Lasers in Surgery and Medicine 42:607–612 (2010)
Non-Ablative 1,550nm Fractional Laser Therapy Versus
Triple Topical Therapy for the Treatment of Melasma:
A Randomized Controlled Split-Face Study
Bas S. Wind, MD,1,2* Marije W. Kroon, MD,1,2Arne A. Meesters, MSc,1Johan F. Beek, MD, PhD,3
J.P. Wietze van der Veen, MD, PhD,1,2,4Ludmila Nieuweboer-Krobotova ´, MD,1,2,4Jan D. Bos, MD, PhD, FRCP,2
and Albert Wolkerstorfer, MD, PhD1,2
1Netherlands Institute for Pigment Disorders (SNIP), Academic Medical Center, University of Amsterdam,
NL-1105AZ Amsterdam, The Netherlands
2Department of Dermatology, Academic Medical Center, University of Amsterdam, NL-1100DD Amsterdam,
3Department of Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam,
NL-1105AZ Amsterdam, The Netherlands
4The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL), NL-1006BE Amsterdam,
disorder, with poor long-term results from all current
Objective: To assess efficacy and safety of non-ablative
1,550nm fractional laser therapy (FLT) as compared to the
gold standard, triple topical therapy (TTT).
Study design: Twenty-nine patients with melasma were
included in a randomized controlled observer-blinded
study with split-face design. Each side of the face was
(15mJ/microbeam, 14–20% coverage) or TTT (hydroqui-
none 5%, tretinoin 0.05%, triamcinolone acetonide 0.1%
cream). TTT was applied once daily for 15 weeks until
the last FLT session. After this last treatment, patients
were asked to apply TTT twice weekly on both sides of
the face during follow-up. Improvement of melasma was
assessed by patient’s global assessment (PGA), patient’s
satisfaction, physician’s global assessment (PhGA), mela-
nin index, and lightness (L-value) at 3 weeks, and at 3 and
6 months after the last treatment.
Results: Mean PGA and satisfaction were significantly
L-value showed a significant worsening of hyperpigmenta-
tion at the FLT side. At the TTT side, no significant change
was observed. At 6 months follow-up, most patients
preferred TTT. Side effects of FLT were erythema, burning
sensation, edema, and pain. Nine patients (31%) developed
PIH after two or more laser sessions. Side effects of TTT
were erythema, burning sensation, and scaling.
Conclusions: Given the high rate of postinflammatory
hyperpigmentation, non-ablative 1,550nm fractional laser
at 15mJ/microbeam is not recommendable in the treatment
of melasma. TTT remains the gold standard treatment.
Lasers Surg. Med. 42:607–612, 2010.
? 2010 Wiley-Liss, Inc.
Key words: Fraxel laser; topical bleaching; pigment
parts of the face, primarily the cheeks, forehead, upper lip,
nose, and chin. It frequently poses a substantial emotional
and psychosocial burden on patients, and adversely affects
patient’s quality of life . Melasma is found in all skin
types but is especially seen in women with Fitzpatrick skin
types IV–VI . The pathogenesis is not fully understood,
but genetic background and sun exposure seem to be the
most important etiologic factors besides pregnancy, sys-
temic drugs, hormonal medications, and phototoxic or
photoallergic cosmetics .
Because of its refractory and recurrent nature, melasma
is difficult to manage. Current treatments include topical
bleaching creams, chemical peels, and laser therapy.
However, results are often disappointing.
Treatment of choice is triple topical therapy (TTT) that
was first introduced in 1975 as the Kligman formula
consisting of hydroquinone (HQ) 5%, tretinoin 0.1%, and
Abbreviations Used: HQ, hydroquinone; PGA, Patient’s Global
Assessment; PhGA, Physician’s Global Assessment; PIH, post-
inflammatory hyperpigmentation; SNIP, Netherlands Institute
for Pigment Disorders; SPF, sun protection factor; SPSS,
Statistical Package for the Social Sciences; VAS, Visual Analogue
Bas S. Wind and Marije W. Kroon contributed equally to this
The authors certify that they have no affiliation with or
financial involvement in any organization or entity with a direct
financial interest in the subject matter or materials discussed in
the manuscript (e.g., employment, consultancies, stock owner-
*Correspondence to: Bas S. Wind, MD, Netherlands Institute
for Pigment Disorders (SNIP), Meibergdreef 35, 1105 AZ
Amsterdam, The Netherlands. E-mail: email@example.com
Accepted 23 April 2010
Published online in Wiley Online Library
? 2010 Wiley-Liss, Inc.
HQ and tretinoin are combined with various moderately
potent to potent corticosteroids [4,5].
In melasma, results of lasers and intense pulsed light
systems are generally disappointing and treatment is
limited by adverse effects, mainly the occurrence of
postinflammatory hyperpigmentation (PIH), especially in
dark-skinned patients. As a result, the use of these devices
is controversial [6,7].
Recently, non-ablative fractional laser therapy (FLT) at
1,550nm was suggested as a treatment for melasma [8–
10]. At this wavelength water absorption is predominant.
FLT generates multiple small sized coagulated zones,
separated by surrounding untreated tissue . It has
been suggested that these microscopic treatment zones
allow transport and extrusion of microscopic epidermal
necrotic debris including melanin from melanocytes
througha compromised dermal–epidermal
these microscopic treatment zones have a diameter
<100mm . The stratum corneum was found to be intact
after 24hours [13,14]. As only part of the skin surface is
treated in one session, recovery is relatively fast.
with melasma, although evidence for efficacy is poor. In a
to be a safe and potentially useful alternative treatment
option for melasma . Given the lack of serious side
effects and relative poorer clearance of melasma in skin
types IV and V, optimization of laser dosimetry was
suggested . Moreover, a high recurrence rate was
observed at 6 months follow-up. The aim of the present
study was to compare non-ablative 1,550nm FLT and TTT
for the treatment of melasma in a split-face design, using
more aggressive settings for FLT and long-term intermit-
tent maintenance bleaching during follow-up.
PATIENTS AND METHODS
A randomized controlled observer-blinded study with a
split-face design was performed in 29 patients. Patients
older than 18 years with Fitzpatrick skin type II–V and
melasma were included from the outpatient clinic of
the Netherlands Institute for Pigment Disorders at the
Academic Medical Center in Amsterdam (Table 1).
The study protocol has been approved by the local
medical ethics committee and registered in the clinical-
trials.govtrial register (clinicaltrials.gov
NCT01085279). Written and verbal information including
creams for at least 4 weeks prior to study entry. Exclusion
the face, history of facial eczema, suspected hypersensitiv-
ity to lidocaine or TTT, use of isotretinoin in the past
6 months, pregnancy, and high exposure to sunlight or
UV light (UVA or UVB). Type of melasma was assessed
by Wood’s lamp examination [15,16]. All patients were
instructed to use sunscreen (SPF 50þ) every 2hours when
randomly allocated to either non-ablative 1,550nm FLT
or TTT. The randomization procedure involved sealed
envelopes were numbered from 1 to 29. Envelopes were
opened in ascending order. The randomization was based
on a digitally created random list (GraphPad Software,
Inc., La Jolla, CA) generated by the independent coopera-
tor. Treatment started in March 2009 and ended in May
2009. Follow-up visits at our institute were scheduled at
3 weeks, 3 months, and 6 months after the last laser
treatment. Hence, follow-up ended November 2009.
Triple Topical Therapy
In all patients, one side of the face was treated with TTT
(HQ 5%, tretinoin 0.05%, triamcinolone acetonide 0.1%
cream) for 15 weeks. Patients were instructed to apply
cream once a day in the evening on all hyperpigmented
macules of one side of the face. After this last treatment,
patients were asked to apply TTT twice weekly on both
sides of the face during follow-up.
Fractional Laser Therapy
The side of the face allocated to FLT was treated with a
Solta Medical, Inc., Hayward, CA). One treatment session
final density of ?2,000–2,500 microscopic treatment zones
per cm2. Four passes were made in one direction and four
perpendicularly. The energy per microbeam was 15mJ.
TABLE 1. Patient Characteristics
Disease duration (years)
Oral anticonception during study
Triple topical therapy
Intense pulsed light
Fractional laser therapy
*As assessed by Wood’s lamp examination.
608 WIND ET AL.
with ?20% coverage (level 7), patients with skin types III
and IV during five sessions with ?17% coverage (level 6),
and patients with skin type V during five sessions with
?14% coverage (level 5). During treatment, cooling of the
skin was achieved using a Zimmer Cryo 6 Cold Air Device
(Phoenix Medical, Inc., Phoenix, AZ). Anesthesia consisted
of topical 0.025% lidocaine and 0.025% prilocaine ointment
1hour prior to each treatment.
The occurrence of side effects was assessed at each FLT
visit and at 3 weeks follow-up. All side effects were
documented and patients were asked to score erythema,
edema, crusting, and blistering on a scale from 0 to 3.
Patients were asked to score the improvement of hyper-
analogue scale from 0 to 10, with 0 as no improvement
and 10 as total clearance (Patient’s Global Assessment,
PGA). Treatment satisfaction was also scored on a visual
analogue scale from 0 to 10. Furthermore, patients were
asked which treatment they preferred and which treat-
ment they would recommend to friends or colleagues. Pain
wasrecorded ona scalefrom0 to10afterthefirst andthird
Reflectance Spectroscopy and Melanin Index
Improvement of hyperpigmentation was assessed by
color measurement through reflectance spectroscopy
(Microflash 200 d; Datacolor International, Lawrenceville,
GA) by a blinded investigator. This instrument, with
an aperture of 4mm, determines color by measuring the
intensity of reflected light of particular wavelengths.
In this study, the obtained L-value, indicating the light-
ness of the measured area of skin, was used. In addition,
melanin index was measured using a chromameter
(Derma-Spectrometer; Cortex Technology ApS, Hadsund,
Denmark) in order to assess changes in the amount
of dermal and epidermal melanin. Measurements were
performed on a selected homogenous macule at both
treated and control site and at normal skin before the first
treatment and at follow-up.
At start, location of measurements was documented
using a charcoal pencil and digital photography. The same
locations were assessed at follow-up.
Physician’s Global Assessment
As recommended in the guidelines for clinical trials in
melasma , a blinded observer dermatologist assessed
the Physician’s Global Assessment (PhGA) as main out-
come parameter using photographs that were taken under
standardized conditions with a digital camera (Canon G6;
Canon Components, Inc., Saitama, Japan) before treat-
was scored on a scale from 0 to 6 (0: total clearance (100%
improvement), 1: almost total clearance (90% improve-
ment), 2: distinct clearance (75% improvement), 3: moder-
ate clearance (50% improvement), 4: mild clearance
(25% improvement), 5: no change, 6: worsening of hyper-
Standard deviations of the difference in response
of matched pairs (s) regarding triple therapy and non-
ablative fractional laser are not reported in the literature.
of 1 with a standard deviation of 1.5 on the PhGA scale.
A sample size of 20 patients was calculated to have a power
of 80% with an alpha of 0.05. To correct for potential drop
out we aimed to recruit 30 patients.
Means, standard deviations, two-tailed homoscedastic
Student’s t-tests, ANOVA tests, and chi-square tests were
performed with Statistical Package for the Social Sciences
16.0 (SPSS, Chicago, IL).
Table 1. Twenty-three patients completed the trial. Mean
energy per laser treatment was 0.74kJ. The laser settings
are summarized in Table 2.
and treatment satisfaction were significantly lower at the
FLT side (P<0.001, Table 3). At 6 months follow-up, a
significantly higher number of patients preferred TTT.
a significant worsening of hyperpigmentation of the
FLT side compared to baseline during follow-up (P<0.05).
TABLE 2. Settings of Non-Ablative 1,550nm Fractional
Skin type II
Level 7 (?20% coverage),
Level 6 (?17% coverage),
Level 5 (?14% coverage),
Skin types III and IV
Skin type V
Number of passes per session
Mean number of treatments
Mean energy per treatment
TABLE 3. Patient-Reported Outcomes
3 weeks3 months6 months
Patient’s Global Assessment (VAS)
Patient’s satisfaction (VAS)
Advise to friends/colleagues (%)
FRACTIONAL LASER VS. TRIPLE THERAPY FOR MELASMA 609
Treatment with TTT did not result in significant changes
during follow-up (P<0.05). At the TTT side, no significant
improvement or worsening was observed.
influenced by the use of oral anticonceptives.
Side effects at the FLT side consisted of sunburn-like
erythema (99%) with an average duration of 4 days and
edema with an average duration of 2 days. Crusting and
blistering were reported by 6% and 4% of patients,
respectively. Patients reported an average pain score of
5.4 on a scale from 0 to 10. All patients returned to work or
normal activity immediately after the laser treatment.
Nine patients (31%) developed PIH at the FLT side after
two or more laser treatments (Fig. 2). All these patients
had Fitzpatrick skin type III or higher. PIH occurred in
frequency (33% and 25%, respectively). Patients who
developed PIH were excluded for further laser treatments.
Hypopigmentation and scarring were not observed.
Reported side effects at the TTT side were erythema
continuous as long as treatment was applied. Forty-
seven percent of patients reported scaling. One patient
was forced to stop TTT after 6 weeks because of severe
erythema. This patient was treated with triamcinolone
acetonide 0.1% instead and later with HQ 5% and
not safe and effective in the treatment of melasma.
Maintenance treatment at the FLT side did not result in
improved clearance of melasma. At the TTT side, no
significant improvement or worsening was observed. At
6 months follow-up, a significantly higher number of
patients preferred TTT.
To date, there are five uncontrolled studies involving a
total of 51 patients with melasma who were treated with
non-ablative FLT using a 1,550nm Fraxel Re:store laser
(Solta Medical, Inc.) [8,9,14,18,19]. Only one randomized
trial has been performed involving 10 patients with
melasma treated with the Fraxel Re:store laser and 10
patients treated with TTT . In one uncontrolled study,
three patients with melasma were treated with a 1,440nm
Affirm laser (Cynosure, Inc., Westford, MA) . In the
studies using the Fraxel Re:store laser, settings ranged
from 2,000 to 3,500 microthermal zones per cm2at 6–
15mJ/microbeam. The number of treatments ranged from
improvement of 20–50% was reported by all six patients
shortly after the last treatment session . At 3 months
follow-up, a mild to excellent clinical improvement was
noted in 20 of 23 patients [9,14,20]. Furthermore, in 10 of
improvement of hyperpigmentation . A remarkable
improvement of melasma up to 6 months posttreatment in
one patient was reported by Tannous and Astner . In
contrast, the two larger studies with a 6-month follow-up
showed a gradual recurrence of melasma during follow-up
The reported side effects such as erythema, burning
sensation, and scaling of the TTT are well known.
In our study, side effects of non-ablative 1,550nm FLT
were comparablewith those
The average pain score of 5.4 is comparable with the
6.3 and 6.4 (both on a scale from 0 to 10) reported by
Rokhsar and Fitzpatrick  and Kroon et al. .
However, the high rate of PIH after non-ablative
Fig. 1. Blinded physician’s global assessment of non-ablative 1,550nm fractional laser
therapy and triple topical therapy during follow-up. Significant worsening of melasma was
seen during follow-up at the FLT side (F(1,18)¼7.84, P<0.05).
610 WIND ET AL.
1,550nm FLT found in this study (31%) contrasts
with the findings in other studies. In the literature,
the occurrence of PIH ranges up to 17% [9,10,14,18,19].
In two studies, involving a total of 20 patients treated
with non-ablative 1,550nm FLT, PIH was not noted at
Non-ablative 1,550nm FLT is widely used in melasma
and the risk for development of PIH is generally thought to
be minimal. However, in the present settings the risk of
PIH is substantial.
Firstly, treatment in spring may have led to a high sun
exposure of the laser treated site, increasing the risk of
of PIH, although patients were instructed to use sunscreen
every 2hours when outside. In addition, as sun exposure
is a risk factor for the development and worsening of
FLT and TTT might be due to the treatment in spring and
follow-up in summer.
Furthermore, the relatively high laser settings used
in this study might be responsible for the occurrence of
PIH. In comparison to most other studies, patients were
treated with a relatively high energy per microbeam
(15mJ). Although some authors state that the occurrence
of PIH is primarily determined by the density of micro-
or that it is not dependent on laser parameters at all,
there are reasons to suppose that the energy per
microbeam does play an important role in the develop-
ment of PIH [21,22]. In a previous randomized study
using the same device, we observed no PIH when treating
with an energy of 10mJ/microbeam . This is in sharp
contrast with our present finding of PIH in 31% of
patients. It should be noted that the present study was
performed in spring and an energy of 15mJ/microbeam
was applied. The latter does not necessarily lead to such a
high rate of PIH. Using the same laser settings, PIH was
found in 13% of 25 patients with skin type III or IV in a
study by Lee et al. .
A minor limitation might be the effect of cooling on
the efficacy and safety of non-ablative 1,550nm FLT.
Although cooling is supposed to minimize patient’s
discomfort during treatment, it also negatively influences
the size of microscopic treatment zones and therefore
compromises treatment efficacy [23,24]. Moreover, cold
air cooling has been suggested to increase the risk for
Although TTT did not show a significant improvement
during treatment and follow-up, possibly due to treatment
in spring, it remains the gold standard for the treatment
of melasma. There is abundant clinical experience and
evidence for the efficacy of TTT in the treatment in
melasma [4–7]. Costs are lower and the treatment is
safer and less painful.
In conclusion, non-ablative 1,550nm FLT is not effective
in the treatment of melasma using 15mJ/microbeam in
spring time. Given the relatively high rate of PIH, caution
is advocated in the usage of non-ablative 1,550nm FLT at
Fig. 2. Clinical photographs of a patient before treatment
(A), at 3 weeks (B), 3 months (C), and 6 months (D). The right
side of the face was treated with triple topical therapy for
FRACTIONAL LASER VS. TRIPLE THERAPY FOR MELASMA611
ACKNOWLEDGMENTS Download full-text
The laser equipment and disposables were kindly
provided by B&Co Laser Medico (Herzele, Belgium) and
Solta Medical, Inc. exclusively for the purpose of this
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