European Journal of Cardiovascular Medicine

Melasma is an acquired skin condition characterized by dark patches and spots typically found on the face, neck, and occasionally the upper limbs. While it primarily affects women of reproductive age with darker skin types such as Fitzpatrick skin types IV, V, and VI [1], individuals of all ages, ethnicities, and skin colors can develop this disorder. Melasma can significantly affect a patient's appearance, leading to psychosocial challenges and emotional distress, ultimately diminishing their quality of life [2].

The exact pathogenesis of melasma is unclear; The predisposing factors could be associated with melasma are genetic susceptibility, ultraviolet (UV) light exposure, pregnancy, sex hormones, contraceptive pills, cosmetics,

phototoxic drugs, and inflammatory processes [3,4]. Melasma area and severity index (MASI) is the most commonly used outcome measure for melasma. MASI or mMASI, either of the scores, can be used for melasma [5].

Various treatment options have been implemented, with hydroquinone being the most widely recognized. Other treatments include retinoic acid, kojic acid, azelaic acid, and various peeling agents such as glycolic acid, trichloroacetic acid, salicylic acid, and lactic acid [6]. Additionally, physical treatments like lasers and dermabrasion have been explored, although managing the condition can be particularly challenging for those with darker skin. Recently developed formulations, such as tranexamic acid (TA), rucinol (4-n-butylresorcinol), oligopeptides, silymarin, and orchid extracts, are under investigation. Tranexamic Acid can be administered orally, topically, or through intradermal microinjections. It works by disrupting the catalytic action of tyrosinase and inhibiting melanin production; it also prevents UV-induced plasmin activity in keratinocytes by blocking plasminogen from binding to these cells, leading to lower levels of free arachidonic acid and reduced prostaglandin synthesis, which subsequently decreases tyrosinase activity in melanocytes [7,8]. The current study aims to compare the effectiveness and safety of intradermal injections versus systemic administration of tranexamic acid in treating melasma.

Methods:

A prospective randomized open-label study was carried out involving 60 patients who were clinically diagnosed with melasma. Participants were chosen from those seeking treatment for various skin conditions in our outpatient department over 11-month period from April 2024 to Feb 2025, following approval from the Institutional Ethical Committee.

This study involved a group of sixty patients suffering from melasma, who were selected from those visiting the Dermatology, Venereology, and Leprosy OPD at Government General Hospital Ananthapuram. The research was carried out between April 2024 and Feb 2025. The study received approval from the local ethics committee for research involving human subjects at Government General Hospital Ananthapuram, and informed consent was obtained from each participant prior to their inclusion in the study.

Inclusion Criteria:

The study focused on females aged 18 to 65 with moderate-to-severe melasma characterized by a bilaterally symmetrical distribution, specifically skin types III-IV-V. 

Exclusion Criteria:

1. Patients undergoing hormone replacement therapy or taking oral contraceptives,
2. Women who are pregnant or breastfeeding,
3. Individuals with a history of bleeding disorders or those using anticoagulants, or any photosensitizing medications such as nonsteroidal anti-inflammatory drugs, tetracycline, spironolactone, phenytoin, and carbamazepine,
4. Known drug allergies or allergic to tranaexemic acid, particularly to the medication being studied,
5. Presence of other medical conditions,
6. Previous use of any depigmenting treatments oral or topical within the last month,
7. Active herpes simplex,
8. Facial warts or other active skin conditions.
9. Patients who had undergone any treatment for melasma in the last six weeks.

Study population:

The study ultimately included 60 female patients with melasma, who were randomly divided into two groups, A and B. The baseline characteristics (age, cause, and distribution of melasma) and other clinical data were found to be statistically comparable between the two groups.

Study Procedure:

Patients were randomly assigned to receive either oral or topical treatment for melasma, with randomization achieved through random number allocation. After acquiring written informed consent, a medical history was taken, and a clinical examination was performed, including assessment of the lesions under a Woods lamp. Baseline evaluations of liver and kidney functions, along with a coagulation profile, were conducted and repeated after three months. The severity of melasma was assessed using the Modified Melasma Area and Severity Index scoring system, allowing for comparison of each patient's response from their initial score to determine percentage improvement.

Patients in the oral therapy group (Group A) received tranexamic acid tablets (250 mg) twice daily for three months. For the intralesional group (Group B), tranexamic acid was administered via intradermal injections. Approximately 2 U of tranexamic acid was drawn into a 40 U/ml 30-gauge insulin syringe and diluted with normal saline to a total volume of 1 ml, achieving a concentration of around 4 mg/ml of tranexamic acid. Intradermal injections were delivered at the melasma site after applying a topical anesthetic, spaced approximately 1 cm apart, with a maximum of 8 mg administered in one session. Six sessions were scheduled at weekly intervals. Patients were instructed on stringent photoprotection measures to enhance and sustain improvement. All participants received the same sunscreen with a sun protection factor of 50 for the entire duration.

To evaluate treatment response, clinical photographs were taken at each visit, and modified melasma area and severity index scores were recorded at both the start and conclusion of therapy. Subjective treatment responses were categorized at the study's end as follows: no response (no improvement), mild response (<25% improvement), moderate response (25% to <50% improvement), good response (50% to <75% improvement), and excellent response (>75% improvement). The final response was assessed based on the melasma area and severity index scores, along with patients' subjective feedback. Any complications and side effects were documented during follow-ups. For an additional three months post-treatment, patients were monitored monthly for any signs of relapse or complications.

Statistical Analysis: All the descriptive quantitative analytical parameters were expressed as number, percentages.

The mean age of Intra dermal group was 36.67±6.95 and the oral group was 37.36±10.33. Age wise the mode of administration of drug to both groups was not statistically significant (Table 1)..

Table 1. Age distribution of study population of both groups

Female predominance was noted in melasma population; almost equal number of populations received the intra dermal and oral management (Table 2).

Table 2. Sex wise distribution of Study participants

Majority of the study population presented with melasma were Home maker, it was 60% of the total study population (Fig 1).

Fig. 1 Occupation of patients with Melasma

Among 66 participants, predominant type observed 33 (55%) patients had Malar epidermal melasma followed by 9 (15%) had malar mixed melasma. Remaining patients presented with centrofacial epidermal, centrofacial mixed and centrofacial dermal types of melasma (Fig 2).

Fig 2. Different types of melasma

MASI score observed during intra dermal tranexamic acid therapy. The mean and SD before treatment was 10.41±7.140 and after treatment was 7.14±3.028. The statistically significant was observed between two groups.

Table 3. Distribution of MASI score before and after treatment by Intradermal TA

MASI score observed during oral tranexamic acid therapy. The mean and SD before treatment was 10.32±4.210 and after treatment was 4.404±2.049. The statistically significant was observed between two groups.

Table 3. Distribution of MASI score before and after treatment by Oral TA

There was significant (p=<0.0001) improvement in both oral and intradermal TA treatment, but mean difference of before and after treatment was higher in oral TA (-6.110) which shows oral TA expressed quick and better improvement than intradermal TA.

In the current study on melasma treatment, group A exhibited the most favorable response, followed by group B. Within group A, an excellent response was observed in 9 patients (30%), a good response in 9 patients (30%), a moderate response in 6 patients (20%), a mild response in 3 patient (10%), and no response in 3 patients (10%). In group B, no patients demonstrated an excellent response (0%), while 6 patient (20%) had a good response, 12 patients (40%) had a moderate response, 6 patients (20%) had a mild response, and 6 patients (20%) showed no response (Fig 1 & Fig 2).

Fig 1. Malar pattern type before (picture 1) and after (picture 2) oral TXA therapy for 2 months

Fig 2. Centrofacial pattern type before (picture 1) and after (picture 2) intra dermal TXA therapy for 4 weeks

In terms of side effects, our findings indicated that they were more commonly reported in group B, while no side effects occurred in group A. In group B, every patient (100%) experienced burning pain, and 20% (4 patients) had erythema.

In our research, we examined two groups. Group A consisted of 30 patients who received oral tranexamic acid at a dosage of 250 mg twice daily for three months. Group B also included 30 patients; they were treated with intradermal injections of tranexamic acid (TXA). After performing a gentle alcohol cleanse, a topical anesthetic cream was applied under an occlusive dressing for one hour. Using a sterile insulin syringe, 0.05 ml of tranexamic acid solution in normal saline (4 mg/ml) was injected into the melasma lesions at 1 cm intervals every week for a total of 6 weeks.

Karrabi et al [9] from Iran and Kaleem et al [10] from Pakistan did clinical trial studies on intradermal TXA therapy in which the mean age of the population is same as this study. All participants in our study were female, suggesting that hormonal factors may influence the outcomes, along with genetic considerations [11,12].

In terms of treatment efficacy in this study, Group A, which received oral tranexamic acid demonstrated the highest effectiveness, followed by Group B who were given intradermal injections. In Group A, there was a significant reduction in the P value (<0.001*) and in the modified Melasma Area and Severity Index (mMASI) score from the baseline to the conclusion of treatment. In Group B, there was also a significant decrease in the P value (<0.001*) and mMASI score from baseline to the end of treatment, although the improvements were less pronounced than those observed in Group A. Hajime et al used oral tranexamic acid for 10 weeks, during which they showed a reduction in the severity of melasma [13]. Lee et al. showed a significant improvement in MASI at the end of treatment following weekly intradermal injection of tranexamic acid [14]. Kaleem et al [10] showed a significant reduction in the mean MASI score with tranexamic acid. Sharma et al conducted a clinical trial on patients with melasma, with one group being given oral tranexamic acid (250 mg twice daily) and the other group receiving 4 mg intradermal tranexamic acid every 4 weeks for a period of 12 weeks, which showed a significant reduction in MASI for oral tranexamic acid [15]. Del Rosario et al also showed similar results with oral tranexamic acid as an effective drug in treating moderate to severe melasma [16]. Panchal VS et al [17] did a study on oral, topical and intra dermal TXA comparative therapy evaluation, found Mean changes in MASI/mMASI score were reported in all 13 studies at 8 weeks and 12 weeks after the beginning of treatment with oral tranexamic acid compared to the other treatment was found to statistically significant (8 weeks, SMD was 1.61 and P < 0.007; 12 weeks, SMD was 2.39 and P < 0.00001). Whereas, the topical TXA or intradermal TXA comparison with other adjuvants therapies at 8 weeks and 12 weeks, in random effect, the P value was high and it was not significant statistically.

Various studies used different modes of administration of TXA therapy in their research works. In a study by Cho et al. in 2011 which used 500 mg/day of tranexamic acid as an additional therapy to the patients treated with intense pulsed light (IPL) or Nd:YAG laser as compared to patients treated with only IPL or Nd:YAG laser showed that modified MASI score was lower in the tranexamic acid group (P < 0.005) [18]. In a triple-blinded randomized control trial by Minni et al., it was shown that oral tranexamic acid + fluocinolone-based triple combination cream (FbTC) results in early response and higher clearance of melasma at 4^th week compared with FbTC alone [19]. An uncontrolled study conducted in 2007 by Kondou et al. studied the effects of 2% topical emulsion of tranexamic acid in 25 patients for 18 weeks which showed that it was effective in 80% of patients within 8 weeks with no side effects [20]. In a study conducted by Budamakuntla et al. in India that evaluated the efficacy of topical TXA with micro-needling in comparison with microinjections of tranexamic acid, there was more reduction in MASI score in micro-needling group than in microinjection group, but the difference was not significant [21].

Both treatment methods yielded favorable outcomes, as the mMASI scores before and after treatment did not differ significantly between the two groups. Batra J et al [11] did a comparative study on oral and transepidermal TXA, noted the baseline MASI score was 11.98 (± 5.47) in Group A and 12.13 (± 3.16) in Group B. The final reduction in MASI score was similar in both the groups. In another study conducted in Korea on melasma patients, TXA was directly administered intradermally (4 mg/mL) weekly for a period of 12 weeks. More than 75% of the patients experienced a statistically significant improvement in MASI score [14].

In the current study on melasma treatment, group A exhibited the most favorable response, followed by group B. Within group A, an excellent response was observed in 9 patients (30%), a good response in 9 patients (30%), a moderate response in 6 patients (20%), a mild response in 3 patient (10%), and no response in 3 patients (10%). In group B, no patients demonstrated an excellent response (0%), while 6 patient (20%) had a good response, 12 patients (40%) had a moderate response, 6 patients (20%) had a mild response, and 6 patients (20%) showed no response. Batra J et al [11] noted at the end of 24 weeks follow-up period, good (51%-75% improvement) and very good (>75% improvement) response occurred in 5 (25%) and 14 (70%) patients in Group A and 11 (55%) and 9 (45%) patients in Group B, respectively. These findings align with those of Vinod K Khurana et al [22], who reported that at the conclusion of the treatment, there was a very good response in all 100% patients who showed > 50% improvement and 8 showed 75% improvement. Shetty V H et al [23] conducted a prospective comparative study involving 40 patients in two groups who received 250 mg of oral tranexamic acid twice daily for 6 months, reporting an overall improvement rate of 98.5% (23% excellent, 63% good, and 12% fair).

In terms of side effects, our findings indicated that they were more commonly reported in group B, while no side effects occurred in group A. In group B, every patient (100%) experienced burning pain, and 20% (4 patients) had erythema. A study by Tahoun et al. exhibited significant diminution in dark fine granules, homogeneous pigmentation, and pseudo-reticular brown network with intradermally treated tranexamic acid [24]. Batra J et al [11] documented only mild adverse effects were noted in the form of epigastric discomfort (two patients) with oral TXA and pain at injection site (seven patients) with transepidermal administration of TXA with microneedling, which did not warrant its discontinuation. Transient reversible hypomenorrhea, which has been commonly seen with oral TXA. Deep vein thrombosis was noted by Lee et al. [14]. These findings align with studies [25] and [26], which also noted burning pain and wheals at the injection site in all the studied group. TA’s other side effects include nausea, vomiting, diarrhea, color vision disturbances, and orthostatic imbalances [27,28].

The strengths of this study are use of modified Melasma Area and Severity Index (mMASI) score to effectively evaluate the melasma score in both intradermal and oral groups. Got the chance to follow up the patients though it is a hospital where the most of the patients hail from rural areas. During the follow up we have assessed the response and side effects to treatment.

The limitations of this study was histopathological examinations were not conducted due to patient apprehension and the facial area involved. Dermoscopy was unavailable, and no prior studies have utilized it to evaluate responses to tranexamic acid.

Tranexamic acid is a safe, well tolerated and promising drug for management of melasma. Female population was predominantly with the mean age of 36 years were affected by melasma in this community. TXA therapy is effective for melasma. Both intra dermal and oral treatment methods yielded favorable outcomes, as the mMASI scores before and after treatment did not differ significantly between the two groups, but on comparison oral tranexamic acid is more effective and give better results than intradermal tranexamic acid. In intra dermal group, every patient (100%) experienced burning pain, and 20% (4 patients) had erythema, while no side effects occurred in oral group. Tranexamic acid appears to be a promising new treatment option for melasma, demonstrating safety, tolerability, and effectiveness. Further studies on different administration modalities of tranexemic acid may help to resolve resistant melasma and recurrence rate of melasma.

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