Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: https://www.tandfonline.com/loi/ieop20

Pharmacotherapeutic management of sleep

disorders in children with neurodevelopmental
disorders

Oliviero Bruni, Marco Angriman, Maria Grazia Melegari & Raffaele Ferri

To cite this article: Oliviero Bruni, Marco Angriman, Maria Grazia Melegari & Raffaele Ferri
(2019): Pharmacotherapeutic management of sleep disorders in children with neurodevelopmental
disorders, Expert Opinion on Pharmacotherapy, DOI: 10.1080/14656566.2019.1674283

To link to this article: https://doi.org/10.1080/14656566.2019.1674283

Published online: 22 Oct 2019.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

https://www.tandfonline.com/action/journalInformation?journalCode=ieop20
EXPERT OPINION ON PHARMACOTHERAPY
https://doi.org/10.1080/14656566.2019.1674283

REVIEW

Pharmacotherapeutic management of sleep disorders in children with

neurodevelopmental disorders
Oliviero Brunia, Marco Angrimanb, Maria Grazia Melegaria and Raffaele Ferric
a
Department of Developmental and Social Psychology, Sapienza University, Rome, Italy; bDepartment of Pediatrics, Child Neurology and
Neurorehabilitation Unit, Central Hospital of Bolzano, Bolzano, Italy; cSleep Research Centre; Department of Neurology I.C., Oasi Institute for
Research on Mental Retardation and Brain Aging (IRCCS), Troina, Italy

ABSTRACT ARTICLE HISTORY

Introduction: Sleep disturbances are highly prevalent in children with neurodevelopmental disabilities. Received 18 June 2019
Without appropriate treatment, sleep disorders can become chronic and last for many years. However, Accepted 26 September 2019
there are no sleep medications approved by the United States Food and Drug Administration and only KEYWORDS
one has been approved by the European Medicines Agency for pediatric insomnia; thus, most medica- Sleep disorders; insomnia;
tions are prescribed off-label. neurodevelopmental
Areas covered: In this narrative review, the authors highlight and summarize the most common drugs disorders; drug effects;
and supplements used for the treatment of sleep problems in children with neurodevelopmental melatonin
disabilities. Recommendations are formulated regarding the use of melatonin and melatonin receptor
agonists, sedating antidepressants, antipsychotics, antihistamines, gabapentin, clonidine and orexin
receptor antagonists, and benzodiazepines and hypnotic benzodiazepine receptor agonists.
Expert opinion: The choice of pharmacological agents and their dosage should be individualized
taking into consideration multiple factors, including the severity and type of sleep problem and the
associated neurological pathology. Melatonin is widely used and safe in children with neurodevelop-
mental conditions. Gabapentin, clonidine, trazodone, and mirtazapine hold promise but require further
study. Supplements (iron, vitamin D, and 5-hydroxytryptophan) might be helpful. Due to the lack of
clinical data, there is still uncertainty concerning dosing regimens and tolerability.

1. Introduction In other cases, sleep disorders represent one of the most

important comorbidities, such as insomnia in Angelman syn-
Sleep disorders in children with neurodevelopmental disabil-
drome, sleep disordered breathing in Down’s Syndrome, exces-
ities (NDDs), mainly represented by difficulty in falling asleep,
sive daytime sleepiness or narcolepsy in Prader Willi syndrome,
night awakenings, and reduced sleep duration, are among the
and low levels of melatonin in ASD [1]. Sleep difficulties may
most common parental complaints to health care profes-
also be related to unrecognized behavioral insomnia in child-
sionals, with a prevalence of up to 86% [1]. In children with
hood, which can be difficult to identify in children with NDDs
NDDs, sleep disturbances impact on cognitive and emotional
due to their reduced communication skills, or factors related to
development, aggravating the functional impairment asso-
poor sleep hygiene or, finally, to co-occurring medical condi-
ciated with these conditions [2], but also affecting the entire
tions (e.g., epilepsy or gastroesophageal reflux). Moreover, sleep
family environment, disrupting the sibling and marital rela-
disorders might be aggravated by common issues linked to
tionships, and increasing the level of stress [3].
NDDs (such as sensory and motor deficits, psychopathological
Children with neuropsychiatric disorders (e.g., autistic spec-
disturbances, respiratory disorders, epilepsy, and mental retar-
trum disorders [ASD] or attention deficit hyperactivity disor-
dation), which can contribute to developmental delay.
ders [ADHD]), neurogenetic disorders (NGD; e.g., Rett’s
A meta-analysis [12] of sleep in ADHD found that children
disorder, tuberous sclerosis, Smith-Magenis Syndrome [SMS],
or their parents reported bedtime resistance, sleep-onset diffi-
and Angelman syndrome), as well as chronic neurologic dis-
culties, night awakenings, difficulties in morning awakening,
orders, such as epilepsy and Tourette’s syndrome, commonly
sleep breathing problems, and daytime sleepiness significantly
exhibit chronic sleep disturbances [4–10].
more often than healthy controls. Sleep problems might be
The pathophysiology of sleep disorders in children with
specific in different syndromes (i.e., sleep apnea in Down’s
NDDs is multifactorial: in some patients, problematic sleep is
syndrome or Prader-Willi syndrome) but sleep complaints in
a phenotypic characteristic of a particular disorder or genetic
children with NDDs are mainly represented by difficulty in
condition (as an example, inverted melatonin secretion in SMS),
settling at night (51%) and nocturnal awakenings (67%) [13].
and knowledge of the distinctive features of sleep disorders in
Children with ASD are more likely to experience chronic sleep
patients with NDDs is crucial for their effective treatment [11].
problems than their age-matched typically-developing peers,

CONTACT Oliviero Bruni oliviero.bruni@uniroma1.it Department of Developmental and Social Psychology, Sapienza University, Via dei Marsi 78, Rome
00185, Italy
© 2019 Informa UK Limited, trading as Taylor & Francis Group
2 O. BRUNI ET AL.
Article highlights
● Sleep disturbances are associated with NDDs in as many as 70% of
cases.
● Both subjective (i.e., detected with questionnaires) and objective (i.e.,
revealed by actigraphy or neurophysiologic tools) sleep alterations
have been found to be significantly more frequent in individuals with
NDDs, compared to controls.
● Clinicians should screen for sleep disturbances in patients with NDDs
at each visit.
● There is a paucity of empirical evidence to guide treatment of sleep
disturbances in NDDs.
● Melatonin and other pharmacological treatments, such as gabapen-
tin, clonidine, trazodone, and mirtazapine, can constitute a valid
option in the case of inefficacy of behavioral treatment.
● More rigorous evaluations of therapeutic strategies for sleep disor-
ders are needed in individuals with NDDs. RCTs of pharmacological
and non-pharmacological interventions will be valuable to support
the clinician in making evidence-based decisions in daily clinical
practice.
This box summarizes key points contained in the article.
with a prevalence of 50–80% [14]. The most prevalent com-
plaints are difficulty falling asleep (∼40%) or maintaining sleep
(∼35%) [15]. In some severe cases, fragmented sleep through-
out the day and night induces daytime sleepiness and an
irregular sleep schedule that may lead to a free-running
rhythm or to a complete reversal of the night-day cycle [16].
There are no US Food and Drug Administration (FDA)
approved medications and only one by the European
Medicines Agency to treat insomnia in pediatric patients,
including those with NDDs, and therefore most of the drugs
are prescribed off-label. In this narrative review, we will
describe the current clinical evidence for the treatment of
chronic insomnia in children and adolescents with NDDs.
2. Non-pharmacological treatment
Sleep disturbances are often present during the early life of
children with NDDs, but they are often neglected by parents
and physicians and frequently become chronic. When dealing
with a chronic disorder, the first approach should always be
a behavioral intervention, and even if a pharmacologic approach
is needed from the beginning behavioral interventions should be
always associated [17]. Correct sleep hygiene should be first
ensured with good sleep practices and cognitive-behavioral
techniques using a gradual approach, such as graduated extinc-
tion, positive bedtime routines, positive reinforcement, etc. that
may be more acceptable for parents as well as being more
appropriate for some children with special needs [18,19].
A systematic review of behavioral treatments for insomnia
reported a moderate-to-low level of evidence supports beha-
vioral interventions in adolescents and children with NDDs
[20]. However, even if no changes were obtained in sleep
measures, sleep hygiene education induced an improvement
in daytime behaviors, quality of life, and sense of competence
in parents. Parental involvement is the only way to achieve
some positive results in sleep pattern and quality of life and
well-being in children with NDDs [11]. Table 1 reports non-
Table 1. Behavioral strategies for insomnia in children with neurodevelopmen-
tal disabilities.
Parents serve as active agents of change
• Dark, quiet, non-stimulating sleeping environment, with dim nightlight
∘ Set up the sleeping area so it looks and feels the same all night. Avoid
having pillows or objects that may scatter as your child sleeps. This
consistency can help your child to stay asleep throughout the night.
∘ Limit visual and auditory stimuli by, for example, turning off electronic
devices.
• Develop a constant bedtime routine tailored to the developmental age
and abilities of the child.
• Conduct stimulating and/or difficult activities early in the evening before
the child’s bedtime routine is to commence.
• Limit the number of activities included within the bedtime routine.
• Create a visual bedtime schedule that your child will understand (e.g.,
checklists, pictures, objects, or drawings).
∘ Put the bedtime schedule in a place where the routine is performed.
The schedule should also be placed at a height at which your child can
reach each item.
∘ Stand behind your child, directing him/her to the schedule. Limit
verbal instructions/prompts while using the visual schedule to
communicate the order of activities.
∘ The same activity icon should be used consistently.
∘ It’s important to reward your child for following his/her schedule
properly.
• Use of bedtime pass
∘ A bedtime pass is a card that is given to the child at bedtime that may
be exchanged for one ‘free’ trip out of bed or one parent visit after
bedtime. If the child gets out of bed after conceding their bedtime
pass, the parent should take the child back to bed with as little
attention as possible.
∘ The goal of the bedtime pass is to teach the child to stay in bed.
• Encourage self-soothing skills that allow the child to manage nocturnal
awakenings.
In the case of difficulties falling asleep:
• Apply bedtime fading (delay bedtime closer to the child target bedtime
of about 30 min, then move bedtime earlier).
• White noise (for example with a fan) could be helpful and should stay on
throughout the night if it is on at bedtime.
• Do not allow the child to make up for lost sleep by going to bed earlier
or sleeping later.
• Favor light exposure when the child gets up, and reduce photic
stimulation in the evening, to reinforce circadian alignment.
• Parents should avoid responding to the child’s disruptive bedtime
behaviors.
• Learn a relaxation technique: slow, deep breathing or imagine a calm
and relaxing place
In the case of frequent nocturnal awakenings:
• Graduate extinction: ignore negative behaviors (i.e., crying) for a given
amount of time before checking on the child. The parent gradually
increases the amount of time between crying and parental response.
Parents provide reassurance through their presence for a short time
duration and with minimal interaction.
• Bedtime pass (see above).
(adapted from [11,21,22])
pharmacological approaches to treating insomnia in children
with NDDs.
It should be emphasized that parent-based education and
behavioral interventions are the first line treatment for insom-
nia, unless symptom severity necessitates early pharmacother-
apy [23]. However, although clinical guidelines recommend
sleep hygiene and/or behavioral intervention as the first-line
treatment, only approximately 25% of cases respond to such
a therapy. Furthermore, the clinical effectiveness of non-
pharmacological interventions is unclear, owing to the limited
number of randomized controlled trials (RCTs), the

heterogeneous nature of the interventions and outcomes
used, and the insufficient power in studies to detect any effect
[24].
3. Pharmacological treatment
The use of a sleep-promoting medication can be considered
for children without significant improvement after behavioral
interventions. In children and adolescents with NDDs, beha-
vioral techniques may be difficult to implement and may take
weeks or months to show benefits, if any; therefore, sleep-
promoting agents should be recommended while continuing
behavioral intervention. Children who do not respond to
behavioral interventions can be candidates for pharmacologi-
cal treatment of insomnia that should always be considered in
combination with behavioral treatment [19,25].
Due to the lack of controlled studies, there are no sleep
medications approved by the FDA and only one medication
(pediatric prolonged release melatonin) approved by the
European Medicines Agency (EMA) for pediatric insomnia. The
most used off-label medications are sedating antihistamines
(e.g., diphenhydramine and hydroxyzine), melatonin, benzodia-
zepines, α2-receptor agonists (e.g., clonidine), pyrimidine deri-
vatives (e.g., zaleplon and zolpidem), antipsychotics (e.g.,
risperidone and quetiapine), and sedating antidepressants
(e.g., trazodone and mirtazapine) [25], but little data exist on
their efficacy for the treatment of insomnia in children [9].
In infants and children, chronic insomnia can lead to mater-
nal depression, family dysfunction, and impaired social func-
tioning [26]. Due to these serious implications for individuals,
the family, and society, it is essential to treat insomnia through
education of parents, teachers, and other caregivers, but also
with an effective drug treatment, when needed. A recent
Australian survey on pharmacological management of insom-
nia in children reported that the most commonly prescribed
medications for poor sleep initiation were melatonin (89.1%),
clonidine (48%), and antihistamines (29%) [27]. Most pediatri-
cians (82%) reported also using behavioral strategies for sleep
disturbances, commonly anxiety relaxation techniques (75%)
for poor sleep initiation and graduated extinction (i.e., ‘con-
trolled crying,’ 52%) for disrupted overnight sleep [27].
In children with NDDs or psychiatric disturbances, different
surveys confirm that drugs are typically prescribed off-label
[28]. A survey by Owens et al. [29] showed that more than
one-third of 1,273 child psychiatrists treated insomnia with
medication in at least half of patients with ADHD, ASD, or
with mental retardation/developmental disabilities (MR/DD).
Moreover, they reported treating 17% of preschoolers and at
least one-quarter of school-aged and adolescent patients with
medication. Overall, 96% of psychiatrists recommended at
least one medication in a typical month, and 88% recom-
mended an over-the-counter medication. In general, psychia-
trists were more likely to use herbal preparations in children
with anxiety or mood disorders than in children with NDDs or
ADHD; melatonin was recommended by more than one-third
of them (39%), although it is unclear whether it was being
used primarily at bedtime for its mild hypnotic effects or as
a chronobiotic. The physicians recommendations for sleep
disorders (mainly insomnia) included non-prescription
EXPERT OPINION ON PHARMACOTHERAPY 3
antihistamines in 69% of cases and α agonists in 67% of
children with MR/DD. Trazodone was the second most fre-
quently prescribed medication for children with MR/DD
(66%), while sedating antidepressants were used in 75.5% of
cases with MR. Atypical antipsychotics were used by more
than half of the psychiatrists in children with MR/DD (52%)
and benzodiazepines were used in 21.6% of cases with MR/
DD. Tricyclic antidepressants were also used for children in
these diagnostic groups (25.5%).
Before beginning a drug treatment in children with NDDs,
different aspects should be taken into account: very often
these children also take other drugs (mainly sedatives, anti-
epileptics, etc.) and the eventual interactions should be con-
sidered cautiously together with eventual previous sleep
medications or over-the-counter preparations, as well as the
age of the child and his/her clinical history. Treatment goals
must be established with the parents and, if possible, with the
patient and should be realistic, clearly defined, and measur-
able. The immediate goal of treatment will usually be to
alleviate or improve, rather than to completely eliminate,
sleep problems. When a drug has been administered, abrupt
discontinuation should be avoided and the treatment should
be carefully monitored since there is a natural inclination of
the parents to give the lowest dose [30].
The choice of the drug, in view of the lack of scientific
evidence, should be guided by an accurate evaluation of the
main complaint (i.e., difficulty falling asleep, night awakenings,
phase advance or delay, nocturnal hyperactivity, mid-night
awakening, etc.) but a correct family history can also be useful.
Despite the increasing use of melatonin in the pediatric popu-
lation, there are still only a few short- and long-term safety
and efficacy-controlled studies of melatonin as well as dosing
regimen data. Therefore, there is an unmet need for appro-
priately tested and approved drugs demonstrated to be effec-
tive and safe for insomnia in this population. Finally, a correct
pharmacological approach should avoid residual daytime
sedation, tolerance, and addiction potential, and improve
sleep maintenance.
3.1. Melatonin
Melatonin (MT; N-acetyl-5-methoxytryptamine) is a neu
rohormone involved in the regulation of the circadian sleep-/
wake rhythm. Its plasma concentration follows a circadian
rhythm, with low levels during the day and high levels at
night. In humans, the peak secretion typically occurs between
2:00 and 4:00 AM [31]. MT is an important modulator of the
sleep/wake cycle by activating MT1 and MT2 receptors, and it
has been hypothesized that it can have MT1/MT2 receptor-
independent hypnotic effects. The two receptor subtypes are
differentially expressed in regions involved in rapid eye move-
ment (REM) or non-REM (NREM) sleep and can have either
complementary or opposing effects in NREM and REM sleep,
likely because of their different expression in brain areas dif-
ferentially implicated in the regulation of the sleep/wake cycle.
These findings partially explain the limited efficacy, as hypno-
tics, of MT or nonselective MT1/MT2 receptor agonists in clin-
ical studies. Further research on selective ligands for the MT1
4 O. BRUNI ET AL.
receptor subtype will permit understanding of the neurobio-
logical role of both MT1 and MT2 receptors in sleep [32].
A Swedish study showed that MT use increased during the
period 2004–2011 in 0- to 17-year-old patients and it was
dispensed in the highest annual amount among all hypnotic
drugs [33]. Approximately 56% of pediatricians prescribed MT
for sleep onset insomnia (89.1%), delayed sleep phase (66.3%),
and nighttime awakenings (30.7%). It is also prescribed in
children with autism (85.2%), NDDs (76.2%), ADHD (54.5%),
behavioral disorders (42.6%), visual impairment (40.6%), anxi-
ety disorders (25.7%), and in those who are developing typi-
cally (54.5%) [27]. MT appears to hold promise for the
treatment of insomnia in children with NDDs [32–35].
A recent meta-analysis [36] has shown that MT significantly
improved total sleep time compared with placebo (mean differ-
ence = 48.26 min, 95% confidence interval (CI) 36.78 to 59.73,
I2 = 31%) in nine studies; sleep onset latency also improved
significantly in 11 studies (mean difference = −28.97, 95% CI
−39.78 to −18.17). No difference was found in the frequency of
nocturnal awakenings (mean difference = −0.49, 95% CI −1.71 to
0.73). No medication-related serious adverse event was reported
[36]. However, the overall quality of the evidence is limited by
heterogeneity and inconsistency.
Other systematic reviews and meta-analyses of RCTs in chil-
dren with NDDs, especially autism, showed that exogenous MT
reduced sleep-onset latency and increased total sleep time
[37,38]. One of the largest placebo-controlled studies in 146
children (age 3–15 years) with intellectual disability showed
that MT in different doses ranging from 0.5 to 12 mg reduced
sleep latency (from 102 to 55 min in 12 weeks) and increased
total sleep time (40 min) [5,37]. Other studies showed that MT
(with doses ranging from 1 to 15 mg, given 30–60 min before
bedtime), alone or in combination with cognitive-behavioral
therapy, is effective in treating insomnia in children with ASD
[34], Angelman syndrome [39], or those with NDDs. Most of these
studies have shown high efficacy in decreasing sleep latency and
a non-significant improvement of total nighttime sleep [40].
In nine girls with Rett syndrome treated with MT (dosage
2.5 to 7.5 mg), the actigraphy evaluation showed that sleep-
onset latency was significantly decreased, while the number of
nighttime awakenings was not affected and the mean total
sleep time increased [41]. An inverted circadian rhythm of MT
is typical in SMS. The most efficacious treatment in SMS is
a combination of acebutolol (a β1-adrenergic antagonist, given
in the morning, which decreases daytime plasma MT levels
during the day) and exogenous MT at night, which restores
plasma circadian MT rhythm and enhances sleep [42]. MT has
also been reported to be effective in children with ADHD with
delayed sleep phase syndrome (DSPS) and sleep onset insom-
nia at a dosage of approximately 5 mg [43–47]. A systematic
review of the literature found that 3 to 6 mg/night MT sig-
nificantly reduced sleep onset latency and increased total
sleep duration, but did not impact on daytime ADHD core
symptoms [48].
In some patients with NDDs, the loss of efficacy of MT
treatment after an initial good response is a major problem,
possibly caused by slow metabolism because of decreased
activity of the CYP1A2 enzyme [49]. This may result in
increased daily MT levels. Consequently, MT levels increase
and, after some time, the circadian MT rhythm is lost. This
loss of circadian rhythm might explain why the effectiveness
of exogenous MT fades over time [50].
A single study reported that MT for the treatment of
chronic sleep onset insomnia in typically developing children
is effective at a dosage of 0.05 mg/kg given at least 1 to 2 h
before the desired bedtime [51].
Pediatric prolonged-release melatonin (PedPRM) is a novel
age-appropriate formulation recently approved in Europe for
sleep disorders in children with NDDs. PedPRM is an oral solid
form of prolonged-release MT mini-tablets to be swallowed as
a whole, which have been designed to gradually release MT
mimicking the physiological secretion profile of MT and pro-
ducing sustained plasma levels of MT for up to 8–10 h. In
a recent multi-center (EU and United States), randomized,
double-blind, placebo-controlled, parallel group study, the
effects of the use of PedPRM for 13 weeks has been investi-
gated in 125 children and adolescents (2–17.5 years) with ASD
and NGD with or without ADHD comorbidity who had not
shown improvement after standard sleep behavioral interven-
tion [52]. The results indicate that PedPRM (2/5 mg) is effica-
cious and safe, compared to placebo, for the treatment of
insomnia in these children, with clinically meaningful improve-
ments in total sleep time (TST), duration of uninterrupted
sleep (longest sleep episode [LSE]), and sleep latency (SL),
and without causing earlier wake-up time [52].
A recent prospective, 39-week, open-label, follow-up
PedPRM treatment of the aforementioned patients for up to
52 weeks (1 year) of continuous PedPRM treatment, reported
an overall improvement of ≥1 h in TST, SL, or both, compared
to baseline, with no evidence of decreased efficacy. In parallel,
child sleep disturbance and caregiver’s satisfaction of their
children’s sleep patterns (p < 0.001 for both), Pittsburg Sleep
Quality Index (PSQI) global (p < 0.001), and WHO-5 (p = 0.001)
improved significantly, both statistically and clinically. PedPRM
was found to be generally safe, and the most frequent treat-
ment-related adverse events were fatigue (5.3%) and mood
swings (3.2% of patients) [53]. Another recent systematic
review of MT treatment reported an improvement in SL,
while the findings on the number of awakenings or the min-
utes of wakefulness after sleep onset (WASO) were not con-
sistent, with only 1 study reporting a statistically significant
reduction of night awakenings [54].
The most frequently reported side effects were general
symptoms (headaches, dizziness, drowsiness, cough, and
rashes) and neurological (tremors, migraine), digestive (nau-
sea, vomiting, abdominal pain), and psychological (night-
mares, irritability) disorders. Most of these common
symptoms are likely to be coincidental or caused by impurities
in the unregulated formulations of MT. Previous reports of
poor seizure control, poor asthma control, and adverse endo-
crinological problems during puberty have not been con-
firmed. Both systematic reviews and meta-analyses of RCTs
suggest that there are no significant adverse side effects
associated with the use of MT.
Unanswered clinical questions include whether slow-
release preparations are superior to immediate-release pre-
parations in increasing TST, and whether a more rational and
optimal prescription of MT might be achieved by measuring

salivary MT before its use. Unlike traditional hypnotics, such as
chloral hydrate and benzodiazepines, MT does not affect poly-
somnographic sleep architecture, maintaining the physiologi-
cal sleep structure [55].
3.2. Ramelteon
Ramelteon, a synthetic MT receptor agonist with high affinity
for the MT1 and MT2 receptors, is approved by the FDA for use
in adults. Only a few case studies have been published in
children with NDDs reporting some efficacy for night awaken-
ings [54–56].
3.3. Antihistamines
Histamine is a wake-promoting agent that plays a key role in
mediating wakefulness [57]. The effect on wakefulness has
been long known because of the drowsiness caused by first-
generation antihistamines, which cross the blood-brain barrier,
prescribed for treating allergies. Overall, an increased hista-
mine concentration promotes wakefulness, while decreased
histamine promotes NREM sleep. The histamine levels in the
brain fluctuate according to the circadian rhythm and corre-
late with neuronal activity in histaminergic neurons during
wakefulness, which is highest during attentive wake, strongly
reduced during NREM sleep, and completely suppressed dur-
ing REM sleep [58].
First generation antihistamines bind to the H1 receptor in
the central nervous system (CNS) and do not affect sleep
architecture. Ethanolamines (such as diphenhydramine) have
potent sedative effects, being piperazine derivatives (such as
hydroxyzine). Diphenhydramine is the most commonly used
antihistamine and is a competitive H1-histamine receptor
blocker. The recommended dosage for adults is 25 to 50 mg,
whereas in children the effective dosage is 0.5 mg/kg up to
a total of 25 mg. Hydroxyzine is effective at 0.5 mg/kg in
children. Although antihistamines are the most prescribed or
obtained over-the-counter agents for pediatric insomnia [59],
randomized controlled data in children are lacking. Conflicting
results have been published in different reports; an old study
showed a significant decrease in sleep latency and in the
number of awakenings [60], while a more recent study in
infants reported inefficacy compared to placebo [61].
Other antihistamine compounds such as trimeprazine or
niaprazine seem to be effective. Trimeprazine (15 mg/5 mL
or 30 mg/5 mL) induced a moderate improvement in 22
children with night awakenings [62], while niaprazine (1 mg/
kg in a single dose at bedtime) induced a decrease in sleep
onset latency and an increase in sleep duration [63], even in
comparison to benzodiazepines [64]. No studies are available
on the efficacy of antihistamines in children with NDDs.
Antihistamines are generally well tolerated, with the most
common side effects being sedation and sleepiness. An overdose
of antihistamines induces anticholinergic effects, including fever,
mydriasis, blurred vision, dry mouth, constipation, urinary reten-
tion, tachycardia, dystonia, and confusion. There are some
reports on the toxicity of diphenhydramine with catatonic stu-
por, anxiety, visual hallucinations and, more rarely, respiratory
insufficiency and seizures [65], with fatal toxicity reported in five
EXPERT OPINION ON PHARMACOTHERAPY 5
6- to 12-week-old infants [66]. Hydroxyzine seems to be safer and
no fatal cases have been reported [67]. Finally, tolerance can
develop quickly and some children can experience dramatic
and paradoxical hyperarousal [68].
3.4. Clonidine
Clonidine, an imidazoline-derivative hypotensive agent is an
α2-adrenergic agonist that acts on presynaptic neurons and
inhibits noradrenergic release and transmission. It crosses the
blood-brain barrier and acts in the hypothalamus to induce
a decrease in blood pressure, as approved by the FDA. Due to
its sedative effects, clonidine is commonly prescribed as
a sleep aid in children, but there are only a few controlled
studies available [69].
It is hypothesized that clonidine produces sedation by
decreasing norepinephrine levels via a negative feedback by
agonism of the α2-adrenergic somatodendritic autoreceptors
at the level of the locus coeruleus, which would increase REM
sleep. However, it is still unclear if this is the primary mechan-
ism by which clonidine produces sleep, since the effects are
dose-dependent. Administration of low doses of clonidine
(range 0.025–0.05 mg) has little effect on sleep and can either
increase or decrease the duration of REM sleep. At moderate-
to-high doses (0.1–0.3 mg), clonidine appears to have post-
synaptic activity on the α2-adrenergic receptors, which results
in a decrease in acetylcholine and an increase in REM latency,
stage 2 sleep, and slow-wave sleep (SWS) [70]. It has been
postulated that clonidine may affect NREM sleep via effects on
serotonin, but animal studies did not confirm this hypothesis.
A relatively old survey on the use of clonidine showed that
more than one third of pediatricians reported using clonidine
specifically for sleep disturbances, including sleep onset, sleep
schedule, nighttime awakenings, early morning awakening,
and parasomnia. Clonidine ranked second only to antihista-
mines as the most commonly used medication for treating
sleep disturbance [59]. Clonidine also showed beneficial
effects on sleep in ADHD, with children and parents reporting
improvement of sleep problems: reduced sleep latency, lower
sleep restlessness, increased total sleep time, and improved
morning awakening [71]. A subsequent study confirmed its
efficacy in 62 children with ADHD and sleep problems [72].
Ingrassia and Turk [73], in a retrospective chart review,
found clonidine to be an effective therapeutic intervention
for alleviating sleep disturbances in six children with NDDs,
aged 6–14 years, at a dose of 0.05–0.1 mg at bedtime. No
relevant side effects were reported.
In a retrospective review, 19 children with ASD were trea-
ted with 0.05 mg oral clonidine, with a slow titration up to
0.100 mg, 30 minutes before bedtime, and reduced sleep
latency and nocturnal awakenings were reported. Adverse
effects were skin irritation with transdermal administration,
and daytime drowsiness with administration of tablets [74].
Moreover, Hollway et al. [35], in a comprehensive literature
search, showed that clonidine was effective for sleep distur-
bances in children with comorbid ASD and other NDDs at
doses ranging from 0.05 to 0.225 mg/day.
The most commonly reported side effects of clonidine
include drowsiness, transient sedation, headache, dizziness,
6 O. BRUNI ET AL.
fatigue, somnolence, insomnia, hypotension, and bradycardia.
In children who are taking concomitant CNS-depressing
agents and in individuals with hemodynamic instability or
cardiac pathology, the use of clonidine should be accurately
monitored [75].
3.5. Guanfacine
Guanfacine is a selective α2A-adrenergic receptor agonist that
stimulates postsynaptic α2A-receptors in the prefrontal cortex
(PFC), potentiating noradrenergic transmission and strength-
ening the connectivity of PFC networks. It can be effective in
treating hyperactivity, stereotyped body movements, self-
stimulation, hypervigilance, and impulsivity in ASD [76].
Guanfacine is usually prescribed ‘off label’ to treat pediatric
insomnia due to its sedating properties [77] . However, guanfa-
cine appears to be less sedating than clonidine [78]. Moreover,
a placebo-controlled study of extended-release guanfacine
(GEXR) in 29 children with ADHD and sleep problems was
terminated early after finding that GEXR was associated with
decreased total sleep time on polysomnography, compared to
placebo [79]. In support of this finding, a more recent study did
not confirm the effectiveness of GEXR as a sleep aid because
sleep was not found to be significantly improved [80].
3.6. Benzodiazepines: clonazepam
The most commonly prescribed benzodiazepines in the treat-
ment of insomnia in adults are triazolam, flurazepam, tema-
zepam, estazolam, quazepam, clonazepam, lorazepam, and
alprazolam; of these, only estazolam, triazolam, flurazepam,
quaepam, and temazepam are FDA approved in the U.S.A. for
the treatment of insomnia [81].
Benzodiazepines bind to the benzodiazepine recognition
site at the interface of alpha and gamma subunits of the γ-
amino butyric acid A (GABAA) chloride receptor complex, and
they promote sleep by inhibiting brainstem monoaminergic
arousal pathways, through facilitation of the ventrolateral pre-
optic nucleus (VLPO) and by inhibiting GABAergic projections
to arousal centers, mediated by the tuberomammillary nucleus
of the anterior hypothalamus, the posterolateral hypothalamic
hypocretin neurons, and the brainstem arousal regions.
These hypnotics have long been the first-choice treatment for
insomnia in adults, but they raise concerns about cognitive
impairment, rebound insomnia, and the potential risk for depen-
dence. These concerns and the lack of evidence-based data
availability in the pediatric population contribute to their limited
use in children [82]. Short-term or as-needed administration are
the most frequently suggested treatment protocols.
In children with Williams syndrome, aged 1.5–10 years,
clonazepam 0.25–0.75 mg at bedtime, induced an immediate
improvement in nighttime awakenings and daytime behaviors
in four of the five patients that persisted at 3–6 months follow-
up [83]. An effect on REM sleep behavior disorder in a child
with ASD has been reported [84].
Clonazepam may represent a treatment option in children
with arousal disorders, periodic limb movement disorder, or rest-
less legs syndrome, but future trials focused on objective sleep
measures and safety issues are needed. Adverse effects include
sedation, cognitive impairment (anterograde short-term mem-
ory loss), motor impairment, and the potential for abuse.
3.7. Non-benzodiazepine sedative-hypnotics
Non-benzodiazepine sedative-hypnotics are non-
benzodiazepine receptor agonists (NBzRAs) (also known as
Z-drugs) that bind preferentially to GABAA receptor com-
plexes containing α1 subunits; they seem to have minimal
effects on sleep architecture with a small increase in SWS
[85]. In the very few studies conducted in children, NBzRA
administration was not effective. One study showed no effi-
cacy on sleep latency in children with ADHD and insomnia
aged 6–11 years or 12–17 years receiving treatment with
zolpidem up to 10 mg/day [86]. Eszopiclone administered in
371 children with a diagnosis of ADHD and sleep disturbances,
aged 6–17 years, failed to show a beneficial effect over pla-
cebo while dose-dependent adverse events were reported in
46–61% of patients [87]. The most frequent adverse events
(>5%) were dizziness and headache, but disinhibition and
hallucinations were also reported [88].
3.8. Gabapentin
Gabapentin was approved by the FDA for the treatment of
partial seizures in 1993. It was originally designed as
a precursor of GABA that easily crosses the blood-brain barrier
and increases brain synaptic GABA. It binds to the alpha-
2-delta subunit of N-type voltage-gated calcium channels,
which decreases the activity of wake promoting glutamate
and norepinephrine systems [89]. It has been approved for
the treatment of neuropathic pain and restless leg syndrome
in addition to its original purpose as an anticonvulsant med-
ication. However, its precise pharmacological mechanism in
humans remains unknown. In addition to its demonstrated
efficacy in these indications, patient-reported sleep assess-
ments among a variety of clinical conditions suggest that
gabapentin has beneficial effects on sleep. The improvement
of sleep might be mediated by the increase in SWS and the
decrease of WASO [90].
In a recent case series, gabapentin was found to be a safe
and a well-tolerated treatment for sleep-onset and sleep main-
tenance insomnia in 23 children, 87% of whom had NDDs.
With gabapentin initiated at an average dose of 5 mg/kg
(range 3–7.5 mg/kg) 30–45 minutes before bedtime, with
titration to a maximum dose of 15 mg/kg (range 6–15 mg/
kg), 78% of children showed improvement in sleep (as
reported by parents). Furthermore, this beneficial response
was noted at much lower doses (5 to 15 mg/kg orally at
bedtime) than those recommended to treat epileptic seizures
(40 mg/kg, divided into three daily doses). Side effects in a few
cases included agitated nighttime awakenings and difficulty
falling asleep [91]. Although data from this study suggest that
gabapentin may be of benefit in children with NDDs, it is not
frequently used in practice as a first-line sleep agent. Recently
we described the case of a toddler with severe insomnia,
bedtime and nocturnal hyperactivity, night awakenings asso-
ciated with leg kicking and rubbing, highly suggestive of rest-
less legs syndrome, responsive to gabapentin [92].

3.9. Antidepressants
Tricyclic and atypical antidepressants (mirtazapine, nefazo-
done, and trazodone) are commonly prescribed in clinical
practice to treat insomnia in adults and children. Their effects
on sleep are mediated by actions on different neurotransmit-
ters involved in sleep regulation, such as serotonin, histamine,
and acetylcholine. One paper reported that they were pre-
scribed more often than the FDA-approved treatments for
insomnia: trazodone was the most frequently prescribed med-
ication for insomnia in 2002, with 34% more prescriptions than
the most frequently prescribed FDA-approved treatment [93].
3.9.1. Tricyclic antidepressants
Tricyclic antidepressants (amitriptyline, trimipramine, and doxe-
pin) cause a reduction of REM and SWS and have been used to
treat insomnia. Both amitriptyline and trimipramine have been
demonstrated to have sedative effects in adults [91,94–96].
There are no data supporting the use of amitriptyline or
trimipramine in children; however, amitriptyline is commonly
used in children with NDDs beginning with a very low dose
(5 mg), with the dose increased until the desired effect is
achieved, but it should not exceed 50 mg. Side effects of
tricyclics include anxiety and agitation, anticholinergic effects
(e.g., blurred vision, dry mouth, urinary retention, orthostatic
hypotension), cardiotoxicity, and worsening of restless legs
syndrome symptoms.
3.9.2. Doxepin
Doxepin is the most potent antihistamine agent among the
tricyclic antidepressants, with four times the potency of ami-
triptyline and 800 times the potency of diphenhydramine at
the H1 receptor. Doxepin inhibits the reuptake of serotonin
and norepinephrine and antagonizes cholinergic, histaminer-
gic, and α-adrenergic activity [89]. In adults, low-dose doxepin
(3–6 mg) has been shown to improve sleep maintenance and
early morning awakenings [97]; when used in children with
pruritus, it led to CNS depression [98].
3.9.3. Mirtazapine
It is known that many hypnotic drugs prescribed off-label
(trazodone, mirtazapine, olanzapine, quetiapine) act through
the 5-HT2A and 5-HT2C receptors to enhance sleep.
Mirtazapine is an α2-adrenergic 5-HT2 receptor antagonist
with a high degree of sedation at low doses [99]. It has been
shown to decrease sleep-onset latency, increase sleep dura-
tion, and reduce WASO, with relatively little effect on REM
sleep [100]. Its effects as a sedative and as a hypnotic are
attributable to its blockade of the histamine H1 receptor as
well as to the antagonism of the α2-adrenergic receptors. By
antagonizing α2-autoreceptors it increases the release of
norepinephrine; by antagonizing α2-heteroreceptors, it
increases serotonin release, although its effect on serotoner-
gic systems is specific to 5-HT1A-mediated neurotransmis-
sion, because it also blocks the 5-HT2 and 5-HT3 receptors
[101]. There is a single, open-label study in children with
ASD and children with other forms of pervasive
EXPERT OPINION ON PHARMACOTHERAPY 7
developmental disorders that suggests some efficacy for
insomnia [102].
3.9.4. Trazodone
Trazodone, the first 5-HT2A antagonist, was initially developed
as an antidepressant, but is currently one of the most common
hypnotics prescribed in the clinic [103]. It is one of the most
sedating antidepressants and the most widely studied antide-
pressants in terms of sleep in adults. It is the most frequently
prescribed insomnia medication for children with mood and
anxiety disorders in a survey of child and adolescent psychia-
trists [29]. Its action is mediated by 5-HT2A/C antagonism and
inhibition of postsynaptic binding of serotonin and blocking of
histamine receptors.
Recent empirical evidence suggests that trazodone may
interact with the MT system: Giannaccini et al. [104] measured
clinical and MT parameters before and after 1 month of ther-
apy with trazodone in insomniac and mood-depressed
patients. Patients with refractory depressed-mood and insom-
nia improved after treatment, and responsive patients
excreted more urinary 6-hydroxy-melatonin sulfate than
before treatment, reflecting an enhanced nighttime produc-
tion of the pineal hormone and suggesting an interaction
between trazodone and the MT system. Based on these data,
the authors suggested a role for MT as a biological indicator of
the pro-hypnotic and antidepressant benefits of trazodone.
Trazodone causes a decrease in REM sleep and increases
SWS; we can speculate that it might have beneficial effects
on memory function in children who are challenged intellec-
tually and who struggle to generalize and maintain adaptive
skills of daily living. As reported above, it is commonly used to
manage insomnia in clinical practice. However, only very few
studies have been conducted in children and adolescents.
Anecdotal reports show the efficacy of trazodone mainly in
mid-night and terminal insomnia.
Trazodone has been used for insomnia in 17 children with
opsoclonus-myoclonus syndrome [105]. The starting dose of
25 mg was increased to a maximum of 100 or 150 mg depend-
ing on age. The effects on sleep were not dose-dependent and
low dosages were effective for insomnia. The most commonly
reported side effects are dry mouth, nausea, vomiting, drowsi-
ness, dizziness/light-headedness, headache, and morning
hangover. Less common or rare side effects are hypotension,
tachycardia, serotonin syndrome, and priapism [106]. It is not
commonly indicated in Rett syndrome for the risk of QT inter-
val prolongation. It should be noted that, since the doses of
trazodone for insomnia are lower than those used for depres-
sion, the incidence of side effects is also lower.
3.10. Chloral hydrate
Chloral hydrate is indicated for nighttime sedation in children
since it was initially considered to be a safe agent in infants and
young children at dosages of 25–100 mg/kg/day. Chloral
hydrate is thought to exert its effect via its metabolite trichlor-
oethanol, which modulates GABAA receptors, similar to barbitu-
rates [107]. However, respiratory depression and hepatotoxicity
8 O. BRUNI ET AL.

have been reported after administration of chloral hydrate [108], 3.12. Orexin antagonists
and it should be avoided in children with NDDs and especially in
Recently, orexin neuropeptides have been identified as regu-
those at risk for obstructive sleep apnea [109].
lators of the sleep/wakefulness transition and documented to
A relatively recent study comparatively assessed the efficacy
aid an initial transitory effect toward wakefulness by activating
of chloral hydrate (50 mg/kg) and hydroxyzine (1 mg/kg) in 282
cholinergic/monoaminergic neural pathways of the ascending
children (age 4–9 years) requiring sedation for sleep electroen-
arousal system [121]. Orexins play an important role in the
cephalography (EEG). Chloral hydrate was found to be more
wakefulness promoting ascending arousal system, having an
effective in decreasing sleep onset latency; no relevant side
excitatory effect on almost every wake-promoting neuronal
effects were reported [110]. However, chloral hydrate can cause
group of the reticular ascending system (RAS) and represent
gastric distress, nausea, and vomiting, drowsiness, dizziness,
critical modulators of sleep/wake cycle homeostasis [122].
malaise, psychomotor impairment, parasomnia, and fatigue.
The orexin receptor antagonists can be classified on the basis
Children may experience idiosyncratic reactions characterized
of receptor binding affinities, as Selective Orexin Receptor
by confusion, disorientation, and paranoia. Used chronically,
Antagonists (SORAs; i.e., selective for OX1 or OX2 receptors) or
chloral hydrate is habit forming and associated with tolerance
Dual Orexin Receptor Antagonists (DORAs; i.e., compounds with
[111]. It is important to note that it is not recommended by
spread binding capacity to OX1 and OX2) [123]. It was hypothe-
pediatric sleep experts for insomnia and is only used as
sized that antagonizing both orexin receptors would elicit the
a sedating agent for neurodiagnostic procedures [112].
most powerful sleep-promoting effects [124]. The most widely
used DORA molecules (almorexant and suvorexant) adminis-
tered to healthy volunteers and patients with insomnia have
3.11. Atypical antipsychotics been shown to effectively reduce the number of awakenings
and SL, while increasing total sleep time [123].
Atypical antipsychotics such as risperidone, quetiapine, aripipra-
There is strong evidence that suvorexant is effective in redu-
zole, and olanzapine are typically used off-label in children with
cing symptoms of insomnia and increasing total sleep time in
psychiatric or developmental disorders [113,114], but they are
adults, at doses of 15–40 mg/day [125]. Lower doses may be
also increasingly prescribed for insomnia. Risperidone and olan-
preferred, per FDA guidelines, to minimize the risk of adverse
zapine are used for sleep disturbances in children, but no studies
effects. One study, in adolescents with psychiatric disorders or
are available evaluating their safety and effectiveness [35,59,115].
NDDs, reported that 56.7% of them (17/30) successfully contin-
The hypnotic effects of most atypical antipsychotics are probably
ued taking suvorexant with a reduction of Clinical Global
attributable to their strong antagonism of the H1 receptor, as
Impression (CGI) scores after 6 months. The adverse effect that
well as to their antagonism of serotonin receptors [116].
led to discontinuation of suvorexant was abnormal dreams [126].
A recent meta-analysis acknowledges that the use of atypical
A more recent case report showed that an adolescent with
antipsychotics may be appropriate in patients in whom other
bipolar I disorder and chronic sleep difficulties, usually sleeping
treatment modalities have failed and in those with a comorbid
for 3–4 hours per night with both initial insomnia and early
condition that could benefit from the primary action of the drug
morning awakenings, successfully regulated his sleep using
(based on consensus of experts in sleep medicine) [117].
suvorexant after failure with several other agents [127].
Similarly, guidelines for the treatment of chronic insomnia report
The most frequent dose-dependent adverse effects are mild
insufficient evidence for atypical antipsychotics as first-line ther-
somnolence, headaches, dizziness, cataplexy, and abnormal
apy, but state that the medications might be suitable for patients
dreams [128]. This category of compounds might be promising
with comorbid insomnia who may benefit from the primary
for children with NDDs since they act on a different neurotrans-
action of these drugs as well as from their sedating effect [118].
mitter system with fewer interactions with other drugs commonly
Atypical antipsychotics should be considered to treat
used in these children. RCTs are needed to assess both the short-
a comorbid condition (i.e., aggressive, self-injurious behaviors
and long-term effects of these medications, as well as their efficacy
in children with ASD) and they might aid relief from insomnia
in comorbid diseases that affect sleep architecture.
when dosed at bedtime. A small randomized and placebo-
controlled study on quetiapine (25 mg – a relatively low dose)
in adults, showed a statistically non-significant trend toward 4. Supplements
improvement in total sleep time and reduced SL [119]. There is
a single open-label trial involving 11 children with ASD who 4.1. Tryptophan/5-hydroxytryptophan (5-HTP)
did demonstrate a reduction in sleep disturbance [120]. Tryptophan is an essential plant-derived amino acid that is
Common side effects include excessive weight gain, which needed for the in vivo biosynthesis of proteins. After consump-
may exacerbate the sleep-disordered breathing that even- tion, it is metabolically transformed to bioactive metabolites,
tually presents, and metabolic consequences, such as hyper- including serotonin, melatonin, kynurenine, and the vitamin
glycemia or hyperprolactinemia, which may be unsafe in niacin (nicotinamide). As early as 1974, the use of L-tryptophan
certain NDDs (i.e., Down Syndrome or Prader-Willy (LT) was suggested as a natural hypnotic and was widely used
Syndrome). Without more definite data, the use of neurolep- in the 80s for the treatment of sleep disorders and headache
tics for insomnia in children is generally not recommended. prophylaxis. LT produces a negligible decrease in REM sleep

and increase in NREM sleep [129], does not have opioid-like
effects, and does not limit cognitive performance or inhibit
arousal from sleep [130]. Several positive effects on sleep have
been reported in the literature: improvement of SL and
decrease in arousal [131,132]. One study with LT at different
doses (250 mg, 1 g, and 3 g) in adults showed improvement in
SL and a reduction in WASO, with a moderate effect on sleep
quality. None of the papers reported systematic information
regarding adverse effects associated with tryptophan
[133–135].
5-hydroxytryptophan (5-HTP) is the intermediate metabolite
of the essential amino acid LT in the biosynthesis of serotonin. It
easily crosses the blood-brain barrier and effectively increases
CNS synthesis of serotonin. The effects of 5-HTP on sleep struc-
ture are conflicting: an increase or decrease in REM sleep and an
increase in SWS have been reported in a review paper [136]. The
exact mechanism of action of the sedative effects of 5-HTP is not
completely clear, and it is unclear if it is mediated only by
conversion into serotonin. Early studies suggested that serotonin
might help produce NREM and possibly REM sleep, but more
recent work indicates that serotonin generally promotes wake-
fulness and suppresses REM sleep [137]. It seems, however, that
the effect of serotonin on sleep-wake behavior might depend
upon the differential activation of the serotonergic system (sys-
temic administration of low vs. high doses of the precursor
5-HTP) and the time at which the activation occurs (light vs.
dark period of the light-dark cycle) [138]. It has been hypothe-
sized that the 5-HTP-related increase in SWS during the dark
period depends upon the synthesis or release of as yet to be
identified sleep-promoting factors [139].
In 1989, LT (not L-5-HTP) caused an epidemic of eosinophi-
lia-myalgia syndrome [140–142]. Because of its chemical and
biochemical relationship to LT, 5-HTP has been under vigi-
lance for its safety. However, no definite cases of toxicity
have emerged despite the worldwide usage of 5-HTP for
several years [143]. On the other hand, there are several recent
reports on the use of L-5-HTP in children without the occur-
rence of side-effects [144–146]. The substances contaminating
previous pharmaceutical preparations of L-5-HTP are no longer
present in measurable amounts in the preparations now avail-
able on the market because of the improved purification and
analysis methods.
In comparison with synthetic antidepressants and hypno-
tics, L-5-HTP is characterized by a particularly low occurrence
of side-effects. Like LT, at therapeutic doses, L-5-HTP does not
affect the normal distribution of sleep stages with both acute
and chronic treatment. Although very limited data are avail-
able on the effects of 5-HTP on insomnia symptoms and none
in children with NDDs, the absence of side-effects and lack of
development of tolerance with long-term use are important
factors in the decision to embark upon a trial with L-5-HTP.
4.2. Iron
The sleep/wake cycle is partially controlled by the dopamine-
opiate system, which requires iron as a co-factor for proper
functioning. Iron is a co-factor for tyrosine hydroxylase, the
EXPERT OPINION ON PHARMACOTHERAPY 9
enzyme responsible for catalyzing the conversion of the amino
acid L-tyrosine to dopamine. Iron deficiency anemia in infancy
has been reported to be associated with higher motor activity
during sleep, shorter night sleep duration, and higher fre-
quency of night waking [147], and supplemental iron is asso-
ciated with longer sleep duration [148]. In some cases, night
awakenings starting in the first year of life might be an early
sign of restless leg syndrome [149,150].
Because iron deficiency is common in children, measuring
the ferritin level is reasonable. Different reports have shown
a relationship between low serum ferritin levels and insomnia
associated with sleep hyperkinesia, i.e., restless leg syndrome
or periodic leg movements during sleep (PLMS) in children
with ADHD or ASD [151–153]. Although published rates of iron
deficiency in children with ASD are variable, as high as 52%
have been found to demonstrate deficiency [154]. A recent
review showed an increased incidence of PLMS (42%) com-
pared to controls (8%) in 53 pediatric patients with ASD with
low serum ferritin levels (below 35 ng/ml); sleep fragmenta-
tion and poor sleep efficiency were associated with lower
median ferritin levels [155]. Although an association between
low ferritin levels and sleep disorders was observed in this
study, a causal relationship could not be ascertained.
In 102 children (68 with ASD, 18 typically developing, and
16 with developmental delay) there was an increase of PLMS
[155] but serum ferritin levels were not significantly correlated
to any sleep parameter. Iron supplementation (6 mg/kg/day of
elemental iron) was carried out in 33 children with ASD. Over
the course of the study, mean ferritin levels significantly
increased from 15.72 to 28.8 ng/ml; however, no relationship
was found between the restless sleep score and serum ferritin
concentrations [153].
Due to the observed correlation of low serum ferritin levels
and poor sleep quality and the potential benefit of iron sup-
plementation on sleep quality, prescribers may extrapolate
these findings to children with NDDs, but this practice is
guided by clinical experience rather than by robust supporting
evidence [156]. When poor sleep is reported in children with
ASD, ADHD, or other NDDs, serum ferritin levels should be
monitored and questions on restless sleep should be asked. If
ferritin levels are less than 50 mcg per L, 1–2 mg/kg/day of
elemental iron (up to 6 mg/kg/day of elemental iron) should
be administered [151,152]. It should be noted that iron sup-
plementation is often not well tolerated in the pediatric popu-
lation due to gastrointestinal adverse effects and poor
palatability, which can lead to poor adherence.
4.3. Vitamin d
Vitamin D is a pro-hormone belonging to the category of fat-
soluble vitamins; it is synthesized in vivo when the solar ultra-
violet B (UVB) radiation interacts with the precursor molecule,
7-dehydrocholesterol, in the skin. Although endogenous pro-
duction is estimated to account for 90% of total vitamin D in
healthy individuals, a minor source of vitamin D comes from
dietary intake and supplementation. Vitamin D is subsequently
transported in the blood to the liver where it is hydroxylated
10 O. BRUNI ET AL.
to 25-hydroxyvitamin D (25-(OH)D), which is further converted
to the metabolically active form, 1a,25-dihydroxyvitamin
D (1a,25-(OH)2D) [157].
Vitamin D, through actions on tryptophan hydroxylases,
can regulate tryptophan conversion into 5-HTP. A recent
study has shown that vitamin D can selectively enhance cen-
tral serotonin by acting in conjunction with the vitamin
D receptor to induce the expression of brain tryptophan
hydroxylase TPH2, the gene that encodes the enzyme catalyz-
ing the rate-limiting step in the synthesis of serotonin from
the dietary essential amino acid tryptophan. Thus, two nutri-
ents, vitamin D and tryptophan, apparently are supportive of
behavioral health through the maintenance of appropriate
serotonin concentrations during development and into late
adulthood [158].
Vitamin D is also related to dopamine metabolism. Clinical
research on the relationship between vitamin D and sleep is
ongoing, and some studies have been published on the role of
vitamin D metabolism and sleep disorders in adults and chil-
dren. Preliminary data suggest the possibility that altered
vitamin D metabolism could play an important role in the
presentation and severity of sleep disorders [159]. Low vitamin
D concentrations may impact sleep quality via increased pain,
myopathy, immune dysregulation, and cardiovascular dis-
ease [148].
In adults, low levels of vitamin D are associated with short
sleep duration [160,161] and poor sleep quality [162], and
vitamin D supplementation improves sleep duration by
about 45 min [163]. A recent systematic review reported that
vitamin D deficiency is associated with increased risk of sleep
disorders, poor sleep quality, short sleep duration, and sleepi-
ness, and serum 25(OH)D < 20 ng/mL significantly increases
the risk of unhealthy sleep by nearly 60% [164].
A specific study in Chinese children showed that 25(OH)D
levels are positively correlated with sleep duration while
insufficiency/deficiency of vitamin D (25(OH)D ≤ 20 ng/mL) is
associated with increased probability of short sleep [164].
Furthermore, a low 25(OH)D level at birth may be associated
with an increased probability of being a persistent short slee-
per in preschool years [165].
The literature, therefore, suggests that vitamin
D supplementation may improve sleep quality. Most patients
show improvement in sleep but only by maintaining
a narrow range of 25(OH) vitamin D3 blood levels of 60–-
80 ng/ml [166]. Although no studies have been carried out in
children with NDDs and insomnia, there is some evidence
that it might be useful to investigate vitamin D levels.
5. Conclusions
Insomnia in children with NDDs, in conjunction with other
neurobehavioral comorbidities, is associated with poorer
developmental outcome and contributes to worsening beha-
vioral disturbances. Its treatment in children is extremely
important in order to increase sleep quality and quantity and
daytime behavior. Improvement in insomnia-related daytime
impairments is beneficial not only for the child but also for the
entire family since a better quality of sleep may ameliorate
daytime behavior, cognitive development delays in the child,
and psychological distress in the family. The assessment
should consider medical and psychiatric contributing factors,
primary sleep disorders, and maladaptive behaviors related to
sleep. The correct treatment should follow a specific pattern:
a thorough sleep history, sleep hygiene, behavioral treatment
strategies involving the parents, circadian rhythm regulation,
and pharmacological treatment.
Since the publication of the 2006 American Academy of
Pediatrics and National Sleep Foundation joint consensus
statement [9], pharmacologic treatment for children with
insomnia continues to be an unmet need and the current
evidence is insufficient to fully evaluate the benefits and
harms of the wide variety of drugs currently being used to
treat sleep disorders in children in primary care. Although MT,
and even diphenhydramine, have evidence supporting at least
some benefit and few harms in the short term, this evidence is
inadequate to support their long-term use.
Despite the widespread use of pharmacological treatment,
the lack of well-designed and controlled studies concerning
the efficacy, tolerability, dosage, and safety profile of hypnotic
medications in children raises the need for further research in
this field of sleep medicine. This will hopefully lead to the
development of a drug with proven efficacy and suitable
safety profile that will allow for better health and quality of
life of children and adolescents with NDDs and their families.
6. Expert opinion
Insomnia represents a relevant clinical problem in both typi-
cally developing children and children with behavioral, neuro-
developmental, and psychiatric conditions. The use of
different psychotropic medications is common, but studies
indicate a highly variable therapeutic approach to insomnia
in the pediatric population.
Similar to adults, recommendations and approval for the
long-term treatment of chronic insomnia are lacking, and
almost all pediatric subjects with NDDs and sleep problems
are treated with off-label substances. Specific guidelines for
insomnia have been developed by the American Academy of
Sleep Medicine (AASM) or the European Sleep Research
Society (ESRS) but no consensus for the pharmacological treat-
ment of insomnia in either typically developing children or in
children with NDDs have been published. However, there is
a current trend to implement pediatric clinical trials on the use
of medications for insomnia employed in adults.
Since age is the most important factor in sleep develop-
ment and consolidation, it should be thoroughly considered
when using a medication. A correct approach in children is to
begin with a very low dose and increase gradually and care-
fully looking at the potential side effects, since sleep medica-
tion might have different consequences in distinct clinical
subpopulations.
Guidelines on medical treatment of sleep disorders in chil-
dren with NDDs should consider the potential subtypes of
insomnia in children. The AASM or ESRS guidelines discrimi-
nate between different types of insomnia (i.e., sleep onset or
sleep maintenance insomnia) and research on neurobiological
correlates of sleep onset, sleep maintenance, and sleep stages
could help to identify pathways and neurotransmitters

involved, in order to implement new medical regimes [167]. In
this respect, a recent study from our group identified three
different types of insomnia in typically developing children,
with each of them probably requiring a different pharmacolo-
gical approach or even treatment with supplements [168]. An
attempt to apply a similar approach should be carried out in
children with NDDs. For this reason, in this narrative review we
also reported scientific evidence on the use of iron, vitamin D,
or 5-hydroxytryptophan.
In a review on the use of pharmacotherapy for insomnia in
child psychiatry practice, most psychiatrists prescribed differ-
ent drugs or over-the-counter medications for insomnia in
different psychiatric disorders [29]. Alpha agonists, trazodone,
and antidepressants are commonly used for children with
psychiatric disorders, followed by atypical antipsychotics,
anticonvulsants, and short-acting hypnotics; MT was also fre-
quently recommended. All these hypnotic and sedative drugs
were often given in the absence of FDA or other regulatory
agencies approval. However, we should suppose that their
frequent use is probably justified at least by their effective-
ness, even if without solid scientific support [169].
A better understanding of the dysfunctional neurotransmitter
pathways involved in sleep disorder in children with NDDs might
help in the development and selection of possibly completely
new drugs. Pharmacological treatment should be used in these
children in association with cognitive behavioral techniques,
since combined approaches might allow a better mitigation of
the effects of sleep disruption on daytime functioning.
Funding
This manuscript has not been funded.
Declaration of interest
O Bruni has served as a consultant and provided expert testimony for both
Angelini and Farmaceutici S.p.A. The authors have no other relevant
affiliations or financial involvement with any organization or entity with
a financial interest in or financial conflict with the subject matter or
materials discussed in the manuscript apart from those disclosed.
Reviewer disclosures
One referee declares that they participated in the development of pro-
longed-release melatonin minitablets for children with ASD which got
approved last year by the EMA. Peer reviewers on this manuscript have
no other relevant financial relationships or otherwise to disclose.
References
Papers of special note have been highlighted as either of interest (•) or of
considerable interest (••) to readers.
1. Robinson-Shelton A, Malow BA. Sleep Disturbances in
Neurodevelopmental Disorders. Curr Psychiatry Rep. 2016 Jan;18(1):6.
2. van de Wouw E, Evenhuis HM, Echteld MA. Prevalence, associated
factors and treatment of sleep problems in adults with intellectual
disability: a systematic review. Res Dev Disabil. 2012;33
(4):1310–1332.
3. Goldman SE, Bichell TJ, Surdyka K, et al. Sleep in children and
adolescents with Angelman syndrome: association with parent
sleep and stress. J Intellect Disabil Res JIDR. 2012;56
(6):600–608.
EXPERT OPINION ON PHARMACOTHERAPY 11
4. Gail Williams P, Sears LL, Allard A. Sleep problems in children with
autism. J Sleep Res. 2004;13(3):265–268.
5. Gringras P, Gamble C, Jones AP, et al. Melatonin for sleep problems
in children with neurodevelopmental disorders: randomised dou-
ble masked placebo controlled trial. BMJ. 2012;345:e6664.
6. Johnson KP, Malow BA. Sleep in children with autism spectrum
disorders. Curr Neurol Neurosci Rep. 2008;8(2):155–161.
7. Krakowiak P, Goodlin-Jones B, Hertz-Picciotto I, et al. Sleep pro-
blems in children with autism spectrum disorders, developmental
delays, and typical development: a population-based study. J Sleep
Res. 2008;17(2):197–206.
8. Melke J, Goubran Botros H, Chaste P, et al. Abnormal melatonin synth-
esis in autism spectrum disorders. Mol Psychiatry. 2008;13(1):90–98.
9. Mindell JA, Emslie G, Blumer J, et al. Pharmacologic management
of insomnia in children and adolescents: consensus statement.
Pediatrics. 2006;117(6):e1223–1232.
10. Rossignol DA, Frye RE. Melatonin in autism spectrum disorders:
a systematic review and meta-analysis. Dev Med Child Neurol.
2011;53(9):783–792.
11. Grigg-Damberger M, Ralls F. Treatment strategies for complex
behavioral insomnia in children with neurodevelopmental
disorders. Curr Opin Pulm Med. 2013;19(6):616–625.
12. Cortese S, Faraone SV, Konofal E, et al. Sleep in children with
attention-deficit/hyperactivity disorder: meta-analysis of subjective
and objective studies. J Am Acad Child Adolesc Psychiatry. 2009;48
(9):894–908.
13. Quine L. Sleep problems in children with mental handicap. J Ment
Defic Res. 1991;35(Pt 4):269–290.
14. Cuomo BM, Vaz S, Lee EAL, et al. Effectiveness of Sleep-Based
Interventions for Children with Autism Spectrum Disorder: A
Meta-Synthesis. Pharmacotherapy. 2017;37(5):555–578.
•• This extensive and complete review summarizes and evaluates
available evidence on the behavioral treatment of sleep dis-
orders in children with autism.
15. Taira M, Takase M, Sasaki H. Sleep disorder in children with autism.
Psychiatry Clin Neurosci. 1998;52(2):182–183.
16. Okawa MSH. Sleep disorders in mentally retarded and brain-
impaired children. In: Guilleminault C, editor. Sleep and its
Disorders in Children. New York, NY: Raven Press; 1987. p. 269–290.
17. Jan JE, Owens JA, Weiss MD, et al. Sleep hygiene for children with
neurodevelopmental disabilities. Pediatrics. 2008;122
(6):1343–1350.
18. Honaker SM, Meltzer LJ. Bedtime Problems and Night Wakings in
Young Children: an Update of the Evidence. Paediatr Respir Rev.
2014;15(4):333–339.
19. Angriman M, Caravale B, Novelli L, et al. Sleep in children with neuro-
developmental disabilities. Neuropediatrics. 2015;46(3):199–210.
20. Meltzer LJ, Mindell JA. Systematic review and meta-analysis of
behavioral interventions for pediatric insomnia. J Pediatr Psychol.
2014;39(8):932–948.
21. Strategies to Improve Sleep in Children with Autism Spectrum
Disorders. Autism Speaks Autism Treatment Network, [cited
2019 Sep 9]. https://vkc.mc.vanderbilt.edu/assets/files/
resources/sleepasd.pdf
22. Quick Tips. Improving Sleep for Children with Autism. Autism
Speaks Autism Treatment Network. [cited 2019 Sep 9]. https://
www.autismspeaks.org/sites/default/files/2018-09/Sleep%
20Quick%20Tips.pdf
23. Malow BA, Katz T, Reynolds AM, et al. Sleep Difficulties and
Medications in Children With Autism Spectrum Disorders:
A Registry Study. Pediatrics. 2016;137 Suppl 2:S98–104.
24. Beresford B, McDaid C, Parker A, et al. Pharmacological and
non-pharmacological interventions for non-respiratory sleep distur-
bance in children with neurodisabilities: a systematic review.
Health Technol Assess Winch Engl. 2018;22(60):1–296.
•• Very extensive review to assess the clinical effectiveness and
safety of pharmacological and non-pharmacological interven-
tions to manage sleep disturbance in children
25. Pelayo R, Yuen K. Pediatric sleep pharmacology. Child Adolesc
Psychiatr Clin N Am. 2012;21(4):861–883.
12 O. BRUNI ET AL.
26. Hiscock H, Bayer J, Gold L, et al. Improving infant sleep and
maternal mental health: a cluster randomised trial. Arch Dis Child.
2007;92(11):952–958.
27. Heussler H, Chan P, Price AMH, et al. Pharmacological and
non-pharmacological management of sleep disturbance in chil-
dren: an Australian Paediatric Research Network survey. Sleep
Med. 2013 Feb;14(2):189–194.
28. Bruni O, Violani C, Luchetti A, et al. Di Donatella Valente C. The
Sleep Knowledge of Pediatricians and Child Neuropsychiatrists.
Sleep Hypnosis J Clin Neurosci Psychopathol. 2004;6(3):130–138.
29. Owens JA, Rosen CL, Mindell JA, et al. Use of pharmacotherapy for
insomnia in child psychiatry practice: A national survey. Sleep Med.
2010;11(7):692–700.
30. Pelayo R, Dubik M. Pediatric sleep pharmacology. Semin Pediatr
Neurol. 2008;15(2):79–90.
31. Kennaway DJ. Melatonin and development: physiology and
pharmacology. Semin Perinatol. 2000;24(4):258–266.
32. Gobbi G, Comai S. Differential Function of Melatonin MT1 and MT2
Receptors in REM and NREM Sleep. Front Endocrinol. 2019;10:87.
• Recent study evaluating in a complete and exaustive manner
the differences of melatonin receptors in relation to sleep
stages.
33. Hartz I, Furu K, Bratlid T, et al. Hypnotic drug use among 0-17 year
olds during 2004-2011: a nationwide prescription database study.
Scand J Public Health. 2012;40(8):704–711.
34. Cortesi F, Giannotti F, Sebastiani T, et al. Controlled-release mela-
tonin, singly and combined with cognitive behavioural therapy, for
persistent insomnia in children with autism spectrum disorders:
a randomized placebo-controlled trial. J Sleep Res. 2012;21
(6):700–709.
35. Hollway JA, Aman MG. Pharmacological treatment of sleep distur-
bance in developmental disabilities: a review of the literature. Res
Dev Disabil. 2011;32(3):939–962.
36. Abdelgadir IS, Gordon MA, Akobeng AK. Melatonin for the manage-
ment of sleep problems in children with neurodevelopmental dis-
orders: a systematic review and meta-analysis. Arch Dis Child.
2018;103(12):1155–1162.
37. Phillips L, Appleton RE. Systematic review of melatonin treatment
in children with neurodevelopmental disabilities and sleep
impairment. Dev Med Child Neurol. 2004;46(11):771–775.
38. Braam W, Smits MG, Didden R, et al. Exogenous melatonin for sleep
problems in individuals with intellectual disability: a meta-analysis.
Dev Med Child Neurol. 2009;51(5):340–349.
39. Braam W, Didden R, Smits MG, et al. Melatonin for chronic insom-
nia in Angelman syndrome: a randomized placebo-controlled trial.
J Child Neurol. 2008;23(6):649–654.
40. Wasdell MB, Jan JE, Bomben MM, et al. A randomized,
placebo-controlled trial of controlled release melatonin treatment
of delayed sleep phase syndrome and impaired sleep maintenance
in children with neurodevelopmental disabilities. J Pineal Res.
2008;44(1):57–64.
41. McArthur AJ, Budden SS. Sleep dysfunction in Rett syndrome: a trial
of exogenous melatonin treatment. Dev Med Child Neurol. 1998;40
(3):186–192.
42. De Leersnyder H, de Blois MC, Vekemans M, et al. beta(1)-
adrenergic antagonists improve sleep and behavioural distur-
bances in a circadian disorder, Smith-Magenis syndrome. J Med
Genet. 2001;38(9):586–590.
43. Van der Heijden KB, Smits MG, Van Someren EJW, et al. Idiopathic
chronic sleep onset insomnia in attention-deficit/hyperactivity dis-
order: a circadian rhythm sleep disorder. Chronobiol Int. 2005;22
(3):559–570.
44. Van der Heijden KB, Smits MG, Van Someren EJW, et al. Effect of
melatonin on sleep, behavior, and cognition in ADHD and chronic
sleep-onset insomnia. J Am Acad Child Adolesc Psychiatry. 2007;46
(2):233–241.
45. Smits MG, van Stel HF, van der Heijden K, et al. Melatonin improves
health status and sleep in children with idiopathic chronic
sleep-onset insomnia: a randomized placebo-controlled trial. J Am
Acad Child Adolesc Psychiatry. 2003;42(11):1286–1293.
46. Appleton RE, Jones AP, Gamble C, et al. The use of MElatonin in
children with neurodevelopmental disorders and impaired sleep:
a randomised, double-blind, placebo-controlled, parallel study
(MENDS). Health Technol Assess Winch Engl. 2012;16(40):i–239.
47. Goldman SE, Adkins KW, Calcutt MW, et al. Melatonin in children
with autism spectrum disorders: endogenous and pharmacokinetic
profiles in relation to sleep. J Autism Dev Disord. 2014;44
(10):2525–2535.
48. Cortese S, Brown TE, Corkum P, et al. Assessment and management
of sleep problems in youths with attention-deficit/hyperactivity
disorder. J Am Acad Child Adolesc Psychiatry. 2013;52(8):784–796.
49. Braam W, Keijzer H, Struijker Boudier H, et al. CYP1A2 polymorph-
isms in slow melatonin metabolisers: a possible relationship with
autism spectrum disorder? J Intellect Disabil Res JIDR. 2013;57
(11):993–1000.
50. Braam W, van Geijlswijk I, Keijzer H, et al. Loss of response to
melatonin treatment is associated with slow melatonin
metabolism. J Intellect Disabil Res. 2010;54(6):547–555.
51. van Geijlswijk IM, van der Heijden KB, Egberts ACG, et al. Dose
finding of melatonin for chronic idiopathic childhood sleep onset
insomnia: an RCT. Psychopharmacology (Berl). 2010;212
(3):379–391.
52. Gringras P, Nir T, Breddy J, et al. Efficacy and Safety of Pediatric
Prolonged-Release Melatonin for Insomnia in Children With Autism
Spectrum Disorder. J Am Acad Child Adolesc Psychiatry. 2017;56
(11):948–957.e4.
•• First study to evaluate the efficacy of a prolonged release
melatonin in children with autism spectrum disorder.
53. Maras A, Schroder CM, Malow BA, et al. Long-Term Efficacy and
Safety of Pediatric Prolonged-Release Melatonin for Insomnia in
Children with Autism Spectrum Disorder. J Child Adolesc
Psychopharmacol. 2018 Oct 11. DOI:10.1089/cap.2018.0020;.
54. McDonagh MS, Holmes R, Hsu F. Pharmacologic Treatments for
Sleep Disorders in Children: A Systematic Review. J Child Neurol.
2019;34(5):237–247.
55. Bruni O, Alonso-Alconada D, Besag F, et al. Current role of melato-
nin in pediatric neurology: clinical recommendations. Eur J Paediatr
Neurol. 2015;19(2):122–133.
•• Following a conference meeting, the authors comprise a group
of pediatrics and formulate consensus recommendations on
the use of melatonin in children with neurodevelopmental
disabilities.
56. Miyamoto A, Fukuda I, Tanaka H, et al. [Treatment with ramelteon
for sleep disturbance in severely disabled children and young
adults]. No Hattatsu Brain Dev. 2013;45(6):440–444.
57. Mignot E, Taheri S, Nishino S. Sleeping with the hypothalamus:
emerging therapeutic targets for sleep disorders. Nat Neurosci.
2002;5 Suppl:1071–1075.
58. Thakkar MM. Histamine in the regulation of wakefulness. Sleep
Med Rev. 2011;15(1):65–74.
• Very comprehensive review on the effect of histamine on the
sleep-wake cycle.
59. Schnoes CJ, Kuhn BR, Workman EF, et al. Pediatric prescribing
practices for clonidine and other pharmacologic agents for children
with sleep disturbance. Clin Pediatr (Phila). 2006;45(3):229–238.
60. Russo RM, Gururaj VJ, Allen JE. The effectiveness of diphenhydra-
mine HCI in pediatric sleep disorders. J Clin Pharmacol. 1976;16
(5–6):284–288.
61. Merenstein D, Diener-West M, Halbower AC, et al. The trial of infant
response to diphenhydramine: the TIRED study–a randomized,
controlled, patient-oriented trial. Arch Pediatr Adolesc Med.
2006;160(7):707–712.
62. France KG, Blampied NM, Wilkinson P. A multiple-baseline,
double-blind evaluation of the effects of trimeprazine tartrate on
infant sleep disturbance. Exp Clin Psychopharmacol. 1999;7
(4):502–513.
63. Ottaviano S, Giannotti F, Cortesi F. The effect of niaprazine on some
common sleep disorders in children. A double-blind clinical trial by
means of continuous home-videorecorded sleep. Childs Nerv Syst.
1991;7(6):332–335.

64. Montanari G, Schiaulini P, Covre A, et al. Niaprazine vs chlordes-
methyldiazepam in sleep disturbances in pediatric outpatients.
Pharmacol Res. 1992;25 Suppl 1:83–84.
65. Dinndorf PA, McCabe MA, Frierdich S. Risk of abuse of diphenhy-
dramine in children and adolescents with chronic illnesses.
J Pediatr. 1998;133(2):293–295.
66. Baker AM, Johnson DG, Levisky JA, et al. Fatal diphenhydramine
intoxication in infants. J Forensic Sci. 2003;48(2):425–428.
67. Magera BE, Betlach CJ, Sweatt AP, et al. Hydroxyzine intoxication in
a 13-month-old child. Pediatrics. 1981;67(2):280–283.
68. Gringras P. When to use drugs to help sleep. Arch Dis Child. 2008
Nov;93(11):976–981.
69. Nguyen M, Tharani S, Rahmani M, et al. A review of the use of
clonidine as a sleep aid in the child and adolescent population. Clin
Pediatr (Phila). 2014;53(3):211–216.
70. Delbarre B, Schmitt H. Sedative effects of alpha-sympathomimetic
drugs and their antagonism by adrenergic and cholinergic blocking
drugs. Eur J Pharmacol. 1971;13(3):356–363.
71. Wilens TE, Biederman J, Spencer T. Clonidine for sleep disturbances
associated with attention-deficit hyperactivity disorder. J Am Acad
Child Adolesc Psychiatry. 1994;33(3):424–426.
72. Prince JB, Wilens TE, Biederman J, et al. Clonidine for sleep dis-
turbances associated with attention-deficit hyperactivity disorder:
a systematic chart review of 62 cases. J Am Acad Child Adolesc
Psychiatry. 1996;35(5):599–605.
73. Ingrassia A, Turk J. The use of clonidine for severe and intractable
sleep problems in children with neurodevelopmental disorders–a
case series. Eur Child Adolesc Psychiatry. 2005;14(1):34–40.
74. Ming X, Gordon E, Kang N, et al. Use of clonidine in children with
autism spectrum disorders. Brain Dev. 2008;30(7):454–460.
75. Spiller HA, Klein-Schwartz W, Colvin JM, et al. Toxic clonidine
ingestion in children. J Pediatr. 2005;146(2):263–266.
76. Handen BL, Sahl R, Hardan AY. Guanfacine in children with autism
and/or intellectual disabilities. J Dev Behav Pediatr JDBP. 2008;29
(4):303–308.
77. Efron D, Lycett K, Sciberras E. Use of sleep medication in children
with ADHD. Sleep Med. 2014;15(4):472–475.
78. Scahill L, McCracken JT, King BH, et al. Extended-Release
Guanfacine for Hyperactivity in Children With Autism Spectrum
Disorder. Am J Psychiatry. 2015;172(12):1197–1206.
79. Rugino TA. Effect on Primary Sleep Disorders When Children With
ADHD Are Administered Guanfacine Extended Release. J Atten
Disord. 2018;22(1):14–24.
80. Politte LC, Scahill L, Figueroa J, et al. A randomized,
placebo-controlled trial of extended-release guanfacine in children
with autism spectrum disorder and ADHD symptoms: an analysis of
secondary outcome measures. Neuropsychopharmacol. 2018;43
(8):1772–1778.
81. Minkel J, Krystal AD. Optimizing the Pharmacologic Treatment of
Insomnia: current Status and Future Horizons. Sleep Med Clin. 2013
1;8(3):333–350.
82. Owens JA. Update in pediatric sleep medicine. Curr Opin Pulm
Med. 2011;17(6):425–430.
83. Arens R, Wright B, Elliott J, et al. Periodic limb movement in sleep
in children with Williams syndrome. J Pediatr. 1998;133(5):670–674.
84. Thirumalai SS, Shubin RA, Robinson R. Rapid eye movement sleep
behavior disorder in children with autism. J Child Neurol. 2002;17
(3):173–178.
85. Zisapel N. Drugs for insomnia. Expert Opin Emerg Drugs. 2012;17
(3):299–317.
86. Blumer JL, Findling RL, Shih WJ, et al. Controlled clinical trial of
zolpidem for the treatment of insomnia associated with
attention-deficit/hyperactivity disorder in children 6 to 17 years of
age. Pediatrics. 2009;123(5):e770–776.
87. Sangal RB, Blumer JL, Lankford DA, et al. Eszopiclone for insomnia
associated with attention-deficit/hyperactivity disorder. Pediatrics.
2014;134(4):e1095–1103.
88. Liskow B, Pikalov A. Zaleplon overdose associated with sleepwalk-
ing and complex behavior. J Am Acad Child Adolesc Psychiatry.
2004;43(8):927–928.
EXPERT OPINION ON PHARMACOTHERAPY 13
89. Atkin T, Comai S, Gobbi G. Drugs for Insomnia beyond
Benzodiazepines: pharmacology, Clinical Applications, and
Discovery. Pharmacol Rev. 2018;70(2):197–245.
90. Rosenberg RP, Hull SG, Lankford DA, et al. A Randomized,
Double-Blind, Single-Dose, Placebo-Controlled, Multicenter,
Polysomnographic Study of Gabapentin in Transient Insomnia
Induced by Sleep Phase Advance. J Clin Sleep Med. 2014 15;10
(10):1093–1100.
91. Robinson AA, Malow BA. Gabapentin shows promise in treating
refractory insomnia in children. J Child Neurol. 2013;28
(12):1618–1621.
92. Bruni O, Angriman M, Luchetti A, et al. Leg kicking and rubbing as
a highly suggestive sign of pediatric restless legs syndrome. Sleep
Med. 2015;16(12):1576–1577.
93. Walsh JK. Drugs used to treat insomnia in 2002: regulatory-based rather
than evidence-based medicine. Sleep. 2004 15;27(8):1441–1442.
94. Holmberg G. Sedative effects of maprotiline and amitriptyline. Acta
Psychiatr Scand. 1988;77(5):584–586.
95. Ware JC, Brown FW, Moorad PJ, et al. Effects on sleep: a
double-blind study comparing trimipramine to imipramine in
depressed insomniac patients. Sleep. 1989;12(6):537–549.
96. Riemann D, Voderholzer U, Cohrs S, et al. Trimipramine in primary
insomnia: results of a polysomnographic double-blind controlled
study. Pharmacopsychiatry. 2002;35(5):165–174.
97. Yeung W-F, Chung K-F, Yung K-P, et al. Doxepin for insomnia:
A systematic review of randomized placebo-controlled trials.
Sleep Med Rev. 2015;19:75–83.
98. Zell-Kanter M, Toerne TS, Spiegel K, et al. Doxepin toxicity in a child
following topical administration. Ann Pharmacother. 2000;34
(3):328–329.
99. Younus M, Labellarte MJ. Insomnia in children: when are hypnotics
indicated? Paediatr Drugs. 2002;4:6.
100. Wichniak A, Wierzbicka A, Jernajczyk W. Sleep and antidepressant
treatment. Curr Pharm Des. 2012;18(36):5802–5817.
101. Anttila SA, Leinonen EV. A review of the pharmacological and
clinical profile of mirtazapine. CNS Drug Rev. 2001;7(3):249–264.
102. Posey DJ, Guenin KD, Kohn AE, et al. A naturalistic open-label
study of mirtazapine in autistic and other pervasive develop-
mental disorders. J Child Adolesc Psychopharmacol. 2001;11
(3):267–277.
103. Bertisch SM, Herzig SJ, Winkelman JW, et al. National use of pre-
scription medications for insomnia: NHANES 1999-2010. Sleep.
2014 1;37(2):343–349.
104. Giannaccini G, Masala I, Palego L, et al. Melatonin and pro-hypnotic
effectiveness of the antidepressant Trazodone: A preliminary eva-
luation in insomniac mood-disorder patients. Clin Biochem.
2016;49(15):1152–1158.
105. Pranzatelli MR, Tate ED, Dukart WS, et al. Sleep disturbance and
rage attacks in opsoclonus-myoclonus syndrome: response to
trazodone. J Pediatr. 2005;147(3):372–378.
106. Bossini L, Coluccia A, Casolaro I, et al. Off-Label Trazodone
Prescription: evidence, Benefits and Risks. Curr Pharm Des.
2015;21(23):3343–3351.
107. Allen BC, Fisher JW. Pharmacokinetic modeling of trichloroethy-
lene and trichloroacetic acid in humans. Risk Anal. 1993;13
(1):71–86.
108. Biban P, Baraldi E, Pettennazzo A, et al. Adverse effect of chloral
hydrate in two young children with obstructive sleep apnea.
Pediatrics. 1993;92(3):461–463.
109. Sheldon. Insomnia in Children. Curr Treat Options Neurol. 2001;3
(1).
110. Sezer T, Alehan F. Chloral hydrate versus hydroxyzine HCL for
sedation prior to pediatric sleep EEG recording. Int J Neurosci.
2013;123(10):719–723.
111. Glaze DG. Childhood insomnia: why Chris can’t sleep. Pediatr Clin
North Am. 2014;51(1):33–50.
112. Fong CY, Tay CG, Ong LC, et al. Chloral hydrate as a sedating agent
for neurodiagnostic procedures in children. Cochrane Database
Syst Rev. 2017;03(11):CD011786.
14 O. BRUNI ET AL.
113. Masi G, Cosenza A, Millepiedi S, et al. Aripiprazole monotherapy in
children and young adolescents with pervasive developmental
disorders: a retrospective study. CNS Drugs. 2009;23(6):511–521.
114. Capone GT, Goyal P, Grados M, et al. Risperidone use in children
with Down syndrome, severe intellectual disability, and comorbid
autistic spectrum disorders: a naturalistic study. J Dev Behav
Pediatr. 2008;29(2):106–116.
115. Meltzer LJ, Mindell JA, Owens JA, et al. Use of sleep medications in
hospitalized pediatric patients. Pediatrics. 2007;119(6):1047–1055.
116. DeMartinis NA, Winokur A. Effects of psychiatric medications on
sleep and sleep disorders. CNS Neurol Disord Drug Targets. 2007;6
(1):17–29.
117. Thompson W, Quay TAW, Rojas-Fernandez C, et al. Atypical anti-
psychotics for insomnia: a systematic review. Sleep Med.
2016;22:13–17.
118. Sateia MJ, Buysse DJ, Krystal AD, et al. Clinical Practice Guideline for
the Pharmacologic Treatment of Chronic Insomnia in Adults: an
American Academy of Sleep Medicine Clinical Practice Guideline.
J Clin Sleep Med. 2017 15;13(2):307–349.
• The 2017 US guideline summarizes and evaluates available
evidence on the treatment of insomnia disorder and formu-
lates recommendations for patients treated within the USA.
119. Tassniyom K, Paholpak S, Tassniyom S, et al. Quetiapine for primary
insomnia: a double blind, randomized controlled trial. J Med Assoc
Thail Chotmaihet Thangphaet. 2010;93(6):729–734.
120. Golubchik P, Sever J, Weizman A. Low-dose quetiapine for adoles-
cents with autistic spectrum disorder and aggressive behavior:
open-label trial. Clin Neuropharmacol. 2011;34(6):216–219.
121. Chow M, Cao M. The hypocretin/orexin system in sleep disorders:
preclinical insights and clinical progress. Nat Sci Sleep.
2016;8:81–86.
122. Sakurai T. The neural circuit of orexin (hypocretin): maintaining
sleep and wakefulness. Nat Rev Neurosci. 2007;8(3):171–181.
123. Kumar A, Chanana P, Choudhary S. Emerging role of orexin antago-
nists in insomnia therapeutics: an update on SORAs and DORAs.
Pharmacol Rep PR. 2016;68(2):231–242.
124. Morairty SR, Revel FG, Malherbe P, et al. Dual hypocretin receptor
antagonism is more effective for sleep promotion than antagonism
of either receptor alone. PloS One. 2012;7(7):e39131.
125. Kishi T, Matsunaga S, Iwata N. Suvorexant for Primary Insomnia:
A Systematic Review and Meta-Analysis of Randomized
Placebo-Controlled Trials. PloS One. 2015;10(8):e0136910.
126. Kawabe K, Horiuchi F, Ochi M, et al. Suvorexant for the Treatment
of Insomnia in Adolescents. J Child Adolesc Psychopharmacol.
2017;27(9):792–795.
127. Prieto DI, Zehgeer AA, Connor DF. Use of Suvorexant for sleep
regulation in an adolescent with early-onset bipolar disorder.
J Child Adolesc Psychopharmacol. 2019;29(5):395.
128. Bennett T, Bray D, Neville MW. Suvorexant, a dual orexin receptor
antagonist for the management of insomnia. P T Peer-Rev J Formul
Manag. 2014;39(4):264–266.
129. Hartmann E. Editorial: L-tryptophan: a possible natural hypnotic
substance. JAMA. 1974 23;230(12):1680–1681.
130. Lieberman JA, Kane JM, Reife R. Neuromuscular effects of mono-
amine oxidase inhibitors. J Clin Psychopharmacol. 1985;5
(4):221–228.
131. Schneider-Helmert D, Spinweber CL. Evaluation of L-tryptophan for
treatment of insomnia: a review. Psychopharmacology (Berl).
1986;89(1):1–7.
132. Hartmann E, Spinweber CL. Sleep induced by L-tryptophan. Effect
of dosages within the normal dietary intake. J Nerv Ment Dis.
1979;167(8):497–499.
133. Hudson C, Hudson SP, Hecht T, et al. Protein source tryptophan
versus pharmaceutical grade tryptophan as an efficacious treat-
ment for chronic insomnia. Nutr Neurosci. 2005;8(2):121–127.
134. Hartmann E, Lindsley JG, Spinweber C. Chronic insomnia: effects of
tryptophan, flurazepam, secobarbital, and placebo.
Psychopharmacology (Berl). 1983;80(2):138–142.
135. Spinweber CL. L-tryptophan administered to chronic sleep-onset
insomniacs: late-appearing reduction of sleep latency.
Psychopharmacology (Berl). 1986;90(2):151–155.
136. Meolie AL, Rosen C, Kristo D, et al. Oral nonprescription treatment
for insomnia: an evaluation of products with limited evidence.
J Clin Sleep Med. 2005 15;1(2):173–187.
137. España RA, Scammell TE. Sleep neurobiology from a clinical
perspective. Sleep. 2011 1;34(7):845–858.
138. Imeri L, Mancia M, Bianchi S, et al. 5-Hydroxytryptophan, but not
L-tryptophan, alters sleep and brain temperature in rats.
Neuroscience. 2000;95(2):445–452.
139. Monti JM. Serotonin control of sleep-wake behavior. Sleep Med
Rev. 2011;15(4):269–281.
• Very comprehensive review on the effect of serotonin on the
sleep-wake cycle.
140. Michelson D, Page SW, Casey R, et al. An eosinophilia-myalgia
syndrome related disorder associated with exposure to
L-5-hydroxytryptophan. J Rheumatol. 1994;21(12):2261–2265.
141. Klarskov K, Johnson KL, Benson LM, et al. Structural characteriza-
tion of a case-implicated contaminant, “Peak X,” in commercial
preparations of 5-hydroxytryptophan. J Rheumatol. 2003;30
(1):89–95.
142. Williamson BL, Klarskov K, Tomlinson AJ, et al. Problems with
over-the-counter 5-hydroxy-L-tryptophan. Nat Med. 1998;4(9):983.
143. Das YT, Bagchi M, Bagchi D, et al. Safety of 5-hydroxy-L-tryptophan.
Toxicol Lett. 2004 15;150(1):111–122.
144. Ribeiro CA. L-5-Hydroxytryptophan in the prophylaxis of chronic
tension-type headache: a double-blind, randomized,
placebo-controlled study. For the Portuguese Head Society.
Headache. 2000;40(6):451–456.
145. Ryan ND, Birmaher B, Perel JM, et al. Neuroendocrine response to
L-5-hydroxytryptophan challenge in prepubertal major depression.
Depressed vs normal children. Arch Gen Psychiatry. 1992;49
(11):843–851.
146. Cross DR, Kellermann G, McKenzie LB, et al. A randomized targeted
amino acid therapy with behaviourally at-risk adopted children.
Child Care Health Dev. 2011;37(5):671–678.
147. Kordas K, Siegel EH, Olney DK, et al. Maternal reports of sleep in 6-18
month-old infants from Nepal and Zanzibar: association with iron
deficiency anemia and stunting. Early Hum Dev. 2008;84(6):389–398.
148. Kordas K, Siegel EH, Olney DK, et al. The effects of iron and/or zinc
supplementation on maternal reports of sleep in infants from
Nepal and Zanzibar. J Dev Behav Pediatr. 2009;30(2):131–139.
149. Kotagal S, Silber MH. Childhood-onset restless legs syndrome. Ann
Neurol. 2004;56(6):803–807.
150. Picchietti DL, Stevens HE. Early manifestations of restless legs
syndrome in childhood and adolescence. Sleep Med. 2008;9
(7):770–781.
151. Abou-Khadra MK, Amin OR, Shaker OG, et al. Parent-reported sleep
problems, symptom ratings, and serum ferritin levels in children
with attention-deficit/hyperactivity disorder: a case control study.
BMC Pediatr. 2013;13:217.
152. Cortese S, Konofal E, Bernardina BD, et al. Sleep disturbances and
serum ferritin levels in children with attention-deficit/hyperactivity
disorder. Eur Child Adolesc Psychiatry. 2009;18(7):393–399.
153. Dosman CF, Brian JA, Drmic IE, et al. Children with autism: effect of
iron supplementation on sleep and ferritin. Pediatr Neurol. 2007;36
(3):152–158.
154. Lane R, Kessler R, Buckley AW, et al. Evaluation of periodic limb
movements in sleep and iron status in children with autism. Pediatr
Neurol. 2015;53(4):343–349.
155. Youssef J, Singh K, Huntington N, et al. Relationship of serum
ferritin levels to sleep fragmentation and periodic limb movements
of sleep on polysomnography in autism spectrum disorders.
Pediatr Neurol. 2013;49(4):274–278.
156. Blackmer AB, Feinstein JA. Management of sleep disorders in chil-
dren with neurodevelopmental disorders: a review.
Pharmacotherapy. 2016;36(1):84–98.

157. Muscogiuri G, Barrea L, Scannapieco M, et al. The lullaby of the sun:
the role of vitamin D in sleep disturbance. Sleep Med.
2019;54:262–265.
158. Kaneko I, Sabir MS, Dussik CM, et al. 1,25-Dihydroxyvitamin
D regulates expression of the tryptophan hydroxylase 2 and leptin
genes: implication for behavioral influences of vitamin D. FASEB
J Off Publ Fed Am Soc Exp Biol. 2015;29(9):4023–4035.
159. McCarty DE, Chesson ALJ, Jain SK, et al. The link between vitamin
D metabolism and sleep medicine. Sleep Med Rev. 2014;18
(4):311–319.
•• Comprehensive review on the potential use of vitamin D for
specific sleep disorders.
160. Massa J, Stone KL, Wei EK, et al. Vitamin D and actigraphic sleep
outcomes in older community-dwelling men: the MrOS sleep
study. Sleep. 2015;38(2):251–257.
161. Bertisch SM, Sillau S, de Boer IH, et al. 25-Hydroxyvitamin
D Concentration and sleep duration and continuity:
multi-ethnic study of atherosclerosis. Sleep. 2015 1;38
(8):1305–1311.
162. Jung YS, Chae CH, Kim YO, et al. The relationship between serum
vitamin D levels and sleep quality in fixed day indoor field workers
in the electronics manufacturing industry in Korea. Ann Occup
Environ Med. 2017;29:25.
EXPERT OPINION ON PHARMACOTHERAPY 15
163. Huang W, Shah S, Long Q, et al. Improvement of pain, sleep, and
quality of life in chronic pain patients with vitamin D
supplementation. Clin J Pain. 2013;29(4):341–347.
164. Gong Q-H, Li S-X, Li H, et al. 25-Hydroxyvitamin D Status and its
association with sleep duration in chinese schoolchildren.
Nutrients. 2018 3;10(8).
165. Yong CY, Reynaud E, Forhan A, et al. Cord-blood vitamin D level
and night sleep duration in preschoolers in the EDEN mother-child
birth cohort. Sleep Med. 2019;53:70–74.
166. Gominak SC, Stumpf WE. The world epidemic of sleep disorders is
linked to vitamin D deficiency. Med Hypotheses. 2012;79
(2):132–135.
167. Frase L, Nissen C, Riemann D, et al. Making sleep easier: pharma-
cological interventions for insomnia. Expert Opin Pharmacother.
2018;19(13):1465–1473.
168. Bruni O, Sette S, Angriman M, et al. Clinically oriented subtyping of
chronic insomnia of childhood. J Pediatr. 2018;196:194–200.e1.
•• First attempt to categorize insomnia of childhood from
a clinical point of view
169. Bruni O, Angriman M, Calisti F, et al. Practitioner review: treatment
of chronic insomnia in children and adolescents with neurodeve-
lopmental disabilities. J Child Psychol Psychiatry. 2018;59
(5):489–508.