the duration of
melasma varied from six months to 10 years
(mean 4.2, SD 3.1). Twenty-eight patients had
a positive family history of melasma, and 22
had a history of previous melasma treatment.
According to the Fitzpatrick Skin Type, 46
participants had Type III and IV, and the other
two patients had Type II and V. The pattern of
melasma was malar in 33 patients, centrofacial
in 13, and mandibular in two patients. The
type of melasma was dermal in three patients,
epidermal in 37 patients, and mixed pattern
in eight patients. Pregnancy was the most
frequent precipitating factor in 15 patients,
followed by UV exposure and oral contraceptives
in 13 and 10 patients, respectively. Baseline
characteristics were adjusted between the two
groups, as shown in Table 1.
According to Table 2, the onset average MASI
score for the HQ group was 7.7 (95% CI, 3.0
SD) and 4.8 (95% CI, 2.9 SD) after 24 weeks
(P=0.001). The initial MASI score for the TA
group was 6.1 (95% CI, 2.5 SD) and 3.5 (95% CI,
2.0 SD) at the end of the study (P<0.001). The
MASI score decreased signi cantly in all follow-
ups compared to the previous one in both
groups (all P-values were <0.001 except for
12-24th weeks follow up, which was 0.007). It
is also worth mentioning that the average MASI
score of the last follow up in the 24th week was
not statistically signi cant between the two
groups (P=0.1), whereas the post-treatment
MASI score in the 12th week was statistically
signi cant between the two groups (P=0.02)
The average MASI reduction for the HQ
group was 62 percent, and for the TA group, 57
percent. The decrease in the MASI score in the
4th week compared to the start of the study
and in the 24th week compared to the 12th was
statistically signi cant between the two groups
(P<0.0001). It was also worth mentioning that
the average MASI score reduction on the last
follow-up compared to the baseline was not
statistically signi cant between the two groups
(P=0.64).
FIGURE 4. Physicians Global Assessment (PGA) in melasma patients injected with tranexamic acid (TA) versus
hydroquinone (HQ).
FIGURE 3. Improvement of melasma lesions in two patients before and after treatment with topical hydroquinone 4%.
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JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY January 2023 • Volume 16 • Number 1
ORIGINAL RESEARCH
A comparison of the e ectiveness of
treatments on the MASI score based on
the melasma types showed no signi cant
di erences in all visits (P>0.05). As presented
in Table 3, the mean MASI score in patients
injected with TA decreased over time from 6.1
(2.6 SD) in the baseline to 3.6 (2.1 SD) in the
24th week in the epidermal melasma type. It
dropped from 6.1 (2.2 SD) in the baseline to 2.8
(1.4 SD) in the 24th week in the mixed pattern.
This decreasing pattern was also observed in the
HQ group. The mean MASI score decreased from
7.8 (3.1 SD) in the baseline to 4.8 (2.9 SD) in the
24th week in the epidermal melasma type and
decreased from 7.3 (2.9 SD) in the baseline to
5.1(3.2 SD) in 24th week in the mixed pattern.
Figures 2 and 3 show melasma lesions in four
patients treated with TA or HQ before and after
six months.
The PGA rated the HQ group as excellent in
three patients, good in eight, poor in six, and
fair in seven. The TA-treated group was rated
outstanding in three, good in twelve, poor in
ve, and fair in four patients (Figure 4). The
results did not show a statistically signi cant
di erence between the two groups (P=0.63).
Despite admitting to topical anesthesia, all
participants developed mild degrees of burning
pain at the injection site. No other serious
adverse e ects were reported.
DISCUSSION
This study compared two treatment
modalities in female patients diagnosed with
melasma, including topical 4% HQ and 100mg/
mL intradermal TA. Our results show that both
TA and topical hydroquinone signi cantly
reduced the MASI score overtime. Still, HQ
was substantially more e ective in reducing
the MASI score in the 24th-week follow-up
compared to the 12th week. These results
suggest that the long-term administration of
HQ could be helpful in treating melasma lesions.
The results also indicated a higher complete
satisfaction rate in the TA group than in the
HQ group. It is also worth mentioning that the
decrease in the MASI score in the HQ group was
signi cantly higher than the TA group.
For many years, HQ was the gold standard
treatment modality for treating melasma.
In recent articles, TA was indicated as an
alternative in treating and hypopigmentation of
melasma lesions. TA is a hemostatic agent and
inhibits ultraviolet-induced pigmentation.13,16
Intradermal injection of TA seems to be an
e ective and safe treatment option for melasma
and can signi cantly reduce the MASI score in
previous studies.17-19 Saki et al20 compared the
e cacy of 2% HQ and 20mg/mL TA on melasma
patients. Both drugs decreased the melanin
index, which was not statistically signi cant
between the two groups. Based on another
study conducted in the southwest of Iran, the
closest study to ours on 50 female patients, the
right side of the patient’s face was injected with
4mg/mL TA, and 10mg/mL TA plus topical 4%
TABLE 1.Patients’ demographic data and characteristics of melasma according to their treatment group; values are presented as number (%) or mean and standard deviation (SD).
VARIABLE CATEGORY GROUP P-VALUE
(BETWEEN GROUPS)
HYDROQUINONE TRANEXAMIC ACID
Age (years) Mean±SD 33.7 ± 6.1 35.9 ± 5.2 0.18
Duration of Melasma (years) Mean±SD 3.0 ± 2.7 4.5 ± 2.5 0.05
Family History N (%) Positive 14 (58.3%) 14 (58.3%) 1
Previous treatment N (%) Positive 10 (41.7%) 12 (50.0%) 0.77
Fitzpatrick Skin Type N (%)
II 1 (4.2%) 0 (0%)
0.55
III 10 (41.7%) 9 (37.5%)
IV 13 (54.2%) 14 (58.3%)
V 0 (0%) 1 (4.2%)
Pattern N (%)
Malar 18(75.0%) 15(62.5%)
0.61Centrofacial 5(20.8%) 8(33.3%)
Mandibular 1(4.2%) 1(4.2%)
Type N (%)
Dermal 2 (8.3%) 1 (4.2%)
0.83Epidermal 18 (75.0%) 19 (79.2%)
Mixed 4 (16.7%) 4 (16.7%)
Predisposing factor N (%)
Pregnancy 7 (29.2%) 8 (33.3%)
0.79
UV 8 (33.3%) 5 (20.8%)
Pregnancy + UV 2 (8.3%) 2 (8.3%)
OCP 4 (16.7%) 6 (25.0%)
Others 3 (12.5%) 3 (12.5%)
Abbreviation: OCP, oral contraceptive pills.
TABLE 2.Comparison of the e ectiveness of treatments
on the Melasma Area and Severity Index (MASI) score
in the tranexamic Acid (TA) versus hydroquinone
(HQ) group. Data are described as mean and standard
deviation (SD).
TIMELINE GROUP
(N=24) MEAN± SD P-VALUE
Baseline TA 6.1±2.5 0.05
HQ 7.7±3.0
4th week TA 5.6±2.5 0.09
HQ 6.9±2.9
8th week TA 4.6±2.4 0.08
HQ 5.9±2.9
12th week TA 3.6±2.1 0.02
HQ 5.2±2.7
24th week TA 3.5±2.0 1
HQ 4.8±2.9
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JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY January 2023 • Volume 16 • Number 1
ORIGINAL RESEARCH
HQ was used on the left side. Topical 4% HQ
had equal e cacy on the 12th week compared
to 10mg/mL TA which was more e ective than
the lower dose of TA. These results showed that
increasing TA dosage can signi cantly increase
the e ectiveness of treatment.15
Despite local anesthesia, all studied patients
in the TA group experienced mild burning pain
at the injection site, which was also reported
in the Pazyar et al15 study. Another study
conducted in 2022 reported that burning
pain was signi cantly higher in the group
treated with TA plus ascorbic acid than TA
alone.17 TA’s other side e ects include nausea,
vomiting, diarrhea, color vision disturbances,
and orthostatic imbalances.12,21 Skin irritation
on the 4% HQ cream application side was
the signi cant adverse e ect that has been
reported.22 Other commonly reported adverse
e ects of HQ include irritant contact dermatitis,
exogenous ochronosis, corneal degeneration,
nail discoloration, erythema, and burning.23,24
Despite multiple treatment modalities for
melasma, the treatment strategy is challenging
due to its chronicity and relapsing state.25 We
suggest a combination therapy of HQ and other
bleaching agents that have been suggested
to be more e ective than monotherapies. The
combination of HQ and kojic acid or triple-
combination of corticosteroid cream has
been well established in the literature.26 The
synergistic process of the triple-combination
agents achieves signi cantly higher
depigmentation in melasma agents than in
HQ monotherapy in eight weeks without any
considerable adverse e ect.27,28 In addition,
a combination of oral TA and HQ cream
signi cantly enhanced the e ectiveness of HQ
alone and had a more signi cant decrease in the
MASI score.21
The usual e ective dose of HQ for melasma
is 2%, while we used 4% HQ as a control group.
Contrary to the previous studies that injected a
lower dose of TA, the advantage of the present
study was using intradermal TA in a higher dose
than previous studies, as mentioned above. A
survey by Mafune et al29 showed that higher
therapeutic doses of TA may be more e ective
in treating melasma lesions.However, other
studies reported that long-term treatment
should have a better e ect than increasing the
dosage.12,30
At last, there are several limitations to this
study. First, we only used the MASI score to
measure melasma degree, whereas other
modalities, including Mexameter and Visioface
photography, can be used to analyze skin
color more comprehensively. Second, greater
generality would have been achieved if the
sample size had been larger. This is a single-
center study with a small sample size, and some
patients in both groups did not show up for the
nal follow-up due to transportation issues.
Third, the before-after photos were not taken
with a high-quality camera. So, the treatments’
improvement cannot be appropriately seen in
the pictures.
CONCLUSION
The results of our study showed that both
TA and continuous HQ signi cantly reduced
the MASI score of patients with melasma
during 12 weeks of treatment without any
signi cant di erences and serious side e ects.
Although several treatment modalities are
used for melasma, it is a challenging condition
for dermatologists with a high recurrence rate
after treatment. Therefore, further comparative
studies with more cases are needed on the
e ectiveness of di erent dosages of these two
modalities.
ACKNOWLEDGMENTS
This article is based on a thesis by Dr.
TABLE 3.Comparison of the Melasma Area and Severity Index (MASI) score based on melasma types in tranexamic acid
(TA) versus hydroquinone (HQ) group. Data are described as mean and standard deviation (SD).
TIME GROUP TYPE MEAN± SD P-VALUE
Baseline
TA
Dermal 6.7±6.7
0.99
Epidermal 6.1±2.6
Mixed 6.1±2.2
HQ
Dermal 7.5±0.0
0.95Epidermal 7.8±3.1
Mixed 7.3±2.9
4th week
TA
Dermal 6.4±6.4
0.79
Epidermal 5.6±2.6
Mixed 5.2±2.2
HQ
Dermal 7.3±0.0
0.98Epidermal 6.9±3.1
Mixed 6.7±3.2
8th week
TA
Dermal 5.8±5.8
0.93
Epidermal 4.6±2.4
Mixed 4.5±2.4
HQ
Dermal 6.9±0.0
0.93Epidermal 5.9±3.0
Mixed 5.7±3.4
12th week
TA
Dermal 4.7±0.0
0.91Epidermal 3.6±2.1
Mixed 3.7±2.5
HQ
Dermal 6.5±0.0
0.90Epidermal 5.2±2.8
Mixed 5.1±3.1
24th week
TA
Dermal –
0.52Epidermal 3.6±2.1
Mixed 2.8±1.4
HQ
Dermal –
0.82Epidermal 4.8±2.9
Mixed 5.1±3.2
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JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY January 2023 • Volume 16 • Number 1
ORIGINAL RESEARCH
Motahareh Babazadeh Dezfuly, a dermatology
resident. The authors would like to thank
the Clinical Research Development Unit,
Imam Khomeini Hospital, Ahvaz Jundishapur
University of Medical Sciences, Ahvaz, Iran, for
their cooperation.
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