Oral Tranexamic Acid (TXA) in the Treatment of Melasma: A Literature Review

1. Introduction to Melasma and Tranexamic Acid

1.1. Overview of Melasma

Melasma is a common acquired hyperpigmentation disorder that particularly affects individuals with darker skin complexions [1]. This condition manifests as brown or greyish patches, primarily on the face, and can significantly impact a person's quality of life [2]. Melasma is more prevalent in women, especially during pregnancy or with the use of hormonal contraceptives, highlighting the role of hormonal influences in its development [3]. The exact causes of melasma are multifaceted, involving a combination of genetic predisposition, ultraviolet (UV) exposure, and hormonal changes [4]. Given its complex etiology and the emotional distress it can cause, effective and safe treatments are highly sought after.

1.2. Introduction to Tranexamic Acid (TXA)

Tranexamic acid (TXA) is a synthetic derivative of the amino acid lysine and functions as an antifibrinolytic agent [5]. Originally used to reduce blood loss in surgeries and various medical conditions, TXA has been found to have promising effects in treating melasma [6]. TXA can be administered through oral, topical, and intradermal routes, offering flexibility in treatment approaches [6]. Its mechanism of action in melasma involves inhibiting plasminogen activation, which in turn reduces melanocyte activity and melanin synthesis [7]. The growing body of evidence supporting TXA's efficacy and safety has led to its increased use in dermatology for melasma and other hyperpigmentation disorders [5].

1.3. Rationale for Using Oral TXA in Melasma Treatment

The rationale for using oral TXA in melasma treatment stems from its ability to address the underlying mechanisms of hyperpigmentation systemically. Oral TXA has demonstrated efficacy in reducing the Melasma Area Severity Index (MASI) score, a standard measure for assessing melasma severity [3]. Studies have shown that low doses of oral TXA (e.g., 250-500 mg daily) over a relatively short period (8-12 weeks) can yield significant improvements in melasma, particularly in individuals with Asian skin [1]. Furthermore, oral TXA is considered a safe therapeutic option with few and mild side effects when patients are appropriately screened for contraindications and risk factors [1]. Its ease of administration and demonstrated efficacy make it a valuable treatment option for refractory melasma cases [1].

2. Mechanisms of Action of Oral TXA in Melasma

2.1. Inhibition of Plasminogen Activation

Tranexamic acid's primary mechanism of action involves the inhibition of plasminogen activation [8]. TXA reversibly blocks lysine-binding sites on plasminogen molecules, preventing plasminogen activators (PA) from converting plasminogen to plasmin [9]. Since plasminogen is present in epidermal basal cells and keratinocytes produce PA, TXA affects keratinocyte function and interaction, reducing melanin synthesis [9]. This inhibition leads to decreased tyrosinase activity, which is essential for melanin production, thereby reducing hyperpigmentation [7].

2.2. Reduction of Melanocyte Activity

By inhibiting plasminogen activation, TXA effectively reduces melanocyte activity [10]. Melanocytes are responsible for producing melanin, the pigment that causes skin darkening [7]. The reduction in melanocyte activity leads to a decrease in melanin synthesis, which helps to lighten the hyperpigmented patches associated with melasma [7]. This process is crucial in managing melasma, as it directly targets the cells responsible for the condition's characteristic pigmentation [10].

2.3. Influence on Keratinocyte Function

TXA's influence on keratinocyte function is another critical aspect of its mechanism of action [9]. Keratinocytes, the primary cells in the epidermis, interact with melanocytes to regulate melanin production [9]. By affecting keratinocyte function, TXA can modulate the transfer of melanin to these cells, further reducing the appearance of hyperpigmentation [9]. This modulation helps to create a more even skin tone and reduce the visibility of melasma patches [9].

2.4. Impact on UV-Induced Pigmentation

Tranexamic acid also plays a role in preventing UV-induced pigmentation [7]. Exposure to ultraviolet (UV) radiation can exacerbate melasma by stimulating melanocyte activity and increasing melanin production [7]. TXA helps to counteract these effects by inhibiting the pathways that lead to UV-induced hyperpigmentation [7]. This protective action makes TXA a valuable component in melasma treatment, especially when combined with sun protection measures [7].

3. Efficacy of Oral TXA in Melasma Treatment: Clinical Evidence

3.1. Studies Demonstrating Reduction in MASI Scores

Multiple studies have demonstrated the efficacy of oral TXA in reducing the Melasma Area and Severity Index (MASI) scores [3]. A meta-analysis of randomized controlled trials showed that oral TXA significantly reduced MASI scores compared to placebo or other treatments [11]. Specifically, at 8 weeks, oral TXA showed a significant change in the standard mean difference (SMD) of 1.61 (95% CI 0.44-2.79, P = 0.007), and at 12 weeks, the SMD was 2.39 (95% CI 1.42-3.35, P < 0.00001) compared to adjuvant treatment [12]. These results indicate that oral TXA is effective in reducing the severity and extent of melasma [11].

3.2. Comparison with Topical Treatments

When compared to topical treatments, oral TXA has shown superior efficacy in several studies [13]. A study comparing oral TXA (250 mg twice daily) with topical TXA (3%) found that the mean percentage reduction in MASI scores was higher in the oral group (52.1%) compared to the topical group (31.9%) [13]. While both oral and topical TXA were effective, oral TXA provided a better proportional response [13]. However, a randomized clinical trial found that both oral (250mg twice daily) and topical TXA (5% cream applied twice daily) significantly reduced MASI scores after 12 weeks, with no statistically significant difference between the two [14]. This suggests that the choice between oral and topical TXA may depend on patient preference and tolerability [14].

3.3. Combination Therapies Involving Oral TXA

Oral TXA is often used in combination with other treatments to enhance its efficacy [15]. A meta-analysis demonstrated that combining oral TXA with triple combination cream (TCC) resulted in a significantly higher decrease in MASI scores compared to TCC alone (mean difference -3.10; 95% CI -5.85 to -0.35) [15]. Furthermore, melasma recurrence was significantly lower in the group treated with TCC and TXA (RR 0.28; 95% CI 0.16-0.49) [15]. Similarly, combining oral TXA with laser therapy has shown enhanced efficacy in melasma management, offering significant clinical improvement, higher patient satisfaction, and lower recurrence rates [2].

3.4. Optimal Dosage and Duration

The optimal dosage and duration of oral TXA treatment vary across studies, but common regimens involve low doses over a period of several weeks [1]. A systematic review indicated that oral TXA is effective at doses of 500-1500 mg/day for 8-12 weeks [3]. Another review noted that doses range from 250 mg per day to 1500 mg, with treatment periods ranging from 2 weeks to 6 months, demonstrating variable efficacy but a generally good safety profile [5]. It is generally observed that a significant decrease in MASI scores is achieved by week 12, suggesting that a treatment duration of at least 12 weeks is beneficial [3].

4. Safety Profile of Oral TXA in Melasma Treatment

4.1. Common Side Effects

Oral tranexamic acid is generally considered safe, but some patients may experience side effects [1]. The most commonly reported side effects are gastrointestinal disorders, such as nausea and abdominal pain [3]. A study comparing oral and topical TXA found that headache was the only adverse effect reported in the oral group, while the topical group experienced erythema, burning, and acneiform eruptions [13]. These side effects are typically mild and do not necessitate the withdrawal of treatment [16].

4.2. Thromboembolic Risk

One of the primary concerns regarding oral TXA is the potential for thromboembolic events due to its antifibrinolytic properties [1]. However, studies have shown that TXA does not significantly increase the thromboembolic risk when used at appropriate doses and with careful patient screening [1]. Patients should be screened for contraindications and risk factors, such as a history of thromboembolism, coagulopathies, severe renal impairment, and the use of photosensitizing drugs [7].

4.3. Contraindications and Precautions

Several contraindications and precautions should be considered before initiating oral TXA therapy [7]. These include pregnancy and lactation, a history of thromboembolism, coagulopathies, severe renal impairment, and allergies to TXA [7]. Patients with thyroid disorders or unrealistic expectations should also be carefully evaluated [7]. Additionally, patients should avoid photosensitizing drugs and discontinue melasma therapies at least 6 months prior to starting TXA [7].

4.4. Monitoring and Management of Side Effects

Regular monitoring is essential to manage potential side effects associated with oral TXA [7]. A complete blood count, coagulation profile, and liver function test should be performed before prescribing TXA and at each follow-up visit to rule out any coagulation abnormalities [7]. Patients should also undergo a detailed ophthalmological examination, with special emphasis on color vision abnormalities and retinal artery occlusion, to detect any potential side effects [7]. Any adverse effects should be promptly addressed to ensure patient safety and adherence to treatment [7].

5. Oral TXA in Combination with Other Melasma Treatments

5.1. Triple Combination Cream (TCC)

Triple combination cream (TCC), typically containing hydroquinone, tretinoin, and a corticosteroid, is a common first-line treatment for melasma [2]. Combining oral TXA with TCC has demonstrated synergistic effects, leading to faster and more significant improvements in melasma [17]. A study by T. Padhi and S. Pradhan (2015) found that the addition of oral TXA (250 mg twice daily) to fluocinolone-based TCC resulted in a faster reduction in pigmentation compared to TCC alone, with statistically significant results at 4 and 8 weeks (P value 0.014 and 0.000, respectively) [17]. Furthermore, a meta-analysis by Oclio Ribeiro Gonalves et al. (2024) showed that the decrease in MASI score from baseline was significantly higher in patients treated with oral TXA as an adjuvant to TCC compared to TCC alone (mean difference -3.10; 95% confidence interval -5.85 to -0.35) [15].

5.2. Laser Therapy

Laser therapy, particularly low-fluence Q-switched Nd:YAG lasers, is another modality used in melasma treatment [2]. Combining oral TXA with laser therapy has shown enhanced efficacy, with studies reporting an additional 12-15% reduction in modified MASI (mMASI) scores compared to laser alone [2]. A review by Shahd Elamin and R. Nalluri (2025) highlighted that patient satisfaction was higher in the combination therapy group, and treatment was well-tolerated with minimal side effects reported [2]. The combination therapy also demonstrated lower recurrence rates (averaging < 20%) 6 months after treatment cessation [2]. This approach may also reduce the risk of adverse effects, such as postinflammatory hyperpigmentation (PIH) [2].

5.3. Topical Agents

Oral TXA can be combined with various topical agents, such as hydroquinone, azelaic acid, and kojic acid, to improve melasma treatment outcomes [7]. While oral TXA addresses the systemic aspects of melasma, topical agents target localized hyperpigmentation [7]. A study by Aditi Bansal and V. Sardesai (2019) compared the efficacy of oral TXA with that of topical modified Kligman's formula and found that both were equally effective in treating melasma [18]. However, oral TXA may be a safer alternative to initiate treatment due to the potential side effects of topical agents [18].

5.4. Platelet-Rich Plasma (PRP)

Combining oral TXA with intradermal platelet-rich plasma (PRP) injections has shown promising results in treating melasma [19]. A randomized controlled trial by Weeratian Tawanwongsri et al. (2024) compared the efficacy and safety of combining PRP and oral TXA with PRP alone in the treatment of facial melasma [19]. The study found that the median change in mMASI scores was significantly larger in the group treated with PRP and oral TXA (2.90, IQR: 2.40) compared to the PRP alone group (0.90, IQR: 0.60) (p < 0.001, U = 160.50) [19]. This combination is effective even in patients with poor prognostic treatment response factors, with no serious adverse reactions observed [20].

6. Oral TXA for Hyperpigmentation Disorders Beyond Melasma

6.1. Postinflammatory Hyperpigmentation (PIH)

Oral tranexamic acid has shown promise in the prevention and treatment of postinflammatory hyperpigmentation (PIH) [21]. PIH is a skin disorder characterized by hyperpigmentation resulting from heightened inflammation and/or damage to the basement membrane, melanocytes, and keratinocytes, leading to abnormal and excessive pigment deposition [21]. Marine Minasyan et al. (2024) reviewed the use of oral TXA in treating PIH and found that all studies demonstrated significant improvement in PIH without significant adverse effects and side effects [21]. Oral TXA is emerging as a safe and effective treatment in the prevention and treatment of postinflammatory hyperpigmentation [21].

6.2. Lichen Planus Pigmentosus

Lichen planus pigmentosus (LPP) is a pigmentary disorder characterized by dark brown macules primarily affecting sun-exposed areas [5]. Oral TXA has been explored as a treatment option for LPP, with some studies suggesting its effectiveness in reducing hyperpigmentation associated with this condition [5]. The dosage typically ranges from 250 mg per day to 1500 mg, with treatment periods varying from 2 weeks to 6 months [5].

6.3. Ashy Dermatosis

Ashy dermatosis, also known as erythema dyschromicum perstans, is a rare pigmentary disorder characterized by asymptomatic, oval-shaped, ashy-gray macules [5]. Oral TXA has been used to treat ashy dermatosis, with some studies reporting positive outcomes [5]. The dosage and duration of treatment are similar to those used for melasma and LPP, ranging from 250 mg per day to 1500 mg for 2 weeks to 6 months [5].

6.4. Riehl Melanosis

Riehl melanosis is a rare form of contact dermatitis that results in hyperpigmentation, typically affecting the face and neck [5]. Oral TXA has been investigated as a potential treatment for Riehl melanosis, with some studies showing promising results in reducing hyperpigmentation [5]. The treatment protocols generally involve oral TXA at doses ranging from 250 mg per day to 1500 mg for 2 weeks to 6 months [5].

7. Limitations and Future Directions

7.1. Limitations of Current Research

Despite the growing body of evidence supporting the efficacy and safety of oral TXA in treating melasma and other hyperpigmentation disorders, several limitations exist in the current research [22]. Many clinical studies have small sample sizes, lack blinding in the study design, and are limited in number [22]. Additionally, there is heterogeneity among studies in terms of TXA dosage, treatment duration, and outcome measures, making it challenging to draw definitive conclusions [12]. Further research is needed to determine the ideal duration of treatment and strategies for preventing melasma recurrence [3].

7.2. Need for More Randomized Controlled Trials

More blinded, randomized controlled trials are needed to determine the efficacy of oral TXA in various types of hyperpigmentation disorders [5]. These trials should include larger sample sizes, standardized treatment protocols, and objective outcome measures, such as MASI scores and melanin index measurements [23]. Additionally, studies should assess the long-term efficacy and safety of oral TXA, as well as its effectiveness in different skin types and ethnicities [12].

7.3. Exploration of Long-Term Outcomes

Long-term outcomes of oral TXA treatment for melasma need further exploration [2]. While some studies have shown sustained improvement with oral TXA, the recurrence rates and potential for long-term side effects remain unclear [2]. Future research should focus on evaluating the long-term efficacy and safety of oral TXA, as well as identifying strategies to minimize recurrence and manage any potential adverse effects [2].

7.4. Investigation of Novel TXA Delivery Systems

The investigation of novel TXA delivery systems, such as topical formulations and intradermal injections, may offer alternative treatment options with potentially fewer systemic side effects [9]. While oral TXA is effective, it can cause gastrointestinal disturbances and other adverse effects in some patients [3]. Topical and intradermal TXA delivery systems may provide targeted treatment with reduced systemic exposure, thereby minimizing the risk of side effects [9]. Further research is needed to evaluate the efficacy and safety of these novel TXA delivery systems in treating melasma and other hyperpigmentation disorders [9].

8. Conclusion

Oral tranexamic acid has emerged as a valuable treatment option for melasma, demonstrating efficacy in reducing hyperpigmentation and improving patient satisfaction [11]. Its mechanism of action involves inhibiting plasminogen activation, reducing melanocyte activity, and influencing keratinocyte function [9]. Clinical evidence supports the use of oral TXA, either as monotherapy or in combination with other treatments such as triple combination cream, laser therapy, and platelet-rich plasma [15]. While oral TXA is generally safe, patients should be carefully screened for contraindications and monitored for potential side effects [1]. Further research is needed to optimize treatment protocols, explore long-term outcomes, and investigate novel TXA delivery systems [2]. Overall, oral tranexamic acid represents a promising approach in the management of melasma and other hyperpigmentation disorders [21].