What are the recommended first‑line and second‑line treatment options for melasma, including topical triple‑combination therapy, alternative topicals, oral tranexamic acid, and procedural interventions?

Melasma Treatment: Evidence-Based Approach

First-Line Treatment

Start with triple combination cream (hydroquinone 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01%) combined with rigorous sun protection as your initial therapy for melasma. 1

Topical Therapy

• Apply triple combination cream once daily for 8-12 weeks as the most effective first-line treatment 1, 2, 3
• If triple combination is unavailable or the patient has allergies, use hydroquinone 4% monotherapy or double combination (hydroquinone 4% + tretinoin 0.05%) 2, 3
• The corticosteroid component reduces irritation and enhances penetration of the other active ingredients 1, 4

Sun Protection Protocol (Mandatory for All Patients)

• Apply broad-spectrum sunscreen SPF 50+ and reapply every 2-3 hours during outdoor exposure 1, 5
• Wear wide-brimmed hats (>3-inch brim) when outdoors 1
• Seek shade during peak UV hours (10 a.m. to 4 p.m.) 1
• Use UV-protective clothing with tight weave fabrics and darker colors 1
• Avoid tanning beds and sunlamps completely 1

Critical pitfall: Forgetting to reapply sunscreen after swimming, sweating, or after 2-3 hours of continuous exposure will undermine all other treatments 1, 4

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Second-Line Treatment for Inadequate Response After 8-12 Weeks

If first-line therapy fails, add intradermal platelet-rich plasma (PRP) injections, which demonstrate superior efficacy compared to all other advanced treatments including tranexamic acid injections. 4, 5

PRP Injection Protocol

• Administer 4 intradermal PRP treatment sessions spaced every 2-3 weeks 1, 5
• Inject intradermally at 1 cm intervals across affected areas 1, 5
• Follow-up evaluation one month after the last treatment 1
• PRP shows mean mMASI score reduction of 45.67% improvement, significantly better than tranexamic acid injections 4
• Patient satisfaction rates exceed 90% with PRP treatment 4

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Oral Tranexamic Acid as Adjunctive Therapy

Consider adding oral tranexamic acid 250 mg three times daily (750 mg total daily dose) for 12 weeks, particularly when combined with PRP injections, as this combination achieves 90.48% total efficacy compared to 73.68% with tranexamic acid alone. 1, 4, 6

Dosing Options

• Optimal dose: 250 mg three times daily for 12 consecutive weeks 6
• Alternative for poorly adherent patients: 250 mg twice daily 1, 6
• Oral tranexamic acid combined with triple combination cream produces faster reduction in pigmentation than triple cream alone, with statistically significant differences at 4 weeks (p=0.014) and 8 weeks (p=0.000) 7

Important nuance: While one study showed no significant difference when adding oral tranexamic acid to triple cream 8, the weight of evidence from network meta-analysis and multiple trials supports its efficacy, particularly at the 750 mg daily dose 6 and when combined with PRP 1, 4

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Alternative Procedural Options

Microneedling

• Consider microneedling as an alternative to PRP if PRP is unavailable or ineffective 1, 4
• Microneedling may be more effective than intradermal PRP injections in some patients 1, 4
• Needle depth should be set between 0.25 mm and 2.5 mm 1
• Apply compounded topical anesthetic at least 30 minutes before the procedure 1
• Ensure skin is well lubricated with topical agent or PRP to prevent pulling sensation 1
• Very low risk of post-inflammatory hyperpigmentation in Fitzpatrick skin types III-VI, markedly lower than laser therapy 1
• Minimal downtime (24-48 hours) 1
• Safe for all skin types including thin, sensitive, and ethnic skin 1

Radiofrequency Microneedling

• Three treatment sessions spaced at least 21 days apart 4
• Maintenance treatments every 6 months as needed 4

Post-Procedure Care

• Sun avoidance for the first 24 hours after treatment 1
• Refrain from using facial creams or products containing strong fragrances for 24 hours post-procedure 1

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Critical Safety Considerations for Darker Skin Types

In individuals with Fitzpatrick skin types IV-VI, laser therapy should be avoided or employed only with extreme caution due to markedly higher risk of burns, post-inflammatory hyperpigmentation, and hypopigmentation from increased melanin absorption of laser energy. 1

• Microneedling is considerably safer than laser for darker skin types 1
• Chemical peels and laser-based therapies are equal or inferior to topicals but carry higher risk of adverse effects 2

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Measuring Treatment Success

• Use standardized modified Melasma Area and Severity Index (mMASI) scores to objectively track improvement 1, 4, 5
• Decreases in MASI >60-90% indicate moderate improvement 1
• Decreases in MASI >90% indicate excellent response 1
• Patient satisfaction assessment should complement objective measurements 1, 4

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Long-Term Maintenance

Melasma is a chronic condition requiring long-term maintenance therapy; discontinuing treatment too early is a critical pitfall. 1, 4, 5

• Continue sun protection indefinitely 1, 5
• Maintenance PRP or microneedling treatments every 6 months 1, 4, 5
• Consider intermittent use of topical agents 5
• Disease recurrence rates are lower with PRP combination therapy 1, 4

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Additional Considerations

Hormonal Influences

• Women with diagnosed melasma may continue using oral contraceptives or hormone replacement therapy when required for other medical indications, despite potential for pigmentation worsening 1
• Counsel patients that hormonal influences (pregnancy, oral contraceptives, hormone replacement therapy) may limit treatment success 1, 4

Lifestyle Modifications

• Counsel patients to avoid smoking, which can worsen melasma 1, 4

Procedural Contraindications

• Avoid microneedling over tattoos or permanent makeup to prevent pigment disturbance 1