First author |
Study design |
Treatment |
Duration |
N |
Outcome(s) [subjective]: Physician- and participant-assessed |
Outcome(s) [objective]: Objective measurements of melasma |
Time elapsed before clinical improvement |
Adverse events |
Comments |
Intense pulsed light |
Wang [88], 2004 |
R, C |
Group A: 4% HQ cream Group B: 4% HQ cream + IPL treatments (4 sessions, every 4 wk) for 16 wk. Daily sunscreen use in both groups |
24 wk |
32 |
35% of patients in Group B had > 50% improvement vs. only 14% in the control group |
IPL group had 40% improvement in relative MI vs. 12% in the HQ-alone group |
16 wk |
IPL group: 13% had transient PIH |
Frequency of HQ not mentioned. SPF of sunscreen, and frequency, unclear |
Goldman [89], 2011 |
R, MB, SF |
One side: TC qd + IPL (2 sessions, at wk 4 and 6) CL side: vehicle + IPL (2 sessions, at wk 4 and 6) |
10 wk |
56 |
IGA showed 57% vs. 23% of subjects were clear or almost clear at week 10 (TC + IPL vs. vehicle + IPL, respectively) [41% vs. 15% clear/almost clear at 6 wk]. Patients preferred TC |
None |
6 wk |
Skin erosions, cutaneous irritation |
None |
Figueiredo Souza [90], 2012 |
R, MB, open-label |
Group 1: IPL (single session) + TC cream Group 2: TC cream alone |
48 wk |
62 |
mMASI showed a 49% reduction at 24 wk and a 45% reduction at 48 wk. 32% of patients in the IPL group showed marked improvement versus 0% in the TC cream-alone group |
None |
24 wk |
Mild erythema, crusting, and PIH |
Investigators used a non-validated scale. Frequency of TC cream was not established |
Chung [91] 2015 |
R, PC, SF |
One side: Topical 2% TXA + IPL (4 monthly sessions) Contralateral side: IPL alone (4 monthly sessions) |
24 wk |
15 |
mMASI decreased on the TXA side (p <0.03) compared with the vehicle side (p =0.306). The TXA-treated side had a continuous and SS decrease at 24 wk (p =0.049) |
SS decrease in MI at 12 wk on the TXA side (p <0.001) vs. the vehicle side. At 24 wk, the TXA-treated side had a greater decrease in MI (p =0.025) vs. the vehicle side |
12 wk |
None |
IPL was effective at decreasing melasma, however 4 sessions were not enough to be statistically significant. TXA was helpful as adjuvant treatment and to prevent rebound after IPL sessions |
Shakeeb [92], 2018 |
R, PC |
Group A: TC cream qd at pm Group B: IPL (4 sessions, every 2 wk) Group C: IPL (4 sessions, every 2 wk) + TC cream qd at pm |
8 wk |
96 |
Decrease in MASI was higher in Group C vs. Groups A and B |
None |
8 wk |
NA |
Short-term followup. Adverse effects were not mentioned. Use of sunscreen is unclear |
Yun [93], 2014 |
Prospective, MB, comp |
Group A: F-IPL and low-fluence QS-Nd:YAG, 6 sessions (every 2 wk) Group B: F-IPL alone, 6 sessions (every 2 wk) |
20 wk |
12 |
Decrease in MASI of 47% in Group A vs. 15% in Group B at 16 wk. Patient's self-assessment was better in Group A vs. Group B |
Decrease in MI of 20% at week 16 in Group A vs. 15% in Group B |
16 wk |
Group A: firstdegree burn |
Use of sunscreen not mentioned. No recurrence observed in either group. Small sample size |
Yun [94], 2015 |
Prospective, SF, comp |
Fractionated IPL (6 sessions, weekly) vs. conventional IPL (3 sessions, biweekly) |
14 wk |
30 |
Decrease in mMASI of 30% in the conventional IPL group vs. 34% in the F-IPL. Rebound was observed in the conventional IPL group after 2 sessions |
Decrease in melanin pigment was noted in the F-IPL group by H&E |
14 wk |
Conventional IPL: erythema and PIH Fractionated IPL: PIH |
Use of sunscreen not Mentioned |
QS-Nd:YAG laser |
Park [95], 2011 |
R, MB, SF |
1064 nm QS-Nd: YAG (6 sessions, 1- to 2-week intervals) to the entire face + 30% GA peel (3 sessions, at 2-week intervals) to one side of the face |
26 wk |
16 |
38% improvement in mMASI on the combined side vs. 17% on the laser-only side. Patient- and physician-assessment were better on the combined side of the face |
33% improvement in Mexameter on the combined side vs. 22% on the laser-only side |
6 wk |
Transient burning and mild edema |
Sunscreen use was unclear |
Lee [96], 2014 |
R, PC |
Group A: QS-Nd: YAG (10 sessions) + placebo (2-week interval) Group B: QSNd: YAG + chemical peel with Jessner's solution (2-week interval) |
20 wk |
52 |
Significant decrease in MASI at 8 wk in Group B vs. Group A. At 20 wk, there was no SS difference in MASI, PGA, and self-assessment |
None |
8 wk |
Jessner's group: 15% had burning sensation on the laser side; mild pain and erythema |
Sunscreen use was unclear |
Ustuner [97], 2017 |
R, MB, SF |
QS-Nd:YAG to the entire face (4 sessions, 4-week intervals) and additional microneedling with vitamin C to one side. SPF15 + used two to three times daily |
24 wk |
34 |
MASI SS lower on the combined side vs. the laser-only side at 1 mo and final follow-up visit. SS improvement in quality of life in the combined treatment group |
None |
12 wk |
Erythema, hyperpigmentation, and hypopigmentation |
Both groups presented with recurrence of melasma |
Kaminaka [98], 2017 |
R, PC, SF |
Low-fluence QS-Nd:YAG 10 weekly sessions (1 mo rest period after the fifth treatment) |
9 mo |
22 |
Patient subjective assessment showed 50% of patients had good to excellent improvement |
Decrease in MI on lesional skin at the fifth and tenth sessions (p <0.0001). Decrease in epidermal and dermal melanophages by histopathological assessment. Decrease in number of vessels and mast cells since the fifth treatment session |
5 wk |
5% PIH, 15% xerosis, 5% pruritus |
Clinical assessment was not properly performed due to the lack of MASI scores |
Jeong [99], 2010 |
R, MB, SF |
Group A: TC cream qd for 8 wk, followed by 8 sessions (weekly) of low-fluence QS-Nd:YAG Group B: 8 sessions (weekly) of low-fluence QS-Nd:YAG, followed by TC cream qd for 8 wk |
16 wk |
13 |
MASI showed a greater decrease in Group A. Greater relapse at 16 wk in Group B |
Spectrophotometer showed a lighter skin tone in Group A only after 8 laser sessions |
8 wk |
TC cream: 30% erythema Laser: mild pain and erythema |
All patients had mild melasma at baseline. Laser treatment was effective only after initial 8 wk of TC cream |
Wattanakrai [100], 2010 |
R, SF |
Low-fluence QS-Nd:YAG (5 weekly sessions) vs. HQ 2% qd on the other side |
17 wk |
22 |
The laser side achieved a 76% improvement by mMASI vs. 24% on HQ side |
The laser side achieved a 93% improvement in relative lightness index vs. 20% on HQ side |
5 wk |
Laser side: 14% mottled hypopigmentation |
SPF60 + was applied. All patients had recurrence of melasma. |
Kar [101], 2012 |
R, MB |
Group A: low-fluence QS-Nd:YAG (10 weekly sessions) Group B: 35–75% GA peel 6 sessions, every 2 wk) Group C: high-fluence QS-Nd:YAG (6 sessions, every 2 wk) |
12 wk |
70 |
MASI showed significant improvement in all three groups at 12 wk. Great improvement in Group A, followed by Groups B and C |
None |
12 wk |
Group A: 5% mottled hypopigmentation Group B: 5% PIH Group C: 24% mottled hypopigmentation, 29% PIH |
All groups showed a rise in MASI at 12 wk. The high fluence group had the greatest adverse effects |
Kim [102], 2013 |
R, MB, SF |
Low-fluence QS-Nd:YAG (10 sessions, at 2-week intervals) to the entire face, followed by 5 sessions, at 4-week intervals of 1550 nm erbium dope fractional photothermolysis (NFP) to the hemiface |
36 wk |
26 |
MASI showed a decrease at 4 and 12 wk follow-up in both groups. No SS difference between groups. Slightly greater improvement in the QS-Nd:YAGalone group. PGA was similar in both groups |
None |
24 wk |
Mild erythema, mild pain |
Recurrence was observed in both groups, slightly higher in the combination group |
Shin [103], 2013 |
R, PC |
Group A: Oral TXA (750 mg PO qd for 8 wk) + low-fluence QS-Nd:YAG (2 sessions, 4-week interval) Group B: Only low-fluence QS-Nd:YAG (2 sessions, 4-week intervals) |
12 wk |
48 |
At 8 wk, decrease in mMASI was higher in the combination group. Clinical improvement was slightly higher in the combination group: 22% with > 50% improvement and 9% with > 75% improvement vs. 11% and 0% in the laser-only group |
None |
8 wk |
Oral group: 8% with heartburn, 4% (1 case) with nausea All cases had transient erythema after laser treatment |
Sunscreen frequency was unclear Oral TXA pill also contained 318 mg ascorbic acid + 240 mg L-cysteine + 24 mg calcium pantothenate + 6 mg pyridoxine hydrochloric acid |
Jalaly [104], 2014 |
R, MB, SF |
5 sessions (every 3 wk) of low-fluence QS-Nd:YAG 1064 nm to the hemiface vs. low-power fractional CO2 laser to the contralateral side |
23 wk |
40 |
mMASI showed a greater improvement on the CO2 side at 4 wk. Both sides had a SS decrease in mMASI at 23 wk. Patient's self-evaluation was better on the CO2-treated side |
MI showed a significant decrease only at 23 wk on both sides (p < 0.001). Greater improvement on the CO2-treated side |
4 wk |
Erythema, edema, burning |
Short follow-up time could not assess the recurrence rate |
Vachiramon [105], 2015 |
R, MB, SF |
Low-fluence QS-Nd:YAG 1064 nm to the entire face (5 weekly sessions) vs. additional IPL (3 sessions, at 2-week intervals) to one side |
12 wk |
20 |
MASI improved 55% on the combination side vs. 37% on the laser-only side. Patients' satisfaction was higher on the combined side |
55% improvement in mean relative lightness index on the combined side at 2 wk vs. 37% improvement on the laser monotherapy side at 3 wk |
2 wk |
Combined side: 70% had microcrusts Both sides had erythema and burning |
Recurrence of melasma was higher on the combined side, however it was still lower compared with baseline |
Vachiramon [106], 2015 |
R, MB, SF |
Low-fluence QS-Nd:YAG 1064 nm to the entire face vs. an additional 30% GA peel to one side (5 weekly sessions). SPF50 + qd |
16 wk |
15 |
No SS difference in MASI. Patients' satisfaction was slightly higher in the combined side |
No significant difference in relative lightness index between sides |
3 wk |
Both sides: burning and stinging, guttate hypopigmentation |
At final follow-up, patients still had severe melasma |
Pulsed-dye laser |
Passeron [107], 2011 |
R, MB, SF |
TC cream qd vs. TC qd + PDL (3 sessions, every 3 wk). SPF50 + sunscreen was used |
21 wk |
18 |
Decrease in MASI score in the combined side at 13 and 21 wk. Patient's satisfaction was higher in the combined treatment group |
None |
13 wk |
PDL side: PIH |
Sunscreen frequency unclear. All patients in the study had mild melasma |
Fractional laser therapy |
Wind [108], 2010 |
R, MB, SF |
Four to five non-ablative FLT vs. TC cream (HQ 5% + tretinoin 0.05% + triamcinolone acetonide 0.1%) to both sides |
24 wk |
29 |
Worsening hyperpigmentation on the FLT side by mean PGA and PhGA. No SS change on the TC side. Patients preferred TC |
Increase in MI on the FLT side |
3 wk |
FLT: Erythema, burning, crusting, facial edema, blistering, PIH TC cream: erythema, burning, scaling |
80% of patients included were skin type III–V. Frequency of FLT sessions is not mentioned |
Kroon [109], 2011 |
R, MB |
Four serial non-ablative 1550 nm NFP sessions at 2-week intervals vs. TC (hydroquinone 5%, tretinoin 0.05%, triamcinolone acetonide 0.1%) qd for 8 wk |
24 wk |
22 |
PGA showed improvement at 3 wk but no difference between groups. At 6 mo, melasma recurred in 5 patients in both groups. Patient satisfaction was higher in the laser group |
None |
3 wk |
Erythema, burning sensation, edema, mild pain |
Small sample size |
Nouri [110], 1999 |
R, PC |
Group A: Pulsed CO2 laser (one pass, 300 mJ/cm2) + Q-switched Alexandrite (one pass, 6 J/cm2) Group B: Pulsed CO2 laser only. TC cream was used 14 days before the laser procedures |
24 wk |
8 |
Investigator subjective assessment established slightly better response in Group A vs. Group B |
None |
4 wk |
Combined group: Hypopigmentation CO2 only: Peripheral hyperpigmentation |
Assessment was performed subjectively. Only a 1 cm2 spot of the melasma was treated |
Angsuwarangsee [111], 2003 |
R, PC, SF |
One side: CO2 + Q-switched Alexandrite 1 session Contralateral side: Q-switched Alexandrite alone 1 session |
24 wk |
6 |
No SS difference between groups. 83% of patients in Group 1 had SS decreased mMASI. Group 2 had non-SS decrease in mMASI. Patient satisfaction score: 50% preferred combination treatment |
Physician assessment performed by MI (Mexameter), with only a SS improvement seen in the combined group |
NR |
16% had temporary hypopigmentation, 50% had PIH, 16% showed no improvement |
2/6 were administered HQ 4% at 3 mo to treat PIH |
Trelles [112], 2010 |
R, MB |
Group A: TC cream only Group B: CO2 fractionated laser (high power, fixed pulsed width, low frequency) Group C: CO2 fractionated laser + TC cream |
48 wk |
30 |
Significant decrease in MASI in group C compared with Groups A and B. Overall efficacy and satisfaction index was similar between groups at mo 1, but decreased through followup in Groups A and B |
None |
4 wk |
NA |
Use of sunscreen is unclear Recurrence occurred in all groups |
Other laser therapies |
Hong [113], 2012 |
R, MB, SF |
One session of 1550 nm (erbium fiber laser) to hemiface vs. 15% TCA (Obagi Blue Peel) to the contralateral side |
12 wk |
18 |
MASI showed SS improvement at 4 wk. At 12 wk, all patients showed relapse, some worse than baseline MASI. Patient assessment showed 43% improvement on the laser treated side vs. 39% on the TCA side. At 12 wk, improvement decreased to 25% in both groups |
None |
4 wk |
50% erythema and PIH, which decreased at 12 wk |
All patients included had mild melasma at baseline. Use of sunscreen was not mentioned. Patient assessment was performed by visual analog scale |
Hammami [114], 2015 |
R, MB, SF |
TC cream (HQ 5% + dexamethasone 0.1% + retinoic acid 0.1%) qhs for 4 wk followed by Bromide Copper laser to the hemiface (wk 4, 6, 9, 12) vs. TC cream to the contralateral hemiface |
24 wk |
20 |
No SS difference in MASI by 6-mo follow-up. No SS difference between the two groups (p =0.33) |
Laser confocal microscopy (VivaScope) did not show a decrease in vascularization on melasma lesional skin |
12 wk |
No scarring, no PIH |
Copper bromide laser was not effective at reducing the vascular component |
Choi [115], 2017 |
R, PC, SF |
One side: Picosecond (1064 and 595 nm), 5 weekly sessions + 2% HQ qd Contralateral side: 2% HQ qd |
18 wk |
39 |
mMASI showed decrease at wk 7 on the laser treated side vs. HQ alone. No SS difference between sides at week 10, 14 and 18. |
Physician assessment performed by relative skin lightness (RL*I performed by colorimeter). Significant decrease in RL*I at 7, 10, 14, and 18 wk compared with the HQ-alone side |
7 wk |
5% mild dermatitis and mild pain |
Despite improvement, patients still had severe melasma at 18 wk suggesting recurrence after cessation of laser treatment |
Chalermchai [116], 2018 |
R, MB, PC, SF |
One side: Fractional picosecond (1064 nm) laser (wk 0, 4, 8) + 4% HQ qd Contralateral side: 4% HQ alone qd |
12 wk |
30 |
Group 1 with 62% decrease in mMASI at 12 wk versus 55% in Group 2 (SS; p =0.035). No difference based on patient satisfaction scale (DLQI) at 4, 8, and 12 wk |
Mexametry showed no SS difference between the treated and untreated side |
8 wk |
6.7% mild erythema, 6.7% mild skin desquamation, 3.3% mild burning sensation |
Despite significant improvement at 8 wk on the treated group, at 12 wk mMASI was similar on both treated sides. Mean mMASI at baseline was 9.47, which represents patients with severe melasma |