Current Anesthesiology Reports (2019) 9:85–91

https://doi.org/10.1007/s40140-019-00316-1

PEDIATRIC ANESTHESIA (J LERMAN, SECTION EDITOR)

Pharmacologic Treatment of Insomnia in Children and Adolescents

with Chronic Pain Conditions
Víctor-Hugo González-Cárdenas 1,2 & Evelyn Constantin 3,4 & Marta Somaini 1 & Anna Radzioch 1 & Pablo M. Ingelmo 1,5,6,7,8

Published online: 22 February 2019

# Springer Science+Business Media, LLC, part of Springer Nature 2019

Abstract
Purpose of Review The purpose of this chapter is to provide a review and expert opinion supporting pharmacological treatments
for insomnia in children and adolescents with chronic pain conditions.
Recent Findings Insomnia as an independent disorder is defined as dissatisfaction with sleep quantity or quality, clinically
significant distress or impairment in daytime functioning, and a specific time pattern of occurrence. Independent of the patho-
logical context, insomnia is more frequent in adolescents than in children. The impact of insomnia on pediatric patients is quite
profound, especially on those affected by chronic pain, where the prevalence of insomnia is significantly greater than in those
without pain. Despite the intense effect of insomnia on physical, emotional, and cognitive health, as well as on the efficacy of
interdisciplinary therapy, currently, there are no pharmacological guidelines for this population. Thus, the diagnosis and success-
ful treatment of insomnia in children with chronic pain conditions often represent a significant challenge for clinicians.
Summary The management of insomnia requires an interdisciplinary team that includes a physician, physiotherapist, and
psychologist. Specific therapies for insomnia include sleep hygiene counseling, cognitive behavioral therapy, and pharmacolog-
ical interventions. This review focuses exclusively on five successful pharmacological treatments for insomnia in children and
adolescents with chronic pain conditions, and presents concepts and recommendations based on current medical evidence and the
knowledge of medical experts in the field.

Keywords Sleep initiation and maintenance disorders . Chronic pain . Child . Adolescent . Drug therapy

Introduction waking up earlier than usual with an inability to return to

Insomnia, as an independent disorder, is defined as dissatis-
faction with sleep quantity or quality, clinically significant
distress or impairment in daytime functioning, and a specific
time pattern of occurrence. [1••, 2••] According to current
criteria, dissatisfaction must include one or more of the fol-
lowing: difficulty initiating and/or maintaining sleep and/or
sleep. The compromise in daytime functioning needs to in-
volve at least one or more of the following: fatigue or low
energy, daytime sleepiness, impaired attention, concentration
or memory, mood disturbance, behavioral difficulties, im-
paired occupational or academic function, impaired interper-
sonal or social function, and/or negative effect on the caregiv-
er or family functioning. Finally, the disorder must occur at

This article is part of the Topical Collection on Pediatric Anesthesia

* Pablo M. Ingelmo 4
Department of Pediatrics, Faculty of Medicine, McGill University,
pablo.ingelmo@mcgill.ca Montreal, Canada
5
1
The Alan Edwards Centre for Research on Pain, McGill University,
Chronic Pain Service, Montreal Children’s Hospital, McGill Montreal, Canada
University Health Center, Montreal, Canada 6
Department of Anesthesia, Faculty of Medicine, McGill University,
2 Montreal, Canada
School of Medicine, University Children’s Hospital Foundation of
San José, University Foundation for Health Sciences (FUCS), 7
CIMPARC (Consortium of Multidisciplinary Pain Researchers and
Bogotá, Colombia Clinicians), Milan, Italy
3 8
Child Health and Human Development Program, Department of Department of Anesthesia, Montreal Children’s Hospital, B042427,
Pediatrics, Montreal Children’s Hospital, Montreal, Canada 1001 Boulevard Decarie, Montreal, QC H4A 3J1, Canada
86
least three nights a week, for not less than 3 months, and
persist despite having an adequate opportunity to sleep. [1••,
2••, 3]
To develop specific objectives for the pharmacological
therapy of pediatric insomnia, it is first necessary to under-
stand that age may be associated with differences in the nor-
mal sleep patterns [4, 5]. There are significant differences both
in sleep onset latency and awakenings in children less than
3 years of age, pre-schoolers (ages 3 to 5), and school-age
children (ages 5 to 13) as well as in the ideal duration of sleep
(Table 1). [6•] Independent of the pathological context, insom-
nia occurs more frequently in adolescents than in children.
Therefore, the age of the patient should always be considered
during the assessment, in developing therapies, and in the
setting of realistic objectives for the treatment of insomnia. [7]
These age-dependent differences in normal sleep should be
considered during the assessment phase, in developing thera-
pies and in the setting of realistic objectives for the treatment
of insomnia. The Assembly of (European) National Sleep
Societies [2••] has established the following diagnostic criteria
for chronic insomnia disorder (Table 2):
(A) A disturbance of nocturnal sleep
(B) Related daytime impairment
The sleep disturbance must occur at least three nights per
week for a period of at least 3 months to be diagnosed as a
clinically relevant disorder and is considered chronic after this
time (ICSD-3). Even if diagnostic criteria are fulfilled for the
co-morbidity of a mental or somatic disorder (i.e., chronic
pain), it is recommended that both should be diagnosed inde-
pendently. [1••, 2••]
Insomnia is the most common sleep disorder in children. Its
frequency increases to 30% in the first 2 years of adolescence
and remain approximately 15% in the third year. [6•] In ado-
lescents, insomnia is characterized by delayed sleep phase or a
mixture of sleep disturbances. In addition, it is frequently as-
sociated with anxiety and bad sleep hygiene. [8–10].
Table 1 Optimal sleep duration,
as defined by the National Sleep Age range
Foundation, 2015. [6]
Newborn (0–3 months)
Infants (4–11 months)
Toddlers (1–2 years)
Pre-schoolers (3–5 years)
School-aged children (6–13 years)
Adolescents (14–17 years)
Young adults (18–25 years)
Curr Anesthesiol Rep (2019) 9:85–91
The most frequently reported sleep disturbances are diffi-
culty falling asleep and/or multiple awakenings, followed by
parasomnias and disturbed breathing. [8] Insomnia of phase
delay (otherwise known as delayed sleep phase syndrome) is a
chronic perturbation of circadian rhythm, which disturbs the
timing of sleep, peak episodes of alertness, the central temper-
ature, and the hormonal cycle. These patients generally fall
asleep hours after midnight and present difficulties waking up
in the daylight. [11, 12]
Chronic sleep onset insomnia is similar with the inability to
fall asleep at the beginning of the night, or at the point of usual
“sleep onset.” It could manifest with daytime fatigue and som-
nolence, loss of attention, and irritability. [13–15] Two-thirds
of patients with a deficit of sleep greater than 2 h show an
extended latency to sleep onset (> 30 min). [6•, 8, 16]
Typically, insomnia leads to parasomnias, a category of dis-
ruptive sleep disorders that affects behavior and emotions. [8]
It is gender discriminatory, linked to hormonal changes as well
as to anxiety-depression, and is very common among girls
ages 11 to 13 years (30%). [17]
Insomnia can have profoundly negative social, academic,
and behavioral impacts. [6•] Optimal management requires an
interdisciplinary team including physician, physiotherapist, or
psychologist to be involved. Specific therapies for treating
insomnia include sleep hygiene counseling, cognitive behav-
ioral therapy, and pharmacological treatments. This protocol
focuses exclusively on the pharmacological treatment of
insomnia.
Insomnia and Chronic Pain
Sleep problems are frequently found in chronic pain patients
[18–20] In fact, meaningful associations between sleep quality
and pain scores have been described. [19••] Furthermore,
sleep disorders have been strongly correlated with pain
catastrophizing by those with chronic pain. [21]
After pain, chronic insomnia is the most common symptom
reported by children and adolescents who are part of a chronic
pain service. [22, 23] Both pain and insomnia lead to school
Ideal hours of sleep Acceptable hours of sleep
Minimum Maximum
14–17 11–13 18–19
12–15 10–11 16–18
11–14 9–10 15–16
10–13 8–9 14
9–11 7–8 12
8–10 7 11
7–9 6 10–11
Curr Anesthesiol Rep (2019) 9:85–91 87

Table 2 Diagnostic criteria for chronic insomnia disorder according to the ICSD-3 [1, 2]

Criterion The patient reports, or the patient’s parent or caregiver observes, one or more of the following:
A 1. Difficulty initiating sleep,
2. Difficulty maintaining sleep,
3. Waking up earlier than desired,
4. Resistance to going to bed on an appropriate schedule,
5. Difficulty sleeping without parent or caregiver intervention.
Criterion The patient reports, or the patient’s parent or caregiver observes, one or more of the following related to the night time sleep difficulty:
B 1. Fatigue,
2. Attention, concentration, or memory impairment,
3. Impaired social, family, occupational, or academic performance,
4. Mood disturbance/irritability,
5. Daytime sleepiness,
6. Behavioral problems (e.g., hyperactivity, impulsivity, aggression),
7. Reduced motivation/energy/motivation,
8. Proneness for errors/accidents,
9. Concerns about or dissatisfaction with sleep.
Criterion The reported sleep/wake complaints cannot be explained purely by inadequate opportunity (i.e., enough time is allotted for sleep) or
C inadequate circumstances (i.e., the environment is safe, dark, quiet, and comfortable) for sleep.
Criterion The sleep disturbances and associated daytime symptoms occur at least three times per week.
D
Criterion The sleep disturbances and associated daytime symptoms have been present for at least 3 months.
E
Criterion F The sleep/wake difficulty is not better explained by another sleep disorder.

absenteeism, significant anxiety, and mood changes. It is not
unusual for children to enter into an increasingly complex
cycle of school absenteeism, pressure to catch up on missed
school material, and increased stress. Insomnia correlates with
depression, functional disability, and reduced quality of life.
The frequency and severity of insomnia is a stronger predictor
of disability and depression than pain. [24••, 25•]
Cross-sectional studies suggest that patients with insomnia
present a significant compromise in their neuropsychological
functioning, independent of the association with pain, fatigue,
or mood disorders. [26•] Half of the patients with chronic neck
pain reported mild or severe insomnia and one in five of those
met the criteria for clinically significant insomnia. [27] Pain
intensity, anxiety, and depression are strongly correlated with
clinical insomnia in patients with chronic pain, suggesting the
need for treatment of insomnia as part of pain management in
chronic pain, especially in patients with depression. [28, 29]
Insomnia should be addressed and treated in every child or
adolescent with chronic pain conditions. However, informa-
tion and evidence concerning the efficacy or risks of pharma-
cological treatment of insomnia in pediatric patients with
chronic pain conditions are limited. [16]
Pharmacological Options
There are currently no medications that have been approved
by Health Canada for the treatment of insomnia in children
and adolescents. However, pharmacological therapy is used
when other strategies prove insufficient and insomnia be-
comes chronic. In such a case, medication should be an
extension of non-pharmacological treatments and is best ac-
companied by proper sleep hygiene and recommended behav-
ioral sleep interventions or strategies. This review provides
information on five medications frequently used in the man-
agement of insomnia in children and adolescents with chronic
pain conditions. The present recommendations are based
mostly on clinical experience, [18] and emphasize the follow-
ing guiding principles:
1. Focus on the main symptoms
2. Treat the primary cause of the insomnia
3. Prevent negative pharmacological interactions
4. Individualize the dose
5. Evaluate efficacy and adverse effects regularly
Melatonin
Melatonin, a hormone that is produced in the pineal gland, is
derived from L-tryptophan obtained in the diet. Its metabolism
is mediated by norepinephrine concentrations, which facili-
tates its release at night. Sunlight, as well as a diet rich in
tryptophan and plasma proteins concentrations, affects mela-
tonin concentrations. The hormone is metabolized and excret-
ed by the liver. [16] Melatonin shortens the onset of sleep and
decreases the number of awakenings. Its effectiveness is
strongly related to the timing of administration rather than
the dose. It acts optimally at the onset of the nocturnal secre-
tion of melatonin, decreasing the excitatory activity of
88
glutamate, and enhancing the inhibitory effect of GABA re-
ceptors to prepare the body for an extended rest. [30]
In children, melatonin is prescribed to extend sleep onset
latency (> 30 min). Recommended doses vary between 1 and
3 mg orally for pre-school-age children, and 3 and 6 mg for
school-age children and adolescents. It should be taken at least
1–2 h before bedtime in chronic sleep onset insomnia. In chil-
dren with insomnia of phase delay, the starting dose is 1 to
6 mg 3 to 5 h before bedtime. [31, 32] We recommend starting
with a dose of 3 mg for a body weight between 20 and 40 kg
or 6 mg for a body weight above 40 kg. [33]
Several studies suggested that melatonin is safe in children
and adolescents; however, the long-term effects of melatonin
remain unclear. Exogenous melatonin does not interfere with
anti-epileptic and anxiety drugs, nor does it compromise en-
dogenous production of melatonin. [34–36] There are not spe-
cific contraindications or major interactions between melato-
nin and most analgesic and adjuvants typically prescribed to
help patients with chronic pain conditions. A patient who
elects to reduce or stop melatonin does not need to be weaned
off the medication over a period of time.
The more common side effects of melatonin are dose-de-
pendent. The potential adverse effects of melatonin include
daytime drowsiness, depressed mood, feeling irritable, stom-
ach pain, headache, and/or dizziness. [37] The prevalence of
adverse effects in children and adolescents is unknown.
Clonidine
The hypnotic effect of clonidine is mediated through its ago-
nist effect on central α-2 adrenergic receptors in the brain. Its
onset of action is within 1 h, with a peak effect in 2 to 4 h.
Clonidine has a variable plasma half-life of 6 to 24 h. [38]
Clonidine reduces the sleep onset time, as well as the num-
ber of awakenings in different clinical conditions. However,
there is no information on the use of clonidine in children and
adolescents with chronic pain conditions. Concurrent admin-
istration of clonidine and antidepressants including trazodone
is reported to be safe and effective in young adults. [38–43]
There are no specific dosing recommendations for cloni-
dine in children with chronic pain. In clinical practice, we
recommend an empirical initial dose of 0.5–1 mcg/kg in pre-
adolescents or 50 to 100 mcg in adolescents, 2 to 3 h before
sleep. The initial dose could be modified on a weekly basis
according to the patient’s response. [38, 39]
In order to prevent rebound hypertension and insomnia
when discontinuing clonidine, we recommend reducing the
daily dose by 25% to 50% every 3 to 7 days. [39, 41]
The adverse effects of clonidine include drowsiness, dizzi-
ness, dry mouth, transient sedation, headache, fatigue, somno-
lence, insomnia, hypotension, and bradycardia. [39]. An over-
dose of clonidine may be associated with drowsiness and
Curr Anesthesiol Rep (2019) 9:85–91
lethargy (72%), bradycardia (12%), hypotension (9%), respi-
ratory depression (7%), coma (4%), and hypertension (4%).
[44]
Clonidine and amitriptyline or nortriptyline may interact,
with manifestations including incremental risks of nausea,
vomiting, sweating, dizziness, headaches, and tachycardia.
Clonidine should be used with caution in patients with sinus
node dysfunction or AV nodal disease.
Trazodone
Trazadone is an antidepressant often prescribed to treat de-
pression, anxiety, and insomnia. Several clinical studies have
supported its efficacy as a hypnotic in depressed adults. [45,
46]
Tazadone’s mechanism of action has been attributed to
blocking the neuronal reuptake of serotonin (5-HT) by the
serotonin transporter (SERT). However, that hypothesis does
not completely explain its effects. Currently, trazodone has
been relabeled as a mixed serotonergic agonist/antagonist with
adrenolytic activity. It antagonizes 5-HT2A and 5-HT2B re-
ceptors, is a partial agonist of 5-HT1A receptors, and inhibits
postsynaptic a1-adrenergic and presynaptic a2-adrenergic re-
ceptors. [45] Due to the combination of its rapid absorption
and oral bioavailability (65–80%), its peak plasma concentra-
tion occurs 1 to 2 h after administration. The terminal half-life
after oral administration is 3–4 h.
Trazodone 0.5 mg/kg at bedtime decreases slow-wave
sleep and REM sleep, and prolongs stage 1 sleep. [47]
Taking 10–20 mg of trazodone at bedtime produced signifi-
cant benefits in child and adolescent patients with insomnia
and clinical depression. [48]
In healthy volunteers, trazodone not only increased sleep
efficiency and total sleep time, but also increased stage 3 sleep
and decreased the number of awakenings. No significant
changes in rapid eye movement [9] sleep were observed; nor
was there any significant adjustment in slow wave activity or
other EEG spectral measures. [49] Trazodone (100 mg at bed-
time for 8 weeks) in combination with cognitive behavior
therapy (CBT) was more effective in treating primary insom-
nia in non-depressed adults compared with either trazodone or
CBT alone. [50] Trazodone (25 mg to 150 mg) is regarded as a
third-line treatment for insomnia in adolescents. [7, 44,
51–53]
To prevent withdrawal or rebound syndrome, trazodone
has to be tapered gradually, over 4 to 8 weeks depending on
the duration of treatment. [54]
The most common side effects of trazodone include dry
mouth, unpleasant taste, blurred vision, confusion, dizziness,
faintness, sedation, sweating, weight changes, headache, nau-
sea, vomiting, weakness, priapism, cutaneous rash, and aller-
gies. [45, 55, 56]
Curr Anesthesiol Rep (2019) 9:85–91
Trazodone interacts with tricyclic antidepressants (amitrip-
tyline, nortriptyline), serotonin and norepinephrine reuptake
inhibitors (citalopram, duloxetine), triptans (sumatriptan,
rizatriptan), and tramadol. The concomitant use of trazodone
and the above medications could produce a serotoninergic
syndrome characterized by confusion, hallucinations, sei-
zures, tachycardia, sweating, chills, blurred vision, stiffness,
tremor, nausea, vomiting, and diarrhea. In severe cases, it can
lead to coma and even death. This medicine should be admin-
istered cautiously in patients with angle closure glaucoma,
mania, and suicidal ideation. [45]
Zolpidem
Zolpidem is an imidazopyridine hypnotic and sedative, non-
benzodiazepine GABA-A receptor agonist. [57] Zolpidem has
a relative brief plasma half-life (2.4 ± 2 h). [58]
This medication has been used for relief of insomnia, not
only in adults but also in children and adolescents [46], and is
well tolerated in patients between 2 and 18 years of age. [59]
Zolpidem can be co-administered with selective serotonin
reuptake inhibitors to improve sleep, without significantly in-
creasing the risk of serotoninergic syndrome or cardiovascular
adverse effects. [46, 57] In adult patients with primary insom-
nia, 8 weeks of treatment with a combination of zolpidem
(5 mg) and paroxetine (10 mg) proved to be more effective
at improving sleep maintenance and early morning awaken-
ings than zolpidem treatment alone. [60] Zolpidem can also be
combined with clonidine; its efficacy is significantly enhanced
when combined with CBT. [61]
Zolpidem is recommended in doses of 0.25 mg/kg (up to
10 mg) orally 30 min before bedtime in children and adoles-
cents who are experiencing difficulties with sleep onset and/or
maintenance. [59] Zolpidem in sublingual, oral, and nasal spray
formulations has also been approved for middle-of-the-night
(MOTN) awakening and difficulty returning to sleep. [46, 62]
Health Canada and the Food and Drug Administration recom-
mend an initial oral dose of 5 mg. [63, 64]
Zolpidem has been associated with headache (10–24%),
drowsiness and dizziness (24%), myalgia, arthralgia, blurred
vision, visual hallucination, anxiety, nausea, tachycardia, rash,
diarrhea, dry mouth, and bizarre behaviors. [57, 65] Although
zolpidem is generally considered to have a modest risk of
potential abuse and physical dependence, there are a number
of cases in adults that document abuse and physical depen-
dence accompanied by serious withdrawal symptoms.
Therefore, a cautious discontinuation program, by tapering
the dose over 4 to 12 weeks, is recommended. [66].
Quetiapine
Quetiapine is a second-generation antipsychotic, approved by
the FDA for the treatment of schizophrenia and bipolar
89
disorders in adults. Its mechanism of action is due to its effects
on different receptors including histamine (H1), serotonin (5-
HT1A-2), dopamine (D1-2), and adrenergic (α1, α2).
Patients who take quetiapine to treat insomnia associated
with addictive behaviors experience a rapid improvement in
sleep, as well as long-term effects extending up to 60 days.
[67] Quetiapine can be used for long periods without devel-
oping tolerance. In addition, Quetiapine does not impair either
cognitive or psychomotor performance. [68] Quetiapine pre-
sents significant sedative properties that have proven useful in
controlling insomnia, especially insomnia directly related to
chronic pain. [46, 69–71]
The recommended dose of quetiapine to control insomnia
in adolescents (> 45 kg) starts at 25 mg QHS, and may be
increased by 25 mg increments, according to the patient’s
responsiveness, up to a maximum of 100 mg daily.
Although weight gain is probably the most common side
effect of quetiapine, it is usually of mild to moderate intensity
and not significantly associated with metabolic stress. [72]
Dry mouth and drowsiness are also frequently reported.
More severe adverse effects might include akathisia, restless
leg syndrome, and fatal hepatotoxicity. [73]
Conclusions
Therapeutic treatments of insomnia include both pharmaco-
logical and non-pharmacological techniques. Non-
pharmacological strategies including cognitive behavior ther-
apy, relaxation therapy, behavioral strategies, cognitive thera-
py, hypnotherapy, yoga, light therapy, and exercise should be
considered first-line therapy. If non-pharmacological tech-
niques fail to produce clinical benefits, medications may be
used for special cases in children/adolescents. Given the di-
versity of the available information and the poor standardiza-
tion of guidelines, each patient should be analyzed individu-
ally, while acknowledging the indications, contraindications,
interactions, and possible adverse effects of each medication.
Finally, a strict follow-up program to re-evaluate the safety
and efficacy of selected treatments is also recommended.
Compliance with Ethical Standards
Conflict of Interest Víctor-Hugo González-Cárdenas, Evelyn
Constantin, Marta Somaini, Anna Radzioch, and Pablo Ingelmo declare
they have no conflict of interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
Publisher’s Note Springer Nature remains neutral with regard to jurisdic-
tional claims in published maps and institutional affiliations.
90
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
1.•• American Psychiatric Association. Diagnostic and statistical man-
ual of mental disorders. In: Arlington, editor. 5th ed: American
Psychiatric Publishing; 2013. Published in 2013, it is the current
psychiatric mental disorder classification and include the diag-
nostic criteria for chronic insomnia.
2.•• Assembly of National Sleep Societies. European guideline for the
diagnosis and treatment of insomnia. J Sleep Res. 2017;27:675–
700. Updated guideline for diagnosis and treatment of insomnia
in Europe.
3. Winkelman JW. Clinical practice. Insomnia Disorder N Engl J
Med. 2015;373(15):1437–44.
4. Owens JA, Rosen CL, Mindell JA. Medication use in the treatment
of pediatric insomnia: results of a survey of community-based pe-
diatricians. Pediatrics. 2003;111(5 Pt 1):e628–35.
5. Owens JA, Rosen CL, Mindell JA, Kirchner HL. Use of pharma-
cotherapy for insomnia in child psychiatry practice: a national sur-
vey. Sleep Med. 2010;11(7):692–700.
6.• Hirshkowitz M, Whiton K, Albert SM, Alessi C, Bruni O,
DonCarlos L, et al. National Sleep Foundation’s sleep time dura-
tion recommendations: methodology and results summary. Sleep
Health. 2015;1(1):40–3. Sleep time duration definitions accord-
ing to age range.
7. Owens JA, Mindell JA. Pediatric insomnia. Pediatr Clin N Am.
2011;8(3):555–69.
8. Hysing M, Pallesen S, Stormark KM, Lundervold AJ, Sivertsen B.
Sleep patterns and insomnia among adolescents: a population-
based study. J Sleep Res. 2013;22(5):549–56.
9. Fossum IN, Nordnes LT, Storemark SS, Bjorvatn B, Pallesen S. The
association between use of electronic media in bed before going to
sleep and insomnia symptoms, daytime sleepiness, morningness,
and chronotype. Behav Sleep Med. 2014;12(5):343–57.
10. Merikanto I, Lahti T, Puusniekka R, Partonen T. Late bedtimes
weaken school performance and predispose adolescents to health
hazards. Sleep Med. 2013;14(11):1105–11.
11. Richardson C, Cain N, Bartel K, Micic G, Maddock B, Gradisar M.
A randomised controlled trial of bright light therapy and morning
activity for adolescents and young adults with delayed sleep-wake
phase disorder. Sleep Med. 2018;45:114–23.
12. Richardson C, Cain N, Bartel K, Micic G, Maddock B, Gradisar M.
Cognitive performance in adolescents with delayed sleep-wake
phase disorder: treatment effects and a comparison with good
sleepers. J Adolesc. 2018;65:72–84.
13. Zwart TC, Smits MG, Egberts TCG, Rademaker CMA, Van
Geijlswijk IM. Long-term melatonin therapy for adolescents and
young adults with chronic sleep onset insomnia and late melatonin
onset: evaluation of sleep quality, chronotype, and lifestyle factors
compared to age-related randomly selected population cohorts.
Healthcare (Basel). 2018;6(1):E23.
14. Heath M, Johnston A, Dohnt H, Short M, Gradisar M. The role of
pre-sleep cognitions in adolescent sleep-onset problems. Sleep
Med. 2018;46:117–21.
15. Solheim B, Langsrud K, Kallestad H, Engstrøm M, Bjorvatn B,
Sand T. Sleep structure and awakening threshold in delayed sleep-
wake phase disorder patients compared to healthy sleepers. Sleep
Med. 2018;46:61–8.
16. Pin Arboledas G, Merino Andreu M, de la Calle CT, Hidalgo
Vicario MI, Rodriguez Hernandez PJ, Soto Insuga V, et al.
Curr Anesthesiol Rep (2019) 9:85–91
Consensus document on the clinical use of melatonin in children
and adolescents with sleep-onset insomnia. An Pediatr (Barc).
2014;81(5):328.e1–9.
17. Calhoun SL, Fernandez-Mendoza J, Vgontzas AN, Liao D, Bixler
EO. Prevalence of insomnia symptoms in a general population
sample of young children and preadolescents: gender effects.
Sleep Med. 2014;15:91–5.
18. Nunes ML, Bruni O. Insomnia in childhood and adolescence: clin-
ical aspects, diagnosis, and therapeutic approach. J Pediatr.
2015;91(6 Suppl 1):S26–35.
19.•• Karaman S, Karaman T, Dogru S, Onder Y, Citil R, Bulut YE, et al.
Prevalence of sleep disturbance in chronic pain. Eur Rev Med
Pharmacol Sci. 2014;18(17):2475–81. Analysis of the association
between sleep disturbances (such as insomnia) and chronic
pain.
20. Purushothaman B, Singh A, Lingutla K, Bhatia C, Pollock R,
Krishna M. Prevalence of insomnia in patients with chronic back
pain. J Orthop Surg (Hong Kong). 2013;21(1):68–70.
21. Park SJ, Lee R, Yoon DM, Yoon KB, Kim K, Kim SH. Factors
associated with increased risk for pain catastrophizing in patients
with chronic neck pain: a retrospective cross-sectional study.
Medicine (Baltimore). 2016;95(37):e4698.
22. Palermo TM, Wilson AC, Lewandowski AS, Toliver-Sokol M,
Murray CB. Behavioral and psychosocial factors associated with
insomnia in adolescents with chronic pain. Pain. 2011;152(1):89–94.
23. Tang NKY, Sanborn AN. Better quality sleep promotes daytime
physical activity in patients with chronic pain? A multilevel analy-
sis of the within-person relationship. PLoS One. 2014;9(3):e92158.
24.•• Vega E, Beaulieu Y, Gauvin R, Ferland C, Stabile S, Pitt R, et al.
Chronic non-cancer pain in children: we have a problem, but also
solutions. Minerva Anestesiol. 2018;84(9):1081–92.
25.• Palermo TM, Law E, Churchill SS, Walker A. Longitudinal course
and impact of insomnia symptoms in adolescents with and without
chronic pain. J Pain. 2012;13(11):1099–106.
26.• Aasvik J, Stiles TC, Woodhouse A, Borchgrevink P, Inge Landrø
N. The effect of insomnia on neuropsychological functioning in
patients with comorbid symptoms of pain, fatigue, and mood dis-
orders. Arch Clin Neuropsychol. 2018;33(1):14–23.
27. Kim SH, Lee DH, Yoon KB, An RJ, Yoon DM. Factors associated
with increased risk for clinical insomnia in patients with chronic
neck pain. Pain Physician. 2015;18(6):593–8.
28. Alföldi P, Wiklund T, Gerdle B. Comorbid insomnia in patients with
chronic pain: a study based on the Swedish quality registry for pain
rehabilitation (SQRP). Disabil Rehabil. 2014;36(20):1661–9.
29. Alföldi P, Dragioti H, Wiklund T, Gerdle B. Spreading of pain and
insomnia in patients with chronic pain: results from a national qual-
ity registry (SQRP). J Rehabil Med. 2017;49(1):63–70.
30. van Geijlswijk IM, van der Heijden KB, Egberts AC, Korzilius HP,
Smits MG. Dose findings of melatonin for chronic idiopatic child-
hood sleep onset insomnia. Ann RCT Psychopharmacology (Berl).
2010;212(3):379–91.
31. Eckerberg B, Lowden A, Nagai R, Akerstedt T. Melatonin treat-
ment effects on adolescent students’ sleep timing and sleepiness in a
placebo-controlled crossover study. Chronobiol Int. 2012;29(9):
1239–48.
32. Ferracioli-Oda E, Qawasmi A, Bloch MH. Meta-analysis: melato-
nin for the treatment of primary sleep disorders. PLoS One.
2013;8(5):e63773.
33. van der Heijden KB, Smits MG, Van Someren EJ, Ridderinkhof
KR, Gunning WB. Effect of melatonin on sleep, behavior, and
cognition in ADHD and chronic sleep-onset insomnia. J Am
Acad Child Adolesc Psychiatry. 2007;46(2):233–41.
34. van Geijlswijk IM, Korzilius HP, Smits MG. The use of exogenous
melatonin in delayed sleep phase disorder: a meta-analysis. Sleep.
2010;33(12):1605–14.
Curr Anesthesiol Rep (2019) 9:85–91
35. Appleton RE, Jones AP, Gamble C, Williamson PR, Wiggs L,
Montgomery P, et al. The use of melatonin in children with
neurodevelopmental disorders and impaired sleep. Health Technol
Assess. 2012;16:i-239.
36. Hoebert M, van der Heijden KB, van Geijlswijk IM, Smits MG.
Long-term follow-up of melatonin treatment in children with
ADHD and chronic sleep onset insomnia. J Pineal Res.
2009;47(1):1–7.
37. Emet M, Ozcan H, Ozel L, Yayla M, Halici Z, Hacimuftuoglu A. A
review of melatonin, its receptors and drugs. Eurasian J Med.
2016;48(2):135–41.
38. Pelayo R, Yuen K. Pediatric sleep pharmacology. Child Adolesc
Psychiatr Clin N Am. 2012;21(4):861–83.
39. Prince JB, Wilens TE, Biederman J, Spencer TJ, Wozniak JR.
Clonidine for sleep disturbances associated with attention-deficit
hyperactivity disorder: a systematic chart review of 62 cases. J
Am Acad Child Adolesc Psychiatry. 1996;35(5):599–605.
40. Barret J, Tracy D, Giaroli G. To sleep or not to sleep: a systematic
review of the literature of pharmacological treatments of insomnia
in children and adolescents with attention-deficit/hyperactivity dis-
order. Journal of Child and Adolescents Psychopharmacology.
2013;23(10):640–7.
41. 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.
42. Steingard R, Biederman J, Spencer T, Wilens T, Gonzalez A.
Comparison of clonidine response in the treatment of attention-
deficit hyperactivity disorder with and without comorbid tic disor-
ders. J Am Acad Child Adolesc Psychiatry. 1993;32(2):350–3.
43. Wilens TE, Biederman J, Spencer T. Clonidine for sleep distur-
bance associated with attention deficit hyperactivity disorder. J
Am Acad Child Adolesc Psychiatry. 1994;33(3):424–6.
44. Nguyen M, Tharani S, Rahmani M, Shapiro M. A review of the use
of clonidine as a sleep aid in the child and adolescent population.
Clin Pediatr (Phila). 2014;53(3):211–6.
45. Mittur A. Trazodone: properties and utility in multiple disorders.
Expert Rev Clin Pharmacol. 2011;4(2):181–96.
46. MacFarlane J, Morin CM, Montplaisir J. Hypnotics in insomnia:
the experience of zolpidem. Clin Ther. 2014;36(11):1676–701.
47. Lawlor BA, Newhouse PA, Balkin TJ, Molchan SE, Mellow AM,
Murphy DL, et al. A preliminary study of the effects of night-time
administration of the serotonin agonist, m-CPP, on sleep architec-
ture and behaviour in healthy volunteers. Biol Psychiatry.
1991;29(3):281–6.
48. Emslie GJ, Kennard BD, Mayes TL, Nakonezny PA, Zhu L, Tao R,
et al. Insomnia moderates outcome of serotonin-selective reuptake
inhibitor treatment in depressed youth. J Child Adolesc
Psychopharmacol. 2012;22(1):21–8.
49. Paterson LM, Nutt DJ, Ivarsson M, Hutson PH, Wilson SJ. Effects
on sleep stages and microarchitecture of caffeine and its combina-
tion with zolpidem or trazodone in healthy volunteers. J
Psychopharmacol. 2009;23(5):487–94.
50. Zavesicka L, Brunovsky M, Horacek J, Matousek M, Sos P, Krajca
V, et al. Trazodone improves the results of cognitive behaviour
therapy of primary insomnia in non-depressed patients. Neuro
Endocrinol Lett. 2008;29(6):895–901.
51. Everitt H, Baldwin DS, Stuart B, Lipinska G, Mayers A, Malizia
AL, et al. Antidepressants for insomnia in adults. Cochrane
Database Syst Rev. 2018;5:CD010753.
52. Savarese M, Carnicelli M, Cardinali V, Mogavero MP, Federico F.
Subjective hypnotic efficacy of trazodone and mirtazapine in pa-
tients with chronic insomnia: a retrospective, comparative study.
Arch Ital Biol. 2015;153(2–3):231–8.
53. Fagiolini A, Amodeo G, Goracci A, Blardi P. Trazodone
Contramid® in clinical practice: personalizing antidepressant inter-
vention. Riv Psichiatr. 51(4):123–8.
91
54. Wichniak A, Wierzbicka A. The effects of antidepressants on sleep
in depressed patients with particular reference to trazodone in com-
parison to agomelatine, amitriptyline, doxepin, mianserine and
mirtazapine. Pol Merkur Lekarski. 2011;31(181):65–70.
55. Chen HC, Tsai SJ. Trazodone-induced severe headache. Psychiatry
Clin Neurosci. 2011;65(7):681–2.
56. Wichniak A, Wierzbicka A, Jernajczyk W. Patients with insomnia
and subthreshold depression show marked worsening of insomnia
after discontinuation of sleep promoting medication. Prog Neuro-
Psychopharmacol Biol Psychiatry. 2011;35(7):1671–6.
57. Monti JM, Spence DW, Buttoo K, Pandi-Perumal SR. Zolpidem’s
use for insomnia. Asian J Psychiatr. 2017;25:79–90.
58. Shuaib W, Beatrice C, Abazid AG. Zolpidem overdose: a medical
and ethical dilemma. Am J Ther. 2016;23(6):e1956-e7.
59. Blumer JL, Reed MD, Steinberg F, O’Riordan MA, Rosen CL,
Springer MA, et al. Potential pharmacokinetic basis for zolpidem
dosing in children with sleep difficulties. Clin Pharmacol Ther.
2008;83(4):551–8.
60. Yu ZH, Xu XH, Wang SD, Song MF, Liu Y, Yin Y, et al. Effect and
safety of paroxetine combined with zolpidem in treatment of pri-
mary insomnia. Sleep Breath. 2017;21(1):191–5.
61. Beaulieu-Bonneau S, Ivers H, Guay B, Morin CM. Long-term
maintenance of therapeutic gains associated with cognitive-
behavioral therapy for insomnia delivered alone or combined with
zolpidem. Sleep. 2017;1(40):zsx002.
62. Valente KD, Hasan R, Tavares SM, Gattaz WF. Lower doses of
sublingual zolpidem are more effective than oral zolpidem to antic-
ipate sleep onset in healthy volunteers. Sleep Med. 2013;14(1):20–
3.
63. Health Canada. Sublinox (zolpidem tartrate), New Dosage
Recommendations to Minimize Risk of Next-Day Impairment in
Both Women and Men www.healthycanadians.gc.ca/recall-alert-
rappelavis/hc-sc/2014/37415a-eng.php.
64. Food and Drug Administration. FDA Drug Safety Communication:
risk of next-morning impairment after use of insomnia drugs; FDA
requires lower recommended doses for certain drugs containing
zolpidem (Ambien, Ambien CR, Edluar, and Zolpimist). www.
fdagov/drugs/drugsafety/ucm334033htm. Accessed September 4,
2013.
65. Blumer JL, Findling RL, Shih WJ, Soubrane C, Reed MD.
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):e770–6.
66. Licata SC, Mashhoon Y, Maclean RR, Lukas SE. Modest abuse
related subjective effects of zolpidem in drug-naive volunteers.
Behav Pharmacol. 2011;22(2):160–6.
67. Terán A, Majadas S, Galan J. Quetiapine in the treatment of sleep
disturbances associated with addictive conditions: a retrospective
study. Subst Use Misuse. 2008;43(14):2169–71.
68. Wiegand MH, Landry F, Brückner T, Pohl C, Veselý Z, Jahn T.
Q u e t i a p i n e i n p r i m a r y i n s o m n i a : a p i l o t s t u d y.
Psychopharmacology. 2008;196(2):337–8.
69. Hermes EDA, Sernyak M, Rosenheck R. Use of second-generation
antipsychotic agents for sleep and sedation: a provider survey.
Sleep. 2013;36(4):597–600.
70. Carney A. Efficacy of quetiapine off-label uses: data synthesis. J
Psychosoc Nurs Ment Health Serv. 2013;51(8):11–8.
71. Fernando A, Chew G. Chronic insomnia secondary to chronic pain
responding to quetiapine. Australas Psychiatry. 2005;13(1):86.
72. Cates ME, Jackson CW, Feldman JM, Stimmel AE, Woolley TW.
Metabolic consequences of using low-dose quetiapine for insomnia
in psychiatric patients. Community Ment Health J. 2009;45(4):
251–4.
73. Coe HV, Hong IS. Safety of low doses of quetiapine when used for
insomnia. Ann Pharmacother. 2012;46(5):718–22.