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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 7  |  Issue : 1  |  Page : 12-25

Tranexamic acid in melasma: a review


1 Department of Dermatology, Venereology and Leprosy, Government Medical College and Hospital, Chandigarh, India
2 Department of Dermatology, Venereology and Leprosy, MAMC, Delhi, India

Date of Submission23-Feb-2020
Date of Decision02-Apr-2020
Date of Acceptance30-May-2020
Date of Web Publication10-Jul-2020

Correspondence Address:
Dr. Mala Bhalla
Department of Dermatology, Venereology and Leprosy, Government Medical College and Hospital, Sector 32 B, Chandigarh, 160030
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/Pigmentinternational.Pigmentinternational_

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  Abstract 


Tranexamic acid (TA), an anti-fibrinolytic agent, originally used for treating blood loss during surgery and various medical conditions, has been found to show promising results in melasma. TA has been tried as oral therapy, topical formulations and even intradermally, with or without adjuvants by various researchers in melasma but still there is no consensus on the optimum route, dose and timing of the treatment. A systematic literature search of the PubMed electronic database was performed using the keywords ‘melasma’, ‘chloasma’ and ‘tranexamic acid’ in the title. The abstracts of the articles were screened and reviewed for relevance. The selected articles were read in detail for inclusion and also the relevant references were traced. This review is an attempt to evaluate the role of TA by various routes in melasma and offer suggestions for future directions of research.

Keywords: Chloasma, melasma, tranexamic acid


How to cite this article:
Kaur A, Bhalla M, Sarkar R. Tranexamic acid in melasma: a review. Pigment Int 2020;7:12-25

How to cite this URL:
Kaur A, Bhalla M, Sarkar R. Tranexamic acid in melasma: a review. Pigment Int [serial online] 2020 [cited 2020 Nov 30];7:12-25. Available from: https://www.pigmentinternational.com/text.asp?2020/7/1/12/289341




  Introduction Top


Tranexamic acid (TA), a derivative of amino acid lysine, was synthesized in 1962 by the Japanese researchers, Shosuke and Okamoto. The antifibrinolytic activity of the trans-isomer of TA was first described in 1964 and since then it has been used in a variety of clinical settings and also to reduce blood loss during various surgeries.[1],[2],[3] The theoretical concern about increased thromboembolic effects, though none have been reported, has resulted in various guidelines not recommending its routine use. At present TA is recommended for use in emergency trauma surgery, cardiovascular surgery, elective oral surgery, hip and knee arthroplasty procedures, spinal surgery, heavy menstrual bleeding and hereditary angioneurotic oedema.[4],[5]

TA has recently been shown to be effective in treating melasma but the researchers have used various empirical protocols, with and without adjuvants, which has made it pretty difficult to understand and assign TA its place in the vast armamentarium of melasma therapies. We have tried to review the basics of TA pharmacology as is already known from its previous non-dermatological uses in order to understand its role in melasma. An attempt has also been made to include and interpret the various relevant studies of TA in melasma to establish the optimum dose and route of administration for the best results.


  Material and methods Top


A systematic literature search of the PubMed electronic database was performed using the keywords ‘melasma’, ‘chloasma’ and tranexamic acid in the title. A total of 54 articles appeared, the abstracts of which were screened and reviewed by two of the authors independently for inclusion. In case of any conflict, the opinion of the third author was sought. The articles included 26 studies on TA used in melasma patients by various routes and used alone or in combination with other therapies.

The relevant references of the included articles were also traced and included.

Tranexamic acid

The basic chemical structure is trans-4-aminomethylcyclohexanecarboxylic acid (trans-AMCHA) [Figure 1].[2] It inhibits the plasminogen activator by reversibly blocking the lysine binding sites on both plasminogen and plasmin, a molecule responsible for degradation of fibrin which is a protein that forms the framework of blood clots [Figure 2]. Thus, it prevents clot breakdown and helps in stopping the bleeding while exhibiting no effect on blood coagulation parameters like platelet count, activated partial thromboplastin time and prothrombin time. The coagulation, inflammation and immunological pathways are known to be inter-related with involvement of certain common factors and steps which affect these responses. Plasmin is also known to play a role in activation of complement, neutrophils and monocytes and its inhibition thus may also have an anti-inflammatory effect.[3],[6]
Figure 1 Structure of Tranexamic acid

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Figure 2 Mechanism of action of Tranexamic acid in clotting system

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Classically TA has been used orally at a dose of 0.5–1.5 g two or three times daily and intravenously 0.5–1 g by slow injection three times daily for controlling the blood loss from major trauma, postpartum bleeding, surgery, tooth removal, nose bleeds and menorrhagia.[4],[5] It has also been used as local intraarticular injections in arthroplasty procedures and as 5% mouthwashes for oral procedures.[7]

Maximum plasma concentration of TA is attained within 3 hours of an oral dose. The presence of food in the gastrointestinal tract has no effect on the pharmacokinetics of the drug. The bioavailability of the drug after oral administration is 34% and it is weakly bound to plasma proteins (3%, which binds almost exclusively to plasminogen). It crosses the blood-brain barrier and the placenta, but excretion into breast milk is minimal.[6] Over 95% of TA is eliminated unchanged in the urine so the dose should be adjusted in patients with renal impairment. In liver impairment, dose adjustment is not needed as only a small amount of the drug is metabolized through the liver. The total cumulative excretion after an intravenous dose is approximately 90% after 24 hours.[4],[5]

TA when used topically as mouthwashes (5% aqueous solution) in patients undergoing oral surgery showed high drug concentrations (mean 200 mg/L) attained in saliva 30 minutes after mouth rinsing for 2 minutes while plasma concentrations remained below 2 mg/L. A Cochrane review by Ker et al.[7] also concluded that topical TA reduces bleeding and need for blood transfusion in surgical patients, though the risk of thromboembolism was unclear but topical administration resulted in a ten-fold less plasma concentration of TA with a potential reduction in adverse effects.

TA is regarded as pregnancy category B drug as no mutagenic activity has been detected in in vitro and in vivo test systems. As it is only minimally excreted in breast milk, breastfeeding may be continued, if required.[3],[6],[7]

The commonly reported side effects of TA are nausea, diarrhoea, vomiting and orthostatic hypotension. Rarely, disturbances in colour vision, anaphylactic shock, skin reaction and acute renal cortical necrosis have also been documented. No harmful foetal effects have been reported. TA has no effect on coagulation parameters and the theoretical thrombotic risk is very low. The risk may be higher in patients of an older age group, those with pre-existing morbidity, who are on other prothrombotic drugs (e.g., oral contraceptive pills), or have hereditary protein C and protein S deficiency.[4],[5] Theoretical risk may appear to be higher with the use of very high dose and long duration of TA but has not been reported.

The conventional use of TA as an antifibrinolytic to decrease blood loss during surgeries and menorrhagia is usually a short duration treatment of 4–7 days in a dosage of 2 to 4 g/day but it has also been used long term for 8–34 months as prophylactic therapy in hereditary angioedema. It has also recently been found to be useful in melasma and post-inflammatory hyperpigmentation.[9],[10],[11]

Formulations available: Tablets: Only TA-500 mg, 250 mg; combination of 250 mg TA with proanthocyanadin

Injections 100mg/ml

Topical creams (0.05g/50 ml) in combination with various whitening agents like kojic acid, mulberry extract, arbutin, vitamin E, etc.[4],[5],[8]

Tranexamic acid in melasma

Melasma, also known as chloasma or mask of pregnancy, is a common, acquired, hyperpigmentary disorder usually affecting females.[12] Though the exact pathomechanism of melasma is unknown many etiological factors have been implicated in its causation as well as aggravation.[2],[3],[4] Though asymptomatic, the overwhelming cosmetic impact for many patients leads to tremendous emotional and psychosocial distress which results in their seeking treatment. Despite the availability of a wide variety of therapeutic options its treatment remains challenging as pigmentation may fade but often recurs. All the therapeutic modalities aim at reducing the formation of melanin from melanocytes (topical agents) and eliminating pre-existing melanin pigment (peeling and laser). However, they inevitably may activate the melanocytes by irritation, inflammation or by injuries to keratinocyte that leads to recurrence or PIH. Various topical and physical therapies are thus, constantly being tried and evaluated both as stand-alone treatments as well as in different combinations.[13],[14],[15]

The effect of TA in melasma was a serendipitous discovery by Nijo Sadako[16] in 1979 when he used TA to treat a patient with chronic urticaria who also had melasma and observed that the melasma severity of the patient also reduced after 2-3 weeks. He then tried oral TA in a dose of 1.5 gram daily along with vitamin B, C, E supplements for 5 months in 12 patients of melasma who showed lightening of lesions within 4 weeks of starting treatment in 11 patients. Human keratinocytes are known to secrete urokinase type plasminogen activator, which increases the activity of melanocytes in vitro. Tranexamic acid is believed to act in melasma by preventing the activation of melanocytes from ultraviolet (UV) light, hormones and injured keratinocyte through the inhibition of plasminogen activator system present in epidermal basal cells and keratinocytes. It also reduces melanocyte tyrosinase activity by suppressing the production of prostaglandins and has an additional effect on the dermal blood vessels as it decreases the angiogenesis via inhibition of vascular endothelium growth factor (VEGF) [Figure 3]. By all these actions it not only improves the melasma, but may also reduce the likelihood of recurrence.[4],[17],[18]
Figure 3 Mechanism of action of Tranexamic Acid in melasma

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Since the report by Sadako, TA has been tried by various investigators in melasma in varying schedules and strengths and even lower doses of tranexamic acid i.e. 500mg/day have been reported to be effective.[5]

Despite the reports of its efficacy in melasma, there were ethical concerns about using an antifibrinolytic drug for a cosmetic condition. As it’s topical use was also seen to be effective in both oral and other surgeries to control blood loss, this encouraged the researchers to evaluate the efficacy of topical formulations and intradermal use of TA even in melasma.

Maeda et al.[1] were the first ones to study the effect of topical TA on skin pigmentation induced by UV exposure in Weiser-Maples guinea pigs. Post-exposure applications of 2% and 3% solutions of topical TA to the exposed regions prevented the pigmentation process. The histopathological examination after staining by the Fontana-Masson method showed a significantly reduced melanin content in the basal layer of UV-exposed epidermis where 2% and 3% topical TA solutions had been applied, compared with the vehicle control.

After that studies of only topical tranexamic acid and in combination with various lasers were conducted which did show response in melasma. Although topical TA is much safer and free from systemic adverse effects of oral TA, still a few studies have shown local side effects of itching, burning and erythema which may hinder the long term use and also lead to reduction in patient compliance.[4],[19]

Intralesional injections are aimed at applying an adequate amount of medication directly at the problematic area and avoiding systemic effects. Furthermore, direct injection to the involved sites allows lower dosage of drugs to be used. TA has also been used as intradermal injections as well as with microneedling at varying intervals from weekly to monthly treatments in melasma. Traditionally used as a collagen induction therapy for facial scars and skin rejuvenation, microneedling is widely used as a transdermal delivery system for therapeutic drugs and vaccines. Microneedling delivery system offers a minimally invasive and painless method of transdermal drug administration but has even shown an improvement when used alone in a preliminary study on melasma.[17]

Physical therapies, like microneedling when used along with conventional TA therapy may have an added effect as they also lead to improvement in the skin texture and results in better patient satisfaction. In melasma, TA has been used by various routes of administration (oral, topical, intralesional) and in various dosages and concentrations and at different time intervals.[20]

Most of the studies have been done on oral TA and fewer on topical and intralesional therapy but the results have been encouraging.

Oral tranexamic acid

A total of 14 studies on oral TA were included for evaluation but they had varying protocols with or without additional topical therapy, doses, treatment duration and outcomes [Table 1].
Table 1 Studies of oral tranexamic acid

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There were only two randomised controlled trials which are considered to have the best level of evidence. One evaluated the role of only oral TA 250 mg B.D in melasma without any other therapy and showed 49% improvement as compared to 18% in the placebo group.[21] The other RCT compared oral TA 250 mg B.D along with topical therapy with patients treated with only topical therapy and showed rapid and sustained improvement in the combination therapy group.[5]

Two studies did a clinical and histopathological analysis. In refractory melasma, a higher dose of 500 mg BD was used and found to be effective. Biopsies done in these patients also showed evidence of decreased epidermal pigmentation and decreased Melan A staining on immunohistochemistry.[22] Oral TA 500 mg TDS along with topical application of TA twice daily for 8 weeks showed decreased melanin index scores and biopsies showed a decrease in epidermal pigmentation, number of vessels and mast cells.[23]

A single study evaluated the different dosages of oral TA (500 mg, 750 mg, 1000 mg and 1500 mg per day) and found all the doses to be effective but lower doses than 500 mg have not been studied as yet for their effect.[24]

Triple combination creams and 4% hydroquinone creams are the usual standard therapy for melasma. Oral TA when used with 4% hydroquinone gave favourable results as compared to the patients using only 4% hydroquinone cream.[25] One study which compared oral TA 250 mg BD along with 3% topical TA with oral TA with 20% Azaleic acid found both to be effective but a better response was noted in the group receiving both oral and topical TA.[26]

Patients treated with IPL or Q switched Nd yag lasers showed better results when oral TA was used along with the procedures.[27] Most of the studies used a dose of 250 mg B.D. added to the already ongoing topical therapy of melasma or laser procedures for a duration of 12 weeks and usually the results showed a greater than 50% improvement in the mMASI (modified melasma area severity index) or MASI(melasma area severity index) or melanin index in the majority of the patients. Subjective satisfaction was usually greater and a significant lightening effect was usually seen by 2 months of therapy. Though in most of the studies oral TA was given for 12 weeks but it was given safely in one study for 8 months and in another even upto 2 years without any significant side effects.[28],[29],[30],[31]

Recently the different routes of TA have also been evaluated vis a vis each other. Two studies compared oral TA 250 mg BD to intradermal TA injections every 4 weeks for a period of 12 weeks and found both routes to be effective (50 to 70 % improvement)[20] but one concluded that oral therapy performed better than intradermal injections (57.5% vs 43.5%).[32]

Oral TA seems to be effective in melasma both as stand-alone therapy and in combination with various topical regimens as evidenced by the histological changes. The usual effective dose of TA in melasma is lower than the dose to reduce excessive bleeding. Though it usually takes at least 1 month to see a clinical response but it is advisable to continue for a minimum of 3 months before declaring it to be ineffective. Some authors have even suggested that the duration of the therapy may be more important than the dose in the efficacy of treatment. Though there are no studies as yet describing the use of lower doses of TA i.e. <500 mg/day but we have used doses as low as 250 mg and even 125 mg daily and found them to be effective in melasma [Figure 4]. The lower doses may also need to be investigated further to elucidate their role in preventing recurrence or even as a maintenance dose at later stages.
Figure 4 Photograph of female patient with centro-facial melasma at baseline (a, b, c) and after 12 weeks (d, e, f) of oral tranexamic acid 125 mg showing 80% decrease in pigmentation

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Topical TA

Different strengths of topical TA have been used ranging for 2% to 5%. There are four studies on topical TA use and three studies where topical TA has been used along with laser or IPL procedures [Table 2].
Table 2 Studies of topical tranexamic acid

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In a clinico-histological study, 2% TA was used twice daily for 12 weeks in mild melasma patients and 22 out of 23 patients showed improvement with lightening visible at 4 weeks. Fontana Masson stain showed a significant decrease in the melanin content in the epidermis. There was a decreased number of CD31-positive vessels, decreased expression of vascular endothelial growth factor and downregulation of Endothelin 1.[33]

Rest of the studies had a split face design with the same patient acting as control. In one study 3% TA on one side was compared to combination of 3% hydroquinone with 0.01 % dexamethasone on the other side which showed similar improvement.[34] Another study compared 5% liposomal TA on one side with 4% hydroquinone on the other and found both to be effective with better results in the TA side though not statistically significant.[35] Another study comparing 5% TA with its own vehicle found similar lightening on both sides with no difference but erythema was more on TA side.[36]

A split face study of low power CO2 fractional laser treatment every 4 to 6 weeks for five sessions over the entire face along with either topical TA 3% applied after the laser treatment or intradermal TA given before the session on one side showed no statistically significant difference between the sides.[37] Another split face study of IPL with topical TA applied immediately after the session on one side and vehicle on the other showed that MASI decreased more on the topical TA side.[38] Chung et al.[39]

Q switched Nd Yag laser treatment over the entire face with topical 3% TA applied on one side for 8 weeks showed more than 50% improvement in 80% patients.

Topical TA also seems to be effective in melasma as seen by the histological changes but the optimum concentration for a beneficial effect still needs to be established as the side effects of erythema and irritation noted with increasing concentration may negate its lightening effect. Also, it seems that regular application of topical TA may be more beneficial than the episodic application during or after laser treatments as was also seen with the regular use of oral TA with the laser treatments which also helped in decreasing the post inflammatory pigmentation which may happen with these procedures.

Intradermal TA

There are three studies in which intralesional TA injections (4 mg/ml) were used, one where the solution was applied after microneedling and one comparing the intralesional injections and microneedling [Table 3].
Table 3 Studies of intradermal tranexamic acid

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The open trial of weekly injections of TA for 12 weeks showed lightening of lesions in 85% of patients.[40] The other two studies comparing TA to topical hydroquinone showed better results with TA.[41],[42] In the split face study where weekly microneedling was done on one side and sham device applied on the other followed by application of 0.5% TA over the entire face showed better results on the microneedling side which may have helped in the better absorption of the TA.[43]

A randomized, open label, comparative study of TA microinjections and TA with microneedling in patients of melasma where treatments were done three times at monthly intervals (0, 4 and 8 weeks) by 4mg/ml TA showed better results in the microneedling group (44.41% improvement in the MASI score vs 35.72%).[5]

In our split face study, 40 patients of melasma were treated by four sessions of two weekly microneedling followed by application of 10 % TA solution on one side and distilled water on the other side. The test side showed a much better improvement than the control side (65% improvement in mean MASI vs 20%) [Figure 5].
Figure 5 Photograph of male patient with malar melasma at baseline (a, b, c) and after 8 weeks (d, e, f) of tranexamic acid with microneedling on test side (right side of face c & f) showing 70–80% decrease in pigmentation and microneedling with distilled water on control side (left side of face b & e) showing 20% decrease in pigmentation

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Intradermal TA also seems to be effective in melasma both as intralesional injections and with microneedling but microneedling seems to have an edge because of its independent skin rejuvenation properties.[44] The studies have used various protocols of weekly to monthly sessions so the optimum time interval still needs to be established as well as the concentration to be used.


  Conclusion Top


Melasma is a recurrent and refractory problem with a wide variety of both medical and procedural therapeutic options available for its management. Appropriate and judicious use of medicines which are effective and can be used for longer time is necessary to treat melasma without any side effects. TA in all forms (oral, topical) have shown promising results over the past few years when used along with other therapies as well as when used as a stand-alone therapy.

TA has been tried at varying oral doses, varying topical concentrations and at varying time intervals intradermally and also with and without various adjuvants. Though almost all the studies show the beneficial effect of TA there is still no consensus on the optimum route, dose and timing of the treatment with TA in melasma. For oral TA effectiveness the duration of therapy has been suggested to be more important than the dose. Though lightening of pigmentation is visible earlier, a minimum of 3 months trial is recommended. Topical TA also seems to be more effective with regular use rather than episodic use. When used along with microneedling, the frequency of the treatment may depend on the size of the dermaroller used i.e. the needle size with sessions at biweekly to monthly intervals while intradermal injections have even been given weekly. Further studies are required to elucidate not only the optimum formulation, concentration but also the role of maintenance doses/ sittings and even if there may be some role of combination or sequential therapy with oral and topical TA in the same patient.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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