SSR Inst. Int. J. Life Sci., 10(1): 3590-3598, Jan 2024

Comparing Oral Tranexamic Acid and Q-Switched Nd-YAG Laser for Melasma: A Randomized Study

 

Abdul Sahid Khan¹, Anjana Sathyanath ¹, Ashitha Mary Kurian¹, Prasenjeet Mohanty², Diptiranjani Bisoyi^3*, Jayashree Mohanty², Manjulata Dash⁴

¹Senior Resident, Department of Dermatology, SCB MCH, Cuttack, Odisha, India

²Professor, Department of Dermatology, SCB MCH, Cuttack, Odisha, India

³Assistant Professor, Department of Dermatology, SCB MCH, Cuttack, Odisha, India

⁴Professor, Department of Dermatology, DD MCH, Keonjhar, Odisha, India

 

^*Address for Correspondence: Dr. Diptiranjani Bisoyi, Department of Dermatology, SCB MCH, Cuttack, Odisha, India

E-mail: diptiranjanibisoyi@gmail.com

 

 

ABSTRACT- Background: Addressing the challenges of limited therapeutic options for melasma, this study explores the novel approach of combining oral Tranexamic acid with Q switched Nd-YAG laser. The aim is to evaluate the efficacy of this combination against oral Tranexamic acid (TNA) alone in treating melasma.

Method: This study was conducted as a prospective, randomized, open-label study with a sample size of 50, Group A (25 patients) received oral Tranexamic acid along with Nd-YAG laser treatment every 15 days for 3 months. Group B received only oral Tranexamic acid for the same duration. Clinical photographs were taken at each session, and patients were followed up for 3 and 6 months.

Result: The study found a 49.96% mMASI change in Group A and a 38.74% change in Group B after 3 months. Both groups exhibited similar percentages of reversal, with the combination group showing a marginally higher percentage. However, the difference was statistically insignificant (p=0.55). A limitation of the study was its small sample size.

Conclusion: The combination therapy demonstrated better responses for both mixed and dermal melasma types. Notably, laser treatment alone did not yield significant outcomes and carried a higher risk of hyperpigmentation, making it unsuitable for treating epidermal melasma.

Keywords: Melasma, Tranexamic Acid, TNA, Q switched Nd-YAG Laser, Laser Therapy

 

INTRODUCTION- Melasma is a form of acquired symmetrical hypermelanosis of the face, mainly affecting the nose, chin, forehead, and malar area. It is characterized by irregular brownish-black macules.^[1] Fitzpatrick skin types IV through VI are predominantly found in females in the reproductive age range and are common in the Indian, Chinese, and Hispanic ethnic groups. Three recognised types of behaviour exist: the most common is centrofacial, while mandibular is the least common. Although the precise origin of melasma is still unknown, Ortonne et al. ^[2] discovered that oral contraceptives, breastfeeding, and pregnancy all increased UVA exposure and had a hormonal effect on the condition's development. Based on the length of the condition, melasmas can be divided into two categories: temporary melasmas, which disappears a year after hormonal stimulation (such as pregnancy or OCP usage), and persistent melasmas, which is typically caused by UVR and continues longer than a year after the hormonal stimulus is stopped. It is possible to distinguish between four types of melasma thanks to Wood's light examination and visible light.

Increased melanin and pigment accentuation on Wood's lamp epidermal type, primarily in the suprabasal and basal epidermis ^[3,4]. Although melanin-loaded macrophages are present in the perivascular distribution of the superficial and deep dermis, the dermal form does not exhibit Wood's lamp accentuation. The inapparent form appears murky in Wood's light; however, the mixed variety has a deep brown colour and features from both. The patient's quality of life has been adversely affected and their emotional and psychological stress levels have escalated due to their cosmetically unacceptable resistance to most forms of therapy. ^[5] Traditional therapeutic treatments include alpha and beta hydroxy acid peels, hydroquinone, tretinoin, mometasone, azeleic acid, and Kojic acid depigmentation lotions. All of these options, meanwhile, have disadvantages of their own.

According to recent studies, the hemostatic medication tranexamicacid (TNA) has a hypopigmentary effect on melasma lesions and lessens UVA-induced pigmentation. These results suggest that TNA may prove to be an effective melasma treatment. TNA reduces the activity of epidermal melanocyte tyrosinase by blocking the plasminogen/plasmin pathway, which keeps melanocytes and keratinocytes from interacting. ^[6] Tranexamic acid also decreases cutaneous vascularity and ^[7-9] the quantity of mast cells by inhibiting fibroblast growth factor, decreasing mast cell activity, and restricting plasmin activity triggered by UV light. ^{[11 13]}

This statement suggests that recent studies have demonstrated the efficacy and rapid action of Q Switched Nd-YAG lasers, highlighting them as more effective and faster-acting than traditional therapeutic approaches.

MATERIALS AND METHODS

This interventional study was conducted in Tertiary care Hospital from August 2020 to November 2021. All the patients with Melasma of age 18 to 50 years attending Dermatology OPD were included. Convenient randomized sampling method was used to divide 50 patients into two groups.

 

Inclusion criteria

       Patients without a history of coagulopathies, cardiac diseases, or severe systemic disorders

       No known allergy to Tranexamic acid

       Absence of oral anticoagulant drug usage or any other photosensitizing drugs (e.g., tetracycline, spironolactone, phenytoin, carbamazepine) in the last 1 month

       No use of other depigmenting oral or topical agents in the past 1 month

       Females without a history of pregnancy or lactation in the last 12 months

       Absence of oral contraceptive pill or hormonal replacement therapy usage in the past 12 months

 

Exclusion criteria

       Patients with a history of coagulopathies, cardiac diseases, or severe systemic disorders

       Use of oral anticoagulant drugs or any other photosensitizing drugs in the last 1 month

       Known allergy to Tranexamic acid

       Use of other depigmenting oral or topical agents in the past 1 month

       Use of oral contraceptive pills or hormonal replacement therapy in the past 12 months

 

Randomization- It was done by computerized random number allocation, 50 patients divided into two groups for oral plus laser therapy and oral therapy alone as Group A and Group B respectively. After obtaining written informed consent, thorough history, clinical examination and baseline investigations were done as per the data collection pro-forma. The lesions were examined under a Woods lamp. The intensity of melasma was evaluated using the modified mMASI method. Throughout treatment and for an extra three months after, all patients were instructed to use wide spectrum sunscreen with an SPF of at least thirty.

In Group A, patients Tab Tranexamic acid 250mg was given orally twice daily for 3 months, along with that Nd-YAG Laser was used simultaneously once in every 15days.In Group B patients only Tab Tranexamic acid 250mg was given orally in twice daily dose for a period of 3 months.

Laser Procedure- Participants in the study were excluded if they had taken any oral anticoagulants or other photosensitizing medications, such as tetracycline, spironolactone, phenytoin, or carbamazepine, in the month prior, or if they had a history of coagulopathies, heart problems, severe systemic disorders, or if they knew they were allergic to tranexamic acid. End point was noted when there was formation of erythema or white crusts. (Fig. 1). Possible side effects like erythema, edema, pain, hyperpigmentation or burning sensation in Group A and oligomenorrhoea or amenorrhoea in both groups patients were asked on every visit. Clinical photographs in front of green background were taken in before each session and at follow-up period up to 3 months.

Fig. 1: Procedures during Q-switched Nd-YAG laser ablation

The intensity of melasma was evaluated using the modified melasma area and severity index scoring (MASI) method as 0.3A(f)D(f)+0.3A(lm)D(lm)+0.3A(rm)D(rm)+0.1A(c)D(c) in a range of 0-24 and was calculated by comparing the percentage of improvement for each patient's response to their original score (Fig. 2).

 

Fig. 2: Modified MASI Scoring

More than 60% change in mMASI after 3 months of treatment was considered as excellent response, 40-60% as good response and <40% was considered as poor response.

Statistical Analysis- The data was analyzed using SPSS 25.0. A component of the statistical analysis was calculating the means and proportions. An unpaired t-test was used to compare the mean mMASI scores of the two intervention groups at 0 and 3 months, as well as 3 and 6 months. The p<0.05 significance level was applied.

Ethical approval- Institutional ethical committee clearance and CTRI Registration was obtained (CTRI/2021/01/030539).

RESULTS- Mean mMASI score among centrofacial pattern and malar pattern was tabulated among the treatment groups who received oral tranexamic acid with Q switched Nd YAG laser and only oral tranexamic acid (Table 1).

Table 1: Mean mMASI score according to pattern of skin involvement

Mean mMASI score among group with epidermal, dermal and mixed involvement in wood s lamp was tabulated among the treatment group A and B Table-2.

Table 2: MeanmMASI score according to woods lamp

 

Table 3 and Table 4 shows association between the mMASI score from 0 to 3 months within the two intervention groups clinically and in wood s lamp examination respectively. There was statistically significant association between the change in the mMASI score from 0 to 3 months.

 

Table 3: mMASI score change from 0 month to 3 months

 

Table 4: 4mMASI score change from 0 month to 3 months according to woods lamp types

 

Table 5 shows association between the mMASI score from 3 to 6 months within the two intervention groups. There was no significant association between the mMASI score within the two intervention groups.

 

Table 5: mMASI score change from 3 months to 6 months within the two intervention groups.

Table 6 shows association of treatment response within the two intervention groups. Excellent treatment response was significantly higher among the patients who received oral Tranexamic acid with Q switched Nd YAG laser compared to those who received only oral tranexamic acid (p-value: 0.02) which was shown in following clinical image (Fig. 3 and 4).

Table 6: Treatment response at 3 months within the two intervention groups.

^#Fisher s Exact Test

Fig. 3: Patient treated TNA+Nd YAG at 0 month(A), showing excellent response at 3 months (B), visible recurrence at 6 months (C)

Fig. 4: Patients with TNA at 0 month (A), at 3 months (B) showing good response, at 6 months mild recurrence (C)

 

Table 7 shows association of treatment response with the type of disease involvement in Group-A according to wood s lamp examination. There was a significant association of treatment response with the type of disease based upon the region involved (p-value: 0.01).

Table 7: Treatment response in Oral Tranexamic acid with Q switched Nd YAG laser (Group-A) in wood s lamp examination

^#Fisher s exact test

Table 8 shows association of treatment response with the type of disease involvement in Group-B patients. There was no significant association of treatment response with the type of disease based upon the region involved.

Table 8: Treatment response with only oral tranexamic acid

^#Fisher s exact test

 

Adverse Events- Treatment with Nd YAG laser resulted in hyperpigmentation in 3 patients (1 of them was lost to follow up). Single case of Hypomenorrhoea was seen in both the groups whereas 1 case of amenorrhoea was reported in Group treated with both Oral Tranexamic acid and Nd YAG laser (Fig. 5, 6).

Fig. 5: Patients treated with TNA+Qs Nd YAG laser showing paradoxical hyperpigmentation at 3mnth, right side image

Fig. 6: Distribution of various adverse events within the two intervention groups

 

DISCUSSION- Tranexamic acid (TNA) is an artificial lysine analogue having antifibrinolytic effects.^[10] When exposed to UV radiation, keratinocytes create more plasminogen activator and increase the activity of plasmin. This ultimately results in the release of arachidonic acid, which employs prostaglandins to facilitate melanogenesis.^{[11 13]} Nijor ^[14] conducted the first review and report on the effects of tranexamic acid on melasma in 1979. Hajime et al. ^[15] discovered in 1985 that the intensity of their melasma was lessened when they took 1 to 1.5 g of oral tranexamic acid every day. In 1998, eleven melasma patients were treated with oral tranexamic acid (0.75 1.5 g/day) ^[16]. But after the drug was withdrawn, the pigmentation came back. For a period of 6 8 weeks, vitamins C and E were given along with 250 mg of tranexamic acid three times a day by Zhu and Yang ^[17] and Liu et al. ^[18]. They saw a noticeable reduction in pigmentation. Mafune et al. ^[19] administered two 750 mg oral tranexamic acid pills three times a day.

In the first controlled trial, conducted in 2013, Cho et al. compared patients treated with neodymium-doped yttrium aluminium garnet laser or intense pulse light with those who received the same treatment but were not prescribed tranexamic acid. As an adjuvant, the patients were given 500 mg each day.^[20-23] Kato et al. ^[21] found that oral TNA at 750 mg/day did not significantly reduce the risk of hyperpigmentation in individuals with senile lentigo following Q-switched ruby laser treatment. Darker skin types should avoid using Q-switched ruby lasers because of the increased risk of hyperpigmentation following treatment.^[25,26] Wattanakrai et al. ^[24] report that there was a transient response to melasma treatment with Qs-Nd: YAG laser^. Conversely, Shin et al. found that melasma patients could receive a minimally invasive treatment option when oral TNA was used in conjunction with a low-fluence QS-Nd: YAG laser.^[28] They discovered a statistically significant drop in the mMASI score, just like we did.

In our study the mean mMASI at the baseline or at 0 months was overall found to be 6.49+3.29 in group A, whereas, the mean MASI by Kar et al was 13.54+7.19.^[21] In group B the baseline mMASI was 4.75+0.78 in our study, and the same by Khurana et al was found to be 7.48+3.73^.[22]

In our study the percentage of mMASI change from baseline to 3 months of treatment was 49.96% (+23.42) in group A patient treated with tranexamic acid and laser, in comparison to the group B patients treated with only tranexamic acid with mean change of 38.74% (+13.71), with statistically significant p-value of 0.04. Kar et al. ^[21] with usage of low fluence QS Nd-YAG laser found the change in MASI of 47.93% which is similar to our study^. The study by Khurana et al. with only oral tranexamic acid treatment had the change in mMASI of 57.48% which is significantly higher to our study^.[22]

In wood s lamp classification of melasma in group A patients treated with the combination therapy has shown change in mMASI percentage in mixed type and dermal type which is statistically significant when compared to the the group B patients of mixed type. The patients with epidermal type of melasma showed similar results in both groups. The study conducted by Agamia et al. the overall change in percentage of mMASI was maximum with epidermal type of melasma, followed by mixed type, and the least improvement was seen in dermal type which is not in accordance to our study^.[23]

All the 49 patients that completed the treatment and follow up period have reported reversal in treatment response at the end of follow up period. Khurana et al. ^[22] reported that 6.25% of patients showed return of the pigmentation, but the percentage the reversal was not mentioned.

All the patients treated with combination therapy showed mild burning sensation and pain over the site of laser therapy, but it was transient and disappeared in 1-2 hours. Three (12%) patients treated with combination therapy showed development of paradoxical hyperpigmentation out of which one patient discontinued the treatment mid-way and was lost to follow up. Kar et al. ^[21] reported paradoxical hyperpigmentation or PIH in 28.5% cases treated with high fluenceNd-YAG laser. The other adverse events included temporary amenorrhoea during the treatment period in 1 patient , and 2 patients complained of hypomenorrhoea. Khurana et al reported gastritis as most common adverse effect is 6.5% of cases and oligomenorrhoea in 3.12% cases^.[22] Agamia et al. reported slight menstrual changes in 33% of cases and GI upset in 16.7% age cases^.[23] No other adverse effects were reported during the treatment and follow up period.

CONCLUSIONS - To our knowledge the comparison of oral tranexamic acid with the combination of oral tranexamic acid and laser has not been studied much in Indian population. The combination therapy was found to act better on dermal and mixed type of melasma. The laser therapy was not found to be suitable for epidermal type of melasma for not been able to provide significant result and with increased rate of hyperpigmentation.

The objective of proving whether concurrent use of oral tranexamic acid with Nd-YAG laser will decrease the adverse effects of laser, could not be established significantly in our study. More such randomised trials in larger study sample are required to establish the above findings.

 

CONTRIBUTION OF AUTHORS

Research concept- Khan Sahid Abdul, Mohanty Prasenjeet

Research design- Mohanty Prasenjeet, Khan Sahid Abdul

Supervision-Mohanty Prasenjeet, Mohanty Jayashree, Bisoyi Diptiranjani

Materials- Khan Sahid Abdul, Mohanty Prasenjeet

Data collection- Khan Sahid Abdul, Dash Manjulata, Mohanty Jayashree, Sathyanath Anjana

Data analysis and Interpretation- Khan Sahid Abdul, Bisoyi Diptiranjani, Sathyanath Anjana

Literature search- Khan Sahid Abdul, Mohanty Prasenjeet, Kurian Mary Ashitha

Writing article-Bisoyi Diptiranjani, Kurian Mary Ashitha, Sathyanath Anjana

Critical review-Mohanty Prasenjeet, Mohanty Jayashree, Kurian Mary Ashitha

Article editing- Dash Manjulata, Bisoyi Diptiranjani, Kurian Mary Ashitha, Sathyanath Anjana

Final approval-MohantyPrasenjeet, Bisoyi Diptiranjani, Khan Sahid Abdul

 

REFERENCES

1.     Grimes PE. Melasma. Etiologic and therapeutic considerations. Arch Dermatol., 1995; 131(12):1453-57.

2.     Ortonne JP, Arellano I, Berneburg M, et al. A global survey of the role of ultraviolet radiation and hormonal influences in the development of melasma. J Eur Acad Dermatol Venereol., 2009; 23(11): 1254‐1262.

3.     Hann SK, Im S, Chung WS, Kim DY. Pigmentary disorders in the South East. Dermatol Clin., 2007; 25(3): 431 38.

4.     Sanchez NP, Pathak MA, Sato S, et al. Melasma: a clinical, light microscopic, ultrastructural, and immunofluorescence study. J Am Acad Dermatol., 1991; 4(6): 698 710.

5.     Guinot C, Cheffai S, Latreille J, et al. Aggravating factors for melasma: a prospective study in 197 Tunisian patients. J Eur Acad Dermatol Venereol., 2010; 24(9): 1060 69.

6.     Maeda K, Tomita Y. Mechanism of the inhibitory effect of tranexamic acid on melanogenesis in cultured human melanocytes in the presence of keratinocyte-conditioned medium. J Health Sci., 2007; 53: 389 96.

7.     Na JI, Choi SY, Yang SH, Choi HR, et al. Effect of tranexamic acid on melasma: a clinical trial with histological evaluation. J Eur Acad Dermatol Venereol., 2013; 27: 1035 39.

8.     Padhi T, Pradhan S. Oral tranexamic acid with fluocinolone-based triple combination cream versus fluocinolone-based triple combination cream alone in melasma: an open labeled randomized comparative trial. Indian J Dermatol., 2015; 60: 520.

9.     Tan AW, Sen P, Chua SH, Goh BK. Oral tranexamic acid lightens refractory melasma. Australas J Dermatol., 2017; 58: e105 08.

10.  Dunn CJ, Goa KL. Tranexamic acid: a review of its use in surgery and other indications. Drugs, 1999; 57: 1005 32.

11.  Akashima A, Yasuda S, Mizuno N. Determination of the action spectrum for UV-induced plasminogen activator synthesis in mouse keratinocytes in vitro. J Dermatol Sci., 1992; 4: 11-17.

12.  Maeda K, Naganuma M. Topical trans4-aminomethylcyclohexanecarboxylic acid prevents ultraviolet radiationinduced pigmentation. J Photochem Photobiol B., 1998; 47: 136 41.

13.  Takashima A, Yasuda S, Mizuno N. Determination of the action spectrum for UV-induced plasminogen activator synthesis in mouse keratinocytes in vitro. J Dermatol Sci., 1992; 4: 11 17.

14.  Nijor T. Treatment of melasma with tranexamic acid. Clin Res 1979; 13: 3129-31.

15.  Hajime M, Mineo T, Yoshio T. Oral administration therapy with tranexamic acid for melasma. Nishinihon J Dermatol., 1995; 47: 1101-04.

16.  Higashi N. Treatment of melasma with oral tranexamic acid. Skin Res., 1998; 30: 676-80.

17.  Zhu HJ, Yang XH. The clinical study of acidumtranex-amicum on melasma. Pharm Program, 2001; 3: 178-81.

18.  Liu H, Kou CC, Yeung CW. Effectiveness of tranexamic acid in treating melasma and observation of its safety. Chin J Med Aesthet Cosmetol., 2005; 11:361-3.

19.  Mafune E, Morimoto Y, Iizuka Y. Tranexamic acid and melasma. Farmacia, 2008; 44: 437-42.

20.  Cho HH, Choi M, Cho S, Lee JH. Role of oral tranexamic acid in melasma patients treated with IPL and low fluence QS Nd: YAG laser. J Dermatol Treat., 2013; 24: 292-96.

21.  Kato H, Araki J, Eto H, Doi K, Hirai R, et al. A prospective randomized controlled study of oral tranexamic acid for preventing post-inflammatory hyperpigmentation after Q-switched Ruby laser. Derm Surg., 2011; 37: 605 10.

22.  Kang HY, Ortonne JP. What should be considered in treatment of melasma. Ann Dermatol., 2010; 22: 373 78.

23.  Kono T, Manstein D, Chan HH, Nozaki M, Anderson RR. Q switched ruby versus long pulsed dye laser delivered with compression for treatment of facial lentigines in Asians. Lasers Surg Med., 2006; 138: 94 97.

24.  Wattanakrai P, Mornchan R, Eimpunth S. Low-fluence Qs witched neodymium-doped yttrium aluminum garnet (1,064 nm) laser for the treatment of facial melasma in Asians. Dermatol Surg., 2010; 36(1): 76 87.

25.  Shin JU, Park J, Oh SH, et al. Oral tranexamic acid enhances the efficacy of low-fluence 1064-nm quality-switched neodymium-doped yttrium aluminum garnet laser treatment for melasma in Koreans: a randomized, prospective trial. Dermatol Surg., 2013; 39 (3pt1): 435 42.

26.  Kar HK, Gupta L, Chauhan A. A comparative study on efficacy of high and low fluence Q-switched Nd: YAG laser and glycolic acid peel in melasma. Indian J Dermatol Venereol Leprol., 2012; 78: 165-71. doi: 10.4103/0378-6323.93633.

27.  Khurana VK, Misri RR, Agarwal S, Thole AV, Kumar S, Anand T. A randomized, open-label, comparative study of oral tranexamic acid and tranexamic acid microinjections in patients with melasma. Indian J Dermatol Venereol Leprol., 2019; 85: 39-43. doi: 10.4103/ijdvl.IJDVL_801_16.

28.  Agamia N, Apalla Z, Salem W, Abdallah W. A comparative study between oral tranexamic acid versus oral tranexamic acid and Q-switched Nd-YAG laser in melasma treatment: a clinical and dermoscopic evaluation. J Dermatolog Treat., 2021; 32(7): 819-26.