Tranexamic Acid for Melasma Treatment: A Split-

Face Study
Howyda M. Ebrahim, MD, Ahmed Said Abdelshafy, MD, Fathia Khattab, MD, and
Khaled Gharib, MD*

BACKGROUND Melasma is an acquired hyperpigmented skin disorder. Tranexamic acid (TXA) prevents
ultraviolet radiation induced pigmentation in melasma through interfering with the plasminogen–plasmin
pathway.

OBJECTIVE This study was conducted to evaluate the therapeutic effect and safety of TXA by intradermal
injection versus TXA with microneedling for melasma treatment.
Downloaded from http://journals.lww.com/dermatologicsurgery by BhDMf5ePHKbH4TTImqenVNlUEzghFiXbrD1jgEMpAHBUi3mJZdB0xEw9crmH3Bev on 10/27/2020

METHODS Fifty-six female patients with bilateral symmetrical melasma were recruited in a split-face study.
All patients received an intradermal injection of TXA on one side of the face, and the other side received TXA
with microneedling for 6 sessions at 2 weeks intervals. Clinical efficacy was assessed using a modified Mel-
asma Area Severity Index (mMASI) score at the baseline and after treatment. Global photographs underwent
blinded review by 2 dermatologists. Patient self-assessment and satisfaction were recorded.

RESULTS After the treatment, the mMASI score was significantly reduced compared with the baseline in
both treated sides (p < .001). No significant difference between both treated sides (p > .05). Patient satisfaction
was higher in the microneedling-treated side than the intradermal-injected side (p < .001). No significant
adverse effects were observed in both treated sides.

CONCLUSION Intradermal injection and microneedling of TXA could be safe and effective in melasma
treatment. Microneedling of TXA was significantly more satisfying to the patients.

The authors have indicated no significant interest with commercial supporters.

M elasma is a common acquired disorder of facial

hyperpigmentation characterized by irregular
brown macules or patches involving mainly sun-
exposed areas of the face. Melasma commonly affects
women during fertile age particularly those with skin
phototypes IV and V. The prevalence of melasma was
ranged between 8.5% and 40% that may represent
different environmental and genetic backgrounds
among discrete geographic conditions. It results in
cosmetic disfigurement that negatively affects the
quality of life. Many etiological factors have been
implicated in pathogenesis of melasma, such as genetic
influences, ultraviolet (UV) exposure, contraceptive
pills, pregnancy, and hormonal therapy.2 Melasma is a
frequently recurrent disease and often refractory to
treatment. Therefore, it requires an appropriate
medicine that can be used for a long time to achieve
good results without significant adverse effects.
Although topical depigmenting agents have good
efficacy, they carry the risk of irritant contact
dermatitis, postinflammatory hypopigmentation, and
exogenous ochronosis.3,4 Tranexamic acid (TXA) is a
plasmin inhibitor that competitively inhibits the
activation of plasminogen into plasmin. It has been
used as an antifibrinolytic agent to prevent excessive
bleeding. Ultraviolet rays stimulate plasminogen

*All authors are affiliated with the Dermatology, Venereology, and Andrology Department, Faculty of Medicine, Zagazig
University, Zagazig, Egypt

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided
in the HTML and PDF versions of this article on the journal’s Web site (www.dermatologicsurgery.org).

© 2020 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. All rights reserved.
· ·
ISSN: 1076-0512 Dermatol Surg 2020;46:e102–e107 DOI: 10.1097/DSS.0000000000002449

e102

© 2020 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.

activator synthesis and subsequently increase plasmin
activity in the basal cells and keratinocytes.
Tranexamic acid inhibits melanin synthesis by
interfering with UV-induced plasmin activity in
keratinocytes. Plasmin stimulates the
a-melanocyte–stimulating hormone and basic fibro-
blast growth factor, which is a potent melanocyte
growth factor. Tranexamic acid inhibits arachidonic
acid and its ability to produce prostaglandins. This in
turn decreases melanocyte tyrosinase activity. There-
fore, TXA plays an essential role in inhibiting mela-
nogenesis and reducing the pigmentation in melasma.
Moreover, it exerts an additional effect in melasma by
inhibition of angiogenesis through suppression of
vascular endothelial growth factor; therefore, TXA
has a role in decreasing of vascularity and erythema in
melasma.5–7
Microneedling is a simple, effective, and minimally
invasive technique. It has been used for the treatment
of acne scar, alopecia, stretch marks, dyspigmenta-
tion, and skin rejuvenation.8 Microneedling is a device
supplied with fine needles to create microchannels into
the skin without causing actual epidermal damage. It
enhances transdermal drug delivery across the skin
barrier. Furthermore, it stimulates the release of
growth factors that help in deposition of new colla-
gen.9 Dermapen is an automated microneedling device
characterized by having a higher speed of action than
traditional dermarollers. Moreover, it is more conve-
nient in the areas difficult to access, such as around the
eyes, lips, and nose.10
Patients and Methods
Patient Design
The study was a split-face design, performed at the
outpatient clinics of Zagazig university Hospital dur-
ing the period from May 2015 to May 2016 after
approval from the Institutional Review Board at
Zagazig university Hospital. In this research, the right
side of the face was subjected to TXA with micro-
needling while the left side of face received an intra-
dermal injection of TXA. Informed consent was
obtained from all of the patients before participating in
the study.
© 2020 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
EBRAHIM ET AL
Participants
Fifty-six female patients who had nearly bilateral
symmetrical melasma and age ranging 27 to 50 years
were enrolled in this study. All of the patients had the
Fitzpatrik skin Phototype III-IV. Exclusion criteria
were as follows: pregnant or nursing women, patients
who are taking contraceptive pills, hormone replace-
ment therapy, anticonvulsant drugs, anticoagulants
drugs, patients with bleeding disorders, active infec-
tion, or using any treatment for melasma during the
past 2 months before the study. All patients were
subjected to dermatological and Wood light exami-
nation to determine the skin phototype, the pattern
(centrofacial, mandibular, and malar), and type of
melasma (dermal, epidermal, and mixed). All patients
were instructed to avoid application of any medication
other than sunscreen for melasma during the study.
Clinical photographs using a digital camera (Nikon,
Japan) were taken at the baseline, before each session,
and 4 weeks after the final session.
Assessment
Assessment of the clinical response was performed by 2
independent investigators who evaluated global pho-
tographs pre-treatment and post-treatment using a
modified Melasma Area Severity Index (mMASI) score.
At the end of treatment, the clinical response was
graded as follows: excellent (>75% improvement), very
good (50%–75%), good (25%–50%), poor (<25%),
and no response. All of the patients were asked to
fulfill a self‐assessment scale, and they categorized their
improvement into poor, fair, good, and excellent.11
Patients graded their satisfaction to the treatment into
very satisfied, satisfied, or unsatisfied. Any adverse
effects or complications were recorded.
Tranexamic Acid (Trans-4-
aminomethylcyclohexanecarboxylic Acid)
Tranexamic acid is available in a 5 mL ampoule
(Kapron ampoule) that contains 500 mg of the drug
(Amoun pharma Co., Cairo, Egypt). Each 1 mL con-
tains 100 mg of the drug; a 4 mg of TXA is withdrawn
in a 100 U/mL insulin syringe and diluted with normal
saline up to 1 mL to get a concentration of 4 mg/mL of
TXA.
46:11:NOVEMBER 2020 e103
 TRANEXAMIC ACID FOR MELASMA TREATMENT
Tranexamic Acid With Microneedling
The device used was a battery-powered microneedling
pen that has disposable tips which carry 12 needles
arranged in rows. The needle length was 1.5 mm
with a diameter of 0.25 mm (Dermapen 3, Avon,
United Kingdom). The penetration depth of the needle
was adjusted from 0.25 to 1 mm, according to the
treated area on the face. The speed was adjusted at a
rate of 108 revolutions per second. After gentle
cleansing, topical anesthetic cream EMLA (AstraZe-
neca AB, Sweden) was applied on both sides of the face
for 30 to 60 minutes. The device was placed perpen-
dicular to the skin on the melasma area supported by
one hand, with gentle traction of the skin performed by
the other hand to help the smooth delivery of TXA by
microneedling. The technique was performed in hor-
izontal, vertical, and oblique directions over the trea-
ted zone for about 2 to 3 passes. This was followed by
application of about 0.5 mL TXA (4 mg/mL) to the
melasma area. Then, an ice pack was applied for
10 minutes. All patients were advised to regularly use
sunscreens. The treatment was conducted by a physi-
cian every 2 weeks for a maximum of 6 sessions
(12 weeks).
Intradermal Injection of Tranexamic Acid
All patients received an intradermal injection of about
0.5 mL of 4 mg/mL TXA on the left side of the face. A
1 mL insulin syringe with 30 gauge needle was used for
injection. An injection of 0.1 mL per point at 1 cm
intervals was conducted on the melasma area.
Statistical Analysis
All analyses were performed with Statistical Package
for Social Sciences (SPSS Inc., Chicago, IL) using
program version 18. The Chi-square (x2) test, paired t-
test, Mann–Whitney U test, and paired Wilcoxon test
were used. For all previous tests, a p-value < .05 was
considered statistically significant.
Follow-up
Patients were followed up for 3 months after the final
session to detect further improvement, any relapse, or
appearance of adverse effects.
e104 DERMATOLOGIC SURGERY
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Results
The study included 56 female patients with melasma,
and their age ranged from 27 to 50 years. Wood’s light
examination revealed that 30 (53.6%) patients had a
mixed type of melasma. The majority of patients
(58.9%) had a skin phototype IV. Clinical data of the
patients are summarized in Supplemental Digital Con-
tent 1, Table S1, http://links.lww.com/DSS/A425. After
the treatment, there was a significant improvement in
the mMASI score from 13.83 6 7.23 to 3.49 6 2.91 in
the injected side and from 13.83 6 7.23 to 3.65 6 2.32
in the microneedling side (p < .001) (See Supplemental
Digital Content 2, Table S2, http://links.lww.
com/DSS/A426 and Figures 1–3). The percent of
change was 74.8% and 73.6% in the injected and
microneedling sides, respectively. There was no statis-
tically significant difference between both treated sides
(p > .05) (See Supplemental Digital Content 2, Table S2,
http://links.lww.com/DSS/A426). The clinical response
of the injected side was excellent in 22 (39.3%) patients,
very good in 26 (46.4%) patients, good in 3 (5.4%)
patients, poor in 3 (5.4%) patients, and 2 (3.6%)
patients had no response. Whereas in the microneedling
side, it was excellent in 20 (35.7%) patients, very good
in 27 (48.2%) patients, good in 5 (12.5%) patients,
poor in 1(1.8%) patient, and 3 (5.4%) patients had no
response (See Supplemental Digital Content 3, Table
S3, http://links.lww.com/DSS/A427). Regarding
patient self-assessment, there was no significant differ-
ence between both treated sides (p > .05). However,
patient satisfaction was higher in the microneedling side
than that of the injected side (p < .001) (See Supple-
mental Digital Content 4, Table S4, http://links.lww.
com/DSS/A428).
Side Effects and Recurrence
The adverse effects were minimal and well tolerated
apart from mild erythema and edema that occurred in
25 (44.6%) of patients of both treated sides. Pain at the
injection side was reported in 24 (42.9%) patients of
the injected side, whereas mild irritation was noted in
11 (19.6%) patients of the microneedling side. All of
the patients completed the study, and 6 dropped out
during the follow-up period. Recurrence was observed
in 8 (16%) patients of both treated sides.
 EBRAHIM ET AL

Figure 1. Percent of changes in the mMASI score in both

treated sides. mMASI, modified melasma area severity
index; Lt side, left side; Rt side, right side.

Discussion
Figure 2. (A) A female patient, aged 35 years had dermal
Melasma is characterized by an unpredictable course type of melasma, before treatment, (B) the same patient
after treatment showing excellent improvement (the right
and high relapse rate. Therefore, there is a constant side treated by TXA with microneedling and the left side
need for finding new interventions for melasma treat- by intradermal TXA injection). TXA, tranexamic acid.
ment. It was reported that TXA is an effective agent in
the treatment of melasma.16–18 To the best of authors’ TXA through the microchannels created by it. In this
knowledge, this is the first study that compared 2 dif- study, although there was no significant difference
ferent modalities of TXA application in a split-face between both treated sides, patient satisfaction was
design. The applications of microneedling in derma- higher in the microneedling side because the dermapen
tology have continuously increased. Dermapen is an can help the drug to reach a uniform depth of pene-
electronic pen used for TXA delivery. Dermapen tration with a controlled speed. In addition, the der-
provides a uniform drug delivery without causing mapen can pierce the skin in a vertical manner that
actual epidermal damage; it can overcome the issues of makes it less traumatizing to the skin than the tradi-
pain and epidermal tear that may occur with the tra- tional dermaroller. Moreover, it has a higher speed of
ditional derma rollers. Intradermal injection is a tech- action that can decrease the pain and also save the time.
nique applied with a small needle into the desired area.
It involves a delivery of highly diluted mixture of drugs
without any associated risks of systemic absorption. In
this study, there was an improvement of the mMASI
score in 74.8% of the injected side compared with
73.6% in the microneedling side. No significant dif-
ference was found between both treated sides. The
authors’ study showed a higher improvement in the
mMASI score than that reported by Budamakuntla and
colleagues5 who compared 2 groups of patients with
melasma; one group received TXA by an intradermal
route while the other group was treated with TXA using
microneedling. The result revealed 35.72% improve-
ment in the MASI score in the injected group compared
with 44.41% in the microneedling group. They con-
cluded that there was no significant difference between Figure 3. (A) A female patient, aged 30 years had dermal
both groups. However, a better therapeutic response type of melasma, before treatment, (B) the same patient
after treatment showing very good improvement (the right
was achieved in the microneedling group. They dem- side treated by TXA with microneedling and the left side
onstrated that microneedling helped the delivery of by intradermal TXA injection). TXA, tranexamic acid.

46:11:NOVEMBER 2020 e105

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 TRANEXAMIC ACID FOR MELASMA TREATMENT
Lee and colleagues 15 used TXA by intradermal injec-
tion for melasma treatment. The results revealed a sig-
nificant decrease in the mMASI score after 12 weeks of
treatment (p < .05). They concluded that intradermal
injection of TXA could be an alternative therapy for
melasma. Another study compared TXA orally versus
its intradermal injection. A significant reduction of the
MASI score was observed with 77.96 6 9.39 and 79.00
6 9.64 in both the oral and microinjection groups,
respectively. The authors found that both modes of
administration were equally effective. However,
microinjection can protect the patients from any sys-
temic side effects, such as epigastric discomfort and
hypomenorrhea.18 Several other studies demonstrated
that microneedling has favorable results in melasma
treatment.20–23 Fabbrocini and colleagues compared a
combination of microneedling with a depigmenting
serum composed of rucinol and sophora-alpha com-
pounds versus the depigmented serum alone in mel-
asma treatment. They evaluated the role of
microneedling in enhancing transepidermal drug
delivery. They observed that the side with combined
treatment (microneedling and serum) has a significant
decrease in the MASI score compared with the other
side treated with the serum alone.20 By contrast, some
authors stated that microneedling may cause skin irri-
tation that could increase the pigmentation, but when
skin biopsy was obtained after microneedling, the
results revealed no change in the epidermal
pigmentation.22,23
In this study, no major adverse effects were observed
except mild erythema and edema. A mild pain was
reported in the TXA-injected side (42.9%) compared
with (19.6%) in the microneedling side. The same side
effects were reported by Budamakuntla and col-
leagues.5 In other study, pain was the main adverse
effect in the microinjection group, whereas in the oral
group mild epigastric discomfort, hypomenorrhea,
and headache were reported. Therefore, local appli-
cation of TXA can bypass many of the side effects that
may result from its systemic administration.18 In this
study, 8 (16%) patients were recurrent. Melasma is a
disease often protracted to treatment; the recurrence of
pigment in some patients may be the result of frequent
sun exposure and presence of some recalcitrant cases
of dermal melasma.
e106 DERMATOLOGIC SURGERY
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The study was limited by a small number of patients
and a short follow-up period. A lack of objective tools
for pigment measurement is another limitation. Fur-
ther large-scale studies with longer duration are rec-
ommended to find out the long-term benefits of TXA
in this recurrent and recalcitrant disease.
Conclusions
Tranexamic acid seems to be safe and effective therapy
for the treatment of melasma. Although there was no
significant difference between both treated sides,
patient satisfaction was significantly higher in the
microneedling side than that in the intradermal-
injected side.
References
1. Sarkar R, Chugh S, Garg K. Newer and upcoming therapies for
melasma. Indian J Dermatol Venereol Leprol 2012;78:417–28.
2. Rathore SP, Gupta S, Gupta V. Pattern and prevalence of physiological
cutaneous changes in pregnancy: a study of 2000 antenatal women. Ind
J Dermatol Venerol Leprol 2011;77:402–6.
3. Chatterjee M, Vasudevan B. Recent advances in melasma. Pigment Int
2014;1:70–80.
4. Sun YLQ, Fu ZH, He C, He Z, et al. Treatment of melasma with oral
administration of compound tranexamic acid: a preliminary clinical
trial. JEADV 2014;28:388–94.
5. Budamakuntla L, Loganathan E, Suresh DH, Shanmugam S, et al. A
randomized, open-label, comparative study of tranexamic acid
microinjections and tranexamic acid with microneedling in patients
with melasma. J Cutan Aesthet Surg 2013;6:139–43.
6. Poojary S, Minni K. Tranexamic acid in melasma: a review. Pigmentary
disorders. J Pig Dis 2015;2:228–33.
7. Tse TW, Edith H. Tranexamic acid: an important adjuvant in the
treatment of melasma. J Cosmet Dermatol 2013;12:57–66.
8. Liebl H, Kloth LC. Skin cell proliferation stimulated by microneedles. J
Am Coll Clin Wound Spec 2012;4:2–6.
9. Arora S, Gupta BP. Automated microneedling device–A new tool in
dermatologist’s kit–A review. J Pak Med Assoc 2012;22:354–7.
10. Bariya SH, Gohel MC, Mehta TA, Sharma OP. Microneedles: an
emerging transdermal drug delivery system. J Pharm Pharmacol 2012;
64:11–29.
11. Abou-Taleb DA, Ibrahim AK, Youssef EM, Moubasher AE. Reliability,
validity, and sensitivity to change over time of the modified Melasma
Area and Severity Index score. Dermatol Surg 2017;43:210–7
.
12. Rigopoulos D, Gregoriou S, Katsambas A. Hyper-pigmentation and
melasma. J Cosmet Dermatol 2007;6:195–202.
13. Gupta K, Gover D, Nouri K, Taylor S. The treatment of melasma:
a review of clinical trials. J Am Acad Dermatol 2006;55:1048–65.
14. Karn D, Kc S, Amatya A, Razouria A, et al. Oral tranexamic acid for
the treatment of melasma. Kathmandu Univ Med J 2012;10:40–3.

15. Lee JH, Park JG, Lim SH, Kim JY, et al. Localized intradermal
microinjection of tranexamic acid for treatment of melasma in Asian
patients: a preliminary clinical trial. Dermatol Surg 2006;32:26–31.
16. Banihashemi M, Zabolinejad N, Jaafari MR, Salehi M, et al. Comparison
of therapeutic effects of liposomal tranexamic acid and conventional
hydroquinone on melasma. J Cosmet Dermatol 2015;14:174–7.
17. Kim SJ, Park JY, Shibata T, Fujiwara R, et al. Efficacy and possible
mechanisms of topical tranexamic acid in melasma. J Clin Exp
Dermatol 2016;41:480–5.
18. Sharma R, Mahajan VK, Mehta KS, Chauhan PS, et al. Therapeutic
efficacy and safety of oral tranexamic acid and that of tranexamic
acid local infiltration with microinjections in patients with
melasma: a comparative study. Clin Exp Dermatol 2017;42:
728–734.
19. RAmaut L, Hoeksema H, Pirayesh A, Stillaert F, et al. Microneedling:
where do we stand now? A systematic review of the literature. J Plast
Reconstr Aesthet Surg 2017;17:30250–4.
© 2020 by the American Society for Dermatologic Surgery, Inc. Published by Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited.
EBRAHIM ET AL
20. Fabbrocini G, De Vita V, Fardella N, Pasrore F, et al. Skin needling to
enhance depigmenting serum penetration in the treatment of melasma.
Plast Surg Int 2011;2011:158241.
21. Alster TN, Graham PM. Microneedling: a review and practical guide.
Dermatol Surg 2018;44:397–404.
22. Aust MC, Reimers K, Repenning C, Stahl F, et al. Percutaneous collagen
induction: minimally invasive skin rejuvenation without risk of
hyperpigmentation-fact or fiction? Plast Reconst Surg 2008;122:1553–63.
23. Cohen BE, Elbuluk N. Microneedling in skin of color: a review of uses
and efficacy. J Am Acad Dermatol 2016;74:348–55.
Address correspondence and reprint requests to: Howyda
M. Ebrahim, MD, Department of Dermatology,
Venereology, and Andrology, Faculty of Medicine,
Zagazig University, Zagazig, Egypt, or e-mail:
howyda1968@gmail.com
46:11:NOVEMBER 2020 e107