10.5826/dpc.1303a195
Introduction: Tranexamic acid (TXA) is a promising treatment modality for melasma. Microneedling (MN) and fractional carbon dioxide (CO2) laser were reported to enhance TXA transepidermal delivery.
Objectives: To compare efficacy and safety of topical TXA alone or in combination with either fractional CO2 laser or MN for treatment of melasma.
Methods: Thirty females with facial melasma were divided randomly into 3 equal groups after excluding pregnant and lactating women and those using oral contraceptives or other hormonal therapy. Patients of group A were treated with fractional CO2 laser and those of group B were treated with MN (4 sessions, 3 weeks apart for both) with immediate topical application of TXA 5% solution after sessions and daily application of 5% TXA cream for both groups. Patients of group C were treated by topical daily application of TXA 5% cream. Evaluation was done by modified melasma area and severity index scores (mMASI), patient satisfaction and dermoscopy.
Results: Statistically significant improvement of mMASI was reported in all studied groups with a significantly better improvement in patients of groups A and B than those of group C, meanwhile the difference between groups A and B was statistically insignificant.
Conclusions: Topical TXA is a safe and fairly effective treatment modality for facial melasma. Combining TXA with either fractional CO2 laser or MN yielded significantly better improvement than when used alone. Fractional CO2 laser carries the risk of post-inflammatory hyperpigmentation in patients with skin types III and IV and requires meticulous patient selection.
text/xml
2160-9381
3102
en
Amal Ahmad El- Ashmawy
https://creativecommons.org/licenses/by-nc/4.0
Dermatology Practical & Conceptual
Melasma
Efficacy and Safety of Topical Tranexamic Acid Alone or in Combination with Either Fractional Carbon Dioxide Laser or Microneedling for the Treatment of Melasma
Text.Serial.Journal
https://dpcj.org/index.php/dpc
Original Article
2023-07-31
2022-12-20
2023-07-31
2023-08-24
e2023195
Dermatol Pract Concept
Introduction: Tranexamic acid (TXA) is a promising treatment modality for melasma. Microneedling (MN) and fractional carbon dioxide (CO2) laser were reported to enhance TXA transepidermal delivery.
Objectives: To compare efficacy and safety of topical TXA alone or in combination with either fractional CO2 laser or MN for treatment of melasma.
Methods: Thirty females with facial melasma were divided randomly into 3 equal groups after excluding pregnant and lactating women and those using oral contraceptives or other hormonal therapy. Patients of group A were treated with fractional CO2 laser and those of group B were treated with MN (4 sessions, 3 weeks apart for both) with immediate topical application of TXA 5% solution after sessions and daily application of 5% TXA cream for both groups. Patients of group C were treated by topical daily application of TXA 5% cream. Evaluation was done by modified melasma area and severity index scores (mMASI), patient satisfaction and dermoscopy.
Results: Statistically significant improvement of mMASI was reported in all studied groups with a significantly better improvement in patients of groups A and B than those of group C, meanwhile the difference between groups A and B was statistically insignificant.
Conclusions: Topical TXA is a safe and fairly effective treatment modality for facial melasma. Combining TXA with either fractional CO2 laser or MN yielded significantly better improvement than when used alone. Fractional CO2 laser carries the risk of post-inflammatory hyperpigmentation in patients with skin types III and IV and requires meticulous patient selection.
Amal Ahmad El- Ashmawy
2023/07/31
10.5826/dpc.1303a195
e2023195
Faculty of Medicine, Dermatology and Venereology Department, Tanta University, Tanta, Egypt
2160-9381
Melasma
en
e2023195
Trivedi MK, Yang FC, Cho BK. A review of laser and light therapy in melasma. Int J Womens Dermatol. 2017;3(1):11-20. DOI: 10.1016/j.ijwd.2017.01.004. PMID: 2849204.; PMCID: PMC5418955.
Efficacy and Safety of Topical Tranexamic Acid Alone or in Combination with Either Fractional Carbon Dioxide Laser or Microneedling for the Treatment of Melasma
https://dpcj.org/index.php/dpc/article/download/3102/2122
      Efficacy and Safety of Topical Tranexamic Acid
      Alone or in Combination with Either Fractional
      Carbon Dioxide Laser or Microneedling for the
                  Treatment of Melasma
                          Safaa Mamdouh Kamal Dawaud1, Doaa Salah Hegab2,
                        Gamal Mohamed El Maghraby3, Amal Ahmad El- Ashmawy2


1 Ministry of Health, Tanta, Egypt
2 Faculty of Medicine, Dermatology and Venereology Department, Tanta University, Tanta, Egypt
3 Pharmaceutical Technology Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt



Key words: Tranexamic Acid, Carbon Dioxide Laser, Microneedling, Melasma
Citation: Mamdouh Kamal Dawaud S, Hegab DS, Mohamed El Maghraby G, Ahmad El- Ashmawy A. Efficacy and Safety of Topical
Tranexamic Acid Alone or in Combination with Either Fractional Carbon Dioxide Laser or Microneedling for the Treatment of Melasma.
Dermatol Pract Concept. 2023;13(3):e2023195. DOI: https://doi.org/10.5826/dpc.1303a195
Accepted: March 4, 2023; Published: July 2023
Copyright: ©2023 Mamdouh Kamal Dawaud et al. This is an open-access article distributed under the terms of the Creative Commons
Attribution-NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted
noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Funding: None.
Competing Interests: None.
Authorship: All authors have contributed significantly to this publication.
Corresponding Author: Doaa Salah Hegab (Hegab DS), MD. Professor of Dermatology and Venereology, Dermatology and Venereology
Department, Faculty of Medicine, Tanta University, El Geish Street, Tanta, 31111, Egypt. Telephone number: 00201224500857
Email: doaasalahhegab@yahoo.com




  ABSTRACT             Introduction: Tranexamic acid (TXA) is a promising treatment modality for melasma. Microneedling
                       (MN) and fractional carbon dioxide (CO2) laser were reported to enhance TXA transepidermal de-
                       livery.
                       Objectives: To compare efficacy and safety of topical TXA alone or in combination with either frac-
                       tional CO2 laser or MN for treatment of melasma.
                       Methods: Thirty females with facial melasma were divided randomly into 3 equal groups after ex-
                       cluding pregnant and lactating women and those using oral contraceptives or other hormonal therapy.
                       Patients of group A were treated with fractional CO2 laser and those of group B were treated with
                       MN (4 sessions, 3 weeks apart for both) with immediate topical application of TXA 5% solution after
                       sessions and daily application of 5% TXA cream for both groups. Patients of group C were treated
                       by topical daily application of TXA 5% cream. Evaluation was done by modified melasma area and
                       severity index scores (mMASI), patient satisfaction and dermoscopy.




Original Article | Dermatol Pract Concept. 2023;13(3):e2023195                                                                    1
                      Results: Statistically significant improvement of mMASI was reported in all studied groups with a
                      significantly better improvement in patients of groups A and B than those of group C, meanwhile the
                      difference between groups A and B was statistically insignificant.
                      Conclusions: Topical TXA is a safe and fairly effective treatment modality for facial melasma. Com-
                      bining TXA with either fractional CO2 laser or MN yielded significantly better improvement than
                      when used alone. Fractional CO2 laser carries the risk of post-inflammatory hyperpigmentation in
                      patients with skin types III and IV and requires meticulous patient selection.




Introduction                                                        Methods
Melasma is an acquired, chronic, recurrent hyperpigmen-             The study was conducted on 30 patients with facial melasma
tary disorder [1]. It is clinically characterized by symmetric      who were collected from the Outpatient Clinics of Derma-
light-brown to bluish-gray macules and patches, with irreg-         tology and Venereology Department- Tanta University Hos-
ular, sharp borders [2].                                            pitals. The approval was obtained from institutional review
    The etio-pathogenesis of melasma is complex and not com-        board-research Ethics Committee of Faculty of Medicine,
pletely understood. It appears that this disorder is an interplay   Tanta University (approval code: 33006/03/20) and fulfilled
of various internal and environmental factors, which may be         all the ethical aspects required in human research. All pa-
responsible for triggering, maintaining or relapsing lesions [3].   tients signed an informed written consent before joining
    Tranexamic acid (TXA) prevents blood loss by acting             the study.
as a plasmin inhibitor. It’s administered to prevent the ab-           Only those patients not using any facial topical treatment
normal fibrinolysis by preventing the plasminogen activator         for melasma within the preceding 8 weeks to incorporation
from converting plasminogen to plasmin. Moreover, plas-             in the study were included. Patients receiving hormonal
min elevates α-melanocyte-stimulating hormone, which ac-            treatment, oral contraceptives, systemic retinoids, anticoagu-
tivates melanin synthesis in melanocytes. TXA is thought to         lants, antiplatelets or chemotherapeutics were also excluded,
block melanogenesis and its efficacy in melasma and other           in addition to pregnant females, lactating mothers and those
light-induced pigmentary disorders might be through its             with hypersensitivity to TXA or photosensitivity. Patients
anti-angiogenic and antimelanogenetic properties [4].               with blood disorders, other dermatological or systemic dis-
    In comparison with other laser modalities, the fractional       eases causing hyperpigmentation (eg chronic liver, kidney
lasers have more advantage. With this modality, the recovery        or thyroid diseases) and those with unrealistic expectations
is faster and the risk of complications such as hyperpigmen-        were also excluded from the study.
tation, hypopigmentation and scarring is lower. Fractional             All patients underwent a thorough history taking and
carbon dioxide (CO2) laser is a hopeful potential therapeutic       clinical examination to assess Fitzpatrick skin phototype. Le-
modality for melasma [5].                                           sional examination and melasma pattern detection was done
    Skin microneedling (MN) or percutaneous collagen in-            by Wood light and dermoscopy (dermalite 4, DL4, 3Gen.
duction by needles, is a minimally invasive procedure that          San Juan Capistrano, magnification x10) performed at fixed
uses short fine needles to puncture the skin and stimulates         facial points per patient (guided by anatomical landmarks).
fibroblast release of growth factors and collagen production.          Patients were randomly divided into 3 equal groups.
Long-term improvement of recalcitrant melasma after MN              Patients of group A were treated with fractional CO2 laser
has been reported, however, the exact mechanism that pro-           (4 sessions, 3 weeks apart) and immediate topical applica-
motes skin lightening is not known [6].                             tion of TXA 5% solution after session (Kapron® 500 mg/5
    Both fractional CO2 laser and MN have been used to              mL ampoules, Amoun Pharmaceutical Company, diluted
increase the transepidermal delivery of several topical drugs       to produce 5% TXA solution) with daily night application
with promising results. Both of them may add a beneficial           of topical 5% TXA cream thereafter. Fractional CO2 la-
effect to the topical TXA for treating facial melasma [7,8].        ser sessions were on the following parameters: power 8-10
                                                                    W (according to the skin type, performed using CO2 laser
                                                                    [SmartXide Dot®-DEKA], spacing 1000 μm (5.3% density),
Objectives
                                                                    dwell time 400 μs, and stack 1). Patients of group B were
This work aimed to compare the efficacy and safety of topi-         treated with MN (also 4 sessions, 3 weeks apart) and im-
cal TXA alone or in combination with either fractional CO2          mediate topical application of TXA 5% solution with daily
laser or MN for the treatment of melasma.                           topical night application of 5% TXA cream. The dermapen

2                                                                       Original Article | Dermatol Pract Concept. 2023;13(3):e2023195
used was Dr. Pen ULTIMA-A1 device, 12 needles with needle         and 0.011, respectively), while the difference between groups
length adjusted according to the skin thickness and site of       A and B was statistically insignificant (Table 1). ­Figures 1-3
melasma lesion (0.25-1 mm). The pen was placed perpendic-         show the clinical and dermoscopic results of some of the in-
ular to the skin, and the technique includes a combination of     cluded patients in the three studied groups (representing the
horizontal, vertical, and oblique 4-5 passes. The end point       average response to the treatment).
was the appearance of erythema with pinpoint bleeding.               Regarding the degree of patients satisfaction, a statisti-
    Patients of group C were treated only by topical daily        cally significant better degree of patient’s satisfaction was
night application of 5% TXA cream for 12 weeks. TXA               detected in groups A and B than group C, while the differ-
cream was prepared as: white soft paraffin (13.5 gm), cetyle      ence between groups A and B was statistically insignificant,
alcohol (13 gm), tween 80 (10 gm), propylene glycol (8 gm),       (P value between A and C and between B and C is < 0.001,
TXA (5 gm) and water to complete 100 gm.                          0.006, respectively) (Table 1).
    All included patients were instructed to avoid sun expo-         Regarding the recurrence of melasma, 3 patients in group
sure as much as possible and to apply a proper daily sun-         A (37.5%), 2 patients of group B (20%) and 5 patients in
screen (SPF +50) throughout the treatment period.                 group C (50%) showed recurrence of their melasma within
    Digital photographs were taken at base line, at the end       3 months after stoppage of treatment with statistically insig-
of treatment then at follow up (after 3 months of treatment       nificant difference among the studied groups (Table 1).
end) to assess treatment efficacy and recurrence. Scoring of         Regarding the side effects, post inflammatory hyperpig-
melasma was done by using the modified melasma area and           mentation was reported in 3 patients (30%) of group A in
severity index score (mMASI). Assessment of treatment effi-       the form of transient post laser hyperpigmentation of the
cacy was done through physician evaluation (three derma-          facial skin which improved before the time of next session.
tologists were asked to calculate mMASI score before and          Dryness and transient irritation were reported in only one
after completion of the treatment to assess percentage of im-     patient (10%) in group A, 2 patients (20%) in group B and
provement. Finally the minimum rate on which the three in-        only one patient in group C (10%). No statistically signifi-
vestigators agreed was considered as the investigator’s view      cant difference was detected among the studied groups re-
in the study), patient satisfaction (patients were asked at the   garding side effects of treatment (Table 1).
end of treatment to rate the overall satisfaction comparing
with the pretreatment condition using the following grades:
                                                                  Discussion
very satisfied (≥ 75% improvement), satisfied (50%-74%),
slightly satisfied (25%-49%), and not satisfied (0%-24%).         Results of the present study showed that the use of fractional
Side effects were reported throughout the treatment period        CO2 laser for drug delivery of TXA in group A resulted in
and during follow up.                                             a statistically significant improvement in facial melasma (P
                                                                  = 0.035). Thirty percent of patients of group A yielded very

Statistical Analysis                                              significant improvement and 50% of them yielded marked
                                                                  improvement of facial melasma. Several previous studies
Data were fed to the computer and analyzed using IBM              reported that fractional CO2 laser has beneficial thera-
SPSS software package version 20.0 (IBM Corp). Quali-             peutic effect in melasma [9,10]. It has been stated that the
tative data were described using number and percent. The          development of fractional resurfacing has led to improve-
Kolmogorov-Smirnov test was used to verify the normality          ments in melasma treatment with decreased incidence of
of distribution. Quantitative data were described using range     post-inflammatory hyperpigmentation [11]. Moreover, TXA
(minimum and maximum), mean, standard deviation, me-              can also inhibit tyrosinase activity and combat melanin syn-
dian and interquartile range (IQR). Significance of the ob-       thesis [12].
tained results was judged at the 5% level. The sample size           Trelles et al reported that melasma patients who under-
was not estimated prior to the beginning of the study which       went combined treatment with CO2 laser and long-term
is considered as a limitation of the present study.               topical lightening cream (Kligman formula) showed the
                                                                  greatest improvement than those treated by either methods

Results                                                           solely and were able to maintain treatment benefits up to
                                                                  12-month post-treatment [13].
Age and clinical data of patients of studied groups are sum-         El Sinbawy et alevaluated the effect of fractional CO2 la-
marized in Table 1.                                               ser on facial melasma clinically and microscopically in eleven
    Regarding the percentage of improvement of mMASI              melasma patients treated by two sessions of fractional CO2
score in the three studied groups, patients of groups A and       laser one month apart and they concluded that repeated ap-
B showed statistically significant higher percentage of im-       plication of low energy fractional CO2 laser on melasma skin
provement in mMASI score than those of group C (P = 0.039         may result in long lasting improvement due to its destructive

Original Article | Dermatol Pract Concept. 2023;13(3):e2023195                                                                 3
       Table 1. Demographic data, clinical evaluation, treatment response and patient satisfaction
                               of patients of the three studied groups.
                                                      Group A                Group B              Group C             Test of
                                                      (N = 10)               (N = 10)             (N = 10)         significance        P
 Sex                                                                                                                      -             -
   Male, N (%)                                           -                       -                   -
   Female, N (%)                                      10(100)                 10(100)             10(100)
 Age (years)
   Range                                               34-50                  37-50                27-50              F = 1.8        0.19
   Mean (SD)                                         41.7(5.46)             44.2(4.96)            39.3(6.8)
 Duration of melasma in years
 Range                                                  3-15                    5-15                3-13              H= 2.2         0.33
 Mean (SD)                                            10(4.16)                8.3(3.6)            9.9(3.4)
 Skin type, N (%)
 • III                                                  2(20)                  2(20)               2 (20)
                                                                                                                      χ2= 2.5        0.7
 • IV                                                   3(30)                  4(40)               6 (60)
 •V                                                     5 (50)                 4 (40)              2 (20)
 Melasma type, N (%)
 • Epidermal                                            2(20)                  3(30)               2 (20)
                                                                                                                     χ2= 20.82       0.96
 • Dermal                                               2(20)                  2(20)               2 (20)
 • Mixed                                                6 (60)                 5 (50)              6 (60)
 Percentage of improvement in mMASI
 score
                                                                                                                      Hd=7.4         0.025
 Range                                                  0-88                  27-83                20-50
 Mean (SD)                                           51.5(31.4)             58.7(19.1)            32.2(8.5)
 Significance between groups                                            P1 = 0.620a, P2 = 0.039 b, P3 = 0.011 c
 Patients satisfaction, N (%)
 • Not satisfied                                        2 (20)                 1 (10)              2 (20)
 • Satisfied                                            1 (10)                 2 (20)              8 (80)            χ2= 19.1        0.001
 • Slightly satisfied                                   5 (50)                 4 (40)                 0
 • Very satisfied                                       2 (20)                 3 (30)                 0
 Significance between groups                                             P1 = 0.693 a, P2 = 0.001 b, P3 = 0.006 c
 Recurrence, N (%)
 • No                                                  5(62.5)                 8(80)                5(50)            χ2= 1.98        0.37
 • Yes                                                 3(37.5)                 2(20)                5(50)
 Side effects, N (%)
 • No                                                   6 (60)                 8(80)                9(90)
 • Post inflammatory                                    3 (30)                   0                    0               χ2= 5.3        0.2
   hyperpigmentation
 • Dryness, transient irritation                        1 (10)                 2(20)                1(10)

mMASI = modified melasma area and severity index scores; SD = standard deviation.
Group A = fractional CO2 laser + topical 5% tranexamic acid; Group B = microneedling + topical 5% tranexamic acid; Group C = topical
5% tranexamic acid.
a
  level of significance for comparing group A and group B; b: level of significance for comparing group A and group C; c level of significance
for comparing group B and group C; dKruskal Wallis test.



effect on melanocytes. No scarring or post inflammatory hy-                  It should be noted that in the present study, 20% of pa-
per or hypopigmentation was reported [14].                               tients of group A (treated by fractional CO2 laser and 5%
    Tawfic et al assessed the combination of fractional CO2              TXA) showed no improvement and that could be attributed
and TXA in melasma treatment and they found that the de-                 to the refractory nature of melasma, multiplicity of aggra-
gree of improvement was higher on the side receiving frac-               vating factors in some cases and skin type of Egyptian pa-
tional CO2 laser combined with intradermal injection of TXA              tients (mostly Fitzpatric III, IV and V) [16,17]. It has been
than on the side receiving fractional CO2 laser alone [15].              previously mentioned that Q-switched Nd:YAG laser toning
    Qu et alfound that low-power fractional CO2 laser com-               is thought to be significantly more effective than low power
bined with topical TXA solution is a comparatively effective             fractional CO2 in the treatment of melasma when used sep-
and safe method for melasma treatment [9].                               arately [16].

4                                                                             Original Article | Dermatol Pract Concept. 2023;13(3):e2023195
  Figure 1. Fifty years old female patient with facial melasma treated by fractional CO2 laser plus topical 5% tranexamic acid. (A,A1)
  Before treatment. (B,B1) Very significant improvement after 1 months from the last treatment session. (C,C1) After 3 months of follow
  up (with no recurrence). (D) Dermoscopic picture of melasma showing pigmented network (red arrow) and hyper vascularity (black
  arrow). (D1) Very significant dermoscopic improvement after treatment showing the decrease in intensity of pigmentation.



    In the present study, hyperpigmentation occurred as a                 This variation in the percentage of improvement among
side effect with fractional CO2 laser sessions in 30% of pa-          patients of group A in the present study, could be attributed
tients of group A and this suggests that the fractional CO2           to variations in patient skin type, type of melasma, season
laser is not always an optimal choice for treatment of facial         in which sessions were done, habitual sun exposure and ad-
melasma especially in patients of skin types IV and V and             herence to sunscreen. The percentage of improvement was
that meticulous patient selection and strict sun avoidance            excellent in lighter skin color, epidermal type of melasma
are key factors for improvement. A previous study reported            and with minimal sun exposure. On the other side, there was
that fractional CO2 laser could increase TXA absorption in            no or less improvement in dark skin color, dermal type of
porcine skin, but when applied to humans, the risk of post            melasma and when sessions were done in summer. So proper
inflammatory hyperpigmentation should be considered [18].             patient selection must be kept in mind when using fractional
    Delgado and Torre concluded that the use of fractional            CO2 laser in facial melasma treatment.
CO2 laser in treatment of melasma for skin types IV to VI is              The current study showed that the use of MN for drug
risky. They claimed that in the best-case scenario in the long        delivery of TXA in group B (treated by MN and 5% TXA)
term, it will end up the same as the starting point, but there        resulted in a statistically significant improvement of facial
is a high possibility that it may worsen the condition [19].          melasma (P = 0.005), and that result was similar to many

Original Article | Dermatol Pract Concept. 2023;13(3):e2023195                                                                            5
    Figure 2. Forty-three year old female patient with malar melasma treated by microneedling plus topical 5% tranexamicacid.
    (A,A1) Before treatment. (B,B1) Marked improvement after 1 month from the last treatment session. (C,C1) Recurrence of me-
    lasma after 3 months of follow up. (D) Dermoscopic picture of melasma showing melanin pigment (red arrow). (D1) Dermoscopic
    picture after treatment showing the decrease in intensity of pigmentation.




previous studies which assisted the pleasant effect of MN in       melanocytes with melanogenic stimuli and improves the pro-
treatment of melasma [10,20,21].                                   tection against UVR owing to epidermal thickening [2].
    Based on low-quality evidence, MN may play a role in               Moreover, MN can provide a minimally invasive means
the treatment of melasma through facilitation of delivery of       of painless delivery of therapeutic molecules through the skin
topical therapies to the epidermis and dermis, and one an-         barrier with precision and convenience. Physically opening
cillary benefit of this approach being the very low risk of        micro tunnels for drug delivery with MN involves a different
postinflammatory hyperpigmentation [22].                           mechanism of action than lasers and is not accompanied by
    Lima et al concluded that MN alone, without the ad-            the risk of post inflammatory hyperpigmentation [21].
dition of any active medication, can cause lightening of               A split face comparative study of safety and efficacy of
skin stains in patients with recalcitrant melasma. Through         MN with TXA versus MN with vitamin C in the treatment
their histological findings, it was found that MN therapy          of melasma concluded that improvement was more with
promotes the proliferation of fibroblasts and helps in su-         TXA than with vitamin C, although not statistically signif-
perior dermal neocollagenesis, decreases the contact of the        icant [23].



6                                                                       Original Article | Dermatol Pract Concept. 2023;13(3):e2023195
      Figure 3. Forty-four year old female patient with facial melasma treated by 5% topical tranexamic acid cream. (A,A1) Before
      treatment. (B,B1) Moderate improvement after 1 month from the end of treatment. (C,C1) Recurrence of melasma after 3
      months of follow up. (D) Dermoscopic picture of melasma showing pigmented network (red arrow), deep melanin pigment
      (yellow arrow) deposition and hypervascularity (black arrow). (D1) Dermoscopic picture after treatment showing the decrease
      in intensity of pigmentation.




    Saleh et al used TXA with MN versus MN alone in treat-           that happened occasionally in group B was mostly due to
ment of melasma, they concluded that although MN alone               TXA cream.
produced significant lightening effect, topical TXA com-                 In the present study both fractional CO2 laser and MN
bined with MN achieved more satisfactory results [24].               were equally effective in TXA delivery and melasma treat-
    Farshi and Mansouri concluded that both MN and me-               ment with no statistically significant difference in either the
soneedling are effective in decreasing melanin content in the        percentage of improvement or patient satisfaction. Mean-
epidermal melasma lesions [25].                                      while, MN can be preferable in melasma treatment than
    On the other hand, Mekawy et al compared both frac-              fractional CO2 laser which carries the risk of hyperpigmen-
tional CO2 laser and MN for delivery of TXA in the treat-            tation in patients with darker skin complexion.
ment of melasma, they found that both methods were equally               The present study also showed that application of daily
effective and safe in treatment of facial melasma [10].              TXA cream 5% in group C (treated by 5% TXA cream only)
    In the present study, MN was safe in melasma treat-              improved facial melasma significantly (P = 0.005).
ment without side effects as hyperpigmentation that hap-                 The role of topical TXA in melasma has been studied in
pened with fractional CO2 laser. The irritation and dryness          several previous researche. Similar to the present work, most



Original Article | Dermatol Pract Concept. 2023;13(3):e2023195                                                                      7
of the previous studies had small sample sizes ranging from            All patients in the current study were re-evaluated af-
13 and 50 patients and most of them demonstrated signif-           ter 3 months from the end of the study to detect the per-
icant differences in mMASI scores after treatment [26-29].         centage of the recurrence. Thirty percent in group A, 20%
A multitude of topical preparations and methodologies of           in group B and 50% in group C experienced recurrence
treatment were used. Those ranged from 3% TXA cream                during follow-up. It should be taken in consideration that
[27], 5% gel [28], 3 % solution and 5% liposome-based              recurrence can be considered as a role in different treatment
formulation [29]. All were used twice daily for 12 weeks.          modalities of facial melasma and appropriate maintenance
In a previous comprehensive review of clinical studies, no         therapy should be selected to avoid relapse of melasma after
statistically significant differences were collectively detected   improvement [33].
between topical TXA and baseline treatment options of me-              Lueangarun et al studied 4mg/mL intradermal TXA in-
lasma including topical hydroquinone [27,29], or combina-          jection for treatment of melasma. They found significant ef-
tion of topical hydroquinone and dexamethasone [27].               ficacy at16th week; however, melasma recurrence occurred
    Kaleem et al compared the efficacy of TXA mesotherapy          during the 48-weeks of follow-up, so they concluded that
versus 0.9% normal saline for melasma by split-face study.         maintenance therapy and sun protection should be consid-
They observed significant improvement in TXA side and con-         ered for patients with melasma [34].
sidered it cost-effective and safe therapy for melasma [30].           In general, pretreatment and post-treatment topical reg-
    On the contrary, Kanechorn et al] treated 23 women             imens in conjunction with laser, light treatments and other
with bilateral epidermal melasma in their split-face trial for     treatment protocols help to reduce the risk of rebound
3 months by using topical 5% TXA gel versus its vehicle            hyper-pigmentation,        post-inflammatory         pigmentation,
[28]. They reported that improvement of pigmentation in-           and increase the longevity of the lightening effect on me-
duced by TXA gel was neither superior nor different com-           lasma [35].
pared to its vehicle although it caused more irritation to the
treated site.
    Four patients in the present study experienced dryness         Conclusions
and irritation from TXA application that was similar to the
                                                                   Topical TXA is a safe and fairly effective treatment modality
result of Kanechorn et al observed irritation and dryness by
                                                                   for facial melasma. Combining TXA with either fractional
using local TXA [28].
                                                                   CO2 laser or MN yielded significantly better improvement of
    As melasma is claimed to respond better to treatment
                                                                   melasma than when it is used alone. No significant difference
with oral and/or locally injected TXA than to topical ap-
                                                                   regarding mean mMASI reduction, degree of improvement,
plication, and as topical TXA is not readily available in the
                                                                   or the level of patients satisfaction was detected between
markets, it seems to be a worthy research point to improve
                                                                   MN and fractional CO2 laser when combined with topical
the pharmacokinetic transepidermal carriage with different
                                                                   TXA for melasma treatment. MN is more recommended in-
vehicles and to handle the matter of irritation [31,32].
                                                                   stead of CO2 fractional laser as a combination with TXA
    It has been claimed that TXA alone is not strong enough
                                                                   in melasma treatment due to the similar efficacy but more
to fight a previously settled melasma by itself and it should
                                                                   favorable side-effect profile. Fractional CO2 laser carries the
be better used in combination with other treatment modal-
                                                                   risk of post-inflammatory hyperpigmentation when used in
ities. TXA is thought to improve UV-induced pigmentation
                                                                   melasma treatment, so proper patient selection with ade-
and hinders the progress of melanogenesis [31].
                                                                   quate parameters must be kept in mind.
    This has been furtherly proved in the present study, as
combining TXA with either fractional CO2 laser or MN gave
a statistically significant better improvement of melasma          References
than when used alone.
                                                                    1. Handel AC, Miot LDB, Miot HA. Melasma. A clinical and
    It is worthy saying that combing of TXA with fractional
                                                                       ­epidemiological review. An Bras Dermatol.. 2014;89(5):771-782.
CO2 laser or MN in the present study raised the degree of               DOI: 10.1590/abd1806-4841.20143063. PMID: 25184917.
patient satisfaction.                                                   PMCID: PMC4155956.
    In the present study, dermoscopy was done at the begin-         2. Freitag FM, Cestari TF, Leopoldo LR, Paludo P, Boza JC. Effect of
ning of treatment to confirm diagnosis and classify the type            melisma on quality of life in a sample of women living in South-
                                                                        ern Brazil. J Eur Acad Dermatol Venereol. 2008;22(6):655-662.
of melasma. A statistically significant better improvement
                                                                        DOI: 10.1111/j.1468-3083.2007.02472.x. PMID: 18410339.
in epidermal melasma than dermal type was detected in the
                                                                    3. Polnikorn N. Treatment of refractory melasma with the Med Lite
studied groups. Dermoscopic improvement included fainting               C6 Q-switched Nd. YAG laser and alpha arbutin. a ­prospective
the color of melanin pigment and decreasing the red color of            study. J Cosmet Laser Ther. 2010;12(3):126-131. DOI: 10.3109
the vascular component of melasma.                                      /14764172.2010.487910. PMID: 20482238.



8                                                                      Original Article | Dermatol Pract Concept. 2023;13(3):e2023195
 4. Cheng L, Pettersen D, Ohlsson B, et al. Discovery of the fi-           18. Hsiao F, Lin YC, Huang CC. Efficacy and safety of a single
    brinolysis inhibitor AZD 6564, acting via interference of a                 treatment using a 10,600-nm carbon dioxide fractional laser
    protein–­protein interaction. ACS Med Chem Lett. 2014;18(5):                for mild-to-moderate atrophic acne scars in Asian skin. Der-
    538-543. DOI: 10.1021/ml400526d. PMID: 24900876. PMCID:                    matologica Sinica. 2013;31(2):59-63. DOI: 10.1016/j.dsi
    PMC4027757.                                                                .2012.09.009.
 5. Alexiades-Armenakas MR, Dover JS, Arndt KA. The spectrum of            19. Delgado RE, Torre Mde L. Use of fractional laser in mixed-race
    laser skin resurfacing, non-ablative, fractional, and ablative laser       patients. Facial Plast Surg. 2013;29(3):161-166. DOI: 10.1055/s-
    resurfacing. J Am Acad Dermatol. 2008;58(5):719-737. DOI:                  0033-1347006. PMID: 23761119.
    10.1016/j.jaad.2008.01.003. PMID: 18423256.                            20. Lima Ede A. Microneedling in facial recalcitrant melasma: report
 6. Tuan-MahmoodTM, McCrudden MT, Torrisi BM, et al.                           of a series of 22 cases. An Bras Dermatol. 2015;90(6):919-921.
    ­Microneedles for intradermal and transdermal drug delivery.               DOI: 10.1590/abd1806-4841.20154748. PMID: 26734882.
     Eur J Pharm Sci. 2013;50(5):623-637. DOI: 10.1016/j.ejps                  PMCID: PMC4689089.
    .2013.05.005. PMID: 23680534. PMCID: PMC4119996.                       21. Xu Y, Ma R, Juliandri J, et al. Efficacy of functional microarray of
 7. Alegre-Sa´nchez A, Jiménez-Gómez N, Boixeda P. Laser-assisted              ­microneedles combined with topical tranexamic acid for melasma: A
    drug delivery. Actas Dermosifiliogr. 2018;109(10):858-867.                  randomized, self-controlled, split-face study. Medicine (Baltimore).
    DOI: 10.1016/j.ad.2018.07.008. PMID: 30266385.                              2017;96(19):e6897. DOI: 10.1097/MD.0000000000006897.
 8. Shende P, Sardesai M, Gaud RS. Micro to nanoneedles. A                      PMID: 28489798. PMCID: PMC5428632.
    trend of modernized transepidermal drug delivery system.               22. Wu SZ, Muddasani S, Alam M. A Systematic Review of the
    Artif Cells Nanomed Biotechnol. 2018;46(1):19-25. DOI:                      Efficacy and Safety of Microneedling in the Treatment of Me-
    10.1080/21691401.2017.1304409. PMID: 28355887.                              lasma. Dermatol Surg. 2020;46(12):1636-1641. DOI: 10.1097
 9. Qu Y, Wang F, Liu J, Xia X. Clinical observation and dermoscopy             /DSS.0000000000002763. PMID: 32897944.
    evaluation of fractional CO2 laser combined with topical tranexamic    23. Menon A, Eram H, Kamath PR, Goel S, Babu AM. A Split
    acid in melasma treatments. J Cosmet Dermatol. 2021;20(4):                  Face Comparative Study of Safety and Efficacy of Micronee-
    1110-1116. DOI: 10.1111/jocd.13992. PMID: 33565243.                          dling with Tranexamic Acid versus Microneedling with Vita-
10. Mekawy KMM, Sadek A, Seddeik Abdel-Hameed AK.                                min C in the Treatment of Melasma. Indian Dermatol Online
    Micro-needling versus fractional carbon dioxide laser for deliv-             J. 2019;11(1):41-45. DOI: 10.4103/idoj.IDOJ_22_19. PMID:
    ery of tranexamic acid in the treatment of melasma: A split-face             32055507. PMCID: PMC7001392.
    study. J Cosmet Dermatol. 2021;20(2):460-465. DOI: 10.1111             24.   Saleh FY, Abdel-Azim ES, Ragaie MH, Guendy MG. Topi-
    /jocd.13537. PMID: 32562337.                                                 cal tranexamic acid with microneedling versus microneedling
11. Neeley MR, Pearce FB, Collawn SS. Successful treatment of ma-                alone in treatment of melasma. Clinical, histopathologic, and
    lar dermal melasma with a fractional ablative CO₂ laser in a pa-             immunohistochemical study. J Egypt Womens Dermatol Soc.
    tient with type V skin. J Cosmet Laser Ther. 2010;12(6):258-260.             2019;16(2):89-96. DOI: 10.4103/JEWD.JEWD_25_19.
    DOI: 10.3109/14764172.2010.538412. PMID: 21142733.                     25.   Farshi S, Mansouri P. Study of efficacy of microneedling and me-
12. Kim HJ, Moon SH, Cho SH, Lee JD, Kim HS. Efficacy and Safety                 soneedling in the treatment of epidermal melasma: A pilot trial.
    of Tranexamic Acid in Melasma: A Meta-analysis and System-                   J Cosmet Dermatol. 2020;19(5):1093-1098. DOI: 10.1111/jocd
    atic Review. Acta Derm Venereol. 2017;97(7):776-781. DOI:                    .13369. PMID: 32196865.
    10.2340/00015555-2668. PMID: 28374042.                                 26.   Steiner D, Feola C, Bialeski N. Study evaluating the efficacy of
13. Trelles MA, Velez M, Gold MH. The treatment of melasma                       topical and injected tranexamic acid in treatment of melasma.
    with topical creams alone, CO2 fractional ablative resurfacing               Surg Cosmet Dermatol. 2009;1(4):174–177.
    alone, or a combination of the two: a comparative study. J Drugs       27.   Ebrahimi B, Naeini FF. Topical tranexamic acid as a promising
    ­Dermatol. 2010;9(4):315-322. PMID: 20514787.                                treatment for melasma. J Res Med Sci. 2014;19(8):753-757.
14. El-Sinbawy ZG, Abdelnabi NM, Sarhan NE, Elgarhy LH. Clinical                 PMID: 25422661. PMCID: PMC4235096.
     & ultrastructural evaluation of the effect of fractional CO2 la-      28.   Kanechorn Na Ayuthaya P, Niumphradit N, Manosroi A, Na-
     ser on facial melasma. Ultrastruct Pathol. 2019;43(4-5):135-144.            kakes A. Topical 5% tranexamic acid for the treatment of
     DOI: 10.1080/01913123.2019.1673861. PMID: 31575311.                         melasma in Asians: a double-blind randomized controlled
15. Tawfic SO, Abdel Halim DM, Albarbary A, Abdelhady M. As-                     clinical trial. J Cosmet Laser Ther. 2012;14(3):150-154. DOI:
     sessment of combined fractional CO2 and tranexamic acid in                  10.3109/14764172.2012.685478. PMID: 22506692.
     melasma treatment. Lasers Surg Med. 2019;51(1):27-33. DOI:            29.   Banihashemi M, Zabolinejad N, Jaafari MR, Salehi M, Jabari A.
     10.1002/lsm.23032. PMID: 30431171.                                          Comparison of therapeutic effects of liposomal Tranexamic Acid
16. Esmat S, Z Elramly A, Shahin D, Hilal RF. Combining Low Power                and conventional Hydroquinone on melasma. J Cosmet Der-
     Fractional CO2 With QS-NdYAG Toning in the Treatment of                     matol. 2015;14(3):174-177. DOI: 10.1111/jocd.12152. PMID:
     Melasma Reduces the Incidence of Punctate Leukoderma. Lasers                26177992.
     Surg Med. 2021;53(10):1325-1340. DOI: 10.1002/lsm.23441.              30.   Kaleem S, Ghafoor R, Khan S. Comparison of efficacy of
     PMID: 34164829.                                                             Tranexamic Acid Mesotherapy versus 0.9% normal Saline
17. Nourmohammadi Abadchi S, Fatemi Naeini F, Beheshtian E.                      for Melasma; A split face study in a Tertiary Care Hospital of
     Combination of Hydroquinone and Fractional CO2 Laser ver-                   Karachi. Pak J Med Sci. 2020;36(5):930-934. DOI: 10.12669/
     sus Hydroquinone Monotherapy in Melasma Treatment: A                        pjms.36.5.2379. PMID: 32704266. PMCID: PMC7372652.
     Randomized, Single-blinded, Split-face Clinical Trial. Indian J       31.   Tse TW, Hui E. Tranexamic acid: an important adjuvant in the
     Dermatol. 2019;64(2):129-135. DOI: 10.4103/ijd.IJD_240_17.                  treatment of melasma. J Cosmet Dermatol. 2013;12(1):57-66.
     PMID: 30983609. PMCID: PMC6440181.                                          DOI: 10.1111/jocd.12026. PMID: 23438143.




Original Article | Dermatol Pract Concept. 2023;13(3):e2023195                                                                                   9
32. Ng SP, Marcant M, Davis AF. In vitro human skin concentra-        34. Lueangarun S, Sirithanabadeekul P, Wongwicharn P, et al. In-
    tions following topical application of 2% tranexamic acid in          tradermal Tranexamic Acid Injection for the Treatment of
    co-enhancer cream and branded cream formulations. J Cosmet            Melasma: A Pilot Study with 48-week Follow-up. J Clin Aes-
    Dermatol. 2020;19(10):2656-2662. DOI: 10.1111/jocd.13301              thet Dermatol. 2020;13(8):36-39. PMID: 33178380. PMCID:
    . PMID: 31961048.                                                     PMC7595366.
33. Arora P, Sarkar R, Garg VK, Arya L. Lasers for treatment of me-   35. Trivedi MK, Yang FC, Cho BK. A review of laser and light ther-
    lasma and post-inflammatory hyperpigmentation. J Cutan Aes-           apy in melasma. Int J Womens Dermatol. 2017;3(1):11-20.
    thet Surg. 2012;5(2):93-103. DOI: 10.4103/0974-2077.99436.            DOI: 10.1016/j.ijwd.2017.01.004. PMID: 2849204.; PMCID:
    PMID: 23060704. PMCID: PMC3461803.                                    PMC5418955.




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