ORIGINAL INVESTIGATION

Microneedling as an adjuvant to topical

therapies for melasma: A systematic
review and meta-analysis
Adrian Joseph Michel Bailey, BSc,a Heidi Oi-Yee Li, BSc,a Marcus G. Tan, MD,a,b Wei Cheng, PhD,c and
Jeffrey S. Dover, MD, FRCPCd,e,f
Ottawa, Ontario, Canada; New Haven, Connecticut; Chestnut Hill, Massachusetts; Providence, Rhode
Island

Background: Microneedling as an adjuvant to topical medications has shown promising but variable
results in the treatment of melasma.

Objective: To conduct a systematic review and meta-analysis on the efficacy of microneedling as an

adjuvant to topical therapies for the treatment of melasma.

Methods: This study followed PRISMA guidelines. All comparative, prospective studies on the use of
topical interventions with microneedling for the treatment of melasma were included. Studies involving
radiofrequency microneedling were excluded.

Results: Twelve eligible studies comprising 459 patients from 7 different countries were included. Topical
therapies included topical tranexamic acid, vitamin C, platelet-rich plasma, non-hydroquinone-based
depigmentation serums, and hydroquinone-based depigmenting agents. Topical therapy with
microneedling improved melasma severity with a large effect (standardized mean difference [0.8) beyond
8 weeks, with best results seen at 12 weeks. Compared to topical therapy alone, topical therapy with
microneedling resulted in an additional improvement in melasma severity with a moderate effect at
8 weeks and a large effect at 12-16 weeks. Microneedling was well tolerated across studies, with no serious
adverse events reported.

Limitations: Heterogeneity in study designs did not allow for a comparison of the efficacy of various
topical therapies with microneedling.

Conclusion: Microneedling is useful adjuvant to topical therapies for the treatment of melasma. ( J Am
Acad Dermatol https://doi.org/10.1016/j.jaad.2021.03.116.)

Key words: ascorbic acid; chemical peels; hydroquinone; laser; melasma; meta-analysis; microneedling;
skin of color; systematic review; topical therapy; vitamin c; tranexamic acid.

INTRODUCTION ranging from 1.5% to 33%.3,4 Photoprotection and

Melasma is an acquired disorder of hyper-
melanosis associated with significant psychosocial
impairment.1 Melasma disproportionately affects
women of darker skin phototypes2 and has a high
prevalence in the general population, with estimates
topical lightening products are the mainstay of
treatment. Second-line treatment options include
lasers, mechanical and chemical peels, and oral
tranexamic acid (TXA).1 Effective management of
melasma remains challenging, as patients often

From the Faculty of Medicine, The University of Ottawaa; Division
of Dermatology, The Ottawa Hospitalb; Department of Biosta-
tistics, Yale School of Public Health, New Havenc; SkinCare
Physicians, Chestnut Hilld; Department of Dermatology, Yale
University School of Medicine, New Havene; and Brown Medical
School, Providence.f
Authors Bailey, Li, and Dr Tan are cofirst authors.
Funding sources: None.
IRB approval status: This study met the definition of Institutional
Review Board exempt research.
Accepted for publication March 26, 2021.
Correspondence to: Jeffrey S. Dover, MD, Yale University School of
Medicine, 1244 Boylston Street, Suite 103, Chestnut Hill, MA
02467. E-mail: JDover@skincarephysicians.net.
Published online May 12, 2021.
0190-9622/$36.00
Ó 2021 by the American Academy of Dermatology, Inc.
https://doi.org/10.1016/j.jaad.2021.03.116

1
2 Bailey et al J AM ACAD DERMATOL
n 2021

experience incomplete clinical resolution and high ‘‘microneedling’’ without any language or date
rates of recurrence. In addition, second-line restrictions. The search was first conducted on
therapies can be associated with significant adverse March 4, 2020 and updated on July 31, 2020. The
events (AEs), including post inflammatory dyspig- full search strategy is outlined in Supplemental Table
mentation, scarring, and venous thromboembolism.1 S1, available via Mendeley at https://doi.org/10.
Microneedling is a minimally invasive procedure 17632/49v2f4r7js.1.
that creates microperforations within the skin and
has shown efficacy in Study selection, data
improving the transcuta- extraction, and risk of
neous delivery of topical CAPSULE SUMMARY bias assessment
agents.5 Microneedling as Titles, abstracts, and full-
an adjuvant to topical medi- d
Current treatment options for melasma text articles were indepen-
cations has shown promising have shown suboptimal results. dently reviewed by 2 authors
but variable results in d
Microneedling is a safe and effective (A.B. and H.L.). Potentially
treating melasma,1,6 and the adjuvant to topical therapies in melasma. relevant titles and abstracts
literature lacks an evaluation For patients with melasma refractory to were recorded and full-text
of its tolerability and efficacy. topical therapies, clinicians should articles were screened for
This combined systematic consider adding microneedling as a step- final eligibility. A.B. and
review and meta-analysis up option, prior to initiating peels, lasers, H.L. independently extracted
addresses this gap by synthe- or systemic medications. data from included studies.
sizing high-level evidence on The Cochrane Risk of Bias
microneedling as an adju- Tool 2.09 assessed the risk of
vant to topical therapies for the treatment of bias of randomized controlled trials (RCTs) and the
melasma. risk of bias in nonrandomized studies of interven-
tions (ROBINS-I) tool10 assessed the risk of bias of
METHODS nonrandomized studies. Discrepancies were
The study followed Preferred Reporting Items for resolved through discussion with a third author
Systematic Reviews and Meta-Analyses (PRISMA) (M.T.). Study authors were contacted for any missing
guidelines.7 The study protocol was preregistered information, if required.
on PROSPERO (CRD42020180352) and prepared
according to the PRISMA Protocol checklist.8 Evidence synthesis
Data collected from studies were preprocessed
Eligibility criteria within Microsoft Excel before meta-analyses were
All English-language, full-text, comparative, conducted, using Review Manager version 5.4
prospective studies on microneedling with topical (Cochrane Collaboration). The standardized mean
interventions for melasma were included. Studies difference (SMD) combined the different measures
involving radiofrequency microneedling and other of melasma severity.11 A positive SMD was defined as
study types, including case-reports, case series, an improvement in melasma severity. An SMD of 0.2,
reviews, editorials, and retrospective studies, were 0.5, or 0.8 represented small, medium, and large
excluded. summary effect estimates, respectively.12
For improvement from baseline, we assumed a
Study outcomes common correlation r between measures reported
The primary outcome was improvement in before and after treatment to impute the correspond-
melasma severity, evaluated through measures ing standard deviation of the reduction.13 We
such as the Melasma Severity Index (MASI) or its attempted to find whether any study had sufficient
variations. The secondary outcomes were improve- information to calculate the value of correlation
ment in patient satisfaction, quality of life, and any r between measures reported before and after
reported AEs. treatment (e.g., standard deviation or standard error
of the mean of the reduction, P value from t-test of
Literature search strategy the within-group change), and assessed whether the
A comprehensive search strategy was developed results of meta-analyses were sensitive to the choice
with an information specialist (Risa Shorr, Librarian, of r.11 Detailed descriptions of methods and
The Ottawa Hospital). MEDLINE, EMBASE, and data pre-processing are found in Supplemental
Cochrane Central Register of Controlled Trials Material and Supplemental Data, respectively. A
were searched using keywords ‘‘melasma’’ and meta-analysis was performed only when 2 or more
J AM ACAD DERMATOL
VOLUME jj, NUMBER j
Abbreviations used:
AE: adverse event
RCT: randomized controlled trial
MASI: melasma area severity index
SD: standard deviation
SMD: standardized mean difference
TXA: tranexamic acid
studies reported the same outcome. The meta-
analyses results were interpreted according to
published guidelines.14 Studies were analyzed
descriptively if they did not provide sufficient data
for inclusion in a meta-analysis.
The meta-analyses compared: 1) improvement in
melasma severity from baseline to each timepoint in
patients receiving topical therapy with micro-
needling, 2) improvement in melasma severity of
patients receiving topical therapy with micro-
needling to topical therapy alone, and 3) efficacy
of topical therapy with microneedling compared to
microinjections of topical therapy.
Heterogeneity was assessed through the I2 statistic
and the x2 test for homogeneity. An I2 of \30%,
30% to 60%, 60% to 90%, or 90% to 100% was
interpreted as low, moderate, substantial, or critical
heterogeneity, respectively.11 A P \.05 was
considered significant for the test for overall effect
and the x2 test for homogeneity. Funnel plots were
assessed to detect potential small-study effects as a
signal of publication bias.
Melasma severity index
The MASI15 is a validated measure of melasma
severity, which ranges from 0 to 48 points. It is
calculated by forehead with the variables of total area
involved (A), darkness (D), and homogeneity of
hyperpigmentation (H): 0.3(D1H)A 1 right malar
0.3(D1H)A 1 left malar 0.3(D1H)A 1 chin
0.1(D1H)A. Other variations of MASI, modified
MASI, and hemi MASI, range from 0 to 24 points. A
reliable determination for the minimal clinically
important difference for MASI is not present in the
literature.
RESULTS
The literature search retrieved 73 unique records.
Fifty records were excluded after title and abstract
screening and a further 11 after full-text screening. In
total, 12 eligible studies16-27 comprising 459 patients
from 7 different countries were included (Fig 1).
Study characteristics can be found in Table I. Four
hundred forty-seven (97.4%) participants were
female. Participants’ ages ranged from 18 to 62 years
and skin phototypes ranged from II-V. A descriptive
Bailey et al 3
summary of study outcomes and efficacy is displayed
in Table II.
Microneedling protocol
Four studies used mechanical microneedling and
8 studies used electric repeating microneedling
(Table I). The most common needle length was
1.5 mm. Some studies varied penetration depths
from 0.1 to 1.5 mm, depending on anatomic location
treated23,24,27 or pressure applied.16,25 Topical
therapies included topical TXA, vitamin C,
platelet-rich plasma, non-hydroquinone-based
depigmenting serums, and hydroquinone-based
depigmenting agents. All studies, except for Xu
et al,22 used a topical anesthetic 30 to 60 minutes
prior to microneedling. Microneedling was applied
to stretched skin in vertical, horizontal, and both
diagonal directions two18 to fifteen19 times per
session, most commonly 5 times, before and/or after
topical therapy application. Most studies performed
microneedling at 2- to 4-week intervals. Most studies
reported the application of topical therapy and
microneedling only to areas affected by
melasma.16,18,20-27 This information was unclear in
other studies.17,19,22
Risk of bias assessment
Of the 12 studies included, 5 were RCTs, 2 were
randomized split face studies, and 5 were
nonrandomized split face studies (i.e., split face
studies that did not report randomization). Of the
RCTs and randomized split face studies, 5 studies had
some concerns for risk of bias (Table I) for the
following reasons (Supplemental Fig S1): 1) 3
studies16,21,22 did not provide adequate information
on allocation concealment but had similar baseline
characteristics between groups, 2) 2 studies had
insufficient information to determine the method of
randomization,16,22 3) 1 study16 did not provide
adequate information to determine whether the
outcome assessors were blinded and another was
unblinded,25 and 4) 5 studies did not provide
adequate information to determine whether their
data were analyzed according to a published,
prespecified protocol. The remaining 2 randomized
controlled studies17,26 had low risk of bias, as they
were randomized and blinded and reported a
prespecified protocol.
Of the nonrandomized split face studies, 5 had a
moderate risk of bias, as 5 studies did not provide
adequate information to determine whether their
data were analyzed according to a published,
prespecified protocol and 4 studies did not provide
adequate information on allocation concealment
(Supplemental Fig S2). No obvious asymmetry in
4 Bailey et al J AM ACAD DERMATOL
n 2021

Fig 1. Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow
diagram for study selection process. RCT, Randomized controlled trial.

the funnel plots or the small-study effects was
detected as a signal of publication bias
(Supplemental Fig S3).
Meta-analysis
We chose the correlation r between measures
before and after treatment as 0.6 for results presented
in the main text, based on the P value from t-test for
the within-group change and standard deviations
before and after treatment reported in Farshi et al25
(Supplemental Data). We found that estimates with
95% CIs were not sensitive to the choice of this
correlation by trying different values of r. Results of
sensitivity analyses assuming no correlation between
measures before and after treatment are presented in
Supplemental Figs S4 and S5.
Efficacy according to treatment time
The improvement in melasma severity in patients
receiving topical therapy with microneedling
increased with treatment time (Fig 2), based on
randomized split face, nonrandomized split face,
and RCTs. Topical therapy with microneedling
improved melasma severity with moderate effect
(SMD 0.42, 95%CI, 0.21-0.61) at 4 weeks and with
large effect (SMD [0.8) beyond 8 weeks. Across
studies, the greatest improvement was seen at
12 weeks (SMD 1.24, 95%CI, 0.97-1.50). One study
 VOLUME jj, NUMBER j
J AM ACAD DERMATOL
Table I. Characteristics of included studies
Author year Dropout
of publication Participants Experimental group Microneedle Side effects/ rate Risk of
(location) Study design characteristics (E) Control group (C) characteristics adverse events (reason) bias
Budamakuntla Randomized 60 patients Microneedling with Intradermal Mechanical roller: 192 E: Itching (10%), 23% (unknown SC
201316 comparative (6M, 54F); 18-60 topical TXA (4 mg/ microinjections of needles, burning (7%), reasons)
(India) study years old; SPT IV-V mL up to 4 mg) 3 topical TXA (4 mg/ L = 1.5 mm, erythema (13%)
3 sessions (4-week mL up to 8 mg) 3 Diam = 0.25 mm, C: Itching (3%),
intervals) 3 sessions (4-week D = 0.1-1.3 mm burning (3%),
intervals) erythema (13%)
Cassiano Evaluator blinded 64 patients (0M, 64F); (1) Microneedling* (1) Oral placebo 3 Mechanical roller E: 3 (9%) patients had 0% LR
202017 randomized $18 years old and oral placebo 3 60 days (Derma roller, Dr. 1 episode of
(Brazil) clinical trial 60 days (2) Oral TXA 250 mg Roller, Seoul, South herpes simplex
(2) Microneedling* BID 60 days Korea): L = 1.5 mm C: NR
and oral TXA All groups received
250 mg BID 3 broad-spectrum
60 days sunscreen SPF50
*Microneedling daily and Tri-Luma
occurred at 0 and nightly for
4 weeks 120 days.
All groups received
broad-spectrum
sunscreen SPF50
daily and Tri-Luma
nightly for
120 days
Fabbrocini Split face study 20 patients (0M, 20F); Clinic microneedling Depigmenting serum Mechanical roller in E: NR 0% SC
201118 32-60 years old, 3 3 sessions (rucinol and clinic (Dermaroller C: NR
(Italy) SPT III-IV (4-week sophora-alpha) Model CIT 8): 192
intervals) 1 home daily 3 60 days needles,
microneedling Sunscreen daily L = 0.5 mm,
daily 1 topical Diam = 0.02 mm
depigmenting Mechanical roller at
serum (rucinol, Home (Dermaroller
sophora-alpha) Model C8): 196
daily 3 60 days needles,
Sunscreen daily L = 0.13 mm
Hofny Split face study 23 patients (4M, 19F); Topical PRP with Intradermal Electrical repeating E: Less downtime in 0% SC
201919 21-50 years, microneedling 3 3 microinjections of needling (Ostar terms of swelling,
(Egypt) SPT III-IV sessions (4-week PRP 3 3 sessions rechargeable redness, and

Bailey et al 5
intervals) (4-week intervals) dermapen, OB-DG soreness after
*Sunscreen, sun *Sunscreen, sun 03N; Ostar Beauty procedure with
avoidance, and avoidance, and Sci-Tech Co, microneedling
topical antibiotic topical antibiotic Beijing, China): 32 C: More pain with
post procedure post procedure needles, L = 2 mm microinjections
Continued
Table I. Cont’d

6 Bailey et al
Author year Dropout
of publication Participants Experimental group Microneedle Side effects/ rate Risk of
(location) Study design characteristics (E) Control group (C) characteristics adverse events (reason) bias
Menon Split face study 30 patients Topical TXA (4 mg/mL Topical vitamin C Mechanical roller: 192 E & C*: Transient, mild 0% SC
202020 (0M, 30F), 30-49 3 1 mL) with (20%) with needles, itching, and
(India) years, SPT IV-V microneedling 3 2 microneedling 3 2 L = 1.5 mm, burning (33%)
sessions (4-week sessions (4-week Diam = 0.25 mm
intervals) intervals)
Photoprotection Photoprotection
Saleh Randomized, 42 patients (0M, 42F); Topical TXA (1-3 mL Microneedling 3 6 Electrical repeating E & C*: Transient 0% SC
201921 evaluator 24-56 years old, of 100 mg/mL) sessions (2-week needling itching and/or
(Egypt) blinded SPT III-IV with microneedling intervals) (Dermapen DPO5; burning
comparative 3 6 sessions (2- Sunscreen SPF50, Kimlida Electronic
study week intervals) topical fusidic acid Technology Co.,
Sunscreen SPF50, post treatment Guangzhou,
topical fusidic acid China): 12 needles,
post treatment L = 1.5 mm
Xu 201722 Randomized, split 28 patients (0M, 28F); 0.5% Topical TXA with Topical TXA with Electrical repeating E & C*: No significant 6.7% (personal SC
(China) face, evaluator 20-50 years old; microneedling 3 sham device 3 12 microneedling adverse events reasons)
blinded, SPT III-IV 12 sessions (1- sessions (1-week (Nanomed Device were reported
sham-controlled week interval) interval) Inc, Suzhou, China):
study 0.5% Topical TXA with 36 needles,
microneedling L = 0.25 mm,
Diam = 80 m
Ustuner Randomized, split 16 patients (1M, 15F); Microneedling, 1,064-nm QS-Nd:YAG Electrical repeating E: Transient erythema 12.5% (lack of clinical SC
201723 face, double- 30-62 years old; 1,064-nm 3 4 sessions needling and slight response or post
(Turkey) blinded study SPT II-III QS-Nd:YAG, (4-week intervals) (Dermapen): 12 hyperpigmentation inflammatory
microneedling, Sunscreen SPF $15 needles, (6.3%), dyspigmentation)
vitamin C 3 4 L = 1.5 mm (cheeks Irritation (12.5%),
sessions (4-week below the Hypopigmentation
intervals) zygomatic area), (12.5%)
Sunscreen SPF $15 L = 0.5 mm C: Transient erythema
(periorbital areas), and slight
1300 hyperpigmentation
microchannels per (14.2%), irritation
cm2 (6.3%)
Ebrahim Evaluator blinded 56 patients (0M: 56F); Topical TXA (0.5 mL of Intradermal TXA Electrical repeating E & C*: Mild erythema 10.7% (reasons SC

J AM ACAD DERMATOL
202024 split face study 27-50 years old; 4 mg/mL) with (0.5 mL of microneedling and edema unspecified)
(Egypt) SPT III-IV microneedling 3 6 4 mg/mL) 3 1 (Dermapen 3, (44.6%), mild
sessions (2-week session Avon, United irritation (19.6%)
interval) Sunscreen Kingdom): 12 C: Pain at injection
Sunscreen needles, site (42.9%)
L = 1.5 mm,

n 2021
Diam = 0.25 mm,
D = 0.25 to 1 mm
 VOLUME jj, NUMBER j
J AM ACAD DERMATOL
Farshi Split face study 20 patients (1M:19F); Microneedling with Microneedling 3 4 Electrical repeating E & C*: Mild, transient 0% SC
202025 18-50 years old; depigmenting sessions (4-week needling (Amiea erythema, skin
(Iran) SPT III-IV solution (contains intervals) Med, MT Derm dryness, itching,
TXA, N-acetyl Sunscreen SPF $50 GmbH): 6 needles, burning sensation
glucosamine, every 3 hours L = 1.5 mm,
vitamin C, Diam = 0.25 mm,
idebenone) 3 4 D = 0.1 = 1.3 mm
sessions (4-week
intervals)
Sunscreen SPF $50
every 3 hours
Meymandi Evaluator blinded 70 patients (0M: 70F); Topical 4% TXA (up to Topical 4% Electrical repeating E: Transient erythema 14% (3 dropped out LR
202026 randomized 18-35 years old; 8 mg) with hydroquinone, needling (Amiea (83.3%), post because of adverse
(Iran) clinical trial SPT II microneedling 3 3 nightly Med, MT Derm inflammatory events, 7 dropped
sessions (4-week Sunscreen SPF 30 GmbH Gustav- hyperpigmentation out because of
intervals) every 2 hours Krone-Strabe.3, (6.7%) pregnancy and far
Sunscreen SPF 30 during daytime 14167): 6 needles, C: Transient erythema distance)
every 2 hours L = 1.5 mm, (23.3%), post
during daytime Diam = 0.25 mm, inflammatory
D = 0.1 to 1.3 mm hyperpigmentation
(13.3%)
Mekawy Randomized, 30 patients (0M: 30F); Topical TXA (4 mg/ Topical TXA (4 mg/ Electrical repeating E: Post inflammatory 0% SC
202027 evaluator blinded, 29-56 years old; mL) with mL) with fractional needling (Dr Pen): hyperpigmentation
(Egypt) split face study SPT II-IV microneedling 3 6 ablative CO2 12 needles, (10%)
sessions (2-week therapy 3 6 D = 0.25-1 mm C: None
intervals) sessions (2-week according to
Broad-spectrum intervals) location on face
sunscreen and Broad-spectrum
moisturizer sunscreen and
moisturizer

BID, Twice daily; C, control group; D, depth; Diam, diameter; E, experimental group; F, female; L, length; LR, low risk; M, Male; MASI, melasma area severity index; NR, not reported; PRP, platelet-rich
plasma; SC, some concerns; SD, standard deviation; SPT, skin phototype; TXA, tranexamic acid.
*Adverse events for both treatments reported together.

Bailey et al 7
Table II. Outcome measures and description of efficacy across studies

Author, year of publication (location)
Budamakuntla 201316 (India)
Cassiano 202017 (Brazil)
Fabbrocini 201118 (Italy)
Hofny 201919 (Egypt)
Menon 202020 (India)
8 Bailey et al
Outcome measures (measurement points) Efficacy
mMASI, Physician Global Assessment, Patient MN 1 TXA vs intradermal microinjections of TXA
Global Assessment (4, 8, 12, 16, and 20 weeks) 1. % Improvement in mMASI at 4 weeks: 32.45% vs 18.39% (P [.05)
2. % Improvement in mMASI at 8 weeks: 40.59% vs 28.63% (P [.05)
3. % Improvement in mMASI at 12 weeks: 42.71% vs 31.32% (P [.05)
4. % Improvement in mMASI at 16 weeks: 44.41% vs 34.21% (P [.05)
5. % Improvement in mMASI at 20 weeks: 44.41% vs 35.72% (P [.05)
Microinjections vs MN
1. % Improvement in mMASI at 4 weeks: 18.39% vs 32.45%
2. % Improvement in mMASI at 8 weeks: 28.63% vs 40.59%
3. % Improvement in mMASI at 12 weeks: 31.32% vs 42.71%
4. % Improvement in mMASI at 16 weeks: 34.21% vs 44.41%
5. % Improvement in mMASI at 20 weeks: 35.72% vs 44.41%
Modified MASI, MELASQol, L* of perilesional skin Control vs oral TXA vs MN vs MN 1 oral TXA
(4, 8, and 12 weeks) 1. % Improvement in mMASI scores from baseline at T30: -11.1% vs 38.0% vs 32.3% vs
59.3%
2. % Improvement in mMASI scores from baseline at T60: 11.1% vs 64.0% vs 46.2% vs
51.9%
3. % Improvement in mMASI scores from baseline at T120: 19.4% vs 42.0% vs 47.7% vs
50.0%
4. % Improvement in MELASQol scores at T30: 23.3% vs 22.3% vs 29.6% vs 46.7%
5. % Improvement in MELASQol scores at T60: 31.7% vs 41.9% vs 59.2% vs 80.9%
6. % Improvement in MELASQol scores at T120: 33.3% vs 45.5% vs 61.2% vs 75.2%
7. % Improvement in DifL& at T30: 10.0% vs 18.5% vs -1.9% vs 17.8%
8. % Improvement in DifL& at T60: 23.9% vs 22.6% vs 7.1% vs 22.9%
9. % Improvement in DifL& at T12: 27.8% vs 13.1% vs 18.2% vs 21.7%
MASI (no reported SD), MN vs None
L* (1 month, 2 months) 1. % improvement in MASI at 1 month: 24.6% vs 14.7%
2. % improvement in MASI at 2 months: 51.8% vs 34.8%
3. % improvement in L* at 2 months: 19.6% vs 11.2% (P \.05)
MASI, mMASI, hemi MASI (12 weeks) Microinjections vs MN
d % Improvement in hemi MASI: 40.7% vs 41.8%
MASI, Physician Global Assessment, Patient Topical TXA vs Topical Vitamin C
Global Assessment (4 and 8 weeks) 1. % improvement in MASI at 4 weeks: 8.2% vs 3.7%

J AM ACAD DERMATOL
2. % improvement in MASI at 8 weeks: 20.5% vs 12.3%
3. % of patients with ‘‘moderate’’ or ‘‘good’’ PGA at 8 weeks: 60% vs 30
4. % of patients with ‘‘modeate’’ PtGA at 8 weeks: 56.7% vs 16.7%

n 2021

Saleh 201921 (Egypt) MASI (12 weeks)
Xu 201722 (China) VISIA Brown Spot’s score, MI, EI, transepidermal
water loss, hydration, skin surface roughness,
elasticity, blinded physician-reported
assessment, patient-reported satisfaction
(12 weeks)
Ustuner 201723 (Turkey) Melasma Quality of Life questionnaire
(6 months)
Clinician evaluation of clinical response
(1, 2, 3, and 4 months)
MASI (1, 2, 3, and 4 months)
Ebrahim 202024 (Egypt) mMASI, patient self assessment scale,
patient satisfaction scale (4 weeks,
8 weeks, 12 weeks, 3 months follow up)
VOLUME jj, NUMBER j
J AM ACAD DERMATOL
TXA 1 MN vs MN
1. % Improvement in MASI at 12 weeks: 62.1% vs 22.5% (P = .001)
2. % reduction in MART-1 positive melanocytes in epidermis: 61.9% vs 34.4%
3. % reduction in MART-1 positive melanophages in dermis: 56.4% vs 27.4%
4. % reduction in MART-1 positive cells: 60.5% vs 36.1% (P = .001)
TXA 1 MN vs TXA at 12 weeks
1. % Improvement in VISIA Brown Spot score: 15.8% vs 3.4% (P = .004)
2. MI: 18.0% vs 2.9% (P = .002)
3. EI: not reported
4. TEWL: 6.5% vs 3.5%
5. Hydration: 0.6% vs -0.2%
6. Skin surface roughness: 1.9% vs 3.7%
7. Elasticity: 1.8% vs 3.7%
8. Blinded physician-reported improvement: 35.5% vs 9.5%
9. Patient-reported satisfaction as ‘‘satisfied’’ or ‘‘very satisfied’’: 64.3% vs 3.6%
Q-switched Nd:YAG 1 MN 1 Vitamin C vs Q-switched Nd:YAG at 6 months post treatment
1. % improvement in MASI: 64.6% vs 26.3% (P = .001)
2. % of patients with ‘‘good’’ or ‘‘very good’’ clinician-evaluated clinical response: 64.3%
vs 14.3% (P = .002)
MN 1 Nd:YAG vs Nd:YAG
1. Improvement in MASI at 1, 2 3, and 4 months (P = .003, P = .001, P = .001, and
P = .001, respectively; P \.01)
2. Improvement in clinician evaluation of clinical response at 1, 2, 3, and 4 months
(P = .005, P = .002, P = .002 and P = .002, respectively; P \ .01)
3. Improvement in melasma quality of life scores before and after treatment in
MN 1 Nd:YAG group, P = .041
Topical TxA 1 MN vs Intradermal TXA at 3 months follow up 1. % improvement in mMASI: 73.6% vs
74.8% (P [ .05)
2. % of patient-reported clinical response as ‘‘excellent’’ or ‘‘very good’’: 83.9% vs 85.7%
(P [ .05)
3. % of patients with ‘‘very satisfied’’ or ‘‘satisfied’’: 92.9% vs 64.3% (P \.001)
TXA 1 MN vs TXA
1. significant improvement in mMASI score from 13.836 to 3.496 in the injected side
and from13.836 to 3.656 in the MN side (P \.001), with percent of change was 74.8%
and 73.6% in the injected and MN sides
2. no statistically significant difference between both treated sides (P [ .05)
3. patient self assessment: no significant difference between both treated sides
(P [ .05)

Bailey et al 9
4. patient satisfaction was higher in the MN side than that of the injected side (P \.001)
Continued
Table II. Cont’d
Author, year of publication (location)
Farshi 202025 (Iran)
Meymandi 202026 (Iran)
Mekawy 202027 (Egypt)
DifL, Difference between colorimetric luminosity (L*) from perilesional skin to melasma; EI, erythema index; L*, colorimetric lumosity/luminance value; MART-1, melanoma antigen recognized by
T-cells 1; MASI, Melasma Area Severity Index; MELASQol, Melasma Quality of Life; MI, melanin index; mMASI, modified MASI; MN, microneedling; PtGA, patient global assessment; SD, standard
deviation; TEWL, transepidermal water loss; TXA, tranexamic acid.
Outcome measures (measurement points)
mMASI, melanin content using Dermacatch
colorimetry, Investigator Global Assessment,
patient self assessment (2 and 4 months)
mMASI, Investigator’s Global Assessment,
patient self assessment, Dermacatch to
measure mean difference in melanin
content (2 and 4 months)
MASI, patient and physician assessments
(4, 8, and 12 weeks)
mMASI, physician-rated improvement,
patient satisfaction
10 Bailey et al
Efficacy
MN1depigmenting solution vs MN alone at 4 months
1. % improvement in mMASI: 40.0% vs 29.2% (P = .0001)
2. % improvement in melanin content in skin: 54.1% vs 35.8% (P = .0001)
3. % of patients with IGA improvement $ 75%: 50% vs 40% (P = .04)
4. % of patients with self-assessed improvement $75%: 45% vs 30% (P = .04)
MN 1 TXA/Vit C vs MN
1. Greater improvement in MASI in MN 1 TXA/Vit C group compared to MN at
2 months (P = .001) and 4 months (P = .0001)
2. Greater reduction in melanin content in MN1TXA/Vit C group compard to MN
groups at 2 and 4 months (P = .0001 for both)
3. Greater improvement in patient’s self assessment (P = .04)
4. Greater improvement in investigator’s global assessment (P = .04)
TXA 1 MN vs Hydroquinone at 12 weeks
1. % improvement in MASI: 46.9% vs 47.2% (P [.05)
2. % of physician-reported ‘‘excellent’’ or ‘‘good’’ clinical response: 43.3% vs 56.0%
(P [ .05)
3. % of patient-reported ‘‘excellent’’ or ‘‘good’’ clinical response: 43.3% vs 56.6%
(P [ .05)
MN 1 topical TXA vs topical hydroquinone
1. Improvement in MASI score in both groups at 12 weeks compared to baseline
(P \ .01 for both).
2. No statistical difference between groups regarding MASI score, physician and patient
assessments during the treatment
3. Percentage of patient satisfaction was significantly higher than physician satisfaction
in both treatment groups (P \ .01).
Topical TXA 1 MN vs Topical TXA 1 Fractional CO2 laser:
1. % reduction in mMASI: 57.7% vs 55.8% (P [ .05)
2. % of physician-evaluated ‘‘excellent’’ or ‘‘good’’ improvement: 70% vs 70% (P [ .05)
3. % of patient-reported ‘‘excellent’’ or ‘‘good’’ satisfaction: 40% vs 46.7% (P [ .05)
J AM ACAD DERMATOL
n 2021
J AM ACAD DERMATOL Bailey et al 11
VOLUME jj, NUMBER j

Fig 2. Forest plot demonstrating improvement in melasma severity in patients receiving topical
therapy with microneedling over time across studies, based on randomized split face,
nonrandomized split face, and randomized controlled trials.

reported persistent improvement 20 weeks after
treatment (SMD 1.21).
Comparison of microneedling plus topical
therapy to topical therapy alone
Microneedling augmented the efficacy of topical
medications (Fig 3) when the difference between
groups in terms of improvement over time were
pooled, based on 1 randomized split face, 1
nonrandomized split face, and 1 RCT. Compared to
topical therapy alone, topical therapy with
microneedling resulted in an additional improve-
ment in melasma severity at 8 weeks with moderate
effect (SMD 0.45, 95%, CI 0.04-0.86) and a large effect
at 12-16 weeks (SMD 1.04, 95%, CI 0.60-1.48).
Topical therapy with microneedling also resulted in
higher patient satisfaction22 and quality of life17
compared to topical therapy alone.
12 Bailey et al
Fig 3. Forest plot demonstrating comparison of improved melasma severity in patients
receiving topical therapy with microneedling compared to topical therapy alone over time,
based on 1 randomized split face, one nonrandomized split face, and one randomized
controlled trial.
Comparison of microneedling plus topical
therapy to microneedling alone
Microneedling alone resulted in improvements in
melasma severity, with 2 studies21,25 demonstrating
23%-29% improvement in melasma severity after
3-4 months. The addition of topical TXA to
microneedling resulted in further reductions in
MASI21 by 39.6%. The addition of a depigmenting
solution containing TXA, N-acetyl glucosamine,
vitamin C, and idebenone to microneedling resulted
in a further reduction in mMASI by 10.8% and
higher patient-reported improvement scores than
microneedling alone.25
Comparison of microneedling to lasers
One study27 reported similar improvements in
melasma severity and AE rates among patients
receiving topical TXA with microneedling and
patients receiving topical TXA with fractional
ablative carbon dioxide laser. Another study23 found
38.3% greater improvement in melasma severity and
12.5% lower recurrence rate among patients with
recalcitrant melasma treated with vitamin C,
microneedling, and non-ablative Q-switched
Nd:YAG laser compared to Q-switched Nd:YAG laser
monotherapy.
Comparison of microneedling to intradermal
microinjections
Microneedling showed similar efficacy to intra-
dermal microinjections across studies (Supplemental
Fig S6). However, 2 studies16,19 found greater patient
satisfaction and tolerance with microneedling due to
J AM ACAD DERMATOL
n 2021
less skin trauma, decreased pain, and shorter
treatment sessions.
Comparison of microneedling with Tri-Luma
to oral tranexamic acid with Tri-Luma
One study17 compared the efficacy of various
combinations of oral TXA, topical Tri-Luma
(Galderma, Texas), and microneedling. Tri-Luma
with microneedling showed greater efficacy than
oral TXA with Tri-Luma at 16 weeks (median MASI
reduction: 52.7% vs 29.5%). Furthermore, the
addition of oral TXA to Tri-Luma with microneedling
did not result in any further improvement of
melasma or quality of life scores.
AEs of oral TXA were more significant than those
reported with microneedling. Some patients
receiving oral TXA reported nausea, abdominal
pain, hair loss, and blurred vision. One patient
stopped oral TXA due to persistent headache.
Side effects and adverse events
Microneedling was well tolerated across studies.
Common side effects included transient burning,
itching, and erythema. Some studies23,26,27 reported
transient, mild postinflammatory dyspigmentation in
5%-12% of patients. One study17 reported 3 cases of
herpes simplex reactivation after microneedling,
which resolved after oral acyclovir. No scarring or
serious AEs were reported in any study.
DISCUSSION
The current evidence demonstrates that micro-
needling is an effective adjuvant to topical therapy in
J AM ACAD DERMATOL
VOLUME jj, NUMBER j
the treatment of melasma. Across studies, patients
receiving microneedling with topical therapy
experienced a large improvement in melasma
beyond 8 weeks, with best results seen at 12 weeks.
In comparison to topical therapy alone, topical
therapies with microneedling resulted in a moderate
improvement in melasma severity at 8 weeks and a
large improvement at 12-16 weeks, in addition to
higher patient satisfaction and better patient-
reported quality of life, while having similar AE
rates.In contrast to intradermal microinjections,
microneedling had similar efficacy, higher patient
satisfaction, and a more tolerable side-effect profile.
Lastly, a high-quality RCT24 demonstrated superior
efficacy and a more favorable AE profile of
microneedling compared to oral tranexamic acid,
when both modalities were used with
hydroquinone-based depigmenting medication.
Across all studies, microneedling was safe and well
tolerated by patients, with transient side effects and
minimal AEs.
The mechanism of action supporting the efficacy
of microneedling in the treatment of melasma
includes: 1) increased transcutaneous delivery of
topical agents through microchannels in the skin
created by microneedles,28,29 2) wounding, which
stimulates the skin healing response, leading
to the proliferation of fibroblasts, resulting in
neocollagenesis, neoelastogenesis and epidermal
thickening,28-30 and 3) improved transcutaneous
elimination of melanin.31 Among the studies
included, most topical therapies targeted either
1) tyrosinase to inhibit melanogenesis,21,26,32
2) plasmin and angiogenic growth factors to inhibit
angiogenesis,21 or 3) proinflammatory cytokines,
such as nuclear factor kappa b or prostaglandin to
inhibit inflammation.26,32 Due to the lack of direct
comparisons in the literature, a comparison of the
efficacy of different topical therapies with
microneedling could not be performed. Future
studies should investigate the efficacy of various
topical therapies with microneedling in the treatment
of melasma.
Microneedling has significant advantages
compared to other methods of transcutaneous drug
delivery. Notably, microneedling has a low
complication rate and minimal downtime,16 and it
can be used in darker skin phenotypes.20,26,28 The
current literature demonstrates increased efficacy of
topical therapy with microneedling regardless of the
range of needle lengths (0.25 to 1.5 mm) used across
studies. This may be due to the stratum corneum,
being the most impermeable layer of the epidermis
and the main obstacle for topical agents, allows for
increased delivery once perforated by the
Bailey et al 13
microneedles.33,34 The thickness of stratum corneum
ranges from 0.01 to 0.02 mm, and the use of a
microneedle with sufficient depth of penetration will
lead to the enhanced delivery of topical therapies.35
It is, however, important to consider that
microneedling may not penetrate as deeply and
uniformly as expected36 and is operator-
dependent. Of note, increased treatment efficacy of
topical therapies with microneedling was observed,
regardless of the fact that some studies used electric
repeating while others used mechanical rolling. It is
plausible that trauma to the skin, regardless of depth,
stimulates the wound-healing response, which
triggers neocollagenesis and neo-elastogenesis.30
Because the current literature demonstrates
increased efficacy of topical therapies regardless of
depth of penetration, home-based microneedling
devices, with proper care instructions, may provide
an accessible and low-cost alternative.18 Future
studies comparing home-based microneedling and
office-based microneedling devices are needed.
This study has a few limitations. Firstly, a variety
of study designs were pooled, specifically
randomized split face, nonrandomized split face,
and RCTs. However, this study’s main conclusions
were unchanged when studies were pooled
according to design, as 1) all study types supported
the fact that topical therapy with microneedling
improves melasma severity with a large effect
beyond 8 weeks with maximal effect at 12 weeks
(Supplemental Fig S7; tests for subgroup difference
yielded P value 0.9 for 12 weeks and 0.58 for
16 weeks) and 2) randomized studies demonstrated
long-term (12 of 16 weeks) improvement of melasma
severity with the use of topical therapy with
microneedling compared to topical monotherapy,
with a large effect (Supplemental Fig S8; tests for
design difference yielded nonsignificant P values).
Second, the efficacy of microneedling in the
treatment of melasma according to topical therapy,
depth of penetration, and microneedling type is
unclear due to limited direct comparisons of these
factors in the literature. Nonetheless, this review
provides a complete summary and the best possible
interpretation of the current evidence.
Third, 5 randomized trials and randomized split
face studies were found to have some concerns for
risk of bias and 5 nonrandomized split face studies
had a moderate risk of bias. However, this study
attempted to capture the best evidence available
through the inclusion of only prospective, controlled
studies. Furthermore, these studies had low risk of
bias in most categories and reported similar results
among themselves and to the low risk studies
(Supplemental Fig S9).
14 Bailey et al
Fourth, moderate heterogeneity was observed in
the meta-analysis of studies according to treatment
duration. However, this heterogeneity is to be
expected, considering the different topical therapies,
treatment protocols, device settings, and patient
populations across studies.
CONCLUSION
Current treatment options for melasma have
shown suboptimal results, with incomplete pigment
clearance and high recurrence rates.1 This combined
systematic review and meta-analysis demonstrates
that microneedling is a useful adjuvant to topical
therapies in melasma. For patients with melasma
refractory to topical therapies, clinicians should
consider adding microneedling as a step-up option,
prior to initiating peels, lasers, or systemic
medications.
Conflicts of interest
None disclosed.
REFERENCES
1. McKesey J, Tovar-Garza A, Pandya AG. Melasma treatment: an
evidence-based review. Am J Clin Dermatol. 2020;21(2):173-225.
2. Sheth VM, Pandya AG. Melasma: a comprehensive update:
part I. J Am Acad Dermatol. 2011;65(4):689-697.
3. Sivayathorn A. Melasma in Orientals. Clin Drug Investig. 1995;
10(Suppl 2):34-40.
4. Werlinger KD, Guevara IL, Gonzalez CM, et al. Prevalence of
self-diagnosed melasma among premenopausal Latino
women in Dallas and Fort Worth, Tex. Arch Dermatol. 2007;
143(3):424-425.
5. Singh A, Yadav S. Microneedling: advances and widening
horizons. Indian Dermatol Online J. 2016;7(4):244-254.
6. Wu SZ, Muddasani S, Alam M. A systematic review of the
efficacy and safety of microneedling in the treatment of
melasma. Dermatol Surg. 2020;46(12):1636-1641.
7. Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA Group.
Preferred reporting items for systematic reviews and meta-
analyses: the PRISMA statement. PLoS Med. 2009;6(7):e1000097.
8. Moher D, Shamseer L, Clarke M, et al. Preferred reporting items
for systematic review and meta-analysis protocols (PRISMA-P)
2015 statement. Syst Rev. 2015;4(1):1.
9. Sterne JAC, Savovic J, Page MJ, et al. RoB 2: a revised Cochrane
risk-of-bias tool for randomized trials. BMJ. 2019;366:l4898.
10. Sterne JA, Hernan MA, Reeves BC, et al. Robins-I: A tool for
assessing risk of bias in non-randomised studies of interven-
tions. BMJ. 2016;355:i4919.
11. Higgins JPT, Green S, eds. Cochrane Handbook for Systematic
Reviews of Interventions version 5.1.0. The Cochrane Collabo-
ration; 2011.
12. Cohen J. Statistical power analysis. Curr Dir Psychol Sci. 1992;
1(3):98-101.
13. Chapter 4. Effect sizes based on means. In: Borenstein M,
Hedges LV, Higgins JPT, Rothstein HR, eds. Introduction to
Meta-Analysis. 2009:21-32.
J AM ACAD DERMATOL
n 2021
14. Treadwell JR, Tregear SJ, Reston JT, Turkelson CM. A system for
rating the stability and strength of medical evidence. BMC Med
Res Methodol. 2006;6:52.
15. Rodrigues M, Ayala-Cortes AS, Rodrıguez-Arambula A,
Hynan LS, Pandya AG. Interpretability of the modified
melasma area and severity index (mMASI). JAMA Dermatol.
2016;152(9):1051-1052.
16. Budamakuntla L, Loganathan E, Suresh D, et al. A randomised,
open-label, comparative study of tranexamic acid microinjec-
tions and tranexamic acid with microneedling in patients with
melasma. J Cutan Aesthet Surg. 2013;6(3):139-143.
17. Cassiano D, Esposito ACC, Hassun K, et al. Efficacy and safety of
microneedling and oral tranexamic acid in the treatment of
facial melasma in women: an open, evaluator-blinded, random-
ized clinical trial. J Am Acad Dermatol. 2020;83(4):1176-1178.
18. Fabbrocini G, De Vita V, Fardella N, et al. Skin needling to
enhance depigmenting serum penetration in the treatment of
melasma. Plast Surg Int. 2011;2011:158241.
19. Hofny ERM, Abdel-Motaleb AA, Ghazally A, Ahmed AM,
Hussein MRA. Platelet-rich plasma is a useful therapeutic
option in melasma. J Dermatolog Treat. 2019;30(4):396-401.
20. Menon A, Eram H, Kamath P, Goel S, Babu A. A split face
comparative study of safety and efficacy of microneedling
with tranexamic acid versus microneedling with vitamin C in
the treatment of melasma. Indian Dermatol Online J. 2020;
11(1):41-45.
21. Saleh FY, Abdel-Azim ES, Ragaie MH, Guendy MG. Topical
tranexamic acid with microneedling versus microneedling
alone in treatment of melasma: clinical, histopathologic, and
immunohistochemical study. J Egypt Women’s Dermatol Soc.
2019;16(2). https://doi.org/10.4103/JEWD.JEWD_25_19.
22. Xu Y, Ma R, Juliandri J, et al. Efficacy of functional microarray of
microneedles combined with topical tranexamic acid for
melasma: a randomized, self-controlled, split-face study. Med
(Baltim). 2017;96(19):e6897.
23. Ustuner P, Balevi A, Ozdemir M. A split-face, investigator-
blinded comparative study on the efficacy and safety of Q-
switched Nd:YAG laser plus microneedling with vitamin C
versus Q-switched Nd:YAG laser for the treatment of recalci-
trant melasma. J Cosmet Laser Ther. 2017;19(7):383-390.
24. Ebrahim HM, Said Abdelshafy A, Khattab F, Gharib K. Tranexa-
mic acid for melasma treatment: a split-face study. Dermatol
Surg. 2020;46(11):e102-e107.
25. Farshi S, Mansouri P. Study of efficacy of microneedling and
mesoneedling in the treatment of epidermal melasma: a pilot
trial. J Cosmet Dermatol. 2020;19(5):1093-1098.
26. Shamsi Meymandi S, Mozayyeni A, Shamsi Meymandi M,
Aflatoonian M. Efficacy of microneedling plus topical 4%
tranexamic acid solution vs 4% hydroquinone in the treatment
of melasma: a single-blind randomized clinical trial. J Cosmet
Dermatol. 2020;19(11):2906-2911.
27. Mekawy KMM, Sadek A, Seddeik Abdel-Hameed AK. Micro-
needling versus fractional carbon dioxide laser for delivery of
tranexamic acid in the treatment of melasma: a split-face study.
J Cosmet Dermatol. 2021;20(2):460-465.
28. Cohen BE, Elbuluk N. Microneedling in skin of color: a review
of uses and efficacy. J Am Acad Dermatol. 2016;74(2):348-355.
29. Fabbrocini G, De Vita V, Monfrecola A, et al. Percutaneous
collagen induction: an effective and safe treatment for
post-acne scarring in different skin phototypes. J Dermatolog
Treat. 2014;25(2):147-152.
30. Cassiano DP, Esp osito ACC, Hassun KM, Lima EVA, Bagatin E,
Miot HA. Early clinical and histological changes induced by
J AM ACAD DERMATOL
VOLUME jj, NUMBER j
microneedling in facial melasma: a pilot study. Indian J
Dermatol Venereol Leprol. 2019;85(6):638-641.
31. Jung JW, Kim WO, Jung HR, Kim SA, Ryoo YW. A face-split
study to evaluate the effects of microneedle radiofrequency
with Q-switched Nd:YAG laser for the treatment of melasma.
Ann Dermatol. 2019;31(2):133.
32. Telang P. Vitamin C in dermatology. Indian Dermatol Online J.
2013;4(2):143-146.
33. Hadgraft J. Skin, the final frontier. Int J Pharm. 2001;224(1-2):
1-18.
Bailey et al 15
34. Trommer H, Neubert RHH. Overcoming the stratum corneum:
the modulation of skin penetration. A review. Skin Pharmacol
Physiol. 2006;19(2):106-121.
35. Verbaan FJ, Bal SM, van den Berg DJ, et al. Assembled
microneedle arrays enhance the transport of compounds
varying over a large range of molecular weight across human
dermatomed skin. J Control Release. 2007;117(2):238-245.
36. Kalluri H, Kolli CS, Banga AK. Characterization of microchannels
created by metal microneedles: formation and closure. AAPS J.
2011;13(3):473-481.