Melasma Treatment: An Evidence-Based Review

Table 1. Studies evaluating topical agents as monotherapy for the treatment of melasma
First author, year	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
Depigmenting agents
Ennes [12], 2000	DB, PC	4% HQ and two sunscreens (SPF15) bid vs. sunscreen alone. Both groups applied SPF30 sunscreen daily	12 wk	48	Complete resolution: 38.1% HQ vs. 8.3% placebo Partial improvement: 57.2% HQ vs. 58.2% placebo Treatment failures: 0% HQ vs. 16.7% placebo	None	3 wk	No SS difference between groups. Five cases of erythema in treatment group and one with contact dermatitis	Outcome based on clinical and photographic observations only, using non-validated scale of 'total improvement' vs. 'partial improvement' vs. 'failure'
Vázquez [13], 1983	R, DB, PC	3% HQ bid and placebo cream vs. 3% HQ bid and BS sunscreen	12 wk	53	96.2% vs. 80.7% improved with HQ + sunscreen vs. HQ alone	None	NA	Mild and transient local irritant effects	Subjective evaluation by investigators and participants only
Verallo-Rowell [14], 1989	R, DB, C	AA 20% bid vs. HQ cream 2% bid. All subjects applied BS sunscreen	24 wk	155	NA	73% of AA patients vs. 19% of HQ patients had good to excellent results based on melasma pigmentary intensity and lesion size	NA	Both groups had mild to moderate skin irritation	Patients were of Indo-Malay-Hispanic origin
Sivayathorn [15], 1995	R, DB, C, MC	2% HQ bid vs. 20% AA bid. Both groups used sunscreen	24 wk	340	68.9% in AA group had 'good' or 'excellent' results vs. 43.7% in HQ group (SS)	None	NA	Mild itching and burning (both groups). 36.5% of AA group had AEs vs. 12.7% in HQ group
Baliña [16], 1991	R, DB, MC	4% HQ cream bid vs. 20% AA cream bid. All subjects applied sunscreen daily	24 wk	243	Good or excellent results in 65% of AA subjects vs. 72% of the HQ group (not SS)	Based on planimetric mapping of melasma lesion size, 60% of AA group and 66% of HQ group achieved 50% reduction in lesion size (not SS)	4 wk	Mild, transient local irritation in both groups Pronounced irritation in 1 HQ subject vs. 18 AA subjects	SPF or frequency of sunscreen use not specified
Farshi [17], 2011	Open-label, R, C	AA 20% bid vs. HQ 4% bid. Both groups applied BS sunscreen every 3 h	2 mo	29	MASI scores decreased from 7.6 ± 3.5 to 3.8 ± 2.8 in the AA group, vs. 7.2 ± 3.2 to 6.2 ± 3.6 (p =0.05) No SS difference between groups after only 1 mo of treatment	None	1 mo	SS more erythema in the HQ group vs. AA in the first month (7.3% vs. 46.6%) No SS difference in erythema, pruritus, irritation in the second month	Studied patients with mild melasma
Sarkar [18], 2002	R, SF, comp	20% AA bid (24 wk) to half of the face vs. clobetasol 0.05% cream qd for 8 wk, followed by 20% AA only bid for 16 wk to the other half of the face. BS sunscreen applied qd	24 wk	30	Melasma lightening was more significant on the side of the face receiving sequential therapy (clobetasol for 8 wk followed by AA for 16 wk) [p <0.001] Both groups had > 90% of cases with good to excellent responses to treatment	None	4 wk	Mild and transient local irritant effects	Enrolled dark-skinned patients. Outcomes were subjective, based on clinical evaluation, photography, and assessment of 'overall response'
Huh [19], 2003	R, DB, PC, SF	Vitamin C iontophoresis vs. distilled water iontophoresis for 8 min twice weekly. Both groups applied sunscreen qd	12 wk	29	Subjects reported the same improvement in both treatment and vehicle-treated skin	Colorimetry showed a significant decrease in luminance value, from 4.60 to 2.78 in the vitamin C-treated side vs. 4.45 to 3.87 in the control side (p <0.01)	NA	21% with mild sense of electric shock, 7% with itching, 7% with erythema, 3% with burning, 3% with dryness
Espinal-Perez [20], 2004	R, DB, SF	5% L-ascorbic acid daily vs. 4% HQ daily. Daily sunscreen was also applied to both sides of the face	16 wk	16	Participants rated improvement as 'good' or 'excellent' in 93% of the HQ group vs. 62.5% in the ascorbic acid group	No SS difference based on colorimetry	1 mo for HQ, 3 mo for ascorbic acid	68.75% of cases had irritation in HQ-treated skin vs. 6.25% in skin treated with ascorbic acid
Khemis [21], 2007	R, DB, PC, SF	Phase 1: rucinol serum 0.3% vs. vehicle bid Phase 2: subjects treated with an additional 3 mo of full-face rucinol serum. All groups applied SPF60 sunscreen	12 wk + 24 wk	28	Good or fair efficacy in 78% of subjects in the treatment group. SS improvement in clinical pigmentation score in the treated skin compared with vehicle based on physician assessment	Colorimetric measurements showed skin was significantly less yellow and lighter, and trended toward significantly reduced redness with rucinol therapy	4 wk	In both groups, few patients reported stinging, burning, and pruritus. One patient had blepharoplasty. There were less AEs on the treated side compared with placebo	The clinically apparent depigmenting effects of rucinol seemed to plateau after 16 wk of treatment. This coincided with the summer months so may have been mitigated by increased UV exposure. However, the colorimetric measurements continued to improve
Huh [22], 2010	R, DB, PC, SF	Liposome encapsulated 4-n-butylresorcinol 0.1% cream vs. vehicle bid	8 wk	23	Subjectively, 4-n-butyl-resorcinol therapy achieved excellent or good response in 65.2% of patients	MI decreased 7.51% in the treatment group vs. 3.26% in the vehicle group (p = 0.043)	4 wk	No AEs reported
Retinoids
Griffiths [25], 1993	R, DB, PC	0.1% tretinoin vs. vehicle qd. Both groups applied SPF15 sunscreen	40 wk	38	68% of tretinoin group showed improvement vs. 5% in vehicle group, based on subjective physician evaluation	Epidermal pigment was decreased by 36% in the tretinoin group vs. a 50% increase in the vehicle group Colorimetry and histological evaluation correlated with clinical assessment	24 wk	Erythema and desquamation in 88% of the treatment group vs. 29% of the vehicle group	Took an average of 24 wk to get significant clinical improvement. All subjects were Caucasian. No subjective assessment completed by subjects
Kimbrough-Green [26], 1994	R, PC	Tretinoin 0.1% vs. vehicle qd. All subjects applied SPF15 sunscreen	10 mo	28	MASI score improved 32% in treatment group vs. 10% in vehicle group	Histologic evaluation showed a significant decrease in epidermal pigmentation in the treatment group	24 wk	67% of the treatment group had skin irritation vs. 7% in the vehicle group	African American subjects Took an average of 24 wk to get significant clinical improvement
Leenutaphong [27] 1999	R, DB, PC	0.05% isotretinoin gel vs. vehicle cream bid. Both groups applied SPF28 qd	40 wk	23	MASI score decreased 68.2% in the isotretinoin group vs. 60% in the vehicle group (not SS)	Melasma Area and MI scores improved by 47% in the treatment group vs. 34% in the control group (no SS difference). It took 12 wk to see a SS reduction in colorimetric measurement	4 wk	Mild, transient dermatitis in 27% of the treatment group vs. 0% in the vehicle group	Thai patients
Dogra [28], 2002	R, comp (preliminary report only)	Adapalene 0.1% gel vs. tretinoin 0.05% cream. All subjects applied SPF15 sunscreen qd	14 wk	30	37% reduction in MASI score in tretinoin group vs. 41% in adapalene group (not SS)	None	NA	63% in tretinoin group had pruritus, burning, dryness, erythema, and scaling vs. 21% in adapalene group (mild erythema and dryness)	Adapalene may be less irritating than tretinoin
Truchuelo [29] 2014	R, DB, PC, SF	Neoretin® Discrom control gel cream daily + Neoretin ® Discrom control serum booster fluid nightly vs. vehicle. All subjects applied SPF50 sunscreen daily	3 mo	28	Treatment group had 74% ± 31% reduction in MASI score vs. 55% ± 36% in vehicletreated side of the face (p =0.009) 70% of subjects reported satisfaction with treatment	None	1.5 mo	2 patients with pruritus, 1 with burning, and 1 with erythema	Product tested retinol encapsulated glycospheres plus hydroxypinacolone retinoate (retinoic acid ester) in addition to other depigmenting agents: N-acetyl-glucosamine, kojic acid, Cromabright® and Natriquest®, Albatin®, Alistin®, and niacinamide. It also contained hydrating, anti-irritant, and anti-inflammatory ingredients
Visible light protection
Castaneda-Cazares [32], 2014	R, C, sunblock alone as control	UV + VL protection with iron oxide vs. UV protection alone (UV only). All groups received 4% hydroquinone	8 wk	68	MASI improved 77.8 ± 11% in UV-VL group vs. 61.9 ± 16% in UV-only group (p <0.001). Based on physician global assessment, 75% of UV-VL group achieved good or excellent results vs. 47% of UV-only group (p =0.03)	SS relative lightening of pigmented lesions in UV-VL group vs. UV-only group based on colorimetry UV-VL group also had significantly superior reduction in melanin and mast cells	NA	Two patients in the UV-VL group and three in the UV-only group reported mild/transient facial irritation from hydroquinone	UV-VL sunscreen enhances depigmentation efficacy of HQ. Applied UV protective creams every 2–3 h between 8:00 am and 5:00 pm
Yousefi [33], 2014	R, DB, C	Zinc sulfate 10% or HQ 4% qd. Each cream was applied for 2 mo, followed by 3 mo of follow-up using sunscreen only	2 mo + 3 mo' follow-up	82	HQ group had superior results, with MASI score improvement of 43.5 ± 15.5% vs. 18.6 ± 20.8% in zinc group (p <0.001). Both groups showed significant improvement in MASI score by 5 mo	None	2 mo	Post-inflammatory hyper-pigmentation in 5.2% of the zinc group (two cases) and 30.9% had skin irritation in HQ group	Did not compare with the sunscreen-only arm to demonstrate the potential UV protective benefits of topical zinc. More patients dropped out in the zinc group due to unsatisfactory treatment, unwillingness to be followed, distance from the treatment center
Topical tranexamic acid
Ebrahimi [34], 2014	R, DB, C, SF	3% topical TXA bid vs. 3% HQ and 0.01% dexamethasone bid	12 wk	39	No SS difference between groups. MASI in the TXA group improved 74.1% vs. 64.5% in the HQ + dexa group On physician grading, both groups had 24–27% of patients with excellent improvement, 42–48% with good improvement, and 3–30% with fair improvement (3% of the HQ group vs. 30.3% of the TXA group)	None	4 wk	23.1% of TXA group experienced adverse effects vs. 51.3% in the HQ + dexamethasone group (p =0.01). Adverse effects of both groups included erythema, irritation, xerosis, and scaling	Although similar efficacy, more adverse effects were experienced in HQ + dexamethasone group over topical TXA group
Banihashemi [35], 2015	R, DB, C, SF	5% liposomal TXA versus 4% HQ cream bid	12 wk	23	Both sides showed SS improvement (trend toward greater improvement with liposomal TXA). TXA group mMASI decreased from 14.72 ± 2.2 to 6.78 ± 2.9 (54% improvement) vs. 14.60 ± 2.3 to 7.60 ± 2.2 (48% improvement) in the HQ group	None	1 mo	Irritation in three patients treated with 4% HQ cream. None in the topical TXA group
Atefi [36], 2017	R, DB, C	Topical 5% TXA bid vs. 2% HQ bid. All subjects applied SPF30 sunscreen	12 wk	60	No SS difference in MASI score between groups (treatment group: 4.80 ± 1.06 reduced to 2.33 ± 0.71 vs. 4.37 ± 0.93 to 2.39 ± 0.65 in the HQ group) Treatment group expressed 33.3% satisfaction vs. 6.7% in the control group (p =0.015)	None	NA	No AEs reported in the TXA group, but 10% of the HQ group experienced erythema and skin irritation	No SS difference between groups based on Wood's lamp examination
Laothaworn [37], 2018	R, C, SF	3% topical TXA for 8 wk and QS-Nd:YAG 1064 nm (0 and 4 wk) vs. laser alone	8 wk	25	48% of subjects with remarkable improvement vs. 20% in the laser-only group SS reduction in mMASI in the combination group vs. no SS change in laser-only	Significant reduction in MI in the combination group by the fourth week of treatment. Negligible decrease in the laser-only group	4 wk	Mild erythema after laser treatment (2/25 patients)
Xu [38], 2017	R, C, SF	Functional microarray of microneedles + 5% TXA solution vs. 5% TXA solution alone	12 wk	30	96.15% in the combined treatment group had > 25% improvement vs. 38.46% in TXA-only group based on physician evaluation Satisfaction scores increased significantly in both groups	More significant reduction of brown spot scores by Visia in the treatment vs. control groups (only seen after 12 wk) MI decreased significantly in both groups without a SS difference between groups	8 wk	No AEs reported
Saki [39], 2017	R, C, SF	TXA intradermal injection 20 mg/mL (monthly for 3 mo) vs. 2% HQ cream qhs	20 wk	37		No SS difference in melanin value between groups although both showed SS reduction by the end of the follow-up period	4 wk	TXA injection: two patients with burning after injection; two who developed acne More patients had erythema in the HQ group	Measured melanin value using Dermacatch® colorimeter
Tehranchinia [40], 2018	R, SB, SF	TXA intradermal injection (1 mL of 100 mg/mL solution every 4 wk for 12 wk) and 4% HQ cream nightly vs. 4% HQ cream alone	16 wk	55	MASI in the combination group decreased from 5.165 ± 1.875 to 1.769 ± 0.981 compared with 5.204 ± 1.935 to 2.926 ± 1.219 in the the control group (p =0.001) Patient satisfaction was significantly higher in the combined therapy group	None	NA	Erythema (47.3%) and pruritus (10.9%) at the site of injection. In the HQ-alone group, 50.9% had erythema and 12.7% had pruritus, with no SS difference in adverse effects between groups
Steiner [41], 2009	R, open-label, comp	Group A: 3% TXA bid (topical) vs. Group B: intradermal TXA 4 mg/mL weekly for 12 wk SPF30 every 4 h	12 wk	17	Investigator assessment of photographs revealed (Group A vs. B): Improvement: 12.5% vs. 66.7% Worsening: 50% vs. 11.1% No change: 37.5% vs. 22.2% mMASI improved in both groups (22% vs. 36% improvement); no SS difference between groups	Colorimetry showed SS improvement in both groups, but no SS difference between the two	NA	Mild erythema, local bruising, and burning	INR and CBC showed no change before and after treatment
Budamakuntia [42], 2013	R, open-label	4 mg/mL TXA injections vs. 4 mg/mL TXA applied after microneedling Therapy performed at weeks 0, 4, and 8 8 wk + 3 mo follow-up	60	mMASI improved 35.7% (microinjection) vs. 44.4% (microneedling). 26% vs. 41% showed > 50% improvement based on PGA No SS difference between groups	None	NA	Mild discomfort, burning, erythema	Authors suggested microneedling may be preferable due to more uniform and deeper delivery of medication 26% of participants dropped out, most from the injection group

Neotone®: 4% DAB, licorice extract, ascorbic acid, glycolic acid, salicylic acid, and α-arbutin
Neotone Radiance®: 4% DAB, 0.05% TGF-β1 biomimetic oligopeptide-68, ascorbic acid, UVA and UVB filters, and spread spectrum SPF50 sunscreen (skin-whitening complex: extract of uvaursi, biofermented Aspergillus, grapefruit extract, rice extract) [Thiospot intensive: ethyl linoleate, thioctic acid, octadecenedioic acid, lactic acid, ethylhexyl methoxycinnamate]
Manufacturer information: GigaWhite® (Pentapharm/DSM, Basel, Switzerland); Thiospot® (Synchroline, Salo, Italy); Melaplex™ (Monheit 2013; Neocutis Inc., San Francisco, CA, USA); Neoretin® Discrom control gel cream daily/Neoretin® Discrom control serum booster fluid nightly (IFC Pharmaceuticals); Neotone® and Neotone Radiance® (ISIS PHARMA, Lyon, France);Tri-luma® (Galderma Laboratories, Fort Worth, TX, USA)
AA azelaic acid, AEs adverse events, bid twice daily, BS broad spectrum, C controlled, CBC complete blood count, comp comparative, DAB diacetyl boldine, DB double-blind, dexa dexamethasone, HQ hydroquinone, INR international normalized ratio, MASI Melasma Area and Severity Index, MC multicenter, MI melanin index, mMASI modified MASI, mo months, N number of subjects, NA not available, PGA Patient Global Assessment, PC placebo-controlled, qd once daily, qhs nightly, QS-Nd:YAG Q-switched neodymium-doped yttrium aluminum garnet, R randomized, SB single-blind, SF split-face, SPF sun protection factor, SS statistically significant, TGF transforming growth factor, TXA tranexamic acid, UV ultraviolet, VL visible light, wk weeks

Table 2. Studies evaluating combinations of topical agents for the treatment of melasma
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
Triple combination cream
Taylor [43], 2003	R, MB, multi	TC cream: HQ 4%, tretinoin 0.05% (RA), fluocinolone acetonide 0.01% (FA) qd vs. dual combinations of the above ingredients qd	8 wk	641	26.1% using TC achieved complete clearing, vs. each of the dual therapy groups (vs. maximum of 9.5% achieving clearance in HQ + tretinoin group). 77% in TC group had complete/near-complete clearing (vs. maximum 46.8% in HQ + tretinoin group)	None	NA	All groups experienced erythema, desquamation, burning, dryness, and pruritus. Less adverse effects in the HQ + FA group than TC, RA + HQ, and RA + FA	Improvement based on subjective physician evaluation. More adverse effects in creams containing RA
Torok [44], 2005	R, MB, multi	TC cream (extension of the Taylor et al., 2003 study)	12 mo	569	Physician's static global assessment showed 80% of subjects were clear/nearly clear by 12 mo	None	1 mo	61% experienced mild/transient AEs. The most common were erythema and desquamation. Atrophy < 1%, telangiectasia 4% 2.5% discontinued due to AEs	When subjects reached resolution or melasma, or had lack of response, subjects were transitioned to sunblock only
Cestari [45], 2007	R, C, open-label	TC cream qd vs. HQ 4% bid. Both groups applied SPF30 sunscreen qd	8 wk	120	MASI scores were SS lower in the TC group vs. the HQ group (p <0.003) at wk 4, 6, and 9. Clearance of melasma in 35% vs. 5.1% (TC vs. HQ); > 75% improvement in 73% vs. 49% (TC vs. HQ). Subjects reported 'excellent' results in 50% using TC cream vs. 34% using HQ-only cream	None	4 wk	Mild erythema, burning, and desquamation (no difference between groups). Telangiectasias in 15% TC vs. 9% HQ-only. Systemic AEs in 33% vs. 35% (TC vs. HQ); headache most common	Brazilian patients There were no cases of skin atrophy
Chan [46], 2008	R, C, MB, multi, parallel comparison study	TC cream qhs vs. HQ 4% bid	8 wk	260	Melasma global severity score showed mild or no melasma in 64.2% of TC patients vs. 39.4% in HQ group (p <0.001). TC was statistically superior as early as week 4. Subjects showed 70.8% satisfaction in the TC group vs. 49.6% in the HQ group	None	4 wk	More AEs in the TC vs. HQ group (48.8% vs. 13.7%) Adverse effects included erythema, irritation, skin exfoliation, and skin discomfort No cases of telangiectasia or skin atrophy	East and South-East Asian patients with moderate to severe melasma
Gong [47], 2015	R, DB, PC, multi	TC cream vs. placebo qhs	8 wk	233	Based on clinical assessment (total target score), TC group was superior to placebo at all time points. 69.91% vs. 0.88% improvement	Integral therapeutic efficacy (based on clinical and instrumental measure) 68.57% in the TC group vs. 0.94% controls (p <0.001) On mexametry, 71.3% improvement vs. 6.6% in placebo	2 wk	30.1% in the TC group with mild AEs, including erythema, pain, peeling, telangiectasia, burning, swelling, xerosis, pruritus, and darker pigmentation. 2.6% of the placebo group reported burning, itching, and skin tightening	Chinese patients
Arellano [48], 2012	R, MB, multi	Maintenance therapy TC cream. All groups initially treated with 8 wk of TC qd, then randomized to either twice-weekly TC or tapering regimen of thrice weekly for 1 mo followed by twice weekly for 1 mo then once weekly for 1 mo	6 mo	242	84% reduction in MASI. All subjects rated their melasma as completely clear or minor by end of the study	Twice-weekly group trended toward a lower relapse rate than the tapering regimen group, most notably in subjects with more severe melasma. 53% of patients remained relapse-free after the 6-mo trial in both groups. Both groups had a mean time to relapse of 190 days	NA	11.6% of subjects in the twice-weekly group experienced AEs, mostly erythema and skin irritation. One subject with skin atrophy. 1.88% of subjects had mild telangiectasia during the first 8 wk. AEs were similar in both groups during maintenance therapy (10.92% in the twice-weekly group vs. 12.2% in the tapering regimen)	Study included 16 centers in Brazil and Mexico. The relapse rate was related to melasma severity at baseline, but not related to melasma severity at the time of transition to the maintenance/tapering regimen. Even in the relapsed group, final MASI scores were still 42% lower than baseline
Other combination topical agents
Guevara [50], 2003	R, DB, PC	4% HQ, 10% buffered glycolic acid, vitamin C and E, sunscreen cream bid vs. sunscreen alone	12 wk	35	70% of the TC group had moderate or greater improvement based on physician global evaluation vs. 20% in vehicle group	75% of the treatment group showed improvement compared with 13% in the sunscreen-only group SS based on mexametry	4 wk	85% mild or moderate erythema; 65% scaling, and 40% edema, 35% with burning sensation, 10% itching, 60% redness, 60% dryness, and 30% peeling 67% of patients in the vehicle group had mild erythema	SPF of study cream unknown
Lim [51], 1999	R, DB, C, SF	2% kojic acid + 10% glycolic acid + 2% HQ gel vs. 10% glycolic acid and 2% HQ only. Applied bid. SPF15 sunscreen qd	12 wk	40	>50% improvement in 60% hemifaces applying kojic acid, compared with 47.5% of hemifaces using gel without kojic acid	None	4 wk	All subjects experienced redness, stinging, and mild exfoliation on both sides of the face. Effects were transient and resolved by 3 wk

AEs adverse events, bid twice daily, C controlled, DAB diacetyl boldine, DB double-blind, FA fluocinolone acetonide 0.01%, HQ hydroquinone, MASI Melasma Area and Severity Index, MB monoblinded, mo months, multi multicenter, N number of subjects, PC placebo-controlled, qd once daily, qhs nightly, R randomized, RA tretinoin 0.05%, SF split-face, SPF sun protection factor, SS statistically significant, TC triple combination cream: 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide unless otherwise specified, TGF transforming growth factor, wk weeks

Table 3. Studies evaluating skin-brightening creams and plant-based extracts as topical agents for the treatment of melasma
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
Haddad [52], 2003	R, DB, PC, SF	Group 1: HQ 4% on hemiface vs. vehicle qhs Group 2: SWC 5% on hemiface vs. vehicle qhs All subjects applied SPF25 sunblock qd	3 wk	25	Group 1: 76.9% improvement, 25% adverse effects Group 2: 66.7% improvement, 0% adverse effects (not SS) Patient satisfaction level 66.7% in the HQ group and 69.2% in the SWC group	None	NA	Skin irritation in 25% of the HQ group. No AEs in the SWC group	Included patients from Brazil with Fitzpatrick skin types III, IV, and V
Francisco-Diaz [53], 2004	R, DB, PC, SF	Gigawhite® 5% solution bid vs. placebo solution bid. Both groups applied SPF60 sunscreen qd	12 wk	26	MASI decreased by 18.5% on the Gigawhite side of the face vs. 13.5% on the placebo side. There was no SS difference between groups based on subjective measurement	Colorimetry showed 6.9% improvement of luminance value on the Gigawhite side of the face vs. 1.03% on placebo side, which was SS	NA	No AEs reported
Thirion [54], 2006	R, DB, PC SF	Thiospot® intensive cream vs. moisturizing cream bid to the forehead	3 mo	27	36% improvement after 3 mo vs. no significant change in placebo	SS improvement seen in the treatment group based on Mexameter, video-recorded UV light reflection, corneomelametry, and physician assessment. No SS change in the control group	2 mo	No AEs reported	Treatment was limited to forehead melasma
Makino [55], 2013	R, DB, SF	Skin-brightening formulation containing SMA-432, a prostaglandin E2 inhibitor, vs. 4% HQ bid	12 wk	68	No difference between groups in overall hyperpigmentation, global improvement. Subjects tended to favour the cream containing SMA-432 regarding improvement of skin tone, skin appearance, and dark spots A dose-dependent reduction in hyperpigmentation was seen with SMA-432 based on physician evaluation	Chroma meter measurements found a SS improvement in luminance (L*) values in the treatment groups by week 8	4 wk	No SS difference in erythema between groups. Treatment group experienced mild burning and transient skin tightness	This was a split-face study with four groups: the first three groups all had slightly different formulations of SMA- 432, and the fourth group was the control group applying HQ
Monheit [56], 2013	R, SB, C, SF	SLC (Melaplex®) + 4% HQ cream vs. TC	12 wk	20	Comparable efficacy of SLC vs. TC cream. After 4 wk of treatment, MASI score decreased 57% for both the SLC and TC groups, which further improved to 77% reduction and 79% reduction, respectively, by 12 wk	None	4 wk	35% of subjects had skin irritation with either cream	SLC contained disodium glycerophosphate, L-leucine, undecylenoyl phenylalanine, and phenylethyl-resorcinol
Wanner [57], 2015	R, SB, C	Four treatment groups: 1. Proprietary LP 2. Proprietary LP with iontophoresis 3. Tretinoin 0.05% cream 4. Vehicle	16 wk	74	Improvement was 22% with LP alone; 17% LP + iontophoresis; 14% tretinoin; and 9% on placebo, based on investigator assessment. Under Wood's light, LP + iontophoresis produced the greatest results, with a 28% reduction in hyperpigmentation (vs. 9.9% in the 'LP only' group and 16% in the tretinoin group)	None	NA	56% of subjects in the tretinoin group had AE vs. 15% with LP only and 21% with iontophoresis and 11% with placebo	Caucasian patients
Pratchyapurit [58], 2016	R, C	DAB 4% cream qhs (Neotone®) + TGF-β1 biomimetic oligopeptide-68 + sunscreen (Neotone Radiance ®) bid vs. control	12 wk	38	2.6% of subjects graded themselves as markedly improved, 76.3% as moderately improved, and 21.1% as slightly improved. 47.4% improvement in MASI by 12 wk	Pigment reduction was most significantly reduced with the combination of DAB (Neotone®) and TGF-β1 and sunscreen (Neotone Radiance®) vs. either ingredient or HQ (4% and 2%) alone	6 wk	2.5% with erythema, 20% with pruritus, 7.5% with skin exfoliation, and 2.5% with skin dryness	The comparison of treatment creams with HQ was performed on unaffected skin. When applying treatment cream to skin affected by melasma, no control was used DAB stabilizes tyrosinase in its inactive form and TGF-β1 inhibits tyrosinase activity
Amer [59], 2000	SF, C	Topical liquiritin 1 g/day vs. vehicle bid	4 wk	20	Treatment group: 80% of patients with an excellent response, 10% had a good response, and 10% had a fair response. One patient in the vehicle group achieved a fair response	None	4 wk	Two patients in the treatment group experienced skin erythema and burning	Tested liver enzymes, serum creatinine, blood urea, and complete blood count, all of which remained normal throughout the study
Costa [60], 2010	R, SB, C	Belides, Emblica, and Licorice 7% bid vs. hydroquinone 2% qhs	60 days	50	Both groups had improved skin depigmentation based on medical and subject evaluation (not SS)	Visea-based pattern of melasma showed improvement in number, size, and tone of UV stains in both groups, but no difference between groups	15 days	Fewer adverse effects in the treatment group then the control group	Belides is an antioxidant from the Bellis perennis flower that inhibits melanin synthesis, transfer of melanosomes to epidermal cells, and endothelin-1 Licorice contains glabridine, a flavonoid from the plant Glycyrrhiza glabra. It acts to inhibit tyrosinase and has anti-inflammatory properties Embilica is derived from the fruit Phyllanthus emblica, which has antioxidant activity
Morag [61], 2015	R, DB, PC	2.5% arbutin cream bid vs. placebo	8 wk	102	75.86% of melasma patients had improved skin lightening and evening skin tone	Melanin level decreased in the treatment group and increased in the placebo group	4 wk	No AEs reported	This product contained a β-anomer of arbutin
Alvin [62], 2011	R, SB, PC	75% mulberry extract oil vs. placebo qd	8 wk	50	MASI score improved from 4.076 ± 0.24 to 2.884 ± 0.25 in the treatment group.	MelasQoL improved most significantly in the treatment group Mexameter scores improved from 356 ± 60 to 313 ± 57 at week 8 in the treatment group compared with 368.24 ± 46.62, worsening to 372.12 ± 44.47, in the placebo group	4 wk	Erythema and pruritus in both the treatment (n =4) and placebo (n =12) groups
Draelos [63], 2015	R, C, SF, paired	Cohort 1: lignin peroxidase vs. control Cohort 2: lignin peroxidase vs. 4% HQ	12 wk	60	Cohort 1: SS improvement with lignin peroxidase in dark spots, roughness, skin discoloration and overall appearance by week 8, and continuing to week 12 Cohort 2: No SS difference in skin appearance or MASI score between lignin peroxidase and HQ	Cohort 1: Improvement in spot size, texture, roughness, lack of clarity, overall appearance, and MASI score. SS reduction in target spot pigment based on spectrophotometer at wk 4, 8, and 12 Cohort 2: No difference between lignin peroxidase and HQ	4 wk	No AEs reported	Lignin peroxidase is an enzyme derived from the tree fungus Phanerochaete chrysosporium. This product breaks down melanin in the outer epidermis
Khosravan [64], 2017	R, C	Parsley (Petroselinum crispum) vs. 4% HQ daily. Both groups applied SPF30 sunscreen qd	8 wk	54	No SS difference between groups. MASI score in parsley group improved 6.66 ± 4.39 to 4.92 ± 3.07 vs. 6.68 ± 3.24 to 5.06 ± 2.66 in the HQ group	HQ group had 10.5 times the expense as those in the parsley group	NA	Two members in each group with redness and irritation	The parsley was brewed and applied with cotton. The article did not elaborate on 'expenses' incurred by either group
Mendoza [65], 2014	R, DB, PC	3% Rumex occidentalis cream vs. 4% HQ cream vs. placebo bid	8 wk	45	Greater decline in MASI score in the HQ group from wk 2 to 6, but R. occidentalis had a slightly greater improvement by week 8 (mean decline in MASI 0.60 ± 0.8 compared with 0.55 ± 0.62 in the HQ group). Investigator assessments showed a slightly more noticeable improvement in the HQ group Subjects reported equal efficacy	Greater decline in melanin content based on mexametry in the treatment group compared with the HQ group	2 wk	One subject in the R. occidentalis group with mild facial peeling
Altaei [66], 2012	R, DB, PC	Group 1, silymarin cream 7 mg/mL bid vs. Group 2, silymarin cream 14 mg/mL bid vs. Group 3, placebo cream. All subjects applied SPF15 sunscreen qd	4 wk	96	Group 1 MASI improved from 17.1 ± 3.12 to 0 at the end of treatment, and Group 2 MASI improved from 16.5 ± 2.8 to 0 at the end of treatment (p =0.0001). No significant improvement in MASI in the control group. Patient satisfaction was 100% in the treatment groups	None	1 wk	No AEs reported	Iraqi patients MASI score reduction was seen in all treatment groups as early as week 1 (SS)
Lee [67], 2002	R, DB	Vehicle (Group A) vs. 2% lincomycin + 0.05% BV (Group B) vs. 2% lincomycin + 0.05% BV + 2% linoleic acid (Group C) qhs. Applied SPF15 sunblock qd	6 wk	47	MASI score decreased by 31.1% in Group C, 14.6% in Group B, and 2% in Group A (vehicle) [p <0.05]. There was no SS difference between Groups A and B	43.7% of patients in Group C had more than moderate improvement, vs. 12.5% in Group B and 0% in Group A	2 wk	No AEs reported	Korean patients. Subjects with a negative family history of melasma and malar involvement of melasma showed better improvement after 6 wk of treatment
Katoulis [68], 2014	R, DB, PC	Topical treatment undecylenoyl phenylalanine 2% vs. vehicle. All subjects applied sunscreen qd	12 wk	37	80% of subjects in the treatment group were 'extremely satisfied' or 'satisfied' Based on physician assessment, 85% of the treatment group had partial response and 0% had complete response. The vehicle group had 23.5% of patients with partial improvement and 76.4% who remained stable or worsened	None	4 wk	Minor erythema, itching, and burning in 30% of the treatment group and 11.7% of the control group	SPF of sunscreen not reported
Mansouri [69], 2015	R, DB, PC	Cysteamine cream 5% vs. placebo qd	4 mo	50	MASI score decreased from 13 ± 8.1 to 7.2 ± 5.5 in the treatment group vs. 17.2 ± 8.1 to 11.6 ± 7.9 in the placebo group. Investigator's global assessment and patient questionnaires indicated superiority of cysteamine	In the treatment group, there was a SS improvement in melanin content based on Mexameter	2 mo	46% erythema, 29% dryness, 42% itching, 43% burning, 32% irritation	One subject experienced hyperpigmentation with cysteamine cream
Farshi [70], 2018	R, DB, PC	Cysteamine cream 5% vs. placebo qd	4 mo	40	MASI score decreased from 18.1 ± 8.1 to 8.03 ± 5.2 in treatment group vs. 13.2 ± 7.4 to 12.1 ± 7.4 in the placebo group (p = 0.04)	Superior results were seen based on Mexameter and Dermacatch measurements of pigment content (p = 0.0001) There was good correlation between the Dermacatch and Mexameter readings	2 mo	35% erythema, 20% dryness, 25% itching, 25% burning, 20% irritation There was no SS difference in AEs between groups	Used the Dermacatch, a portable visible-spectrum reflectance skin colorimeter (Colorix, Neuchatel, Switzerland) to measure erythema and melanin content in the skin and compared with Mexameter
Adalatkhah [71], 2015	R, C	1% flutamide cream qhs vs. 4% HQ cream qhs. All subjects applied SPF30 sunscreen three times daily	4 mo	74	Patients were more satisfied in the flutamide group based on improvement of melasma, satisfaction with adverse effects, skin succulence, and skin darkness. More SS improvement in MASI score in the flutamide group	Mexameter melanin assay did not show any difference between the two groups	2 mo	None reported	Overall comparative outcomes between groups, but higher patient satisfaction with flutamide. Flutamide is an anti-androgenic agent
Eshghi [72], 2016	R, C	Intralesional TAC (4 mg/cc at 5 mm intervals) vs. TC controls	8 wk	42	MASI score decreased from 11.57 ± 4.22 to 8.01 ± 3.1 in the intralesional TAC group vs. 10.46 ± 5.61 to 8.96 ± 4.96 in the control group. The intralesional group had superior results (p <0.001)	None	4 wk	Atrophy and telangiectasias observed in the treatment group	TC, Kligman's formula: HQ 5%, tretinoin 0.1%, dexamethasone 0.1%

Neotone®: 4% DAB, licorice extract, ascorbic acid, glycolic acid, salicylic acid, and α-arbutin
Neotone Radiance®: 4% DAB, 0.05% TGF-β1 biomimetic oligopeptide-68, ascorbic acid, UVA and UVB filters, and spread spectrum SPF50 sunscreen (skin-whitening complex: extract of uvaursi, biofermented Aspergillus, grapefruit extract, rice extract) [Thiospot intensive: ethyl linoleate, thioctic acid, octadecenedioic acid, lactic acid, ethylhexyl methoxycinnamate]
Manufacturer information: GigaWhite® (Pentapharm/DSM, Basel, Switzerland); Thiospot® (Synchroline, Salo, Italy); Lignin Peroxidase Study Lotion (Elure, Syneron Medical Ltd, Yokneam, Israel); Melaplex™ (Monheit 2013; Neocutis Inc., San Francisco, CA, USA); Neoretin® Discrom control gel cream daily/Neoretin® Discrom control serum booster fluid nightly (IFC Pharmaceuticals); Neotone® and Neotone Radiance® (ISIS PHARMA, Lyon, France); Tri-luma® (Galderma Laboratories, Fort Worth, TX, USA)
AEs adverse events, bid twice daily, BV betamethasone valerate, C controlled, DAB diacetyl boldine, DB double-blind, HQ hydroquinone, LP lightening product, MASI Melasma Area and Severity Index, MelasQoL Melasma Quality of Life Score, mo months, NA not available, PC placebo-controlled, qd once daily, qhs nightly, R randomized, SB single-blind, SF split-face, SPF sun protection factor, SS statistically significant, SLC skin-lightening cream, SWC skin-whitening complex, TAC triamcinolone, TC triple combination cream: 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide unless otherwise specified, TGF transforming growth factor, UV ultraviolet, wk weeks

Table 4. Studies evaluating chemical peels for the treatment of melasma
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
Glycolic acid peels
Lim [73], 1997	R, MB, SF	2% HQ, 10% GA gel bid, followed by 20–70% GA peel (every 3 wk for 24 wk) vs. pretreatment with 8% GA cream bid for 2 wk then 2% HQ, 10% GA gel bid for 24 wk. Daily SPF15 sunscreen	26 wk	10	Melasma and fine wrinkles improved on both sides. No SS difference between sides of the face	None	7 wk	Erythema and stinging, 10% PIH	Small sample size. Sunscreen frequency unclear
Hurley [74], 2002	R, MB, SF	4% HQ bid for 8 wk vs. 4% HQ cream bid + 20% GA peel (every 2 wk for 4 wk) followed by 30% GA peel (every 2 wk for 4 wk). SPF25 sunscreen was used	12 wk	18	Significant decrease in MASI score from baseline to follow-up visit. No SS difference between groups	Significant improvement based on mexametry. No SS difference between groups	8 wk	Erythema, dryness, and scaling	Small sample size
Ilknur [75], 2010	R, MB, SF	GA 20%, 35%, 50%, 70% (12 sessions, every 2 wk) vs. amino fruit acid 20%, 30%, 40%, 50%, 60% (12 sessions, every 2 wk). SPF30 sunscreen was used	24 wk	24	MASI scores decreased in both groups at 3 and 6 mo. No SS difference between groups	None	12 wk	Erythema, edema, and frosting	Amino fruit acid peel found to be more tolerable
Kumari [76], 2010	R, MB	Group A: 20–35% GA peel (7 sessions, every 2 wk) Group B: 10–20% TCA (7 sessions, every 2 wk) Daily SPF15 was used in all subjects	24 wk	40	79% reduction in MASI score at 12 wk in the GA group vs. 73% in the TCA group. No SS difference between groups	None	8 wk	95% mild burning in the GA group. 75% moderate to severe burning in the TCA group	Quicker initial improvement in the TCA group, but response was comparable at the end of the study. Most patients were skin type IV–VI. The relapse rate was low
Faghihi [77], 2011	R, SF	GA 70% on one side of the face vs. tretinoin 1% on the opposite side (4 sessions, every 2 wk)	12 wk	63	No SS difference observed between MASI scores on both sides of the face	None	8 wk	Erythema, stinging, and scaling	Tretinoin 1% peel was more tolerable than GA peel. Use of sunscreen Unclear
Sarkar [78], 2002	R, PC	Group A: Serial 30–40% GA peel (6 sessions, every 3 wk) + TC cream (2% HQ, 0.05% tretinoin, 1% hydrocortisone) Group B: TC cream alone SPF15 + used in all subjects	21 wk	40	SS decrease in MASI by 46% at week 12 and 80% at week 21 in Group A, and 33% (week 12) and 63% (week 21) in Group B (both SS). Group A SS was superior. Subjective improvement by patients was higher in Group A	None	12 wk	Mild erythema, desquamation in both groups 10% PIH in Group A	All patients were skin type IV–V
Erbil [79], 2007	R, PC	Group A: GA peel + 20% AA bid + 0.1% adapalene gel qhs Group B: 20% AA bid + 0.1% adapalene qhs	20 wk	28	Decrease in MASI in both groups. SS superior results in Group A	None	8 wk	PIH in the GA group	Use of sunscreen is unclear
Dayal [80], 2017	R, MB	Group A: GA peel (8 sessions, every 3 wk) + 20% AA bid Group B: 20% AA bid alone SPF50 was applied by all subjects	24 wk	60	Significant decrease in MASI and MelasQoL at 12 wk compared with controls	None	12 wk	Post-peel erythema, pruritus, burning sensation, and PIH	Adverse effects were higher in Group A
Sarkar [81], 2016	R, MB	Group A: 35% GA peel Group B: 20% salicylic and 10% mandelic acid Group C: 50% phytic acid combination 6 sessions, every 2 wk	20 wk	90	Decrease in MASI score in all three groups. More significant reduction in Group A vs. Group C and Group B vs. Group C, but no difference between Groups A and B	None	4 wk	Group A: 19% mild erythema and desquamation, 15% PIH Group B: 25% burning sensation Group C: 32% burning sensation	All patients were skin type IV–V SPF sunscreen not Clear
Salicylic acid peels
Ejaz [82], 2008	R, DB	Jessner's solution (14% SA, 14% lactic acid, 14% resorcinol) peel for 5 min, every 2 wk for 12 wk vs. 30% SA peel for 5 min, every 2 wk for 12 wk. Daily SPF60 sunscreen used	24 wk	60	Both groups had a decrease in MASI scores. No SS difference found between groups	None	4 wk	Erythema and scaling	Subjects underwent 2 wk of priming with 0.05% tretinoin before treatment
Kodali [83], 2010	R, SF	20–30% SA peel (every 2 wk) on one side of the face, and concomitant use of 4% HQ to both sides of the face bid. SPF30 sunscreen was used	8 wk	18	mMASI scores decreased on both sides of the face. No SS difference between sides in mMASI and Global Assessment	Narrowband reflectance spectrophotometry showed SS reduction in pigment on both sides. No SS difference between the sides	2 wk	20% erythema, burning, peeling	Small sample size
Balevi [84], 2017	R, MB	Group A: 30% SA peel (every 2 wk for 2 mo) Group B: 30% SA peel (every 2 wk for 2 mo) + vitamin C mesotherapy SPF15 + was used two to three times a day	24 wk	50	MelasQoL and MASI score decreased in both groups. No SS difference between groups	None	8 wk	Burning sensation	Quality of life was slightly higher in Group A
Azzam [85], 2009	R, PC	Group A: 2 wk priming with 0.05% retinoic acid qd and Jessner's solution (6 weekly sessions) Group B: 2 wk priming with 0.05% retinoic acid qd and TCA 20% (6 weekly sessions) Group C: Topical 2% HQ qhs for 8 wk Group D: Topical 2% kojic acid qhs for 8 wk	16 wk	45	Group B with SS reduction in MASI score compared with the other groups. There was a SS difference between Groups A vs. B and Groups B vs. C	None	6 wk	20–30% erythema PIH was more common in the TCA group vs. Jessner's group	Sunscreen use not Mentioned
Trichloroacetic acid peels
Murtaza [86], 2016	R, MB	Group A: 20% TCA peel (6 sessions, weekly) + magnesium ascorbyl phosphate cream qd Group B: 20% TCA (6 sessions, weekly)	6 wk	148	Significant MASI score decrease in Group A (80%) vs. Group B (66%)	None	6 wk	Erythema, burning sensation, desquamation	Short-term followup. Use of sunscreen unclear
Abdel-Meguid [87], 2017	R, MB, SF	TCA 20–25% plus Jessner's solution on one side of the face vs. TCA 20–25% alone on the opposite side (6 sessions, 2-week interval)	12 wk	24	MASI score reduction on both sides of the face, significantly lower on the side treated with combined treatment	None	12 wk	10% PIH on the combined side Transient erythema, burning, discomfort, itching, and crusting	Significant negative correlation between improvement and age of the patients and duration of melasma. Only patients with skin types III–IV were included

AA azelaic acid, bid twice daily, DB double-blind, GA glycolic acid, HQ hydroquinone, MASI Melasma Area and Severity Index, MB monoblinded, mMASI modified MASI, MelasQoL Melasma Quality of Life Score, mo months, PC placebo-controlled, PIH post-inflammatory hyperpigmentation, qd once daily, qhs nightly, R randomized, SA salicylic acid, SF split-face, SPF sun protection factor, SS statistically significant, TC triple combination cream: 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide unless otherwise specified, TCA trichloroacetic acid, wk weeks

Table 5. Studies evaluating laser- and light-based therapies for the treatment of melasma
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 (RLI performed by colorimeter). Significant decrease in RLI 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

C controlled, comp comparative, DLQI Dermatology Life Quality Index, F-IPL fractionated IPL, FLT fractional laser therapy, GA glycolic acid, H&E hematoxylin and eosin, HQ hydroquinone, IGA Investigator's Global Assessment, IPL intense pulsed light, MASI Melasma Area and Severity Index, MB monoblinded, MI melanin index, mMASI modified MASI, mo months, NA not available, NR not reported, PDL pulsed dye laser, PGA Patient Global Assessment, PhGA Physician's Global Assessment, PC placebo-controlled, PIH post-inflammatory hyperpigmentation, qd once daily, qhs nightly, QS-Nd:YAG Q-switched neodymium-doped yttrium aluminum garnet, R randomized, RL*I relative skin lightness, SF split-face, SPF sun protection factor, SS statistically significant, TC triple combination cream: 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide unless otherwise specified, TCA trichloroacetic acid, TXA tranexamic acid, wk weeks

Table 6. Studies evaluating systemic agents for the treatment of melasma
First author, year	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
Oral tranexamic acid
Zhu [121], 2001	PC, prospective	TXA oral 250 mg tid plus vitamins C and E vs. placebo (30 controls)	6–8 wk	158	Of the treatment group, 20% had > 95% improvement, 30% had > 60% improvement, and 33% had 20–60% improvement Improvement was SS superior to controls	None	NA	Mild GI upset
Karn [122], 2012	R, C	250 mg TXA bid vs. HQ (unknown percentage) + sunscreen	12 wk	260	mMASI decreased from 11.08 ± 2.91 to 7.84 ± 2.44 in the treatment group (70% improvement) vs. 11.60 ± 3.40 to 9.26 ± 3.0 in the control group (29.3% improvement) 45.5% of the treatment group reported 'excellent' satisfaction vs. 8.5% in the control group	None	8 wk	Oligomenorrhea (14.7%), belching (9.2%), abdominal cramps (6.9%), palpitation (1 patient), urticarial rash with angioedema (1 patient)	Compared with improvement at 8 vs. 12 wk, the treatment group continued to show SS improvement from 8 to 12 wk, whereas the control group no longer showed significantly different improvement
Wu [123], 2012	Prospective, interventional	Oral TXA 250 mg bid	6 mo	74	After 6 mo of treatment, excellent results in 10.8% of patients; 54% with good results, 31.1% with fair results, and 4.1% with poor results. Total improvement rate of 95.9%	Monthly testing of PT, aPTT, and clotting parameters showed no significant changes over the course of oral TXA treatment	1 mo	5.4% with mild GI discomfort, 8.1% with hypomenorrhea; 'rare': rash, dizziness, alopecia, drowsiness, hyposexuality	9.5% recurrence after 6-mo follow-up Grading of results: Excellent: 90% reduction in size, vanishing of hyperpigmentation Good: 60% decrease in size or significant diminishment of hyperpigmentation Fair: size decrease 30% or visible diminishment of hyperpigmentation Poor: < 30% decrease in size or no visible diminishment of hyperpigmentation
Li [124], 2013	Prospective, open-label	Compounded oral TXA 250 mg tid	16 wk	32	On physician assessment, 75% of subjects showed marked improvement, and 25% showed moderate improvement. 100% of subjects were satisfied	85% of patients improved in 4 wk, 97% by 12 wk, and 100% in 16 wk. Evaluation was performed using the Skin Tone Color Scale	4 wk	Elevation of ALT (3%), GI upset (12.5%), changes in menstruation (6%), drowsiness (3%)	Enrolled subjects with mild to moderate melasma
Lajevardi [125], 2017	R, C, MB	TXA 250 mg tid + 4% HQ cream qhs vs. 4% HQ qhs	3 mo treatment + 3 mo follow-up	88	After 3 mo of therapy, the MASI reduced by 51% vs. 33% in the treatment vs. control groups (p <0.001). The treatment group expressed moderate-to-complete satisfaction in 82.2% versus 34.9% in the control group (p <0.001)	None	4 wk	Mild abdominal pain and spotting (1 patient each)	The relapse rate after 3 mo was 30% in the treatment group vs. 26% in the control group (not SS)
Padhi [126], 2015	Open-label, R, C	TXA 250 mg bid + TC cream (fluocinolone acetonide 0.01%, tretinoin 0.05%, and hydroquinone 25%) vs. TC alone	8 wk	40	88% reduction in MASI score at 8 wk in the TXA + TC group vs. 54.65% in the control group (p <0.05)	None	4 wk	10% erythema, 10% burning, 10% hypopigmentation, 5% oligomenorrhea. The frequency of AEs was not SS from the control group (15% erythema, 10% burning, 0% hypopigmentation, 0% oligomenorrhea)	No recurrence after 6-mo follow-up
Tan [127], 2017	Retrospective analysis	TXA 250 mg bid + TC cream	3.7 ± 0.33 mo plus 6 mo follow-up	25	MASI score improved 69%	None	1.7 ± 0.3 mo	None reported	72% of patients relapsed within 2 mo of stopping oral TXA despite continuing TC
Sharma [128], 2017	Open-label, R, comp	TXA 250 mg bid vs. intradermal micro-injections of TXA 4 mg/mL q4w. All subjects applied SPF19 sunscreen qd	12 wk	80	77.96 ± 9.39% reduction in MASI in the oral TXA group vs. 79 ± 9.64% reduction in the intradermal injection group (equally as effective)	None	4 wk	15.4% of oral TXA had hypomenorrhea. Two patients with epigastric discomfort 26% of the injection group had injection site pain and transient edema	Two (5%) patients in the oral group had relapse at 24 wk. No relapses were seen in the intradermal injection group
Colferai [129], 2018	R, DB, PC	TXA 250 mg bid vs. placebo	12 wk	37	80% in the treatment group reported melasma lightening vs. 58.82% in the placebo group	50% in the treatment group improved vs. 5.9% in the placebo group The treatment group improved in MASI, MelasQoL, and colorimetry measurements, but the placebo group improved in the MelasQoL only	NA	The treatment group had GI upset (33%), headache (14%), and altered menstruation (10%)
Del Rosario [130], 2018	R, DB, PC	TXA 250 mg bid vs. placebo. All subjects applied sunscreen qd	3 mo treatment + 3 mo follow-up	39	After 3 mo, the treatment group had a 49% reduction in mMASI score vs. 18% in the placebo group After drug discontinuation, mMASI worsened in the treatment group, but remained 26% improved from study baseline	Reduction in MI was similar to the mMASI results	4 wk	GI upset (22.7%), menstrual changes (18.2%), headache (13.6%), myalgias (9.1%), somnolence (9.1%), arthralgias (4.5%), blurry vision (4.5%) Adverse effects were mild and transient. One subject withdrew due to mild myalgias	Studied Hispanic women with moderate to severe melasma After 3 mo of drug discontinuation, mMASI and MI worsened, but remained improved from baseline
Oral polypodium leucotomos extract
Martin [135], 2012	R, DB, PC	Oral PLE vs. placebo bid + SPF45 sunscreen qd	12 wk	21	SS improvement in MASI score and MelasQoL for the treatment vs. placebo groups. Mean MASI score improved from 5.7 to 3.3. Plain and UV-lamp photographs revealed 43% of subjects vs. 17% in the placebo group had mild improvement, and 14% vs. 0% had marked improvement. In the treatment group, 38% reported no change and no patients reported worsening of melasma (vs. 67% and 17% in the placebo group)	None	NA	There was no difference in AEs between groups	Patients with epidermal melasma were included. The dose of PLE was not reported
Ahmed [136], 2013	R, DB, PC	Oral PLE 240 mg tid vs. placebo. All subjects applied SPF55 sunscreen qd	12 wk	33	No SS difference in MASI scores There was minimal change in MelasQoL scores	Both groups showed SS improvement in MI (28.8% in the PLE group vs. 13.8% in the placebo group) and MASI score, however there was no difference between groups	NA	No AEs reported	Hispanic women. There was only a 5.1-point difference in MI between groups. The improvement in MASI and MI may be attributed to daily sunblock application
Goh [137], 2018	R, DB, PC	Oral PLE 240 mg vs. placebo bid. Both groups were treated with 4% HQ cream qhs + SPF50 + sunscreen	12 wk	40	mMASI score improved 54.9% in the treatment group vs. 44.4% in the placebo group (SS) 31.3% of the PLE group had > 75% improvement in mMASI score vs. 6.3% in the placebo group (p =0.070) MelasQol improved in both groups, with a greater improvement seen in the treatment group There was no difference in investigator evaluation based on photographs	The erythema index was reduced in both groups There was no SS difference in MI between groups, however there was a 28.8% reduction in MI from baseline in the treatment group vs. 13.8% in the placebo group (p =0.140)	28 days. Trend toward improved mMASI vs. placebo at this time	Two subjects from the PLE group and one from the placebo group had mild pruritus and stinging with the use of HQ	The authors suggest that PLE may accelerate pigment clearance as the improvement over placebo was seen as early as 28 days
Other systemic agents
Handog [138], 2018	R, DB, PC	Procyanidin (24 mg) + vitamin A (6 mg β-carotene), vitamin C (60 mg), vitamin E (15 IU) bid. All patients applied SPF24 sunscreen qd	8 wk	56	MASI score improved significantly in both groups, however was more significant in the treatment group. Patients in the treatment group stated that they were slightly improved (10%), moderately improved (60%), or obviously improved (30%) compared with the placebo group, who mostly noted no improvement/slight improvement	Mexametry demonstrated a SS decrease in average MI on bilateral malar cheeks after 8 wk of treatment	4 wk	No AEs reported	Filipino women
Teo [139], 2015	R, DB, PC	Crystal Tomato® dietary supplement (800 mg caplet) and L-cysteine (50 mg caplet). All subjects applied daily sunblock and reapplied every 2 h	84 days	44		There was no SS difference between the treatment and placebo groups based on mexametry and MASI scores. The Mexameter erythema score showed significant improvement in both groups, with a greater improvement in the treatment group at 56 days of treatment	NA	Two patients from the active arm reported burning/redness and pruritus. One patient from the placebo group reported skin tone darkening
Hamadi [141], 2009	R, DB, PC	Group A: Topical melatonin 5% cream bid Group B: Topical melatonin 5% cream bid + SPF50 sunscreen qd Group C: Topical melatonin 5% cream bid + oral melatonin (3 mg qd) Group D: 4% HQ cream bid Control group: Placebo	120 days (90 days treatment + 30 days placebo)	46	Group D (HQ) had superior results compared with all other groups, and there was no SS difference between Groups B and C All groups had a SS reduction in MASI score after 90 days of treatment; however, after the 30-day follow-up, Group A (topical melatonin) had a non-significant reduction in MASI compared with baseline	Plasma MDA and GSH were also measured, showing a decrease in MDA and an increase in GSH in the groups treated with melatonin Decreased MASI generally correlated with decreased plasma MDA and increased plasma GSH, but was not SS in any cases	NA	No AEs reported	Topical melatonin cream had the least effect on the treatment groups The HQ group had the lowest rate of relapse

Manufacturer information: Crystal Tomato® (Gromark Consumers Enterprise Pte Ltd, Singapore)
AEs adverse events, ALT alanine aminotransferase, APTT activated partial thromboplastin time, bid twice daily, C controlled, comp comparative, DB double-blind, GI gastrointestinal, GSH glutathione, HQ hydroquinone, MASI Melasma Area and Severity Index, MB monoblinded, MDA malondialdehyde, MelasQoL Melasma Quality of Life Score, MI melanin index, mMASI modified MASI, mo months, NA not available, PC placebo-controlled, PLE polypodium leucotomos extract, PT prothrombin time, qd once daily, qhs nightly, q4w every 4 weeks, R randomized, SPF sun protection factor, SS statistically significant, TC triple combination cream: 4% hydroquinone, 0.05% tretinoin, and 0.01% fluocinolone acetonide unless otherwise specified, tid three times daily, TXA tranexamic acid, UV ultraviolet, wk weeks

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