Research

Original Investigation

Melatonin Supplementation for Children

With Atopic Dermatitis and Sleep Disturbance
A Randomized Clinical Trial
Yung-Sen Chang, MD, MPH; Ming-Hung Lin, MD, MS; Jyh-Hong Lee, MD, PhD; Pei-Lin Lee, MD, PhD;
Yang-Shia Dai, MD, MS; Kuan-Hua Chu, PhD; Chi Sun, MD; Yu-Tsan Lin, MD, PhD; Li-Chieh Wang, MD, PhD;
Hsin-Hui Yu, MD; Yao-Hsu Yang, MD, PhD; Chun-An Chen, MD, PhD; Kong-Sang Wan, MD, PhD;
Bor-Luen Chiang, MD, PhD

Supplemental content at
IMPORTANCE Sleep disturbance is common in children with atopic dermatitis (AD), but jamapediatrics.com
effective clinical management for this problem is lacking. Reduced levels of nocturnal
melatonin were found to be associated with sleep disturbance and increased disease severity
in children with AD. Melatonin also has sleep-inducing and anti-inflammatory properties and
therefore might be useful for the management of AD.

OBJECTIVE To evaluate the effectiveness of melatonin supplementation for improving the

sleep disturbance and severity of disease in children with AD.

DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial used a double-blind,
placebo-controlled crossover design to study 73 children and adolescents aged 1 to 18 years
with physician-diagnosed AD involving at least 5% of the total body surface area. The study
was conducted at the pediatric department of a large tertiary care hospital in Taiwan from
August 1, 2012, through January 31, 2013. Forty-eight children were randomized 1:1 to
melatonin or placebo treatment, and 38 of these (79%) completed the cross-over period of
the trial. Final follow-up occurred on April 13, 2013, and data were analyzed from January 27
to April 25, 2014. Analyses were based on intention to treat.

INTERVENTIONS Melatonin, 3 mg/d, or placebo for 4 weeks followed by a 2-week washout

period and then crossover to the alternate treatment for 4 weeks.

MAIN OUTCOMES AND MEASURES The primary outcome was AD severity evaluated using the
Scoring Atopic Dermatitis (SCORAD) index, with scores ranging from 0 to 103 and greater
scores indicating worse symptoms. Secondary outcomes included sleep variables measured
by actigraphy, subjective change in sleep and dermatitis, sleep variables measured by
polysomnography, nocturnal urinary levels of 6-sulfatoxymelatonin, and serum IgE levels.

RESULTS After melatonin treatment among the 48 children included in the study, the
SCORAD index decreased by 9.1 compared with after placebo (95% CI, −13.7 to −4.6;
P < .001), from a mean (SD) of 49.1 (24.3) to 40.2 (20.9). Moreover, the sleep-onset latency
shortened by 21.4 minutes after melatonin treatment compared with after placebo (95% CI,
−38.6 to −4.2; P = .02). The improvement in the SCORAD index did not correlate significantly
with the change in sleep-onset latency (r = −0.04; P = .85). No patient withdrew owing to
adverse events, and no adverse event was reported throughout the study.

CONCLUSIONS AND RELEVANCE Melatonin supplementation is a safe and effective way to

improve the sleep-onset latency and disease severity in children with AD. Author Affiliations: Author
affiliations are listed at the end of this
TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01638234 article.
Corresponding Author: Bor-Luen
Chiang, MD, PhD, Department of
Medical Research, National
Taiwan University Hospital,
7 Chung-Shan S Rd,
JAMA Pediatr. 2016;170(1):35-42. doi:10.1001/jamapediatrics.2015.3092 Taipei 100, Taiwan
Published online November 16, 2015. ([email protected]).

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 Research Original Investigation Melatonin Supplementation for Atopic Dermatitis With Sleep Disturbance

A
topic dermatitis (AD) is a common chronic, relapsing,
pruritic inflammatory skin disease affecting 15% to At a Glance
30% of all children and 2% to 10% of all adults. 1
• Sleep disturbance is common in children with atopic dermatitis
Disturbed sleep is reported in 47% to 60% of children with AD (AD), but effective clinical management for this problem is
and is a major factor leading to an impaired quality of life.2-4 lacking. A reduced level of nocturnal melatonin was found to be
At present, limited studies are available to guide effective associated with sleep disturbance and greater severity of disease
clinical management of sleep disturbances in AD. Some in children with AD. Our study evaluated the effectiveness of
investigators5,6 have studied whether treatment targeted at melatonin supplementation for children with AD.
• After melatonin treatment, the sleep-onset latency shortened
skin inflammation in patients with AD also improves their
by 21.4 minutes compared with placebo (95% CI, −38.6 to −4.2;
sleep, but the results have been inconsistent, and most of these P = .02).
studies used a subjective visual analog scale rather than • Severity of AD also improved after melatonin treatment, with a
objective measures to evaluate sleep. decrease in the Scoring Atopic Dermatitis index of 9.1 compared
Previous studies7 have found that reduced nocturnal mela- with placebo (95% CI, −13.7 to −4.6; P < .001).
tonin secretion was associated with sleep disturbance and • No adverse events were reported throughout the study.
greater severity of disease in children with AD. Melatonin is a
hormone secreted by the pineal gland and is important in sleep
regulation.8 Oral melatonin has a sedative effect and has been of medication for insomnia or of antidepressants within 4
used for the management of insomnia and jet lag. Previous weeks before the baseline visit.
studies9-11 have shown that melatonin could shorten sleep-
onset latency and increase total sleep time and sleep effi- Randomization and Masking
ciency, possibly owing to its ability to decrease the core body The study participants were randomly assigned to 2 groups
temperature.12 Melatonin also has immunomodulatory, anti- in a 1:1 ratio (Figure 1), with a block size of 4. One group re-
inflammatory, and antioxidative effects,13-15 which might im- ceived melatonin first and then placebo, and the other group
prove the skin inflammation and help to maintain a func- received placebo first and then melatonin. Randomization was
tional epidermal barrier in patients with AD.15 Furthermore, performed with a computer-generated sequence by special-
melatonin has been found to be safe with minimal adverse ef- ized personnel who had no further involvement in the rest of
fects, which makes it a favorable choice for children.9,16 There- the trial. The melatonin and placebo tablets were identical in
fore, we aimed to investigate whether melatonin supplemen- appearance. The participants and their caregivers, treating phy-
tation is effective for improving the skin inflammation and sicians, those assessing outcomes, and those analyzing the data
sleep disturbances in children with AD. were all masked to group assignment. Allocation codes were
disclosed only after the entire clinical trial was completed.

Procedures
Methods The participants first underwent a 2-week prescreening
Study Design period in which they kept a sleep diary, adhered to a fixed
We performed a randomized clinical study with a double- sleep schedule, and avoided caffeinated drinks. They were
blind, placebo-controlled crossover design at a single tertiary then randomized to receive oral melatonin, 3 mg/d (General
care hospital in Taiwan. The institutional review committee Nutrition Corporation), or placebo (Standard Chem & Pharm
of National Taiwan University Hospital approved the study pro- Co, Ltd) at bedtime for 4 weeks. After a 2-week washout
tocol (the protocol is available in Supplement 1). This study con- period, participants crossed to the alternate treatment. The
formed to the principles of the Declaration of Helsinki.17 Pa- study medication served as an add-on therapy to each
tients or their guardians provided written informed consent. patient’s original treatments for AD, which were maintained
to be the same throughout the study period. Visits occurred
Participants at the start of the trial (screening) and on the first and last
Patients aged 1 to 18 years with physician-diagnosed AD in- day of each treatment period, during which AD disease
volving at least 5% of the total body surface area were re- severity was assessed, blood and urine samples were col-
cruited from the pediatric and dermatology outpatient depart- lected, questionnaires evaluating subjective symptoms were
ments of the National Taiwan University Hospital from August filled out, and pill count and adverse events were recorded.
1, 2012, through January 31, 2013. Follow-up was completed Severity of AD was assessed using the Scoring Atopic Derma-
on April 13, 2013. Those patients with sleep problems occur- titis (SCORAD) index (range, 1-103, with greater scores indi-
ring more than 3 days per week during the previous 3 months cating worse symptoms)18 by the same physician (Y.-S.C.)
were eligible. A sleep problem was defined as any difficulty with blinded to the treatment randomization. The SCORAD index
sleep initiation or maintenance that led to impaired quality of includes subjective visual analog scale scores from 0 to 10
life or interfered with daytime activities for the child or for fam- (with greater numbers indicating worse symptoms) for
ily members. Exclusion criteria included documented sleep dis- degree of pruritus and sleep loss, which are referred to as the
orders, such as dyssomnias, parasomnias, and circadian pruritus score and the subjective sleep score, respectively, in
rhythm sleep disorders; neuropsychiatric disorders or any other this study. The objective SCORAD index,19 which excludes
medical condition that might produce sleep problems; or use the SCORAD score for subjective symptoms (range, 0-83,

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 Melatonin Supplementation for Atopic Dermatitis With Sleep Disturbance Original Investigation Research

Figure 1. CONSORT Diagram of the Randomization and Follow-up of the Study Participants

73 Patients assessed for eligibility

25 Ineligible
2 Subjective sleep problems
improved before enrollment
23 Did not offer consent

48 Enrolled

48 Randomized

24 Randomized to 24 Randomized to
melatonin (weeks 1-4) placebo (weeks 1-4)

6 Withdrew Washout period 4 Withdrew

3 Other family members disagreed (weeks 5-6) 2 Other family members disagreed
2 Changed their minds 2 Changed their minds
1 Poor compliance

20 Randomized to 18 Randomized to
melatonin (weeks 7-10) placebo (weeks 7-10)

20 Underwent evaluation 18 Underwent evaluation

with greater scores indicating worse symptoms), was raphy, nocturnal urinary levels of 6-sulfatoxymelatonin, and
also used for analysis. Sleep was evaluated by actigraphy serum total and allergen-specific IgE levels. Definitions of the
(Mini-Mitter Actiwatch; Philips-Respironics). Each partici- sleep variables recorded in this study are described in eTable
pant wore the actigraphic device on the nondominant wrist 1 in Supplement 2.
for 3 consecutive nights starting 3 nights before each treat-
ment period and for the last 3 nights of each treatment Statistical Analysis
period. In a subgroup of patients who offered consent, poly- Data were analyzed from January 27 to April 25, 2014. Effi-
somnography was performed on the night before the first cacy analyses were conducted by modified intention to
day and on the last night of each treatment period. The first treat, excluding the patients who withdrew consent within 1
urine sample on the morning after each actigraphic exami- week after randomization. We used linear mixed-effects
nation was obtained. Levels of urinary 6-sulfatoxymelatonin models to compare the mean change in outcomes after vs
were assayed by enzyme-linked immunosorbent assay with before treatment between the melatonin and placebo
a commercialized kit (IBL International GmbH) and were phases. The model included an indicator variable for phase
used to represent the melatonin level throughout the previ- (melatonin or placebo), time (before or after treatment),
ous night.20,21 A peripheral blood sample was taken from phase × time interaction, sequence (melatonin first or pla-
each participant at 9 AM on the morning after the last night cebo first), and period (before or after the crossover). We
of the sleep examination and stored at −80°C until measure- adjusted for age and sex as potential confounders. Patient-
ments were performed. The serum total IgE level and levels specific random intercepts were used to account for the cor-
of allergen-specific IgE to Dermatophagoides pteronyssinus relation owing to repeated measures. A carryover effect was
(Derp), Dermatophagoides farinae (Derf ), Staphylococcus defined as a statistically significant sequence effect. Owing
aureus enterotoxin A, and S aureus enterotoxin B were mea- to the relatively small sample size, we also performed the
sured with a fluorescence enzyme immunoassay (Immuno- Wilcoxon signed rank test as a sensitivity analysis to com-
CAP; Phadia AB). Allergen-specific IgE levels higher than pare the difference of each outcome measure before and
0.35 kU/L were defined as positive. after treatment between melatonin and placebo. The Wil-
coxon signed rank test was also used for subgroup analyses.
Outcomes We used the McNemar test to analyze binary outcomes. For
The primary study outcome was the SCORAD index for the sample size calculation, we considered a SCORAD index
evaluation of AD severity. Secondary outcomes included the decrease of 5.0 to be significant, and with the assumption
objective sleep variables measured by actigraphy, the pa- that the SD is 10, we needed 32 patients to achieve 80%
tient’s subjective description of the change in sleep and der- power at α = .05. Assuming a withdrawal rate of 33%, we
matitis severity, the sleep variables measured by polysomnog- randomized a total of 48 patients. Statistical analyses were

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 Research Original Investigation Melatonin Supplementation for Atopic Dermatitis With Sleep Disturbance

Table 1. Baseline Characteristics of the Patients at Randomization

Patients by Treatment Groupa

All Patients Melatonin Placebo
Characteristic (N = 48) (n = 24) (n = 24)
Female, No. (%) 23 (48) 13 (54) 10 (42) Abbreviations: SCORAD, Scoring
Atopic Dermatitis; WASO, wake after
Age, y 7.5 (3.7) 7.6 (4) 7.3 (3.5)
sleep onset.
SCORAD indexb 47.3 (22.7) 48.0 (24.9) 46.6 (20.7) a
Determined by which treatment
Objective SCORAD indexc 37.0 (21.3) 38.7 (22.8) 35.2 (20.1) was received first. Unless otherwise
Pruritus scored 5.6 (2.3) 5.0 (2.4) 6.3 (2.0) indicated, data are expressed as
mean (SD). For all between-group
Subjective sleep loss scored 4.7 (2.8) 4.3 (2.4) 5.1 (3.1)
comparisons, P > .05.
Sleep-onset latency, min 36.5 (39.9) 41.8 (42.7) 31.4 (37.2) b
Scores range from 0 to 103, with
Sleep efficiency, % 77.4 (12.0) 75.3 (12.3) 79.3 (11.7) greater scores indicating worse
WASO, min 74.2 (44.5) 73.5 (41.8) 74.9 (47.8) symptoms.
c
Wake in sleep interval, % 15.2 (9.2) 16.1 (9.7) 14.4 (8.8) Scores range from 0 to 83, with
greater scores indicating worse
Total sleep time, min/night 415.8 (81.0) 393.0 (88.1) 437.7 (68.3) symptoms.
Mobility in sleep, % 10.6 (6.9) 11.6 (7.9) 9.6 (5.9) d
Scores range from 0 to 10, with
Fragmentation indexe 15.6 (8.7) 17.3 (9.2) 14.0 (8.1) greater scores indicating worse
symptoms.
Serum IgE level, kU/L 2130.5 (3222.9) 1882.6 (2451.7) 2389.7 (3915.2)
e
Greater scores indicate more
Urinary 6-sulfatoxymelatonin level, ng/mL 53.5 (62.7) 54.0 (66.0) 52.9 (61.1)
fragmented sleep.

performed with SAS software (version 9.3; SAS Institute Evaluation of sleep variables measured by actigraphy
Inc). All the tests were 2 sided with an α level of .05. showed that the melatonin group had a greater decrease in
the sleep-onset latency than the placebo group in the first
(from 42.8 [48.5] to 24.4 [17.6] minutes vs 34.5 [31.0] to 22.9
[16.5] minutes) and the second (from 46.7 [31.3] to19.1 [22.8]
Results minutes vs 27.9 [25.3] to 37.5 [28.7] minutes) treatment
We recruited 73 children with AD from August 1, 2012, periods (eTable 2 in Supplement 2). The linear mixed-effects
through January 31, 2013. After exclusion, 48 patients model showed that after adjusting for age and sex, melato-
underwent randomization (median age, 7 years; age range, nin treatment resulted in a decrease of the sleep-onset
1.8-17.1 years). Baseline demographic and clinical character- latency by 21.4 minutes more than placebo (95% CI, −38.6
istics are detailed in Table 1. Withdrawals all occurred dur- to −4.2; P = .02) (Table 2). We found no significant carryover
ing the first treatment period (6 patients from the melatonin effect or period effect (eTable 3 in Supplement 2). The effect
group and 4 from the placebo group). Reasons for with- on the other sleep variables measured by actigraphy did not
drawal were similar between groups. Of the 38 patients differ significantly between the melatonin and placebo
undergoing evaluation by modified intention to treat, 18 phases (Table 2). The results from the Wilcoxon signed rank
were randomized to the melatonin phase first, and 20 were test arrived at the same conclusions (Table 2 and Figure 2D).
randomized to the placebo phase first (Figure 1). The reduction in the sleep-onset latency did not correlate
Regarding AD severity, we found that the melatonin significantly with the degree of improvement in the
group had a greater decrease in the mean (SD) SCORAD SCORAD index with melatonin treatment (r = −0.04;
index than the placebo group in the first treatment period P = .85).
(from 49.5 [25.7] to 42.3 [21.6] vs from 49.0 [21.6] to 48.8 More patients subjectively believed that their dermatitis
[20.2]) and the second treatment period (from 48.7 [23.6] to had improved after melatonin treatment compared with pla-
38.3 [20.7] vs from 46.8 [22.8] to 44.6 [20.5]) (eTable 2 in cebo (17 of 36 [47%] vs 12 of 38 [32%]), and more patients be-
Supplement 2). The linear mixed-effects model showed that lieved that their sleep had improved after melatonin treat-
after adjusting for age and sex, melatonin treatment resulted ment compared with placebo (17 of 37 [46%] vs 13 of 38 [34%]),
in a decrease of the SCORAD index by 9.1 compared with pla- but neither difference reached statistical significance (P = .20
cebo (95% CI, −13.7 to −4.6; P < .001) (Table 2). We found no and P = .30, respectively; eTable 4 in Supplement 2). Thir-
significant carryover effect (P = .67) (Figure 2B and eTable 3 teen patients underwent polysomnography in addition to ac-
in Supplement 2). The period effect was signific ant tigraphy. Melatonin and placebo treatment did not have a sig-
(P = .009). Melatonin treatment also resulted in a decrease nificantly different effect on the stages of sleep and limb
of the objective SCORAD index by 8.7 compared with pla- movement (P > .05).
cebo (95% CI, −12.6 to −4.8; P < .001) (Table 2), with no sig- Nocturnal urinary 6-sulfatoxymelatonin levels signifi-
nificant carryover effect (P = .81) and a significant period cantly increased after treatment with melatonin compared with
effect (P = .02) (eTable 3 in Supplement 2). The Wilcoxon placebo (P < .001). We found no significant difference be-
signed rank test yielded results consistent with the linear tween the effects of melatonin and placebo on total IgE level
mixed-effects model (Table 2 and Figure 2A and C). or on allergen-specific IgE levels to Derp, Derf, or S aureus

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 Melatonin Supplementation for Atopic Dermatitis With Sleep Disturbance Original Investigation Research

Table 2. Effects of Melatonin vs Placebo

Results by Study Phase, Mean (SD) Difference of Treatment

Effect From the Linear
Melatonin Placebo Mixed-Effects Modela
Measure Before After Difference Before After Difference Mean (95% CI) P Value P Valueb
SCORAD indexc 49.1 (24.3) 40.2 (20.9) −9.9 (7.6) 48.0 (21.9) 46.8 (20.2) −0.7 (8.6) −9.1 (−13.7 to −4.6) <.001 <.001
Objective 38.6 (22.1) 31.3 (19.2) −8.2 (7.2) 37.4 (20.8) 37.6 (19.4) −0.6 (6.3) −8.7 (−12.6 to −4.8) <.001 <.001
SCORAD indexd
Pruritus scoree 5.6 (2.5) 5.1 (2.5) −0.6 (2.0) 5.7 (2.1) 5.1 (2.4) −0.5 (2.9) 0.0 (−1.2 to 1.2) .99 .70
Subjective 4.8 (2.7) 3.8 (2.4) −1.1 (2.5) 4.9 (2.6) 4.1 (2.5) −0.7 (2.8) −0.4 (−1.6 to 0.9) .57 .54
sleep scoree
Sleep-onset 44.9 (39.5) 21.6 (20.4) −23.4 (36.1) 31.5 (28.3) 29.6 (23.8) −1.2 (31.5) −21.4 (−38.6 to −4.2) .02 .005
latency, min
Sleep 74.4 (12.5) 76.7 (12.8) 2.4 (13.0) 78.0 (11.0) 77.7 (10.1) 0.6 (9.2) 2.2 (−3.1 to 7.4) .41 .74
efficiency, %
WASO, min 83.6 (63.8) 74.5 (53.5) −9.0 (68.5) 74.0 (53.5) 75.9 (46.9) −2.3 (38.1) −8.2 (−31.9 to 15.4) .49 .91
Wake in sleep 17.6 (11.6) 15.6 (10.7) −2.1 (13.1) 14.8 (10.3) 15.7 (9.7) −0.2 (7.4) −2.3 (−6.8 to 2.3) .33 .59
interval, %
Total sleep time, 380.1 (87.0) 390.1 (73.8) 10.0 (80.3) 410.5 (73.0) 391.7 (89.2) −10.5 (88.2) 24.8 (−14.5 to 64.2) .21 .20
min/night
Mobility 11.6 (7.3) 9.7 (4.7) −2.0 (7.6) 9.5 (4.0) 10.4 (4.6) 0.9 (4.4) −2.9 (−5.9 to 0.0) .05 .21
in sleep, %
Fragmentation 16.0 (7.8) 13.6 (5.8) −2.4 (9.2) 14.7 (5.5) 15.3 (6.6) 0.7 (6.9) −3.2 (−6.8 to 0.5) .09 .40
indexf
IgE level, 2337.2 2483.8 108.4 2457.1 2755.9 243.6 −113.6 .57 .56
kU/L (3327.5) (3685.2) (463.2) (3585.3) (4184.6) (900.7) (−511.2 to 283.9)
Abbreviations: SCORAD, Scoring Atopic Dermatitis; WASO, wake after sleep placebo treatment by the Wilcoxon signed rank test.
onset. c
Scores range from 0 to 103, with greater scores indicating worse symptoms.
a
Estimated difference of the effect of melatonin vs placebo by the linear mixed d
Scores range from 0 to 83, with greater scores indicating worse symptoms.
model, adjusted for age and sex (coefficient of the phase × time interaction e
Scores range from 0 to 10, with greater scores indicating worse symptoms.
term).
f
b Greater scores indicate more fragmented sleep.
Comparisons of the absolute difference from baseline after melatonin and

enterotoxins A or B (P > .05). No adverse effect of medication or neurodevelopmental disabilities with impaired sleep
was reported throughout the study. onset.22-24 Few studies have examined the efficacy of som-
nolent therapies for patients with AD, and trials in the pedi-
atric population are especially lacking.25 Clinicians wishing
to target the disturbed sleep of patients with AD mostly rely
Discussion on conventional experience or expert opinion with limited
Our study found that oral melatonin significantly improved evidence.25 First-generation antihistamines are traditionally
the sleep-onset latency and disease severity in children and used for sleep problems in patients with AD because they
adolescents with AD. Although the magnitude of the effect is can antagonize the inflammatory effects of histamine
not great, many patients might benefit from this dual effect. released from mast cells and basophils and can cross the
Sleep disturbance is highly prevalent in children with AD blood-brain barrier and thereby affect histamine’s role in
and is a troubling problem that leads to impaired quality of maintaining central nervous system arousal, which results in
life for the patients and their families.2,3 A previous study7 a sedating effect.25 However, tolerance often occurs after 4
found that children with AD had significantly reduced sleep to 7 days of treatment and the sedating effect vanishes, lim-
efficiency, longer sleep-onset latency, more sleep fragmenta- iting its usefulness.26,27 Anticholinergic adverse effects, such
tion, and less non–rapid eye movement sleep compared with as blurred vision and dry mouth, are also major concerns.
healthy control individuals. In addition, sleep disturbance in Benzodiazepines have sedating and anxiolytic effects, but
children with AD was associated with scratching move- they carry the risks for tolerance to sedating effects, rebound
ments, greater severity of dermatitis, and reduced nocturnal worsening of sleep problems at discontinuation, and addic-
melatonin secretion.7 Worse sleep increases the likelihood tion. Negative adverse effects, including muscle relaxation
that these children will scratch, which will further exacer- and memory problems, also make them less favorable for
bate the skin inflammation and lead to increased severity of use in children.25 Chloral hydrate and clonidine have also
skin disease. We hypothesized that melatonin, with its been used, but supporting evidence was limited.25 Melato-
sleep-promoting and anti-inflammatory properties, could nin has a good safety profile and has been suggested for the
break this vicious cycle. management of sleep problems in AD; however, no random-
Our study found that melatonin significantly shortens ized clinical trial had been performed.15,25 Our study is the
sleep-onset latency by a mean of 23.4 minutes (52.1%). This first, to our knowledge, to use a validated objective measur-
magnitude of effect is comparable to melatonin’s effect ing tool7 to show evidence of improvement of sleep by mela-
on children with attention-deficit/hyperactivity disorders tonin supplementation in children with AD.

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 Research Original Investigation Melatonin Supplementation for Atopic Dermatitis With Sleep Disturbance

Figure 2. Severity of Atopic Dermatitis and Sleep-Onset Latency Before and After Melatonin Treatment

A SCORAD index B Treatment sequence

60 60
P < .001 P = .67
55 55

50 50
SCORAD Index

SCORAD Index
45 45

40 40

35 35

30 30
Pretreatment Posttreatment Pretreatment Posttreatment Pretreatment Posttreatment Data are expressed as both patient
groups combined. A, The mean
Melatonin First Placebo First
(N = 18) (N = 20)
Scoring Atopic Dermatitis (SCORAD)
index decreased significantly after
melatonin treatment compared with
C Objective SCORAD index D Sleep-onset latency Melatonin placebo. B, The treatment sequence
Placebo (melatonin first vs placebo first) did
45 60 not result in a significant difference in
P < .001 P = .005 the treatment effect. C, The mean
50 objective SCORAD index decreased
Sleep-Onset Latency, min
Objective SCORAD Index

40 significantly after melatonin

40 treatment compared with placebo.
D, The mean sleep-onset latency
35 30
decreased significantly after
melatonin treatment compared with
20
placebo. Error bars indicate standard
30
errors. The SCORAD index ranges
10
from 0 to 103, and the objective
25 0 SCORAD index ranges from 0 to 83,
Pretreatment Posttreatment Pretreatment Posttreatment with greater scores indicating worse
symptoms.

Melatonin significantly improved AD severity by a mean locytes, monocytes, and mast cells. 15,30 Furthermore,
reduction of the SCORAD index by 9.9 in 4 weeks. To avoid through the upregulation of antioxidant enzymes, melato-
confounding by the patient’s subjective scores of pruritus nin efficiently neutralizes several free radicals and stabilizes
and sleeplessness, the objective SCORAD index, which rep- cell membranes.31 In addition, melatonin might have a role
resents the degree of severity based on the skin, was also in the pathophysiological mechanism of AD.7,32 Cikler et al33
analyzed, and results still showed that melatonin had an found that long-term melatonin treatment of stress-induced
improving effect. Melatonin might help to reduce excessive skin disorders in an experimental rat model reduced infil-
scratching before sleep onset, a common clinical complaint tration and activation of mast cells in the dermis. Kim et al34
in patients with AD, and therefore aid improvement in the found that melatonin suppressed the development of
skin inflammation by breaking the itch-scratch cycle. How- AD-like dermatitis in NC/Nga mice by reducing the total
ever, we found no significant correlation between improve- serum IgE level and production of IL-4 and interferon-γ by
ment in the SCORAD index and reduction in the sleep-onset activated CD4+ T cells. Our study is the first, to our knowl-
latency. Furthermore, melatonin did not improve the sleep edge, to find that melatonin could improve AD severity in
variables other than sleep-onset latency, including sleep humans. However, we found no significant change in the
efficiency, mobile percentage in sleep, sleep fragmentation, serum total or allergen-specific IgE levels after melatonin
and sleep architecture. Therefore, the effect of melatonin on treatment in our study. Whether and how melatonin modu-
AD might not be totally attributable to its effect on sleep but lates the complex inflammatory pathways in AD is an inter-
instead through its immunomodulatory or antioxidative esting field to explore in future studies.
properties. Various immunomodulatory mechanisms of We found no significant carryover effect from the cross-
melatonin have been reported. Helper T cells TH1 and TH2 over study design. However, the period effect was signifi-
express membrane and nuclear receptors for melatonin. Via cant for the SCORAD index and the objective SCORAD
these receptors, melatonin induces the synthesis of index, demonstrating that melatonin improved disease
interferon-γ, interleukin 2 (IL-2), IL-6, and IL-12 by lympho- severity significantly more in the second than in the first
cytic and monocytic cell lines; amplifies melatonin recep- treatment period. This result might have occurred because
tors; and alters the balance of T H 1 and T H 2 cells mainly the participants became more familiar with the study proto-
toward TH1 responses.15,28,29 Melatonin also influences the col and thus exhibited better adherence in the second treat-
activity of natural killer cells, T and B lymphocytes, granu- ment period, and they might have established more stable

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 Melatonin Supplementation for Atopic Dermatitis With Sleep Disturbance Original Investigation Research

methods of skin care and sleep hygiene as the trial pro- we might not have had enough statistical power to detect an
gressed, and thereby more effectively demonstrating the effect of melatonin on the sleep architecture. In addition,
influence of melatonin. This finding supports a true effect owing to our relatively small sample size, we could not
of melatonin on improvement of dermatitis severity in investigate whether the treatment effect of melatonin differs
children with AD. between subgroups of patients with different ages or initial
As expected, a high dropout rate occurred in our study. disease severity. However, the improvement in sleep-onset
Most of the dropouts resulted from withdrawal of consent be- latency and dermatitis severity after melatonin treatment
cause family members other than the parent who gave con- reached statistical significance despite our small sample
sent found out about the study and decided against it. This con- size, which reflects the substantiality of the effect. Finally,
sequence reflects the general concern of family members about further studies are needed to evaluate the optimal dose and
giving a child medication for sleep. One attractive property of duration of melatonin treatment for these patients.
melatonin is that it is safe with minimal adverse effects and
does not have addictive or withdrawal concerns.9 A meta-
analysis found that the most commonly reported adverse ef-
fects of melatonin included drowsiness, dizziness, nausea, and
Conclusions
headaches, but the occurrence of these events did not differ Melatonin significantly improved the severity of dermatitis and
significantly between melatonin and placebo.9 No adverse reduced sleep-onset latency in children with AD and sleep dis-
event was reported throughout our study. turbance. We recommend melatonin supplementation for these
This study has some limitations. Only a small subgroup patients because it is a potentially safe and effective way to
of patients received the polysomnographic examination, so improve their sleep and skin condition simultaneously.

ARTICLE INFORMATION Conflict of Interest Disclosures: None reported. condition and sleep disturbance in children with
Accepted for Publication: August 26, 2015. Funding/Support: This study was supported by atopic dermatitis. J Allergy Clin Immunol. 2004;114
joint grants 99-TYN01 and 100-TYN01 from the (3):691-693.
Published Online: November 16, 2015.
doi:10.1001/jamapediatrics.2015.3092. National Taiwan University Hospital and the Yonghe 7. Chang YS, Chou YT, Lee JH, et al. Atopic
Cardinal Tien Hospital. dermatitis, melatonin, and sleep disturbance.
Author Affiliations: Department of Pediatrics, Pediatrics. 2014;134(2):e397-e405.
Taipei City Hospital Renai Branch, Taipei, Taiwan Role of the Funder/Sponsor: The funding sources
(Chang, Wan); Graduate Institute of Clinical had no role in the design and conduct of the study; 8. Brzezinski A. Melatonin in humans. N Engl J Med.
Medicine, College of Medicine, National Taiwan collection, management, analysis, and 1997;336(3):186-195.
University, Taipei, Taiwan (Chang); School of interpretation of the data; preparation, review, or 9. Buscemi N, Vandermeer B, Hooton N, et al.
Medicine, National Yang-Ming University, Taipei, approval of the manuscript; and decision to submit Efficacy and safety of exogenous melatonin for
Taiwan (Chang); Department of Pediatrics, Yonghe the manuscript for publication. secondary sleep disorders and sleep disorders
Cardinal Tien Hospital, New Taipei City, Taiwan Additional Contributions: Miguel Hernan, MD, accompanying sleep restriction: meta-analysis. BMJ.
(M.-H. Lin); Department of Pediatrics, National PhD, Department of Epidemiology, Harvard T. H. 2006;332(7538):385-393.
Taiwan University Children’s Hospital, Taipei, Chan School of Public Health, and Chin-Hao Chang, 10. Brzezinski A, Vangel MG, Wurtman RJ, et al.
Taiwan (J.-H. Lee, Chu, Sun, Y.-T. Lin, Wang, Yu, PhD, National Translational Medicine and Clinical Effects of exogenous melatonin on sleep:
Yang, Chen, Chiang); Department of Internal Trial Resource Center and the Department of a meta-analysis. Sleep Med Rev. 2005;9(1):41-50.
Medicine, National Taiwan University Hospital, Medical Research, National Taiwan University
Taipei, Taiwan (P.-L. Lee); Department of Hospital, assisted with statistical analysis. None of 11. Ferracioli-Oda E, Qawasmi A, Bloch MH.
Dermatology, National Taiwan University Hospital, these individuals received any compensation for Meta-analysis: melatonin for the treatment of
Taipei, Taiwan (Dai); Graduate Institute of their contributions. primary sleep disorders. PLoS One. 2013;8(5):e63773.
Immunology, College of Medicine, National Taiwan 12. Arendt J, Skene DJ. Melatonin as a chronobiotic.
University, Taipei, Taiwan (Chiang); Department of REFERENCES Sleep Med Rev. 2005;9(1):25-39.
Medical Research, National Taiwan University 1. Bieber T. Atopic dermatitis. N Engl J Med. 2008; 13. Haldar C, Ahmad R. Photoimmunomodulation
Hospital, Taipei, Taiwan (Chiang). 358(14):1483-1494. and melatonin. J Photochem Photobiol B. 2010;
Author Contributions: Drs Chang and Chiang had 2. Camfferman D, Kennedy JD, Gold M, Martin AJ, 98(2):107-117.
full access to all the data in the study and take Lushington K. Eczema and sleep and its relationship 14. Radogna F, Diederich M, Ghibelli L. Melatonin:
responsibility for the integrity of the data and the to daytime functioning in children. Sleep Med Rev. a pleiotropic molecule regulating inflammation.
accuracy of the data analysis. 2010;14(6):359-369. Biochem Pharmacol. 2010;80(12):1844-1852.
Study concept and design: Chang, J.-H. Lee,
P.-L. Lee, Dai, Sun, Y.-T. Lin, Wang, Yang, Wan, 3. Ricci G, Bendandi B, Bellini F, Patrizi A, Masi M. 15. Marseglia L, D’Angelo G, Manti S, et al.
Chiang. Atopic dermatitis: quality of life of young Italian Melatonin and atopy: role in atopic dermatitis and
Acquisition, analysis, or interpretation of data: children and their families and correlation with asthma. Int J Mol Sci. 2014;15(8):13482-13493.
Chang, M.-H. Lin, J.-H. Lee, Dai, Chu, Wang, Yu, severity score. Pediatr Allergy Immunol. 2007;18(3): 16. Rossignol DA, Frye RE. Melatonin in autism
Chen, Chiang. 245-249. spectrum disorders: a systematic review and
Drafting of the manuscript: Chang, J.-H. Lee, 4. Lewis-Jones S. Quality of life and childhood meta-analysis. Dev Med Child Neurol. 2011;53(9):
P.-L. Lee, Chu, Y.-T. Lin. atopic dermatitis: the misery of living with 783-792.
Critical revision of the manuscript for important childhood eczema. Int J Clin Pract. 2006;60(8): 17. World Medical Association. World Medical
intellectual content: M.-H. Lin, Dai, Sun, Wang, Yu, 984-992. Association Declaration of Helsinki: ethical
Yang, Chen, Wan, Chiang. 5. Hon KL, Lam MC, Leung TF, Chow CM, Wong E, principles for medical research involving human
Statistical analysis: Chang, Yu, Chen. Leung AK. Assessing itch in children with atopic subjects. JAMA. 2013;310(20):2191-2194.
Obtained funding: Yu. dermatitis treated with tacrolimus: objective versus doi:10.1001/jama.2013.281053.
Administrative, technical, or material support: subjective assessment. Adv Ther. 2007;24(1):23-28.
Chang, P.-L. Lee, Chu, Wang, Chen, Chiang. 18. European Task Force on Atopic Dermatitis.
Study supervision: M.-H. Lin, J.-H. Lee, Dai, Sun, 6. Leo HL, Bender BG, Leung SB, Tran ZV, Leung Severity scoring of atopic dermatitis: the SCORAD
Y.-T. Lin, Wang, Yang, Wan, Chiang. DY. Effect of pimecrolimus cream 1% on skin

jamapediatrics.com (Reprinted) JAMA Pediatrics January 2016 Volume 170, Number 1 41

Copyright 2016 American Medical Association. All rights reserved.

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 Research Original Investigation Melatonin Supplementation for Atopic Dermatitis With Sleep Disturbance

index: consensus report of the European Task Force 24. Van der Heijden KB, Smits MG, Van Someren 30. Moore CB, Siopes TD. Melatonin can
on Atopic Dermatitis. Dermatology. 1993;186(1):23-31. EJ, Ridderinkhof KR, Gunning WB. Effect of produce immunoenhancement in Japanese quail
19. Oranje AP. Practical issues on interpretation of melatonin on sleep, behavior, and cognition in (Coturnix coturnix japonica) without prior
scoring atopic dermatitis: SCORAD index, objective ADHD and chronic sleep-onset insomnia. J Am Acad immunosuppression. Gen Comp Endocrinol. 2002;
SCORAD, patient-oriented SCORAD and Three-Item Child Adolesc Psychiatry. 2007;46(2):233-241. 129(2):122-126.
Severity score. Curr Probl Dermatol. 2011;41:149-155. 25. Kelsay K. Management of sleep disturbance 31. García JJ, López-Pingarrón L, Almeida-Souza P,
20. Kovács J, Brodner W, Kirchlechner V, Arif T, associated with atopic dermatitis. J Allergy Clin et al. Protective effects of melatonin in reducing
Waldhauser F. Measurement of urinary melatonin: Immunol. 2006;118(1):198-201. oxidative stress and in preserving the fluidity of
a useful tool for monitoring serum melatonin after 26. Richardson GS, Roehrs TA, Rosenthal L, biological membranes: a review. J Pineal Res. 2014;
its oral administration. J Clin Endocrinol Metab. Koshorek G, Roth T. Tolerance to daytime sedative 56(3):225-237.
2000;85(2):666-670. effects of H1 antihistamines. J Clin Psychopharmacol. 32. Muñoz-Hoyos A, Espín-Quirantes C,
21. Graham C, Cook MR, Kavet R, Sastre A, Smith 2002;22(5):511-515. Molina-Carballo A, et al. Neuroendocrine and
DK. Prediction of nocturnal plasma melatonin from 27. Levander S, Ståhle-Bäckdahl M, Hägermark O. circadian aspects (melatonin and β-endorphin) of
morning urinary measures. J Pineal Res. 1998;24 Peripheral antihistamine and central sedative atopic dermatitis in the child. Pediatr Allergy Immunol.
(4):230-238. effects of single and continuous oral doses of 2007;18(8):679-686.

22. Wasdell MB, Jan JE, Bomben MM, et al. cetirizine and hydroxyzine. Eur J Clin Pharmacol. 33. Cikler E, Ercan F, Cetinel S, Contuk G, Sener G.
A randomized, placebo-controlled trial of controlled 1991;41(5):435-439. The protective effects of melatonin against water
release melatonin treatment of delayed sleep phase 28. García-Mauriño S, Pozo D, Calvo JR, Guerrero avoidance stress-induced mast cell degranulation in
syndrome and impaired sleep maintenance in JM. Correlation between nuclear melatonin dermis. Acta Histochem. 2005;106(6):467-475.
children with neurodevelopmental disabilities. receptor expression and enhanced cytokine 34. Kim TH, Jung JA, Kim GD, et al. Melatonin
J Pineal Res. 2008;44(1):57-64. production in human lymphocytic and monocytic inhibits the development of
23. Weiss MD, Wasdell MB, Bomben MM, Rea KJ, cell lines. J Pineal Res. 2000;29(3):129-137. 2,4-dinitrofluorobenzene-induced atopic
Freeman RD. Sleep hygiene and melatonin 29. Srinivasan V, Spence DW, Trakht I, dermatitis–like skin lesions in NC/Nga mice. J Pineal
treatment for children and adolescents with ADHD Pandi-Perumal SR, Cardinali DP, Maestroni GJ. Res. 2009;47(4):324-329.
and initial insomnia. J Am Acad Child Adolesc Immunomodulation by melatonin: its significance
Psychiatry. 2006;45(5):512-519. for seasonally occurring diseases.
Neuroimmunomodulation. 2008;15(2):93-101.

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