Lasers in Surgery and Medicine 42:607–612 (2010)

Non-Ablative 1,550 nm 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,1,2 Arne A. Meesters, MSc,1 Johan F. Beek, MD, PhD,3
J.P. Wietze van der Veen, MD, PhD,1,2,4 Ludmila Nieuweboer-Krobotová, MD,1,2,4 Jan D. Bos, MD, PhD, FRCP,
2

and Albert Wolkerstorfer, MD, PhD1,2

1
Netherlands Institute for Pigment Disorders (SNIP), Academic Medical Center, University of Amsterdam,
NL-1105AZ Amsterdam, The Netherlands
2
Department of Dermatology, Academic Medical Center, University of Amsterdam, NL-1100DD Amsterdam,
The Netherlands
3
Department of Biomedical Engineering and Physics, Academic Medical Center, University of Amsterdam,
NL-1105AZ Amsterdam, The Netherlands
4
The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital (NKI-AVL), NL-1006BE Amsterdam,
The Netherlands

Background: Melasma is a uichronic, often relapsing skin INTRODUCTION

disorder, with poor long-term results from all current Melasma is a common cause of hyperpigmentation and is
therapies. hallmarked by irregular brown macules on the sun-exposed
Objective: To assess efficacy and safety of non-ablative parts of the face, primarily the cheeks, forehead, upper lip,
1,550 nm fractional laser therapy (FLT) as compared to the nose, and chin. It frequently poses a substantial emotional
gold standard, triple topical therapy (TTT). and psychosocial burden on patients, and adversely affects
Study design: Twenty-nine patients with melasma were patient’s quality of life [1]. Melasma is found in all skin
included in a randomized controlled observer-blinded types but is especially seen in women with Fitzpatrick skin
study with split-face design. Each side of the face was types IV–VI [2]. The pathogenesis is not fully understood,
randomly allocated to either 4–5 non-ablative FLT sessions but genetic background and sun exposure seem to be the
(15 mJ/microbeam, 14–20% coverage) or TTT (hydroqui- most important etiologic factors besides pregnancy, sys-
none 5%, tretinoin 0.05%, triamcinolone acetonide 0.1% temic drugs, hormonal medications, and phototoxic or
cream). TTT was applied once daily for 15 weeks until photoallergic cosmetics [3].
the last FLT session. After this last treatment, patients Because of its refractory and recurrent nature, melasma
were asked to apply TTT twice weekly on both sides of is difficult to manage. Current treatments include topical
the face during follow-up. Improvement of melasma was bleaching creams, chemical peels, and laser therapy.
assessed by patient’s global assessment (PGA), patient’s However, results are often disappointing.
satisfaction, physician’s global assessment (PhGA), mela- Treatment of choice is triple topical therapy (TTT) that
nin index, and lightness (L-value) at 3 weeks, and at 3 and was first introduced in 1975 as the Kligman formula
6 months after the last treatment. consisting of hydroquinone (HQ) 5%, tretinoin 0.1%, and
Results: Mean PGA and satisfaction were significantly dexamethasone 0.1%. Nowadays, different concentration of
lower at the FLT side (P<0.001). PhGA, melanin index, and
L-value showed a significant worsening of hyperpigmenta-
tion at the FLT side. At the TTT side, no significant change Abbreviations Used: HQ, hydroquinone; PGA, Patient’s Global
was observed. At 6 months follow-up, most patients Assessment; PhGA, Physician’s Global Assessment; PIH, post-
inflammatory hyperpigmentation; SNIP, Netherlands Institute
preferred TTT. Side effects of FLT were erythema, burning for Pigment Disorders; SPF, sun protection factor; SPSS,
sensation, edema, and pain. Nine patients (31%) developed Statistical Package for the Social Sciences; VAS, Visual Analogue
PIH after two or more laser sessions. Side effects of TTT Scale.
Bas S. Wind and Marije W. Kroon contributed equally to this
were erythema, burning sensation, and scaling. work.
Conclusions: Given the high rate of postinflammatory The authors certify that they have no affiliation with or
financial involvement in any organization or entity with a direct
hyperpigmentation, non-ablative 1,550 nm fractional laser financial interest in the subject matter or materials discussed in
at 15 mJ/microbeam is not recommendable in the treatment the manuscript (e.g., employment, consultancies, stock owner-
of melasma. TTT remains the gold standard treatment. ship, honoraria).
*Correspondence to: Bas S. Wind, MD, Netherlands Institute
Lasers Surg. Med. 42:607–612, 2010. for Pigment Disorders (SNIP), Meibergdreef 35, 1105 AZ
ß 2010 Wiley-Liss, Inc. Amsterdam, The Netherlands. E-mail: [email protected]
Accepted 23 April 2010
Published online in Wiley Online Library
Key words: Fraxel laser; topical bleaching; pigment (wileyonlinelibrary.com).
disorder DOI 10.1002/lsm.20937

ß 2010 Wiley-Liss, Inc.

608 WIND ET AL.

HQ and tretinoin are combined with various moderately TABLE 1. Patient Characteristics
potent to potent corticosteroids [4,5]. Male/female ratio 2:27
In melasma, results of lasers and intense pulsed light Mean age 41 (29–59)
systems are generally disappointing and treatment is Skin type
limited by adverse effects, mainly the occurrence of II 6
postinflammatory hyperpigmentation (PIH), especially in III 12
dark-skinned patients. As a result, the use of these devices IV 8
is controversial [6,7]. V 3
Recently, non-ablative fractional laser therapy (FLT) at Melasma type*
1,550 nm was suggested as a treatment for melasma [8– Epidermal 21
10]. At this wavelength water absorption is predominant. Mixed 8
FLT generates multiple small sized coagulated zones, Disease duration (years) 5 (1–17)
separated by surrounding untreated tissue [11]. It has Oral anticonception during study 5
been suggested that these microscopic treatment zones Previous therapy
allow transport and extrusion of microscopic epidermal Corticosteroid 1
necrotic debris including melanin from melanocytes Azelaic acid 13
through a compromised dermal–epidermal junction Hydroquinone 3
[11,12]. Generally, a visible wound does not appear because Triple topical therapy 25
these microscopic treatment zones have a diameter Peeling 11
<100 mm [11]. The stratum corneum was found to be intact Intense pulsed light 1
after 24 hours [13,14]. As only part of the skin surface is Fractional laser therapy 4
treated in one session, recovery is relatively fast.
Currently, non-ablative FLT is regularly used in patients *As assessed by Wood’s lamp examination.
with melasma, although evidence for efficacy is poor. In a
previous randomized parallel group study conducted at our
institute, non-ablative FLT at 10 mJ per microbeam proved by Wood’s lamp examination [15,16]. All patients were
to be a safe and potentially useful alternative treatment instructed to use sunscreen (SPF 50þ) every 2 hours when
option for melasma [10]. Given the lack of serious side outside.
effects and relative poorer clearance of melasma in skin On the day of the first treatment each side of the face was
types IV and V, optimization of laser dosimetry was randomly allocated to either non-ablative 1,550 nm FLT
suggested [10]. Moreover, a high recurrence rate was or TTT. The randomization procedure involved sealed
observed at 6 months follow-up. The aim of the present envelopes in which the allocation was indicated. The sealed
study was to compare non-ablative 1,550 nm FLT and TTT envelopes were numbered from 1 to 29. Envelopes were
for the treatment of melasma in a split-face design, using opened in ascending order. The randomization was based
more aggressive settings for FLT and long-term intermit- on a digitally created random list (GraphPad Software,
tent maintenance bleaching during follow-up. Inc., La Jolla, CA) generated by the independent coopera-
tor. Treatment started in March 2009 and ended in May
PATIENTS AND METHODS 2009. Follow-up visits at our institute were scheduled at
3 weeks, 3 months, and 6 months after the last laser
Study Design/Patients treatment. Hence, follow-up ended November 2009.
A randomized controlled observer-blinded study with a
split-face design was performed in 29 patients. Patients Triple Topical Therapy
older than 18 years with Fitzpatrick skin type II–V and In all patients, one side of the face was treated with TTT
melasma were included from the outpatient clinic of (HQ 5%, tretinoin 0.05%, triamcinolone acetonide 0.1%
the Netherlands Institute for Pigment Disorders at the cream) for 15 weeks. Patients were instructed to apply
Academic Medical Center in Amsterdam (Table 1). cream once a day in the evening on all hyperpigmented
The study protocol has been approved by the local macules of one side of the face. After this last treatment,
medical ethics committee and registered in the clinical- patients were asked to apply TTT twice weekly on both
trials.gov trial register (clinicaltrials.gov identifier: sides of the face during follow-up.
NCT01085279). Written and verbal information including
risks, benefits, and potential complications was given to the Fractional Laser Therapy
patients, and written informed consent was obtained. None The side of the face allocated to FLT was treated with a
of the patients had used bleaching creams or topical steroid 1,550 nm Er:glass non-ablative laser (Fraxel Re:store laser,
creams for at least 4 weeks prior to study entry. Exclusion Solta Medical, Inc., Hayward, CA). One treatment session
criteria were: history of keloid, active eczema, active acne in involved eight fractional laser passes to create an estimated
the face, history of facial eczema, suspected hypersensitiv- final density of 2,000–2,500 microscopic treatment zones
ity to lidocaine or TTT, use of isotretinoin in the past per cm2. Four passes were made in one direction and four
6 months, pregnancy, and high exposure to sunlight or perpendicularly. The energy per microbeam was 15 mJ.
UV light (UVA or UVB). Type of melasma was assessed Patients with skin type II were treated during four sessions
 FRACTIONAL LASER VS. TRIPLE THERAPY FOR MELASMA 609

with 20% coverage (level 7), patients with skin types III TABLE 2. Settings of Non-Ablative 1,550 nm Fractional
and IV during five sessions with 17% coverage (level 6), Laser
and patients with skin type V during five sessions with Pulse energy 15 mJ
14% coverage (level 5). During treatment, cooling of the Level
skin was achieved using a Zimmer Cryo 6 Cold Air Device Skin type II Level 7 (20% coverage),
(Phoenix Medical, Inc., Phoenix, AZ). Anesthesia consisted 4 sessions
of topical 0.025% lidocaine and 0.025% prilocaine ointment Skin types III and IV Level 6 (17% coverage),
1 hour prior to each treatment. 5 sessions
Skin type V Level 5 (14% coverage),
Patient-Reported Outcomes
5 sessions
The occurrence of side effects was assessed at each FLT Number of passes per session 8
visit and at 3 weeks follow-up. All side effects were Mean number of treatments 3.6 (1–5)
documented and patients were asked to score erythema, Mean energy per treatment 0.74 kJ
edema, crusting, and blistering on a scale from 0 to 3.
Patients were asked to score the improvement of hyper-
pigmentation at both sides of the face separately on a visual
analogue scale from 0 to 10, with 0 as no improvement Statistical Analysis
and 10 as total clearance (Patient’s Global Assessment, Standard deviations of the difference in response
PGA). Treatment satisfaction was also scored on a visual of matched pairs (s) regarding triple therapy and non-
analogue scale from 0 to 10. Furthermore, patients were ablative fractional laser are not reported in the literature.
asked which treatment they preferred and which treat- However, we estimated that the difference would be a mean
ment they would recommend to friends or colleagues. Pain of 1 with a standard deviation of 1.5 on the PhGA scale.
was recorded on a scale from 0 to 10 after the first and third A sample size of 20 patients was calculated to have a power
treatment. of 80% with an alpha of 0.05. To correct for potential drop
out we aimed to recruit 30 patients.
Reflectance Spectroscopy and Melanin Index
Means, standard deviations, two-tailed homoscedastic
Improvement of hyperpigmentation was assessed by Student’s t-tests, ANOVA tests, and chi-square tests were
color measurement through reflectance spectroscopy performed with Statistical Package for the Social Sciences
(Microflash 200 d; Datacolor International, Lawrenceville, 16.0 (SPSS, Chicago, IL).
GA) by a blinded investigator. This instrument, with
an aperture of 4 mm, determines color by measuring the RESULTS
intensity of reflected light of particular wavelengths. The characteristics of the 29 treated patients are listed in
In this study, the obtained L-value, indicating the light- Table 1. Twenty-three patients completed the trial. Mean
ness of the measured area of skin, was used. In addition, energy per laser treatment was 0.74 kJ. The laser settings
melanin index was measured using a chromameter are summarized in Table 2.
(Derma-Spectrometer; Cortex Technology ApS, Hadsund, An intention to treat analysis was performed. Mean PGA
Denmark) in order to assess changes in the amount and treatment satisfaction were significantly lower at the
of dermal and epidermal melanin. Measurements were FLT side (P<0.001, Table 3). At 6 months follow-up, a
performed on a selected homogenous macule at both significantly higher number of patients preferred TTT.
treated and control site and at normal skin before the first Assessment by the blinded dermatologist (PhGA) showed
treatment and at follow-up. a significant worsening of hyperpigmentation of the
At start, location of measurements was documented FLT side compared to baseline during follow-up (P<0.05).
using a charcoal pencil and digital photography. The same
locations were assessed at follow-up.
TABLE 3. Patient-Reported Outcomes
Physician’s Global Assessment
As recommended in the guidelines for clinical trials in 3 weeks 3 months 6 months
melasma [17], a blinded observer dermatologist assessed Patient’s Global Assessment (VAS)
the Physician’s Global Assessment (PhGA) as main out- FLT 5.7 (0–10)* 4.9 (0–9)* 4.7 (0–10)*
come parameter using photographs that were taken under TTT 5.0 (0–9) 5.7 (1–10) 6.1 (0–9)
standardized conditions with a digital camera (Canon G6; Patient’s satisfaction (VAS)
Canon Components, Inc., Saitama, Japan) before treat- FLT 5.7 (0–10)* 3.5 (0–8)* 5.3 (1–10)*
ment and at follow-up. Improvement of hyperpigmentation TTT 5.1 (0–8) 5.5 (1–10) 6.2 (0–8)
was scored on a scale from 0 to 6 (0: total clearance (100% Advise to friends/colleagues (%)
improvement), 1: almost total clearance (90% improve- FLT 50 37 26
ment), 2: distinct clearance (75% improvement), 3: moder- TTT 28 42 48
ate clearance (50% improvement), 4: mild clearance No preference 22 21 26
(25% improvement), 5: no change, 6: worsening of hyper-
pigmentation) [17]. *P < 0.001.
610 WIND ET AL.

Fig. 1. Blinded physician’s global assessment of non-ablative 1,550 nm 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) ¼ 7.84, P<0.05).

Treatment with TTT did not result in significant changes Maintenance treatment at the FLT side did not result in
(Fig. 1). improved clearance of melasma. At the TTT side, no
Melanin index and L-value showed a significant increase significant improvement or worsening was observed. At
of hyperpigmentation at the FLT side compared to baseline 6 months follow-up, a significantly higher number of
during follow-up (P<0.05). At the TTT side, no significant patients preferred TTT.
improvement or worsening was observed. To date, there are five uncontrolled studies involving a
PhGA, melanin index, and L-value were not significantly total of 51 patients with melasma who were treated with
influenced by the use of oral anticonceptives. non-ablative FLT using a 1,550 nm Fraxel Re:store laser
Side effects at the FLT side consisted of sunburn-like (Solta Medical, Inc.) [8,9,14,18,19]. Only one randomized
erythema (99%) with an average duration of 4 days and trial has been performed involving 10 patients with
burning sensation (86%) with an average duration of 1 day. melasma treated with the Fraxel Re:store laser and 10
Sixty percent of patients reported moderate-to-severe facial patients treated with TTT [10]. In one uncontrolled study,
edema with an average duration of 2 days. Crusting and three patients with melasma were treated with a 1,440 nm
blistering were reported by 6% and 4% of patients, Affirm laser (Cynosure, Inc., Westford, MA) [20]. In the
respectively. Patients reported an average pain score of studies using the Fraxel Re:store laser, settings ranged
5.4 on a scale from 0 to 10. All patients returned to work or from 2,000 to 3,500 microthermal zones per cm2 at 6–
normal activity immediately after the laser treatment. 15 mJ/microbeam. The number of treatments ranged from
Nine patients (31%) developed PIH at the FLT side after 1 to 6. Follow-up ranged from 0 to 6 months. In one study, an
two or more laser treatments (Fig. 2). All these patients improvement of 20–50% was reported by all six patients
had Fitzpatrick skin type III or higher. PIH occurred in shortly after the last treatment session [18]. At 3 months
both epidermal and mixed type melasma with a comparable follow-up, a mild to excellent clinical improvement was
frequency (33% and 25%, respectively). Patients who noted in 20 of 23 patients [9,14,20]. Furthermore, in 10 of
developed PIH were excluded for further laser treatments. these 23 patients, histological analysis showed a significant
Hypopigmentation and scarring were not observed. improvement of hyperpigmentation [14]. A remarkable
Reported side effects at the TTT side were erythema improvement of melasma up to 6 months posttreatment in
(46%) and burning sensation (19%), which was occasionally one patient was reported by Tannous and Astner [8]. In
continuous as long as treatment was applied. Forty- contrast, the two larger studies with a 6-month follow-up
seven percent of patients reported scaling. One patient showed a gradual recurrence of melasma during follow-up
was forced to stop TTT after 6 weeks because of severe [10,19].
erythema. This patient was treated with triamcinolone The reported side effects such as erythema, burning
acetonide 0.1% instead and later with HQ 5% and sensation, and scaling of the TTT are well known.
triamcinolone 0.1%. In our study, side effects of non-ablative 1,550 nm FLT
were comparable with those reported by others.
The average pain score of 5.4 is comparable with the
DISCUSSION 6.3 and 6.4 (both on a scale from 0 to 10) reported by
Using 15 mJ/microbeam, non-ablative 1,550 nm FLT was Rokhsar and Fitzpatrick [9] and Kroon et al. [10].
not safe and effective in the treatment of melasma. However, the high rate of PIH after non-ablative
 FRACTIONAL LASER VS. TRIPLE THERAPY FOR MELASMA 611

1,550 nm 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 1,550 nm FLT, PIH was not noted at
all [10,14].
Non-ablative 1,550 nm 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
laser-induced PIH. This may partially explain the high rate
of PIH, although patients were instructed to use sunscreen
every 2 hours when outside. In addition, as sun exposure
is a risk factor for the development and worsening of
melasma, the limited efficacy of both non-ablative 1,550 nm
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
(15 mJ). Although some authors state that the occurrence
of PIH is primarily determined by the density of micro-
scopic treatment zones and not the energy per microbeam,
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 10 mJ/microbeam [10]. 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 15 mJ/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. [19].
A minor limitation might be the effect of cooling on
the efficacy and safety of non-ablative 1,550 nm 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
PIH [25].
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 1,550 nm FLT is not effective
Fig. 2. Clinical photographs of a patient before treatment in the treatment of melasma using 15 mJ/microbeam in
(A), at 3 weeks (B), 3 months (C), and 6 months (D). The right spring time. Given the relatively high rate of PIH, caution
side of the face was treated with triple topical therapy for is advocated in the usage of non-ablative 1,550 nm FLT at
15 mJ/microbeam.
612 WIND ET AL.

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