Assignment 1: Short Answer Assessment

Please review the complete instructions. Use at least 2 of the resources, see complete list and attached document. 

Assignment 1: Short Answer Assessment

As a psychiatric nurse practitioner, you will likely encounter patients who suffer from various mental health disorders. Not surprisingly, ensuring that your patients have the appropriate psychopharmacologic treatments will be essential for their overall health and well-being. The psychopharmacologic treatments you might recommend for patients may have potential impacts on other mental health conditions and, therefore, require additional consideration for positive patient outcomes. For this Assignment, you will review and apply your understanding of psychopharmacologic treatments for patients with multiple mental health disorders.

To complete:

Address the following Short Answer prompts for your Assignment. Be sure to include at least 2 references to the Learning Resources for this week. (See below Resources) and attached documents

1. In 3 or 4 sentences, explain the appropriate drug therapy for a patient who presents with MDD and a history of alcohol abuse. Which drugs are contraindicated, if any, and why? Be specific. What is the timeframe that the patient should see resolution of symptoms?

2. List 4 predictors of late onset generalized anxiety disorder.

3. List 4 potential neurobiology causes of psychotic major depression.

4. An episode of major depression is defined as a period of time lasting at least 2 weeks. List at least 5 symptoms required for the episode to occur. Be specific.

5. List 3 classes of drugs, with a corresponding example for each class, that precipitate insomnia. Be specific. 

6. APA 7

7. At least 5 references.

Resources:

SLEEP DISORDERS (RM BENCA, SECTION EDITOR)

Insomnia and its Impact on Physical and Mental Health

Julio Fernandez-Mendoza & Alexandros N. Vgontzas

Published online: 5 November 2013
# Springer Science+Business Media New York 2013

Abstract In contrast to the association of insomnia with
mental health, its association with physical health has
remained largely unexplored until recently. Based on findings
that insomnia with objective short sleep duration is associated
with activation of both limbs of the stress system and other
indices of physiological hyperarousal, which should adversely
affect physical and mental health, we have recently
demonstrated that this insomnia phenotype is associated with
a significant risk of cardiometabolic and neurocognitive
morbidity and mortality. In contrast, insomnia with normal
sleep duration is associated with sleep misperception and
cognitive-emotional arousal, but not with signs of physiological
hyperarousal or cardiometabolic or neurocognitive morbidity.
Interestingly, both insomnia phenotypes are associated with
mental health, although most likely through different
pathophysiological mechanisms. We propose that objective
measures of sleep duration may become part of the routine
evaluation and diagnosis of insomnia, and that these two
insomnia phenotypes may respond differentially to biological
versus psychological treatments.

Keywords Cardiometabolic morbidity . Insomnia .

Mortality . Neurocognitive impairment . Physiological
hyperarousal . Polysomnography . Poor sleep . Psychiatric
morbidity . Short sleep duration . Sleep disorders . Psychiatry

Introduction

The prevalence of insomnia in the general population ranges
between 8 % and 40 %, depending on the definition used.
While 20–30 % of the general population has poor sleep (i.e.,
insomnia, symptoms of difficulty initiating or maintaining
sleep, early morning awakening, or non-restorative sleep at
any given time), another 8–10 % of the population suffers
from chronic insomnia [1, 2]. Also, about 4 % of the
population uses sleeping pills on a regular basis [3]. However,
the connection of insomnia with significant medical morbidity
has not been examined until very recently. This has led to
the view of insomnia and its associated mental and
physical health complaints as a minor problem from a
public health perspective.

A factor that may have contributed to this lack of firm
association between insomnia and significant medical
morbidity is the definitions used for this disorder and the lack
of validated objective/biological markers. Sleep disorders
were included for the first time in the Diagnostic and
Statistical Manual of Mental Disorders (DSM)-III-R [4] in
1987, and provided overall diagnostic criteria for “insomnia
disorders” based on the subjective complaints of difficulty
initiating or maintaining sleep or of non-restorative sleep,
occurring at least three times a week for at least 1 month,
and associated daytime functioning complaints. The DSM-IV-
TR eliminated the overall diagnostic criteria for “insomnia
disorders”, as well as the frequency criterion, maintained the
diagnoses of “primary insomnia”, “dysomnia NOS [not
otherwise specified]”, insomnia “related to another mental
disorder”, “due to a general medical condition”, and
introduced “substance-induced insomnia” [5]. The DSM-5
has eliminated the different insomnia diagnoses in DSM-IV-
TR to reintroduce overall diagnostic criteria for “insomnia
disorder” with specification of comorbid mental and/or
physical conditions, so that no causal attributions between

This article is part of the Topical Collection on Sleep Disorders

J. Fernandez-Mendoza: A. N. Vgontzas (*)
Sleep Research and Treatment Center, Department of Psychiatry,
Pennsylvania State University College of Medicine, 500 University
Drive H073, Hershey, PA 17033, USA
e-mail: avgontzas@hmc.psu.edu

J. Fernandez-Mendoza
e-mail: jfernandezmendoza@hmc.psu.edu

Curr Psychiatry Rep (2013) 15:418
DOI 10.1007/s11920-013-0418-8

insomnia and the physical/mental condition are made, and has
extended the duration criterion from 1 month to 3 months [6].
The latter change is an acknowledgement that chronicity is
what differentiates insomnia as a disorder versus insomnia
symptoms, that is, poor sleep due to underlying, identifiable
physical, emotional, or drug-related factors.

The International Classification of Sleep Disorders
(ICSD), and its revised form ICSD-R (1997), also defined
insomnia based on subjective sleep and daytime functioning
complaints, but, in contrast, attempted to identify subtypes
based on “intrinsic” factors, such as etiology (i.e.,
“psychophysiological”), age of onset (i.e., “idiopathic insomnia”),
degree of discrepancy between objective sleep findings and
subjective perception of sleep (i.e., “sleep state misperception”),
or “extrinsic” environmental factors, such as “inadequate sleep
hygiene”, “food-allergy”, or “altitude insomnia”. However, these
subtypes, even when refined in the ICSD-2 [7], have not proven to
be clinically useful, and the reliability and validity of DSM and
ICSD diagnoses is modest, at best [8••].

Although the objective sleep of insomniacs is different than
that of normal sleepers, polysomnography (PSG) variables are
not required or recommended for the diagnosis of the disorder. In
fact, PSG criteria have not proven to be useful in terms of
differential diagnosis or severity assessment, and are not
currently used in clinical practice. The sleep laboratory is useful
for the evaluation of patients with sleep-disordered breathing
(SDB), the diagnosis of narcolepsy, and the differential diagnosis
of idiopathic versus psychogenic hypersomnia [9, 10], as well as
the study of the initial effectiveness, continued efficacy or
tolerance, and potential withdrawal effects of a hypnotic drugs.
The validity and clinical utility of sleep laboratory testing for
diagnosing insomnia has been evaluated in large studies [11, 12]
that have shown that PSG measures, such as latency to sleep
onset, total sleep time, number of arousals and awakenings, sleep
efficiency, or sleep stages, are not useful in the diagnosis or
differential diagnosis, including subtyping of insomnia, except
to confirm or exclude other sleep pathologies when there is
reasonable evidence from clinical history (e.g., SDB or periodic
limb movements). The current consensus is, therefore, that PSG
is not recommended for routine, differential diagnosis, or severity
assessment of insomnia in clinical practice [13].

In this review article, we present evidence that objective
measures of sleep are useful in predicting the medical severity
of insomnia (i.e., cardiometabolic and neurocognitive
morbidity and mortality) and that should be considered in
the new classification of insomnia.

Insomnia and the Stress System

In the last two decades, several models have been proposed to
understand the etiology and pathophysiology of insomnia, and
most of them have emphasized the importance of the joint

effect of stress and psychological factors in the pathogenesis
of insomnia [14]. The characteristic psychological profile of
patients with insomnia, consisting of cognitive–emotional
hyperarousal (i.e., obsessive, anxious, ruminative, and
dysthymic personality traits) and emotion-oriented coping
strategies [14–16], is thought to be present pre-morbidly and
play a key role in the etiology of the disorder [14, 17–19, 20••].
Insomnia is associated with precipitating life events [21] and
cognitive-emotional arousal [14], and is perceived by the
patient as stressful on its own. Thus, insomnia should be
expected to be associated with activation of the stress system.

Stress has been associated with the activation of the
hypothalamic–pituitary–adrenal (HPA) and the sympatho-
adrenal-medullary axes, whereas corticotropin-releasing
hormone (CRH) and cortisol (products of the hypothalamus
and adrenals, respectively), and catecholamines (products of
the sympathetic system) are known to cause arousal and
sleeplessness in humans and animals. However, sleep, and
particularly deep sleep, appears to have an “anti-stress” effect,
as it is associated with an inhibitory effect on the stress system,
including its main two components, the HPA axis and the
sympathetic system.

While the majority of early studies reported no difference
between subjectively defined “poor sleepers” and controls in
the levels of cortisol secretion [22–24], later studies found that
24-h urinary free cortisol, norepinephrine, and catecholamine
metabolites levels were either increased in patients with
insomnia with objective sleep disturbances compared with
controls, or were correlated with PSG indices of sleep
disturbance in insomnia patients [25–31]. The few exceptions
might be related to the fact that the objective sleep of patients
with insomnia was very similar to that of controls [32] or to lack
of statistical power and controls not being carefully selected
[33, 34]. In addition, it was shown that middle-aged healthy
individuals were more vulnerable to the sleep-disturbing effects
of the stimulating hormones of the HPA axis, that is, CRH,
which may explain physiologically the increased prevalence of
insomnia in older patients [35].Furthermore, other studies have
demonstrated that this type of insomnia is associated with
increased nocturnal heart rate and impaired heart rate variability
[36, 37], increased overall oxygen consumption (VO2), a
measure of whole-body metabolic rate [38, 39], and increased
pupil size, indicative of sympathetic system activation [40], but
not in insomnia defined only on subjective measures [41, 42].

Another paradox with patients with insomnia who typically
complain that they are fatigued and sleepy during the day is
that during the Multiple Sleep Latency Test (MSLT) they have
either similar or increased daytime sleep latencies when
compared with controls [42–45]. In fact, several studies have
shown that, within patients with insomnia, those with shorter
objective sleep duration show longer sleep latencies in the
MSLT [44, 46–48] and are more alert in vigilance tests [38,
39, 46]. This is in contrast to normal individuals who, after

418, Page 2 of 8 Curr Psychiatry Rep (2013) 15:418

sleep deprivation, experience significantly reduced sleep
latencies on the MSLT and decreased alertness in vigilance
tests, that is, physiological sleepiness [49, 50]. Thus, long
latencies in the MSLT may represent a reliable marker of
physiological hyperarousal in insomnia patients.

Finally, evidence about the presence of central nervous
system hyperarousal in insomnia comes from studies in human
subjects using neuroimaging [51, 52], and spectral [53, 54],
arousal [55], and event-related [56] electroencephalography
analyses, as well as from studies on the neural circuitry of
stress-induced insomnia in rats [57]. Increased cortical arousal
during sleep is present to a variable degree in all patients with
insomnia [53–56] and may explain why they perceive their
sleep as wake and as non-restorative [58, 59••].

Insomnia and Cardiometabolic Morbidity

Until recently, chronic insomnia has not been firmly linked with
significant medical morbidity, such as cardiovascular disease.
Several surveys have shown a significant relationship between
difficulty falling asleep or poor sleep with cardiometabolic
outcomes such as hypertension [60–62] and diabetes [63–66].
For example, persistent complaints of difficulty initiating or
maintaining sleep were associated with an increased risk of
hypertension [61], acute myocardial infarction [62], and
incident type 2 diabetes [63–66]. However, these studies
showed relatively small effect sizes and did not include a
PSG evaluation so as to control for SDB or other sleep
pathology. The findings of these early studies were dismissed
as methodologically flawed by many clinicians and researchers
alike [67, 68]. In fact, at least one report showed a reduced
mortality rate for those individuals complaining of sleep
difficulties after 6 years of follow up [69].

Given the well-established association of hypercortisolemia
with significant medical morbidity (i.e., hypertension, diabetes,
metabolic syndrome, osteoporosis, and others) [25–31], we
hypothesized that insomnia with objective short sleep duration
is associated with significant cardiometabolic morbidity and
mortality. A series of recent epidemiological studies from the
Penn State Adult Cohort [1], which used in-laboratory PSG,
have shown that insomnia with objective short sleep duration is
associated with a high risk of hypertension [70••, 71••], diabetes
[72••], and mortality [73]. For example, compared with normal
sleepers who slept ≥6 h per night, the highest odds of
hypertension or diabetes was in patients with insomnia who
slept ≤5 h [odds ratio (OR)=5.1 and OR=2.95, respectively)
and the second highest in patients with insomnia who slept 5–
6 h (OR=3.5 and OR=2.07, respectively), while patients with
insomnia who slept ≥6 h were not at significantly increased risk
of hypertension or diabetes (OR=1.3 and OR=1.1,
respectively). Recent longitudinal data from the same cohort
have shown that patients with insomnia who slept <6 h were at

a significantly higher risk of incident hypertension (OR=3.75)
[71••], suggesting that insomnia precedes the onset of
hypertension. Interestingly, in a recent longitudinal study we
found that non-obese chronic insomniacs, despite sleeping
objectively shorter than controls or poor sleepers, did not have
a significantly increased risk of incident obesity; in fact, they
were less likely to become obese than controls or poor sleepers
[74]. These data indicate that insomnia with objective short
sleep duration may be linked to medical morbidity, such as
hypertension and diabetes, through mechanisms other than
weight gain and obesity (i.e., activation of the stress system
and inflammation process). Furthermore, other longitudinal
research showed that mortality risk in men was significantly
increased in patients with insomnia who slept <6 h compared with normal sleepers (OR=4.00), and that there was a marginally significant trend toward higher mortality from insomnia with short sleep duration in men with diabetes or hypertension (OR=7.17) than in those without these comorbid conditions (OR=1.45). Thus, the impact of insomnia with short sleep duration was much stronger in those with diabetes and hypertension at baseline versus those who were healthy [73]. In women, mortality was not associated with insomnia with short sleep duration, most likely related to the fact that women were followed-up for a shorter time period.

Consistent with the findings of these population-based
studies, other recent studies have shown (1) higher night-
time systolic blood pressure and reduced day-to-night systolic
blood pressure dipping [75]; (2) impaired heart rate variability
[76••]; (3) lower cardiac pre-ejection period [77]; and (4)
poorer indices of glucose metabolism [78•] in patients with
insomnia. Cumulatively, these data suggest that objective
short sleep duration may predict the medical severity of
chronic insomnia [59••].

Insomnia and Neurocognitive Morbidity

Patients with insomnia typically complain of difficulty
concentrating, memory problems, and difficulty focusing
attention. However, studies using objective neuropsychological
testing have produced inconsistent findings. This has led some
researchers to question the existence of true cognitive
impairments in insomnia [79] and attribute the daytime
complaints to excessive attention to the expected consequences
of poor sleep [14].

The role of objective sleep measures in the association of
insomnia with cognitive impairment has been addressed in a
recent study from the Penn State Adult Cohort [80••]. This
study showed that patients with insomnia, based solely on a
subjective complaint, did not differ significantly from controls
on either PSG variables or neurocognitive performance.
However, significant interactions between insomnia and
objective short sleep duration (i.e., <6 h) on specific

Curr Psychiatry Rep (2013) 15:418 Page 3 of 8, 418

neurocognitive tests were found. Specifically, patients with
insomnia with objective short sleep duration showed poorer
neuropsychological performance on tests of processing speed,
switching attention, and number of short-term visual memory
errors and omissions compared with control groups with
normal or short sleep duration. In contrast, patients with
insomnia with normal sleep duration group showed no
significant deficits when compared with controls. Based on
these findings, it seems that insomnia with objective short
sleep duration is associated with deficits in switching
attention, a key component of the “executive control of
attention” [80••]. Importantly, the presence of a group of good
sleepers with short sleep duration allowed to demonstrate that
deficits in executive attention were associated with underlying
physiological hyperarousal, a characteristic of chronic
insomnia, rather than to short sleep per se [80••]. Another
recent study by Edinger et al. [81••] examined the association
between physiological hyperarousal, as measured by the
MSLT, and response accuracy on reaction time tasks among
89 individuals with primary insomnia compared with 95 well-
screened normal sleepers. Interestingly, the authors found that
individuals with MSLT mean onset latency >8 mins showed
lower night-time sleep efficiencies and increased wake after
sleep onset, suggesting 24-h physiological hyperarousal,
particularly in the primary insomnia group. Importantly, they
found a significant interaction between insomnia and
increased MSLT mean onset latency so that individuals with
primary insomnia and with MSLT mean onset latency >8 mins
showed greater error rates in switching attention tasks than
normal sleepers with MSLT mean onset latency >8 mins, who
showed no significant deficits. The authors concluded
that physiological hyperarousal in insomnia may lead to
increased daytime alertness yet dispose these individuals
to higher error rates on tasks of switching attention
[81••], a finding consistent with those of a study by
Fernandez- Mendoza et al. [80••], in which
physiological hyperarousal was ascertained by objective
short sleep duration.

A recent meta-analysis has shown that individuals with
insomnia exhibit performance impairments of small-to-
moderate magnitude in several cognitive functions, including
working memory, episodic memory, and some aspects of
executive functioning [82]. However, an important factor that
has been neglected in meta-analytic research of the
neurocognitive literature is the role of the degree of objective
sleep disturbance in this association. As we have recently
reviewed [59••], most studies have shown that cognitive
performance is impaired in patients with insomnia with
objective sleep disturbances or that it correlates with objective
markers of sleep disturbance in patients with insomnia,
whereas those studies in which performance was not
significantly impaired established insomnia diagnoses using
solely subjective criteria [59••].

Cumulatively, the data from these studies indicate
that objective short sleep duration may predict its effect
on cognitive functions. Future studies should examine
whether insomnia with objective short sleep duration
may be a premorbid risk factor for mild cognitive
impairment and dementia.

Insomnia and Psychiatric Morbidity

Many studies have established that insomnia is highly
comorbid with psychiatric disorders and is a risk factor for
the development of depression, anxiety, and suicide [83•].
However, the mechanisms by which insomnia precedes the
development of psychiatric disorders, for example depression,
are unknown. In a recent study from the Penn State Adult
Cohort, insomnia with objective short sleep duration was
associated with a psychological profile consistent with
depressed mood, fatigue, concerns about health and physical
functioning, somatically focused anxiety, and poor health
status, which is typical of medical outpatients [58]. In contrast,
insomnia with normal sleep duration was associated with
sleep misperception (i.e., the underestimation of time asleep
and overestimation of time awake during the night) and a
psychological profile consistent with depressed mood,
rumination, anxiety, intrusive thoughts, and poor coping
resources [58]. These data have led us to suggest that both
insomnia subtypes are associated with (or are at risk of
developing) psychiatric disorders, but that different
pathophysiological mechanisms may account for such an
association [59••]. For example, it is possible that biological
mechanisms, that is, hyperactivity of the HPA axis, may play a
role in the development of depression in insomniacs with
objective short sleep duration, while psychological
mechanisms, that is, poor coping resources and ruminative
traits, may play such a role in insomniacs with normal sleep
duration. However, these hypotheses have yet to be tested.

Natural History of Insomnia: Chronic Insomnia Versus
Poor Sleep

As mentioned in the Introduction, about 20 % of the general
population has poor sleep (i.e., insomnia symptoms at any
given time) and about another 10 % has chronic insomnia.
Natural history studies have shown that chronic insomnia is a
highly persistent condition, whereas the course of poor sleep
is more variable and has a higher remission rate [17, 19, 20••,
84, 85•]. This suggests that insomnia is a disorder, while poor
sleep is a symptom of underlying mental and physical health
problems [19, 20••, 85•]. Furthermore, objective short sleep
duration has been shown to be a risk factor for poor sleep
evolving into the more severe form of chronic insomnia

418, Page 4 of 8 Curr Psychiatry Rep (2013) 15:418

[20••], as well as of chronic insomnia becoming persistent
[85•]. These latter findings suggest that objective short sleep
duration may be a biologic marker of genetic predisposition to
chronic insomnia [20••], and of the severity and chronicity of
the disorder [85•].

Conclusion

As a result of the above-reviewed literature we have suggested
two phenotypes of chronic insomnia. The first phenotype is
primarily associated with physiological hyperarousal (i.e.,
short sleep duration and activation of both limbs of the stress
system), significant medical sequelae (e.g., hypertension,
diabetes, cognitive impairment, increased mortality), and a
persistent course. The second phenotype is associated with
cognitive–emotional and cortical arousal, but not with

physiological hyperarousal (i.e., normal sleep duration and
normal activity of the stress system) or significant medical
sequelae, and is more likely to remit over time. Furthermore,
the first phenotype is associated with a psychological profile
typical of medical outpatients, whereas the second phenotype
is associated with sleep misperception, anxious–ruminative
traits, and poor coping resources [59••]. Table 1 summarizes
the findings of key studies, while Fig. 1 depicts a heuristic
model of the underlying pathophysiological mechanisms and
clinical characteristics of the two insomnia phenotypes.

Our proposed model for the two insomnia phenotypes may
have an impact on how we diagnose and treat chronic
insomnia. As we stated earlier, previously proposed subtypes
of insomnia are based on subjective tools such as clinical
interviews, questionnaires, and specific scales, and their
diagnostic reliability is, at best, modest. The data reviewed
here suggest that objective measures of sleep can be useful in
detecting the most severe form of insomnia. Thus, we propose
the inclusion of objective sleep duration as a criterion in
future diagnostic manuals for insomnia in order to
differentiate these two clearly different and clinically
relevant subtypes of insomnia.

Further, our data suggest that objective measures of sleep,
in addition to a thorough clinical evaluation, should become
part of the standard diagnostic procedures for insomnia [59••].
Although our studies have focused on the utility of sleep
duration, other studies suggest that other variables of sleep
efficiency and continuity or of physiological hyperarousal
(i.e., MSLT) may also serve as markers of the biological

Table 1 Insomnia with short sleep duration: association with
physiological hyperarousal, cardiometabolic morbidity, neurocognitive
impairment, and a persistent course

Insomnia with normal
sleep duration

Insomnia with short
sleep duration

Physiological hyperarousal

Increased cortisol levels
[27, 28]

✓

Impaired heart rate
variability [37, 76••]

✓

Increased whole body
metabolic rate [38]

✓

Increased daytime
alertness [44, 48]

✓

Cardiometabolic morbidity

Hypertension [70••, 71••] ✓

Diabetes [72••] ✓

Mortality [73] ✓

Neurocognitive impairment

Set-switching attention
[80••, 81••]

✓

Short-term memory
[38, 80••]

✓

Sleep misperception

Accurate or
overestimation [58]

✓

Underestimation [58] ✓

Psychological profile

Depressed mood [58, 92] ✓ ✓

Anxious-ruminative
traits [58, 92]

✓

Poorcopingresources[58] ✓

Dysfunctional beliefs
about sleep [92]

✓

Natural history

Persistent course [85•] ✓

Remitting course [85•] ✓

Fig. 1 Heuristic model of the underlying pathophysiological
mechanisms and clinical characteristics of the two insomnia phenotypes
based on objective sleep duration. The common characteristics of the two
phenotypes are presented in the overlapping area, while their unique
characteristics are presented in the areas of each phenotype that do not
overlap. Reprinted from Sleep Medicine Reviews, 17(4), Vgontzas AN,
Fernandez-Mendoza J, Liao D, Bixler EO [59••], Insomnia with objective
short sleep duration: The most biologically severe phenotype of the
disorder, 241-54, 2013, with permission from Elsevier

Curr Psychiatry Rep (2013) 15:418 Page 5 of 8, 418

severity of the disorder [20••, 26, 81••, 86–88]. However, a
potential disadvantage of biomarkers such as stage 1, slow
wave sleep (SWS), or MSLT is that they require a full PSG
study or daytime laboratory assessment, whereas sleep
duration perhaps could be obtained with simpler methods,
for example actigraphy. In this regard, several studies suggest
the potential usefulness of actigraphy to assess sleep patterns
for a period of days or weeks in the “habitual home
environment”, to characterize the severity of the insomnia
disorder [88]. A similar amount of home sleep monitoring
with PSG would be difficult and impractical for clinical
venues. However, several problems associated with the use
of actigraphy, such as lack of an industry standard for the sleep
algorithms used in different actigraphic devices and the
propensity to over- or underestimate sleep time, make its
current use limited. Future studies using cost-effective
methods should examine which variables, that is, sleep
duration versus night-to-night variability, and which methods,
that is, actigraphy, salivary cortisol, and peripheral measures
of sympathetic activation, are better predictors of
cardiometabolic and neurocognitive morbidity.

Finally, our findings may affect the way we treat
chronic insomnia. The insomnia phenotype with short
sleep duration may respond better to treatments that
primarily aim at decreasing physiological hyperarousal
and increasing sleep duration, such as medication or other
biological treatments [30]. Previous studies have shown
that sedative antidepressants such as trazodone or doxepin,
used at low dosages, down-regulate the activity of the
HPA axis, decrease cortisol levels, and increase sleep
duration [30, 89, 90]. Needless to say that biological
treatments should be part of a multidimensional approach
that combines behavioral changes, that is, sleep hygiene,
and psychological interventions, for example cognitive–
behavioral therapy (CBT), when indicated. The second
phenotype, that is, insomnia with normal sleep duration,
may respond better to treatments that primarily aim at
decreasing cognitive–emotional arousal, changing sleep-
related beliefs and behaviors, and altering sleep
misperception, such as CBT [91]. Psychotherapeutic
medication may be indicated based on the presence of
comorbid psychiatric conditions, that is, anxiety or
depressive disorders. The differential treatment response
of these two phenotypes should be tested in future
placebo-controlled clinical trials. In any event, the
treatment of insomnia with objective short sleep duration
should become a priority given its severity and its effects
on physical health. Finally, in the prevention of chronic
insomnia, our strategies should focus on (1) those with
premorbid cognitive–emotional hyperarousal and short
sleep duration, (2) stress-related poor sleep with short
objective sleep duration, and (3) a family history of sleep
problems [18, 19, 20••].

Acknowledgment This paper was supported by National Institutes of
Health grants R01 51931, R01 33 40916, and R01 64415 to Alexandros
N. Vgontzas.

Compliance with Ethics Guidelines

Conflict of Interest Julio Fernandez-Mendoza and Alexandros N.
Vgontzas declare that 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.

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418, Page 8 of 8 Curr Psychiatry Rep (2013) 15:418

Reproduced with permission of copyright owner. Further reproduction
prohibited without permission.

SLEEP, Vol. 30, No. 12, 2007 1705

IntroductIon

EXCESSIVE DAYTIME SLEEPINESS HAS A SIGNIFICANT
DETRIMENTAL IMPACT ON PSYCHOLOGICAL, SOCIAL
AND VOCATIONAL FUNCTION AND PERSONAL SAFETY,
thus adversely affecting quality of life. Sleepiness is an important
public health issue among individuals who work in fields where
the lack of attention can result in injury to self or others such as
transportation and healthcare. Hypersomnia of central origin is a
category of disorders in which daytime sleepiness is the primary
complaint, but the cause of this symptom is not due to “disturbed
nocturnal sleep or misaligned circadian rhythms.”1

Narcolepsy, a disorder characterized by excessive daytime
sleepiness and intermittent manifestations of REM sleep during
wakefulness, is the best characterized and studied central hyper-

somnia. The use of stimulants for treatment of narcolepsy was
the subject of an American Academy of Sleep Medicine (AASM)
review paper in 1994, and formed the basis for practice param-
eters published by the Standards of Practice Committee (SPC) of
the AASM on therapy of narcolepsy with stimulants.2,3 In 2000,
the SPC published a combined review and updated practice pa-
rameters on treatment of narcolepsy that included therapies other
than stimulants.4

Since the publication of the 2000 paper, there have been signif-
icant advances concerning the treatment of hypersomnia to justify
a practice parameters update. In addition, since the publication of
the previous practice parameters, the AASM published a revised
coding manual, the International Classification of Sleep Disor-
ders, Second Edition (ICSD-2).1 The ISCD-2 includes 12 disor-
ders under the category of hypersomnia of central origin. This
updated parameter paper and the accompanying review expanded
the scope of the review and practice parameters to a subset of
disorders in which the primary pathophysiology of hypersomnia
is not related to sleep restriction, medication use or psychiatric
disorder. For these disorders, the use of alerting medications of-
ten represent the primary mode of therapy. The specific disorders
included in these practice parameters are narcolepsy (with cata-
plexy, without cataplexy, due to medical condition and unspeci-
fied) idiopathic hypersomnia (with long sleep time and without
long sleep time), recurrent hypersomnia, and hypersomnia due to
a medical condition. For the remainder of this manuscript, use of

Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of
Central Origin
An American Academy of Sleep Medicine Report

Timothy I. Morgenthaler, MD1; Vishesh K. Kapur, MD, MPH2; Terry M. Brown, DO3; Todd J. Swick, MD4; Cathy Alessi, MD5; R. Nisha Aurora, MD6; Brian Boehlecke,
MD7; Andrew L. Chesson Jr., MD8; Leah Friedman, MA, PhD9; Rama Maganti, MD10; Judith Owens, MD11; Jeffrey Pancer, DDS12; Rochelle Zak, MD6; Standards of
Practice Committee of the AASM

1Mayo Clinic, Rochester, MN; 2University of Washington, Seattle, WA; 3St. Joseph Memorial Hospital, Murphysboro, IL; 4Houston Sleep Center,
Houston, TX; 5VA Greater Los Angeles Healthcare System-Sepulveda and University of California, Los Angeles, CA; 6Mount Sinai Medical Center,
New York, New York; 7University of North Carolina, Chapel Hill, NC; 8Louisiana State University, Shreveport, LA; 9Stanford University, Stanford, CA;
10Barrow Neurological Institute, Phoenix, AZ; 11Rhode Island Hospital Providence, RI; 12Toronto, Canada

Practice Parameter—Morgenthaler et al

disclosure Statement
This is not an industry supported study. The authors have indicated no finan-
cial conflicts of interest.

Submitted for publication September, 2007
Accepted for publication September, 2007
Address correspondence to: Standards of Practice Committee, American
Academy of Sleep Medicine, One Westbrook Corporate Center, Suite 920,
Westchester IL 60154, Tel: (708) 492-0930, Fax: (780) 492-0943, E-mail:
aasm@aasmnet.org

These practice parameters pertain to the treatment of hypersomnias of
central origin. They serve as both an update of previous practice param-
eters for the therapy of narcolepsy and as the first practice parameters to
address treatment of other hypersomnias of central origin. They are based
on evidence analyzed in the accompanying review paper. The specific
disorders addressed by these parameters are narcolepsy (with cataplexy,
without cataplexy, due to medical condition and unspecified), idiopathic
hypersomnia (with long sleep time and without long sleep time), recur-
rent hypersomnia and hypersomnia due to medical condition. Successful
treatment of hypersomnia of central origin requires an accurate diagno-
sis, individual tailoring of therapy to produce the fullest possible return of
normal function, and regular follow-up to monitor response to treatment.
Modafinil, sodium oxybate, amphetamine, methamphetamine, dextroam-
phetamine, methylphenidate, and selegiline are effective treatments for
excessive sleepiness associated with narcolepsy, while tricyclic antide-
pressants and fluoxetine are effective treatments for cataplexy, sleep pa-
ralysis, and hypnagogic hallucinations; but the quality of published clinical

evidence supporting them varies. Scheduled naps can be beneficial to
combat sleepiness in narcolepsy patients. Based on available evidence,
modafinil is an effective therapy for sleepiness due to idiopathic hyper-
somnia, Parkinson’s disease, myotonic dystrophy, and multiple sclerosis.
Based on evidence and/or long history of use in the therapy of narcolepsy
committee consensus was that modafinil, amphetamine, methamphet-
amine, dextroamphetamine, and methylphenidate are reasonable options
for the therapy of hypersomnias of central origin.
Keywords: Narcolepsy, idiopathic hypersomnia, recurrent hypersomnia,
Parkinson’s disease, myotonic dystrophy, multiple sclerosis, modafinil,
sodium oxybate, amphetamine, methamphetamine, dextroamphetamine,
methylphenidate, selegiline, tricyclic antidepressants, fluoxetine
citation: Morgenthaler TI; Kapur VK; Brown TM; Swick TJ; Alessi C; Au-
rora RN; Boehlecke B; Chesson AL; Friedman L; Maganti R; Owens J;
Pancer J; Zak R; Standards of Practice Committee of the AASM. Practice
parameters for the treatment of narcolepsy and other hypersomnias of
central origin. SLEEP 2007;30(12):1705-1711.

HyperSomnIA

SLEEP, Vol. 30, No. 12, 2007 1706

content experts in 2005 to perform a comprehensive review of the
medical literature regarding treatment of hypersomnias of central
origin, and to grade the strength of evidence for each citation.
The literature search was performed using Medline, and details
regarding search terms, exclusions, and methods for screening by
Task Force members, and questions addressed are provided in the
accompanying review paper. The grading of evidence was per-
formed by the Task Force in accordance with the scheme shown
in Table 1. Three members of the Standards of Practice Commit-
tee (VK, TB, and TS) served as liaisons to facilitate communica-
tion between the Standards of Practice Committee and the Task
Force. The Standards of Practice Committee used the evidence
review of the Task Force, the prior practice parameters on narco-
lepsy, and the reviews upon which they were informed to develop
these updated practice parameters, and rated the levels (strength)
of recommendations using the AASM codification shown in Ta-
ble 2. This practice parameter paper is referenced, where appro-
priate, using square-bracketed numbers to the relevant sections
and tables in the accompanying review paper, or with additional
references at the end of this paper. When scientific data were ab-
sent, insufficient or inconclusive, committee consensus was used
to develop recommendations at an “Option” level (Table 2).

The Board of Directors of the AASM approved these recom-
mendations. All members of the AASM Standards of Practice
Committee and Board of Directors completed detailed conflict of
interest statements and were found to have no conflicts of inter-
est with regard to this subject. These practice parameters define
principles of practice that should meet the needs of most patients
in most situations. These guidelines should not, however, be con-
sidered inclusive of all proper methods of care or exclusive of
other methods of care reasonably directed to obtaining the same
results. The ultimate judgment regarding propriety of any specific
care must be made by the physician, in light of the individual cir-
cumstances presented by the patient, available diagnostic tools,
accessible treatment options, and resources. The AASM expects
these guidelines to have an impact on professional behavior, pa-
tient outcomes, and, possibly, health care costs. These practice
parameters reflect the state of knowledge at the time of publica-
tion and will be reviewed, updated, and revised as new informa-
tion becomes available.

Table 2—AASM Levels of Recommendations

Term Definition
Standard This is a generally accepted patient-care strat-

egy that reflects a high degree of clinical cer-
tainty. The term standard generally implies
the use of level 1 evidence, which directly
addresses the clinical issue, or overwhelming
level 2 evidence.

Guideline This is a patient-care strategy that reflects
a moderate degree of clinical certainty. The
term guideline implies the use of level 2 evi-
dence or a consensus of level 3 evidence.

Option This is a patient-care strategy that reflects un-
certain clinical use. The term option implies
either inconclusive or conflicting evidence or
conflicting expert opinion.

Adapted from Eddy8

the term “hypersomnia of central origin” will refer to this subset
of disorders.

Idiopathic hypersomnia presents as constant and severe exces-
sive sleepiness with naps that are unrefreshing. Post awakening
confusion (sleep drunkenness) is often reported. Idiopathic hyper-
somnia with long sleep time includes a prolonged sleep episode
of at least 10 hours duration and is felt to be a unique disease
entity.1

Recurrent hypersomnia is a rare disorder characterized by re-
current episodes of hypersomnia.1 The Klein-Levin syndrome is
the best characterized type and presents with associated behavior-
al abnormalities including binge eating and hypersexuality. Hy-
persomnia due to a medical condition refers to hypersomnia due
to a co-existing medical condition in the absence of cataplexy.1
Important subtypes of this diagnostic category include hypersom-
nia secondary to Parkinson’s disease, posttraumatic hypersomnia,
genetic disorders (e.g., Prader-Willi syndrome and myotonic dys-
trophy) and hypersomnia due to central nervous system lesions.

The purpose of this practice parameter paper is to present rec-
ommendations on therapy of hypersomnia of central origin. It
updates the prior parameters for the treatment of narcolepsy and
provides the first practice parameters on the therapy of other hy-
persomnias of central origin. Recommendations are based on the
accompanying review paper produced by a Task Force established
by the SPC.5 The review paper provides a systematic and compre-
hensive review of the medical literature regarding treatment of
hypersomnias of central origin and grades the evidence contained
within the literature using the Oxford evidence grading system.6

metHodS

The Standards of Practice Committee of the AASM developed
the clinical questions and scope of practice to be addressed in the
present practice parameters. The AASM appointed a Task Force of

Table 1—AASM Classification of Evidence

Evidence Levels Study Design
I Randomized, well-designed trials with low

alpha and beta error,* or meta-analyses of
randomized controlled trials with homogene-
ity of results

II Randomized trials with high alpha and beta
error, methodologic problems, or high qual-
ity cohort studies*

III Nonrandomized concurrently controlled
studies (case-control studies)

IV Case-control or cohort studies with method-
ological problems, or case series

V Expert opinion, or studies based on physiol-
ogy or bench research

Oxford levels adapted from Sackett 6,7 *Alpha (type I error) refers
to the probability that the null hypothesis is rejected when in fact it
is true (generally acceptable at 5% or less, or P<0.05). Beta (Type II error) refers to the probability that the null hypothesis is mistakenly accepted when in fact it is false (generally, trials accept a beta error of 0.20). The estimation of Type II error is generally the result of a power analysis. The power analysis takes into account the variability and the effect size to determine if sample size is adequate to find a difference in means when it is present (power generally acceptable at 80%-90%).

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SLEEP, Vol. 30, No. 12, 2007 1707

recommendAtIonS

Recommendations concerning narcolepsy which are similar to,
or are an expansion of previous ones, and new recommendations
are noted as such in the text. The recommendations concerning
other hypersomnias of central origin represent the first recom-
mendations on treatment of these disorders. Recommendations
regarding use of medications apply only to adults except when
specified.

1. An accurate diagnosis of a specific hypersomnia disorder
of central origin should be established. the evaluation should
include a thorough evaluation of other possible contributing
causes of excessive daytime sleepiness. (Standard).

Prior to committing to long-term therapy of hypersomnia, an
accurate diagnosis is important in order to choose an appropriate
therapy. The ICSD-2 specifies necessary diagnostic tests and crite-
ria for each disorder of hypersomnia of central origin.1 Many other
conditions produce such sleepiness and can mimic or coexist with
a hypersomnia of central origin. These include sleep disordered
breathing syndromes, periodic limb movements, insufficient sleep,
psychiatric disorders, medications, and circadian rhythm disorders.
All need to be considered in the differential diagnosis as possibly
causing or contributing to the excessive sleepiness in a patient with
a hypersomnia of central origin. Management of these primary or
concomitant disorders will require specific therapeutic interven-
tions apart from the use of CNS alerting agents or CNS neuromod-
ulator agents. We acknowledge that this recommendation is based
on committee consensus and is only slightly revised from a previ-
ous recommendation which was restricted to narcolepsy.4 Typically
consensus only merits an “Option” level of recommendation. Al-
though there are no articles addressing the need for an accurate di-
agnosis, all subsequent evidence evaluating efficacy of treatments
assumes an accurate diagnosis has been established. Therefore, the
SPC left this recommendation at a “Standard” level.

2. treatment objectives should include control of sleepiness and
other sleep related symptoms when present. (Standard)

It has been previously recommended that a major objective of
treatment of narcolepsy should be to alleviate daytime sleepiness.
The goal should be to produce the fullest possible return of normal
function for patients at work, at school, at home, and socially. This
recommendation was revised by committee consensus to apply to
the disorders of hypersomnia of central origin. A recommendation
to control nocturnal symptoms of disrupted sleep is added to the
previous recommendation to control cataplexy, hypnagogic hal-
lucinations, and sleep paralysis, when present and troublesome
in patients with narcolepsy. As previously recommended for nar-
colepsy, a healthcare provider should consider the benefit to risk
ratio of medication for an individual patient, the cost of medica-
tion, convenience of administration, and the cost of ongoing care
including possible laboratory tests when selecting a medication
for treatment of any hypersomnia of central origin.

3. the following are treatment options for narcolepsy.

Most of the agents used to treat excessive sleepiness have little
effect on cataplexy or other REM sleep associated symptoms.

Conversely, most antidepressants and anticataplectics have little
effect on alertness. However, some compounds act on both symp-
toms. We have indicated which symptoms are addressed by the
various agents below. Compounds should be selected depending
on the diagnosis and the targeted symptoms. Co-administration
of two or more classes of compounds may be needed in some
patients to adequately address their symptoms.

a. modafinil is effective for treatment of daytime sleepiness due to
narcolepsy [4.1.1.2] (Standard).

This recommendation is unchanged from the previous recom-
mendation. Fourteen additional studies including four level 1
studies and two level 2 studies support this recommendation.9-14,15
The approved recommended dose of modafinil is 200 mg given
once daily, but higher doses and split dose regimens have been
investigated. Three level 1 studies indicated that the use of a split
dose strategy provides better control of daytime sleepiness than
a single daily dose.12,14 One of the studies demonstrated that add-
ing a dose of modafinil 200 mg at 12:00 after a 400 mg dose at
07:00 improved late day maintenance of wakefulness test (MWT)
scores relative to a single 400 mg morning dose alone.14 A second
study demonstrated that a split dosing strategy either with 200
mg of modafinil at 07:00 and 12:00 or 400 mg in the morning and
200 mg at noon was significantly superior to a single morning
200 mg dose at 07:00.12 Statistical comparisons to a group that
received a 400 mg dose in the morning alone were not provided,
but split dosing strategies trended towards improved control of
sleepiness in the evening. A third study assessed subjects with
reported persistent late afternoon or evening sleepiness despite
a positive response to modafinil therapy. Subjects who received
400 mg per day in a divided dosage experienced improvement in
subjective and objective measures of sleepiness in the afternoon
or evening compared with those on a single 200 mg or 400 mg
dosage.13 A level 1 study by Black et al. compared combinations
of active and placebo preparations of modafinil and sodium oxy-
bate.9 Subjects who received active modafinil showed improve-
ment in objective and subjective sleepiness compared to placebo
modafinil. Those subjects receiving both active modafinil and ac-
tive sodium oxybate showed the most improvement suggesting an
additive effect of the combination. One level 4 open label study
showed modafinil was effective in improving sleepiness and was
generally well tolerated in 13 children (mean age 11 years) with
narcolepsy or idiopathic hypersomnia.10

One additional level 1 study of 196 subjects involved assess-
ment of armodafinil (the longer half-life enantiomer of modafinil)
for treatment of excessive sleepiness in patients with narcolepsy.
Subjects receiving armodafinil experienced significant improve-
ment in sleepiness as measured by the MWT mean sleep latency,
and in the Clinical Global Impression of Change.16

b. Sodium oxybate is effective for treatment of cataplexy, daytime
sleepiness, and disrupted sleep due to narcolepsy [4.2.1, 4.1.1.3,
4.3.1](Standard). Sodium oxybate may be effective for treatment of
hypnagogic hallucinations and sleep paralysis [4.4.1] (option).

This is a new recommendation, and is based on three level 1
and two level 4 studies. Three level 1 studies support the efficacy
of sodium oxybate in treating cataplexy.17-19 One of these studies
also supported its efficacy in treating daytime sleepiness and dis-

Practice Parameter—Morgenthaler et al

SLEEP, Vol. 30, No. 12, 2007 1708

rupted sleep but found no significant improvement in hypnagogic
hallucinations or sleep paralysis.17 Two additional level 1 studies
supported its efficacy in treating daytime sleepiness.9,20 There was
one level 4 study that supported its efficacy in improving daytime
sleepiness, nocturnal awakenings, sleep paralysis, and hypnago-
gic hallucinations.21 Studies that supported efficacy in improving
daytime sleepiness showed greater treatment effects and statisti-
cally significant effects most consistently at the highest dose (9
g/night). In addition, there was one level 4 study that supported its
efficacy for cataplexy and daytime sleepiness.22

c. Amphetamine, methamphetamine, dextroamphetamine, and
methylphenidate are effective for treatment of daytime sleepiness
due to narcolepsy [4.1.1.1] (Guideline).

This recommendation is unchanged from the previous recom-
mendation. These medications have a long history of effective use
in clinical practice but have limited information available on ben-
efit-to-risk ratio.4 This lack of information may reflect the limited
sources of research funding for medications available in generic
form rather than clinical utility of these medications.

d. Selegiline may be an effective treatment for cataplexy and
daytime sleepiness. [4.1.1.4] (option)

This recommendation was downgraded from the previous rec-
ommendation based on committee consensus. The current litera-
ture review did not identify additional studies that met inclusion
criteria. The use of selegiline is limited by potential drug inter-
actions and diet-induced interactions. Because of limited clinical
experience with the use of this medication for narcolepsy and po-
tential drug and diet interactions, the committee had significant
reservations about this agent being used as the preferred initial
choice for treatment of sleepiness in narcolepsy.

e. ritanserin may be effective treatment of daytime sleepiness due
to narcolepsy [4.1.1.6] (option).

This is a new recommendation based on two level 2 studies of
ritanserin, a 5-HT2 antagonist. One study demonstrated improve-
ment in subjective sleepiness, but not in mean sleep latency on
MSLT in narcolepsy patients (N=28) when ritanserin 5 mg/day
was added to the medication regimen.23 The other study, which
compared 5 mg, 10 mg, or placebo in 134 subjects with narco-
lepsy, did not demonstrate significant improvement in sleepiness,
but showed improvement in subjective sleep quality.24 Ritanserin
is not available for use in the United States.

f. Scheduled naps can be beneficial to combat sleepiness
but seldom suffice as primary therapy for narcolepsy [4.1.2]
(Guideline).

This recommendation is unchanged from the previous rec-
ommendation. The current search identified an additional level
2 study which supports the use of scheduled naps in narcolepsy
patients who remain sleepy despite the use of medications.25 The
combination of regular bedtimes and two 15-minute regularly
scheduled naps reduced unscheduled daytime sleep episodes and
sleepiness when compared to stimulant therapy alone.

g. pemoline has rare but potentially lethal liver toxicity, is
no longer available in the united States, and is no longer
recommended for treatment of narcolepsy [4.1.1.7] (option).

This is a new recommendation based on committee consensus.

h. tricyclic antidepressants, selective serotonin reuptake
inhibitors (SSrIs), venlafaxine, and reboxetine may be effective
treatment for cataplexy [4.2.2] (Guideline).

This recommendation is changed from the previous recom-
mendation addressing treatment of cataplexy, hypnagogic hal-
lucinations, and sleep paralysis. The medications recommended
for treatment of cataplexy have been expanded to include SSRIs,
venlafaxine, and reboxitine. A separate recommendation regard-
ing treatment of hypnagogic hallucinations and sleep paralysis
is addressed below as a separate parameter. There was limited
evidence regarding treatment of cataplexy in the prior practice
parameters. In the updated review, only one level 4 study26 in-
volving treatment of cataplexy with a medication other than so-
dium oxybate was identified. Reboxetine, a selective norepineph-
rine reuptake inhibitor, decreased cataplexy in 12 subjects with
narcolepsy with cataplexy. Reboxetine is not available for use in
the United States. The previous recommendation for the SSRI
fluoxetine was based on one level 2 and one level 5 study sup-
porting its efficacy for treatment of cataplexy. Additional studies
of other SSRIs in the treatment of cataplexy and related symp-
toms did not meet our inclusion criteria as most were case reports
and small open label studies. However, the clinical experience of
sleep specialists and committee consensus, as well as the more
limited open label studies with small numbers of subjects, reflect
that additional SSRIs are useful for treating cataplexy in patients
with narcolepsy. The antidepressant venlafaxine, which increases
serotonin and norepinephrine uptake, may also reduce cataplexy,
based on clinical experience, committee consensus, and a case
study of 4 patients that did not meet inclusion criteria for our
review.27

i. tricyclic antidepressants, selective serotonin reuptake inhibitors
(SSrIs), and venlafaxine may be effective treatment for treatment
of sleep paralysis and hypnagogic hallucinations [4.4.2] (option).

By consensus, this recommendation is revised from the prior
recommendation. The recommendation level is reduced from
guideline to option. Additional antidepressant medications are
also recommended. No new pertinent studies have been identified
in the current review. Recommendation level was downgraded to
reflect that this recommendation is based on anectodal experience
of committee members. These treatments may be considered for
this indication when the treating physician and patient believe that
the benefits of treatment outweigh the risks. In addition, based
on clinical experience and committee consensus, the recommen-
dations are extended to include additional antidepressant agents
(SSRIs and venlafaxine).

4. modafinil may be effective for treatment of daytime sleepiness
due to idiopathic hypersomnia [4.8] (option).

One level 4 study that included 24 patients with narcolepsy
and 18 with idiopathic hypersomnolence examined the efficacy

Practice Parameter—Morgenthaler et al

SLEEP, Vol. 30, No. 12, 2007 1709

of modafinil in adults with idiopathic hypersomnia.28 There were
improvements in the mean number of drowsy episodes and sleep
attacks as recorded in sleep diaries for both patient groups on this
medication. This is a new recommendation.

5. the following medications may be effective treatments for
specific types of hypersomnia due to a medical condition [4.9].

a. modafinil may be effective for treatment of daytime sleepiness
due to parkinson’s disease (option).

This conclusion is based on: one level 1 study which showed
improvement in the Epworth Sleepiness Scale (ESS) but no
change in MWT29; one level 2 study which showed no improve-
ment in subjective or objective measures of excessive daytime
sleepiness30; one level 4 study which showed improvement in
ESS31; and Committee consensus. However the benefit to risk
ratio is not well documented because the published clinical trials
include only small numbers of patients. This is a new recom-
mendation.

b. modafinil may be effective for treatment of daytime sleepiness
due to myotonic dystrophy (option).

This conclusion is based on one level 1 study which showed
improvement in MWT but no significant change in ESS, and on
committee consensus. The benefit to risk ratio is not well docu-
mented because the published clinical trial included only small
numbers (n=20) of patients.32 This is a new recommendation.

c. methylphenidate may be effective for treatment of daytime
sleepiness due to myotonic dystrophy (option)

This conclusion is based on one small (N=11) level 4 study
of methylphenidate for treatment of sleepiness associated with
myotonic dystrophy that demonstrated improvement in subjec-
tive sleepiness in 7 of 11 subjects at doses up to 40 mg/day, and
committee consensus.

d. modafinil may be effective for treatment of daytime sleepiness
due to multiple sclerosis (Guideline).

This conclusion is based on one level 2 study (N=72) and one
level 4 study (N=50) which showed improvement on the ESS.33,34
This is a new recommendation.

6. Lithium carbonate may be effective for treatment of recurrent
hypersomnia and behavioral symptoms due to Kleine-Levin
syndrome. [4.6] (option)

This recommendation is based on one small case series (N=5)
that indicated that the duration of hypersomnia episodes was
shorter and there were no behavioral symptoms during episodes
that were treated with lithium carbonate,35 and committee con-
sensus.

7. the following medications may be effective for treatment of
daytime sleepiness in idiopathic hypersomnia (with and without
long sleep time), recurrent hypersomnia, and hypersomnia
due to a medical condition: amphetamine, methamphetamine,

dextroamphetamine, methylphenidate, and modafinil [4.7, 4.8, 4.9]
(option)

The literature supporting the efficacy of these medications for
other specific disorders such as narcolepsy have been reviewed.
Where published evidence meeting search criteria is available for
the use of any of these medications in the conditions listed, this
has been provided in sections 4 and 5. This recommendation ap-
plies to those medications and conditions combinations for which
published literature meeting search criteria is not available. Al-
though there is no reason to suspect they will not improve alert-
ness, individualized therapy and close follow-up to ensure effica-
cy and monitor for side effects is needed. The recommendations
for these disorders are based on committee consensus.

8. the following are treatment recommendations previously
applied to narcolepsy only. their application is now extended
to the hypersomnias of central origin covered by this practice
parameter paper by committee consensus.

a. combinations of long- and short-acting forms of stimulants may
be indicated and effective for some patients (option).

Some stimulants have a short (3 to 4 hours) effective period
(e.g., methylphenidate). Others have longer duration of activity
and longer onset of action (e.g., modafinil, sustained-release am-
phetamine, sustained-release methylphenidate). By combining
stimulants with different activity characteristics, it may be pos-
sible to achieve alertness quickly and for longer periods of time
and succeed in avoiding insomnia as an unwanted side effect.4

b. treatment of hypersomnias of central origin with
methylphenidate or modafinil in children between the ages of 6
and 15 appears to be relatively safe. [4.1.1.2, 4.8, 5.1.1](option)

There is considerable experience with the use of methylpheni-
date for treatment of attention deficit disorder.4 There is one level
4 study of modafinil in children with narcolepsy or idiopathic
hypersomnolence that indicated it was safe and well tolerated in
children who did not have other preexisting neurologic or psychi-
atric conditions.10

c. regular follow-up of patients with hypersomnia of central origin
is necessary to monitor response to treatment, to respond to
potential side effects of medications, and to enhance the patient’s
adaptation to the disorder [4.10] (Standard).

i. A patient previously stabilized on stimulant medication
should be seen regularly by a health care provider at least once
per year, and preferably once every 6 months, to assess the devel-
opment of medication side effects, including sleep disturbances,
mood changes, and cardiovascular or metabolic abnormalities.

ii. Follow-up is necessary to determine adherence and response
to treatment; to monitor for the safety of medications in individ-
ual patients; and to assist the patient with occupational and social
problems.

iii. Patients with severe sleepiness should be advised to avoid
potentially dangerous activities at home and at work, and should
not operate a motor vehicle until sleepiness is appropriately con-
trolled by stimulant medications.

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SLEEP, Vol. 30, No. 12, 2007 1710

iv. Of the stimulants used to treat hypersomnia of central ori-
gin, amphetamines, especially at high doses, are the most likely to
result in the development of tolerance

v. Patients who fail to respond to adequate doses of stimulant
medication should be carefully assessed for other sleep disorders
that may contribute to excessive sleepiness such as insufficient
sleep, inadequate sleep hygiene, circadian rhythm disorders, ob-
structive sleep apnea syndrome, or periodic limb movement dis-
order.

vi. For side effects, dosage ranges, use in pregnancy and by
nursing mothers, and contraindications , see Tables 6 and 7 in the
accompanying review paper.4

vii. Health care providers should assist the patient with occu-
pational and social accommodation for disabilities due to hyper-
somnia of central origin.

viii. Polysomnographic re-evaluation of patients should be
considered if symptoms of sleepiness increase significantly or if
specific symptoms develop that suggest new or increased sleep
abnormalities that might occur in disorders such as sleep apnea or
periodic limb movement disorder.

Areas for Future research

The preparation of this practice parameter and the accompany-
ing review highlighted the need for additional research regarding
treatment of hypersomnia of central origin.

1. comparisons of traditional stimulants to newer somnolytic
agents for hypersomnia due to narcolepsy.

Several large randomized, placebo-controlled studies indicate
that modafinil and sodium oxybate are effective for treatment of
hypersomnia associated with narcolepsy. The traditional stimu-
lants (amphetamine, methamphetamine, dextroamphetamine, and
methylphenidate) which are available in generic form and are less
expensive, have a long history of use in clinical practice, but have
limited high-level evidence from published studies. There is a
need for randomized trials that compare the newer agents to the
traditional stimulants to establish relative efficacy and safety of
these agents to guide the clinician in choosing between them for
individual patients.

2. Additional assessment of antidepressants and comparison to
sodium oxybate for treatment of cataplexy.

The recommendation for use of antidepressants for cataplexy
is based largely on clinical experience and lower evidence level
clinical trials. Randomized controlled trials of these agents, par-
ticularly with comparison to sodium oxybate, a more expensive
medication that has high level evidence of efficacy, are needed to
assist the clinician in medication selection.

3. new therapies for treatment of hypersomnia due to narcolepsy.

As indicated by the accompanying review, traditional stimu-
lants, modafinil and sodium oxybate provide, at best, only moder-
ate improvement in sleepiness in patients with narcolepsy. Future
investigations should be directed toward development of more ef-
fective and better tolerated therapies, and primary prevention.

4. need for studies on treatment of hypersomnias of central origin
other than narcolepsy.

The review identifies very few studies that address the treat-
ment of sleepiness in specific hypersomnia disorders other than
narcolepsy. There is a need for studies, particularly testing the use
of traditional stimulants in these disorders.

5. need for peer-reviewed literature regarding special populations
including children, elderly patients, and pregnant and nursing
women.

The review identified very few studies that involve special
populations with hypersomnia such as children, older adults, or
pregnant or nursing women. There is a need for studies that ad-
dress safety issues specific to these populations.

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Evidence Table—Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin An American Academy of Sleep Medicine Report

Author (yr);
Oxford
Grade; Patient
Group.

Intervention/
Comparison
Intervention

Outcomes
Measures

Study Description/
Study type/

Blinding

Method

Recruitment
Source/ Funding

Source/
Recruitment

# patients
enrolled/

completed/
Patients’ Age
+ SD [range]/

%male

# controls enrolled/
completed/Controls’
Age + SD [range]/

%

male

Dose/Dosing Strategy Primary Study Outcomes Conclusions

Bastuji (1988);
4; N, IH

Modafinil EDS (subj) Pre and 1-2 months
post treatment

comparison of number
of drowsiness and

sleepiness attacks per
day reported in a diary
using Modafinil /cohort

study/no

blinding

NR/NR/Expert-
Assigned or Selected

Grps

24/22 with N/ 40
±17 yrs/ 70.8%,

17/14 with IH, 45
±15 yrs/52.9%

NA 200 mg-500 mg/ day in
divided doses/BID (in am and

at noon)

There were significant decreases
in the mean number of drowsy
episodes and number of sleep
attacks reported by both pt.

groups; no effect on C.

Modafinil was effective for reducing EDS in pts.
with N or IH.

Becker, P. M.
et al. (2004);
4; N.

Modafinil Mood/Quality
of Life, safety/

AE

A 6-week open label
multicenter trial to

determine if Modafinil
reduced fatigue,

improved mood and
health related quality
of life compared to

baseline/cohort study/
no blinding

Clinic population/
Pharmaceutical/

Expert-Assigned or

Selected Grps

151/123/39 [18-
68]/

46%

NA 200 or 400 mg, optimal dose
determined at end of second

week and participant remained
on that dose for duration of the

trial/q day, 1 hour before or
after first meal

Modafinil significantly
improved health related quality

of life component summary
scores on the SF-36, and

significantly improved, scores in
all domains of the POMS.

Treatment with Modafinil significantly improved
health related quality of life as assessed by SF-36

and all POMS-associated factors, in comparison to
abstinence from

treatment.

Black 2006;
1; N.

Modafinil, sodium
oxybate/Placebo

Daytime
Sleepiness

(Subjective),
Daytime

Sleepiness
(Objective),

Mood/Quality
of Life

Characterization
of the efficacy of

sodium oxybate as
a single agent, or in
combination with
modafinil, for the

treatment of EDS in
narcolepsy.

44 sites in the
United States,
Canada, the

Czech Republic,
France, Germany,
the Netherlands,

Switzerland, and the
United Kingdom/
Pharmaceutical/

Expert-Assigned or
Selected Grps

278/222/Sodium
oxybate group:

35.1 +/- 12.9/52%;
modafinil

group: 38.9+/-
15.6/50.8%;

sodium oxybate/
modafinil

group: 38.9+/-
15.9/46.3%.

Crossover
study/41.0+/-
13.4/43.6%

Usual modafinil dose between
200-600 mg/day. Sodium

oxybate 6 g nightly for the
initial 4-weeks of the double-
blind study then increased to
9g nightly for the duration
of the study./Following a

2-week single-blind baseline
period during which patients
took their customary doses of
modafinil (200 to 600 mg/day)

and nightly placebo sodium
oxybate solution (equally
divided doses at bedtime

and then 2.5-4 hours later),
patients were randomized in
a double-blind fashon to 1 of
4 groups: Group 1: placebo
sodium oxybate + placebo

modafinil, Group 2: sodium
oxybate + placebo modafinil,

Group 3: placebo sodium
oxybate + modafinil, Group 4:
sodium oxybate + modafinil.

EDS as defined by the MWT
which was performed following
nocturnal PSG at visits 2, 3, 4,
and 5 according to validated

standards (Four 20 min tests 2
hours apart).

Sodium oxybate and modafinil are both effective
for treating EDS in narcolepsy, producing additive

effects when used together. Sodium oxybate is
beneficial as both monotherapy and adjunctive
therapy for the treatment of EDS in narcolepsy.

Dauvilliers, Y.
et al. (2002);
4; N.

Modafinil EDS (subj)
GCIS

To determine if the
COMT genotype

affects the response
to treatment with

Modafinil and if the
differences in COMT
genotype distribution

between men and
women is associated

with response to
Modafinil/cohort
study/single blind

NR/private
foundation, Univ

Hospital of Geneva/
Expert-Assigned or

Selected Grps

84/84/ 48.21
+19.25 [14-
80]/61.9%

NA W 262.5 ± 16.65 mg M 343.34
± 16.17mg

52/84 classified as good
responders; 25/84 classified

as moderate responders; 7/84
classified as non responders to
Modafinil;An equal number

of men and women were
categorized as good responders;

optimal daily dosage of
Modafinil was significantly
lower in women than men

(262 mg compared to 343 mg);
optimal daily dose somewhat
affected by COMT genotype.

91% of narcolepsy patients showed moderate to
good response to Modafinil; response to Modafinil
is affected by COMT genotypes, which suggests
that Modafinil affects dopaminergic transmission.

SLEEP, Vol. 30, No. 12, 2007 S2

Author (yr);
Oxford
Grade; Patient
Group.
Intervention/
Comparison
Intervention
Outcomes
Measures

Study Description/
Study type/Blinding

Method
Recruitment
Source/ Funding
Source/
Recruitment
# patients
enrolled/
completed/
Patients’ Age
+ SD [range]/
%male
# controls enrolled/
completed/Controls’
Age + SD [range]/

%male

Dose/Dosing Strategy Primary Study Outcomes Conclusions

Group (2005);
1; N, C.

Sodium oxybate/
Placebo

Improve
Cataplexy

8 week DB PC trial
to evaluate sodium

oxybate in the
treatment of cataplexy/
Randomized Control
Trial/Double-Blind

Testing

42 sleep clinics/
Pharmaceutical/

Expert-Assigned or
Selected Grps

228/209/40.5 [16-
75]/34.6%

NA 4.5 g, 6.0 g, 9.0 g (all in
2 divided doses) after

washout from anticataplectic
medications/All patients

on active drug started with
4.5 g per night; one group

continued this dose for
duration of study; a second

group increased to 6.0 g after a
week and continued this dose
for duration of study ; a third

group increased to 6.0 g after a
week, then 7.5 g after a week,
then 9.0 g and continued this

dose for duration of study

Significant reduction in weekly
cataplexy with nightly doses
of 4.5, 6.0 and 9.0 g sodium
oxybate for 8 weeks, with

median decreases of 57.0, 65.0
and 87.7%, respectively; overall
reduction of cataplexy greater at

8 weeks than at 4 weeks.

Sodium oxybate highly effective in treating
cataplexy in a time and dose-dependent manner;

weekly titration appears to be well-tolerated.

Group, 2005;
1; N.

Sodium oxybate/
Placebo
Daytime
Sleepiness
(Subjective),
Daytime
Sleepiness
(Objective),

Mood/Quality
of Life, Safety/

Adverse
Events

A multi-center
randomized, double

blind, placebo
controlled study
evaluating the

effectiveness of sodium
oxybate on sleepiness

in narcolepsy pts
with cataplexy over

8 weeks/Randomized
Control Trial/Double-

Blind Testing

Subset of narcolepsy
subjects in a mulit-
center drug trial/

Expert-Assigned or
Selected Grps/
Pharmaceutical

228/209 (401 pts
originally entered
a larger ongoing
trial but only 228
entered the double
blind phase)/40.5

(16-75) 34.6%

NA 4.5, 6 or 9g/Two equally
divided doses taken

immediately before bed and
2.5-4 hours later; all pts in

treatment groups started at 4.5
but 2/3 were then titrated up to
either their assigned group of

6g or 9g

ESS and CGI showed dose
related significant improvement

at all doses. MWT latencies
showed significant increases
only at 4.5 and 9 g dose (1.75

and 10 min respectively).
Inadvertent sleep attacks

showed dose related decrease
but only significant for 6 and 9g

Sodium oxybate when taken with other traditional
stimulants significantly decreases daytime

sleepiness in a dose related manner as measured by
ESS and number of sleep attacks. MWT scores are
also significantly improved for the 4.5 and 9g dose

with 9g showing a robust increase.

Guilleminault,
C.et al (2000);
3; N with C.

Modafinil EDS (subj) Four groups of N
pts. with EDS were

switched to Modafinil
from their current
medication: 1) no

medication regimen
(naïve); 2) only

stimulant medications;
3) only anticataplectic

medications; 4)
both stimulant and

anticataplectic
medications/cohort
study/no blinding

Three sleep clinics,
two in Europe and
one in the United
States/NR/Expert-

Assigned or Selected
Grps

60/60; 31 from
USA; 29 from
Europe/ 41±18
[19-68]/55%

NA 100-600mg/after withdrawal,
pts. were switched to 100

mg of Modafinil; dosage was
increased by 100-mg every 3
days; most common dosage

was 400-mg divided into two
dosages given morning and

noon

Naive pts. accepted Modafinil
best; pts. withdrawn

from amphetamine had the
most problems and failure to

withdraw; use of a progressive
withdrawal protocol may

reduce problems; Venlafaxine
hydrochloride combined well

with Modafinil to control
cataplectic attacks.

Modafinil is an appropriate medication to
counteract daytime sleepiness, but caution is
warranted in switching from amphetamine to

Modafinil in some pts., and presence of C may
warrant both Modafinil in combination with

anticataplectic agent.

SLEEP, Vol. 30, No. 12, 2007 S3

Author (yr);
Oxford
Grade; Patient
Group.
Intervention/
Comparison
Intervention
Outcomes
Measures
Study Description/
Study type/Blinding
Method
Recruitment
Source/ Funding
Source/
Recruitment
# patients
enrolled/
completed/
Patients’ Age
+ SD [range]/
%male
# controls enrolled/
completed/Controls’
Age + SD [range]/
%male
Dose/Dosing Strategy Primary Study Outcomes Conclusions

Harsh 2006;
1; N.

Armodafinil/Placebo Daytime
Sleepiness

(Subjective),
Daytime
Sleepiness
(Objective),

Safety/
Adverse
Events

12 week DB RCT
with placebo control
to assess efficacy and
safety of armodafinil

in patients with
narcolepsy

47 centers in
6 countries/

pharmaceutical
industry/Expert-

Assigned or Selected
Grps

132/105 (65/49
for 150 mg group;

67/56 for 250
mg group)/40.4
+12.5/44% for

150mg dose group;
35.0+12.5/37% for
250 mg dose group

64/55/39.2+12.0/51% 150 mg or 250 mg /Once daily
for 12

weeks

At final visit, mean MWT
SL increased 1.3, 2.6 and 1.9
min from baseline in the 150
mg, 250 mg and armodafinil

combined groups, respectively;
proportion of patients with at
least minimal improvement
in CGI-C was significantly

higher for 150 mg, 250 mg and
armodafinil combined groups

compared to placebo at all
time points (p<0.0001); ESS, global fatigue rating per BFI,

some measures of attention and
memory per CDR improved

with armodafinil compared to
placebo; naps and unintentional
sleep periods were reduced per
diaries in armodafinil groups

compared to placebo; no change
in cataplexy with armodafinil;

no adverse effects on PSG
parameters with armodafinil.

In patients with narcolepsy, armodafinil at doses
of 150 or 250 mg/day significantly improved
wakefulness during the day, CGI-C and some

measures of memory and attention compared to
placebo.

Hogl, (2002);
2; PD.

Modafinil/placebo EDS (subj),
EDS (obj)

This cross-over study
was designed to

test the efficacy of
Modafinil compared

to placebo for the
treatment of increased
daytime sleepiness in
pts. with PD/cohort
study/double blind

Clinic population/
Pharmaceutical/

Expert-Assigned or
Selected Grps

15/12/65.0
±7.6/75%

NA 100 mg the first week of
treatment and 200 mg the

second week/q am

Although there was significant
improvement of subjective

sleepiness (ESS scores)
there was no improvement in

objective measures of sleepiness
(MWT).

Modafinil produces significant improvement in
subjective alertness, but not objective alertness in

patients with PD.

Ivanenko, A. et
al. (2003); 4;
N, IH.

Modafinil EDS (subj),
EDS (obj),
safety/AE

The effects of
Modafinil on daytime
sleepiness in children

with IH or N was
assessed over 15.6 +
7.8 months./cohort
study/no blinding

Clinic population/
NR/Expert-Assigned

or Selected Grps

13 / 13/ 11.0 + 5.3
years, [2 – 18]/

46%

NA Mean dose = 346 ± 120 mg/
typically in the morning and

at noon

Parents reported improvements
in daytime sleep attacks, EDS,
and daytime naps; Mood and
academic performance also
improved with Modafinil;

average MSL on the MSLT
increased with treatment

(10.2 + 4.8 min) as compared
to baseline (6.6 + 3.7); one
child failed to improve with
Modafinil and three showed

partial improvement requiring
an additional medication/ 12

children respondeded.

Modafinil produced a modest but significant
decrease in sleepiness in children and appears to be

safe and well tolerated in this population.

Lammers
(1991); 2; N.

Ritanserin/Placebo Daytime
Sleepiness

(Subjective),
Daytime
Sleepiness
(Objective),

Improve
Cataplexy,

Mood/Quality
of Life, Safety/
Adverse
Events

Randomized double-
blind placebo

controlled trial of
Ritanserin, a potent
long-acting 5-HT2

receptor blocker, in 28
narcolepsy patients./
Randomized Control
Trial/Double-Blind

Testing

NS, presumably
expert assigned./

Private Foundation/
Expert-Assigned or

Selected Grps

28/28 ( 16 received
Ritanserin & 12

received placebo)/
43 (range 16-67)

NA 2.5 milligrams/Following a
1-week “baseline” period,

Ritanserin was dosed twice a
day for 4 weeks in addition to
their usual medical regimen

for narcolepsy

Ritanserin reduced subjective
EDS and increase feeling of
refreshed in morning. There

was no effect on MSLT latency,
cataplexy or sleep attacks.

Ritanserin, as “add on” therapy for narcolepsy,
reduces subjective EDS and increases the feeling
of being refreshed in the morning. There was no
effect on objective sleepiness (MSLT mean sleep
latency), frequency of cataplexy or sleep attacks,

or the mood rating scale. Ritanserin increased
slow-wave sleep (stage 3+4), and reduced wake

after sleep onset.

SLEEP, Vol. 30, No. 12, 2007 S4

Author (yr);
Oxford
Grade; Patient
Group.
Intervention/
Comparison
Intervention
Outcomes
Measures
Study Description/
Study type/Blinding
Method
Recruitment
Source/ Funding
Source/
Recruitment
# patients
enrolled/
completed/
Patients’ Age
+ SD [range]/
%male
# controls enrolled/
completed/Controls’
Age + SD [range]/
%male
Dose/Dosing Strategy Primary Study Outcomes Conclusions

Larrosa, O. et
al. (2001); 4; N
with C.

Reboxetine EDS (subj
and obj)

using ESS,
VAS, MSLT/

Catplexy
subscale of
Ullanlinna
N Scale/

Mood (Beck
Depression
Inventory)/
Quality of
Life, TST,
safety/AE

Pre-post test study to
determine if reboxitine

was effective for
reducing EDS and C

compared to baseline/
cohort study/no

blinding

Clinic Population/
Pharmaceutical/

Expert-Assigned or
Selected Grps

12 enrolled,
12 complet-

ed/36.6±11.7/50%

NA 10 mg per day/6 mg q am, 4
mg at lunchtime

Roboxitine was effective
in reducing all measures of

subjective sleepiness including
ESS, VAS sleepiness as well
as objective EDS based on

pre- and post MSLT data as well
as C subscale of the Ullanlinna
N Scale; Roboxitine increased
% stage 1 and REM latency
at night, with decreased #

SOREM’s on MSLT; no change
in BDI; performance still below

healthy normal controls.

Preliminary results demonstrate improvement of
subjective sleepiness and reduction in C; effect

on MSLT less consistent in those with mean sleep
latency < 6 mins.

Mamelak, M.
et al. (2004);
4; N.

Sodium oxybate EDS (subj),
EDS (obj),
Safety/AEs,

TST

The authors
investigated the effects
of escalating doses of

sodium oxybate on
sleep architecture and
daytime functioning/

Cohort Study/No

Blinding

4 clinical trial sites/
Pharmaceutical

29/25/52.6 + 8.8
years, [range NR]/

28% male

NA 4.5 g/night, 6.0 g/night, 7.5 g/
night, 9.0 g/night/ One-half of
total dose taken twice nightly.
Dose escalated every 2 weeks
following a 4-week period of

4.5 g/night

Sodium oxybate produced dose-
related increases in SWS and
delta power; daytime SOL on

MWT increased; and nocturnal
awakenings decreased. The ESS

score decreased and all scales
of the narcolepsy symptom

questionnaire improved.

Sodium oxybate produced dose-related
improvements in narcolepsy symptoms.

Mayer (2003);
2; N.

Ritanserin/ placebo EDS (subj),
EDS (obj),
Safety/AEs,

TST

The effect of
ritanserin (a 5-HT2

antagonist) on daytime
sleepiness and

daytime functioning
in narcoleptics was

assessed/RCT/Double-
Blind

Testing

NR 134 enrolled /122
completed/Placebo
group: 40.9 + 14.2,
5 mg group: 43.2 +
12.5; 10 mg group:
43.2 + 15.0. range:

16 – 65 years;
62.7% male

NA Ritanserin 5mg or 10 mg or
placebo was taken once daily
after breakfast for 28 days;
subjects were allowed to

continue receiving their usual
medication regimes

Subjective symptoms: 5 mg
improved “refreshed” feeling
in am., sleep attacks, daytime
sleepiness, work & activities,
social life and partners rated

improvements in daytime
sleepiness and work &

activities. 10 mg improved sleep
quality and sleep attacks.

Ritanserin had very little effect on improving
narcolepsy symptoms. While ritanserin did

improve some parameters of PSG-recorded sleep,
corresponding subjective improvements were not
found. Ritanserin should not be used as a primary

stimulant or hypnotic.

Mitler (2000);
4; N.

Modafinil/NA Daytime
Sleepiness

(Subjective),
Daytime
Sleepiness
(Objective),
Safety/
Adverse
Events

long-term (40 weeks)
open label efficacy
and safety study of
modafinil/Cohort or

Ecological Studies/No
Blinding

Patients who had
participated in

one of two prior
clinical studies/
Pharmaceutical/

Expert-Assigned or
Selected Grps

478/341 (9.0%
discontinued
treatment due
to AE; 11.5%
discontinued

treatment due to
lack of efficacy)/42
+/- 13 (18-65)/46%

NA 200, 300, 400 mg; 1st group:
200, 300 or 400 mg daily at

discretion of investigator; 2nd
group: 200 mg/day for one
week, then 400 mg/day for

one week, then either 200 mg
or 400 mg daily for duration
of study at the discretion of

the investigator/NR

CGI-Change: 80% of patients
improved, 10% unchanged, 10%
worsened; mean ESS: improved
from 16.5 to 12.4; QoL scores

improved in 6 of 8 SF-36
domains.

Modafinil (most patients received 400 mg)
significantly reduced EDS and generally

improved QoL in patients with N; the medication
was generally well-tolerated and there was no

indication of tolerance.

SLEEP, Vol. 30, No. 12, 2007 S5

Author (yr);
Oxford
Grade; Patient
Group.
Intervention/
Comparison
Intervention
Outcomes
Measures
Study Description/
Study type/Blinding
Method
Recruitment
Source/ Funding
Source/
Recruitment
# patients
enrolled/
completed/
Patients’ Age
+ SD [range]/
%male
# controls enrolled/
completed/Controls’
Age + SD [range]/
%male
Dose/Dosing Strategy Primary Study Outcomes Conclusions

Moldofsky
(2000); 2; N.

Modafinil/placebo Daytime
Sleepiness

Subjective

and Objective,
Mood/Quality
of Life, Safety/
Adverse Event

16 week open label
study with modafinil

and followed by
2 week RCT with
placebo control to
evaluate continued

efficiacy and safety in
narcoleptic patients

taking modafinil
(participants had

completed a prior 6
week RCT crosover
study)/Randomized

Control Trial/Double-
Blind Testing – for

RCT portion and No
Blinding – open label

portion

Subjects who
completed prior

clinical trial
with modafinil/
Pharmaceutical/

Expert-Assigned or
Selected Grps

69/63 for open
label portion;

30/28 for 2 week
RCT/45 +/- 16 /
33.3% for open

label portion

33/33 for 2 week
RCT/ns/ns for 2 week

RCT portion

200-400 mg daily for most
patients; 1 patient took 150

mg daily; 2 patients took 500
mg daily/Open label portion:

patients started with 200 mg in
a.m. and 100 mg at noon; dose
then adjusted up or down by
100 mg increments based on
clinical assessment; patients
randomized to modafinil arm
during 2 week RCT portion

continued their individualized
dose from open label portion

At end of 2nd week RCT
portion, MWT mean SL were

70% longer on modafinil
than on placebo (p=0.009);
in patients switched from

modafinil to placebo MWT SL
decreased by 37% (p=0.006),

compared to decrease in 7% in
group remaining on modafinil

(p=0.35); 24.3% of MWT
sessions ended without sleep

on modafinil compared to 6.1%
on placebo (p<0.001); few

changes on PSG measures of
sleep architecture; compared to
placebo, modafinil reduced total
number of reported episodes of
severe somnolence plus sleep
attacks plus naps (p=0.017);

ESS scores lower on modafinil
(13.2+/-5.7) compared to

placebo (15.4+/-5.8) at end of
study (p=0.023); no changes in
FCRRT; no changes in POMS

Modafinil continued to be an effective and well-
tolerated drug after 16 weeks of treatement of EDS

in patients with narcolepsy

Nieves, A. V.
et al. (2002);
4; PD.

Modafinil/none ESS and
Unified PD

Rating Scale
part III

a 4-week open-label
trial of Modafinil

in 10 patients with
PD, who also had
EDS and were on

various dopaminergic
drugs/Cohort Study/No

Blinding

Movement Disorders
Center/NR

10/9/≥18, [66.9+_
7]/ 80%

NA Titrated as needed from 100-
400mg/day, not to exceed
400mg/day for 4 weeks/1

dose of 100mg “early in the
morning,” and were allowed

to increase the dose by 100 mg
every week up to a maximum

of 400 mg divided in two
doses

Mean ESS score at baseline of
patients completing the study
(n = 9) was 14.22 (± 3.03) and
post-study (on an average dose

of 172 mg/day), mean ESS
score was 6.0 (± 4.87). Unified
PD Rating Scale scores were

NOT affected.

Modafinil is effective in reducing subjective EDS
in patients with PD treated with dopaminergic
drugs — it did not seem to worsen parkinsonian

symptoms and may allow further increase in
dopaminergic therapy in patients previously unable

to tolerate certain dosages.

Ondo, W. G. et
al. (2005); 2;
PD.

Modafinil/ Placebo EDS (subj),
EDS (obj),
Safety/AEs

Mood/Quality
of Life

Study designed to
test the efficacy of

modafinil in reducing
the symptoms of

EDS in patients with
PD/RCT/Double-Blind

Testing

Clinic population
at a tertiary

referral center/
Pharmaceutical

40/37[64.8 ±
11.]/3/72-5%

NA 200 mg/day or 400 mg/day/
half the dosage taken after

waking and the other half at
noon

Modafinil did not reduce EDS
(subj) or EDS (obj).

Modafinil is not effective for reducing EDS
experienced by patients with PD.

Poppe (2003);
4; Recurrent
Hypersomnia.

Lithium carbonate/NS Frequency and
duration of

hypersomnic
episodes

Case series of 5
patients with Kleine-

Levin Syndrome
(KLS) treated with

lithium prophylaxis/
Case Studies/ No

Blinding

Children’s Hospital,
Technical University
Dresden/NA/Expert-
Assigned or Selected

Grps

5/5/13 to 17 years
old; /60% male

NA Lithium retard tablet at a dose
that maintained serum levels

between 0.6-0.9 mmol/l./
Between 20 and 36 months of

therapy

Influence of lithium therapy on
frequency and/or duration of

KLS episodes.

The risk of episodes under treatment with lithium
dropped from 100% to 93% per preceeding month

of therapy (Odds Ratio =0.09; 95% confidence
interval 0.89-0.96; p<0.001). Quantitatively, lithium therapy reduces the mean duration of

episodes by 19% (p=0.012).

SLEEP, Vol. 30, No. 12, 2007 S6

Author (yr);
Oxford
Grade; Patient
Group.
Intervention/
Comparison
Intervention
Outcomes
Measures
Study Description/
Study type/Blinding
Method
Recruitment
Source/ Funding
Source/
Recruitment
# patients
enrolled/
completed/
Patients’ Age
+ SD [range]/
%male
# controls enrolled/
completed/Controls’
Age + SD [range]/
%male
Dose/Dosing Strategy Primary Study Outcomes Conclusions

Rammohan
(2002); 2; MS.

Modafinil/ Placebo Fatigue
Severity Scale,

modified
fatigue impact

scale; ESS;
a visual

analogue scale
for fatigue
(VAS-F)

9-week, single blind,
pilot study designed

to assess efficacy and
safety of modafinil for
the treatment of fatigue
in patients with (MS)./
Cohort Study/Single

Blinding

NS/Pharmaceutical 72/65/44 (23-
61)/75%

NA 200mg/day; 400mg/day/All
patients received placebo

during weeks 1–2, 200 mg/day
modafinil during weeks 3–4,
400 mg/day modafinil during

weeks 5–6, and placebo during
weeks 7–9.

200 mg/day Dose: compared to
placebo run-in, sig improvement

in fatigue was demonstrated
— mean scores post-treatment

were: FSS, 4.7 vs 5.5 for
placebo (p<0.001); MFIS,

37.7 vs 44.7 (p<0.001); and VAS-F, 5.4 vs 4.5 (p=0.003).

400mg/day Dose: Fatigue scores
not significantly improved

versus placebo run in. Mean
ESS scores were significantly
improved (p<0.001) with 200

mg/day modafinil (7.2) and 400
mg/day (7.0) vs the score at

baseline (9.5).

200mg/day of modafinil improves fatigue in MS
patients. Mean ESS scores were significantly
improved with 200mg/day and 400mg/day in

comparison with baseline scores.

Rogers, A. E.
et al. (2001);
2; N.

Naps, regular
schedule,combo

naps/regular bedtimes/
Other Treatment and

Schedules

Narcolepsy
Symptom

Status
Questionnaire
(NSSQ); 24

hr ambulatory
PSG

monitoring

To determine if
the combination

of scheduled sleep
periods and stimulant
medications was more
effective than stimulant
therapy alone/RCT/No

Blinding

Clinic population/
Oxford Medilog Inc

29/29/43.7 ±13.9
[18-64], 41.4%

NA NA Only the combination of naps
and scheduled bedtimes reduced

the amount of unscheduled
daytime sleep compared

to stimulant therapy alone
(baseline).

Although the scheduled naps are often
recommended, they were not more effective than

stimulant medications alone. Only the combination
of scheduled naps and regular bedtimes was more
effective in reducing unscheduled daytime sleep
episodes than stimulant stimulant therapy alone.

Saletu, M. et al.
(2004); 2; N.

Modafinil/ Placebo EDS (subj),
EDS (obj)

This study examined
narcoleptics and

normal controls in a
crossover study of
a three-week fixed

titration of modafinil
(200, 300, 400 mg) and

placebo to identify
brain regions

associated with
vigilance in

untreated and
modafinil-treated

narcoleptic patients by
means

of low resolution
brain electromagnetic

tomography
(LORETA)/RCT/

Double-

Blind Testing

NS/Pharmaceutical 16/15/[39.1±13.3],
62.5%

16/16[/37.1±13.5]/
62.5%

200, 300, 400 mg modafinil (3
week fixed titration schedule)

The EEG differences between
groups were characterized by
significant decrease in alpha-2
power, mainly in the frontal,
temporal and parietal areas of

the right hemisphere, along with
a global decrease in beta power,
also accentuated over the right
cortical brain areas. ESS score
decreased from median 14.5

after 3 weeks of placebo to 12.5
after 3 weeks of modafinil. In

the MSLT latency to sleep stage
S1 significantly increased from
a median of 3.2 min after three

weeks of placebo to 6.6 min
after three weeks of modafinil

(p<0.05).

Modafinil is associated with improvement
in subjective and objective daytime

sleepiness;LORETA provided evidence of a
functional deterioration of the

fronto-temporo-parietal network of the right-
hemispheric vigilance system in narcolepsy

and a therapeutic effect of modafinil on the left
hemisphere, which is less affected by the disease.

Schwartz
(2003); 1; N.

Modafinil/placebo Daytime
Sleepiness
(Subjective),
Daytime
Sleepiness
(Objective),
Safety/
Adverse
Events

Double-blind,
randomized,

multicenter study
of 3 Modafinil

dosing regimens in
patients with a prior
positive response to
the medication who

were dissatisfied with
late-afternoon or

evening sleepiness./
Randomized Control
Trial/Double-Blind

Testing

NR/Pharmaceutical/
Expert-Assigned or

Selected Grps

32/NR/43 +/- 12
[28-61]/27 for 200
mg QD group; 47
+/- 16 [28-71]/64
for 400 mg QD
group; 39 +/- 15
[19-60]/50 for

400 mg split dose
group

NR/NR/Crossover
study design; one
week of modafinil

washout followed by
randomization to one
of 3 dosing regimens
for a 3 week period

200 mg QD; 400 mg QD;
200 mg BID/All groups took
200 mg at 0700 hrs + placebo
at noon for 1 week; group A
continued this regimen for 2
more weeks; group B took

400 mg at 0700 and placebo at
noon for 2 more weeks; group

C took 200 mg at 0700 and
200 mg at noon for 2 more

weeks

CGI-change improved in all
groups compared to baseline;
ESS scores improved in all
groups (trend toward more

improvement in 400 mg QD
compared to 200 mg QD, but
not statistically significant);
mean MWT sleep latency

improved in all groups (more
improvement in both 400 mg

groups than in 200 mg group);
improvement in evening

sleepiness was greater in the
split-dose group.

A split-dose 400 mg regimen is superior to once
daily dosing for sustaining wakefulness throughout

the entire waking day.

SLEEP, Vol. 30, No. 12, 2007 S7

Author (yr);
Oxford
Grade; Patient
Group.
Intervention/
Comparison
Intervention
Outcomes
Measures
Study Description/
Study type/Blinding
Method
Recruitment
Source/ Funding
Source/
Recruitment
# patients
enrolled/
completed/
Patients’ Age
+ SD [range]/
%male
# controls enrolled/
completed/Controls’
Age + SD [range]/
%male
Dose/Dosing Strategy Primary Study Outcomes Conclusions

Schwartz, J. R.
(2005); 1; N.

Modafinil This study was
designed to determine

if a split dose of
modafinil would be
more effective than

a single morning
dose for reducing

sleepiness in the late
afternoon and evening/
Randomized Control
Trial/Double-Blind

Testing

Clinic population/
Pharmaceutical

56/56/42 years
[18-70 years, with
one 14 year old],

52% male

NA 200 mg, 400 mg, and 600
mg/200 mg q am (0700), 400
mg q am (0700), 200 mg BID
(0700 and 1200), and 400 mg
q am (0700) with 200 mg at

noon

Significantly higher percentages
of patients receiving the split
dosage regimen were able to
sustain wakefulness on MWT
during the late afternoon and
evening, as compared only to

the 200mg once daily regimen.

Split dosing regimens for modafinil(≥400mg) are
more effective than 200 mg once daily dosing for

maintaining alertness in the late afternoon and
early evening, but significant differences were not
noted with respect to 400 mg once daily dosing.

Schwartz, J. R.
et al. (2003);
4; N.

Modafinil EDS (subj),
EDS (obj)

Efficacy of 200
– 400 mg of modafinil

was assessed in
narcoleptics reporting
dissatisfaction with

psychostimulant
treatment taken to
alleviate daytime
sleepiness/NR/No

Blinding

20 sleep centers
around the

United States/
Pharmaceutical

151 enrolled / 123
completed/Mean
age 39, range: 18
– 68 years; 46%

male

NA 200 mg or 400 mg/There was
a 2 week washout period from

all stimulant medications.
Then, subjects received

modafinil 200 mg for first
week, then 200 mg or 400

mg for weeks 2 – 6 depending
on best dose for individual

subject.

Compared to a post-washout
baseline, all doses of modafinil

improved the ESS score and
CGI-C scores. 70% of the

patients were taking 400 mg
modafinil daily at the end of the

study.

Modafinil was an effective and well-tolerated
treatment for daytime sleepiness in narcoleptics

previously treated with and reporting
dissatisfaction with stimulant medications

Schwartz, J. R.
et al. (2004);
1; N.

Modafinil (400 mg qam
and 200 mg q noon vs.
400 mg qam)/placebo

EDS (subj
and obj), AE,
and Executive
Functioning
using ESS,
CGI, MWT,
and WCST

This double-blind
study assessed if an
additional afternoon

dose of modafinil
(600 mg total daily

dose) would be more
effective than a single

morning dose (400 mg)
for reducing afternoon
and evening sleepiness/

randomized control
trial/Double-Blind

Testing

Expert assigned or
selected groups from
a clinic population/

pharmaceutical

industry

24/24/400mg
treatment group
(40; 18-61), 600

mg treatment
group (45; 14-60)/

58%

NA 400 mg modafinil and 600
mg modafinil/400 mg q am

(0700); and split-dose (400mg
qam, 200mg qnoon)

A significantly higher
percentage of patients receiving

the higher split dose of
modafinil were able to remain

awake during the late afternoon
and evening than patients

on single dosage (either 200
or 400 mg q am). Executive

functioning was also improved.

Higher, split doses of modafinil were more
effective than single morning doses of modafinil
for improving alertness in the late afternoon and

evening.

Talbot (2003);
1; Myotonic
Dystrophy.

Modafinil/placebo EDS (subj
and obj) using

ESS, SF36,
PSG, MWT

A randomized double-
blind crossover study
of modafinil versus

placebo for the
treatment of EDS in

patients with Myotonic
Distrophy/randomized
control trial/Double-

Blind Testing
Expert assigned or
selected groups from
a clinic population/

pharmaceutical
industry

20/19/43 [18-
65]/68%

Within subject design 100 mg, 200 mg/ 100 mg on
days 1-5, followed by 200 mg

on days 6-28

Non-significant reduction
in ESS. SL on MWT was

prolonged by treatment (31.7-
40min, p=.006).

Modafinil at 100 and 200 mg showed a non-
significant reduction in median ESS, however
median SL on MWT score was prolonged by

treatment.

U.S. Xyrem
Multicenter
Study Group
(2004); 1; N C.

Sodium oxybate/placebo C
improvement,

AE using
diaries

This double blind
treatment withdrawal
study examining the
long-term efficacy of
sodium oxybate on

cataplexy/randomized
control trial/Double-

Blinding

Expert assigned
or selected groups

/pharmaceutical

industry

56/55/≥16
[47.7]/42%

NA Sodium oxybate ranging
from 3.0 to 9.0 g nightly/

sodium oxybate or placebo
was administered in equally
divided doses immediately

upon going to bed and again
2.5–4 hr

later

During the 2-week double-blind
phase, the abrupt cessation of
sodium oxybate therapy in the
placebo patients resulted in a

significant increase in the
number of cataplexy attacks

(median change = 21; P 0.001)
compared to patients who

remained on sodium oxibate.

This randomized controlled trial provides evidence
supporting the long-term efficacy of sodium
oxybate for the treatment of cataplexy. There

appeared to be no evidence of rebound cataplexy
upon abrupt discontinuation of treatment, nor any

symptoms of frank withdrawal.

SLEEP, Vol. 30, No. 12, 2007 S8

Author (yr);
Oxford
Grade; Patient
Group.
Intervention/
Comparison
Intervention
Outcomes
Measures
Study Description/
Study type/Blinding
Method
Recruitment
Source/ Funding
Source/
Recruitment
# patients
enrolled/
completed/
Patients’ Age
+ SD [range]/
%male
# controls enrolled/
completed/Controls’
Age + SD [range]/
%male
Dose/Dosing Strategy Primary Study Outcomes Conclusions

U.S. Xyrem®
Multicenter
Study Group
(2003); 4; N C.

Sodium oxybate/14-21
day baseline period

EDS (subj), C
improvement,
AE using CGI,

ESS, logs

This study evaluated
the safety and efficacy
of five different doses

(3-9 g) of sodium
oxybate during a

multicenter 12-month
open-label trial/cohort

study/No Blinding

Expert assigned
or selected groups

from clinical
populations ≥ 18

yo/pharmaceutical
industry

118/80/43.7 [18-
79]/43.5%

NA 3 mg, 4.5 mg, 6 mg, 7.5 mg,
or 9 mg of sodium oxybate

nightly/initial dose at bedtime
and second dose 2.5-4 hours

later

Cataplexy episodes decreased
signficantly the first month

(compared to baseline numbers)
in all treatment groups, and

continued to remain at a lower
level throughout the 12 month
trial period. ESS decreased at

1-month for all tx groups except
4.5 g (n=6).

3 to 9 g of sodium oxybate produced significant
and long-term reductions in cataplexy and

subjective daytime sleepiness.

US Xyrem
Multi-center
Study Group
(2002); 1; N.

Sodium oxybate/placebo EDS (subj and
obj)/Catplexy
and AE using

ESS, CGI, and
logs/number
of nocturnal
awakenings/
HH and SP

This multi-site double-
blind trial investigated
the effects of 3 doses
of sodium oxybate
on the treatment of

narcolepsy symptoms/
randomized control
trial/Double-Blind

Testing

Random selection
from sleep disorders

centers in the
United States/
pharnaceutical

industry

136/120/43.1/
41.9% male

NA 3 g, 6 g, 9 g/half at bedtime,
the other half 2.5 – 4 hrs later;

dose was started after an
extended washout period of

other anticataplectic drugs (as
long as 6 weeks)

The 9 g dose reduced the # of
cataplexy attacks compared
to placebo. CGI exhibited

change from baseline at 9 g
dose. Inadvertent naps/sleep

attacks reduced at both 6 g and
9 g doses. 9 g dose decreased

nocturnal awakenings.

Sodium oxybate is an effective and safe treatment
for EDS associated with narcolepsy, particularly at

the 9 g dose.

Van der Meche
(1994); 4;
Myotonic
Dystrophy.

Methylphenidate/NA EDS (subj)
using a

“standard
questionnaire”

This unblinded study
evaluated if EDS in

MD is caused by OSA,
and if not whether or
not methylphenidate

would reduce the
hypersomnia/case
series/No Blinding

Expert assigned
or selected groups

/Netherlands

22/median age for
males 36, females
50 [16-67]/63.6%

male

NA 10 mg/10 mg daily increased
to 10-20 mg BID

Methylphenidate produced
increased daytime alertness

in 7 of 11 patients/3 of the 17
patients tested had OSA.

Methylphenidate is effective in reducing
hypersomnia associated with Myotonic Distrophy.

Weaver (2006);
1; N, C.

Sodium Oxybate
/Placebo

Mood/Quality
of Life

Randomized, double
blind, placebo-

controlled parallel-
group clinical trial

of 285 patients with
narcolepsy treated with

sodium oxybate (4.5
to 9 g/day in divided
doses) for 4 weeks

following withdrawl
of their baseline anti-

cataplexy medications.
The effect on quality of
life was assessed with
Functional Outcomes

of Sleep Questionnaire
(FOSQ)./Randomized
Control Trial/Double-

Blind Testing

Outpatient facility
of 42 sleep centers

in the United States,
Canada, and Europe/

Pharmaceutical/
Expert-Assigned or

Selected Grps

217
randomnized/181
intent to treat/4.5

g/day 41.8+/-
16.7/32.8; 6 g/day
39.2+/- 15.9/37.9;

9 g/day 39.9+/-
12.5/34.6

68 randomized/47
intent to treat/Placebo

40.8+/- 15.5/28.8

4.5, 6 or 9 g/day in divided
doses. First dose QHS, second
dose 2.5 to 4 hours later./The

first 14 days was a lead in
period, followed by a 21 day

withdrawl from anticataplectic
therapy, then a 5 to 18 day

washout period, concluding
with randomization to the

2 treatment arms and doses
of 4.5, 6 or 9 g/day of

sodium oxybate. Participants
randomized to sodium oxybate
all received 7 days of the 4.5
g dose, followed by titration
to their final dose according

to the randomization scheme.
Participants on active

treatment were on study
medication for at least 7 days
before proceeding to the next

dose

When compared to
placebo, the 9 g/day group

demonstrated improvement in
all components of the FOSQ

except the intimacy and sexual
relationships scale. The 6g/day

dose demonstrated improvement
in 2 of 5 subscales. A dose

effect was evident for the total
score and all FOSQ subscales
except the intimacy and sexual
relationships scale. There was
no significant change at the 4.5

g/day dose.

Compared with placebo-treated patients,
participants treated with doses of sodium oxybate

of 6 g/day and 9g/day experienced significant
improvements in functional status as measured by

the FOSQ.

SLEEP, Vol. 30, No. 12, 2007 S9

Author (yr);
Oxford
Grade; Patient
Group.
Intervention/
Comparison
Intervention
Outcomes
Measures
Study Description/
Study type/Blinding
Method
Recruitment
Source/ Funding
Source/
Recruitment
# patients
enrolled/
completed/
Patients’ Age
+ SD [range]/
%male
# controls enrolled/
completed/Controls’
Age + SD [range]/
%male
Dose/Dosing Strategy Primary Study Outcomes Conclusions

Zifko (2002);
4; MS.

Modafinil/NA EDS (subj),
QOL, AE

using ESS,
Fatigue
Severity

Scale, clinical
outcome

rating, and
patient self-
appraisal in

fatigue

This unblinded
study assessed the

tolerability, optimal
dose, and efficacy of
modafinil in patients

with multiple sclerosis
and fatigue and

EDS/cohort study/No
Blinding

Expert assigned
or selected gropus

from 2 centers
specializing in MS/
governent sources,

pharmaceutical
industry

50/47/40.4 +/-
10.3/40% male

NA 50 – 300 mg daily/started at
100 mg daily and increased

to 200 mg or 300 mg daily as
needed. Maximum doses were

achieved in 4 weeks or less

Both the Fatigue Severity Scale
and ESS decreased significantly

during the 3 months of study.
Both the patients’ self-reported

fatigue and the clinicians’
impression of fatigue improved.

Fatigue and sleepiness were significantly improved
by modafinil in patients with MS. The drug was

generally well-tolerated.

Abbreviations

N = Narcoplepsy

C = Cataplexy

IH = Idiopathic Hypersomnia

PD = Parkinson disease

MS = Multiple sclerosis

307 Journal of Clinical Sleep Medicine, Vol

.

13, No. 2, 2017

Introduction: The purpose of this guideline is to establish clinical practice recommendations for the pharmacologic treatment of chronic insomnia in adults,

when such treatment is clinically indicated. Unlike previous meta-analyses, which focused on broad classes of drugs, this guideline focuses on individual
drugs commonly used to treat insomnia. It includes drugs that are FDA-approved for the treatment of insomnia, as well as several drugs commonly used to
treat insomnia without an FDA indication for this condition. This guideline should be used in conjunction with other AASM guidelines on the evaluation and
treatment of chronic insomnia in adults.
Methods: The American Academy of Sleep Medicine commissioned a task force of four experts in sleep medicine. A systematic review was conducted
to identify randomized controlled trials, and the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) process was used to
assess the evidence. The task force developed recommendations and assigned strengths based on the quality of evidence, the balance of benefits and
harms, and patient values and preferences. Literature reviews are provided for those pharmacologic agents for which sufficient evidence was available to
establish recommendations. The AASM Board of Directors approved the final recommendations.
Recommendations: The following recommendations are intended as a guideline for clinicians in choosing a specific pharmacological agent for treatment
of chronic insomnia in adults, when such treatment is indicated. Under GRADE, a STRONG recommendation is one that clinicians should, under most
circumstances, follow. A WEAK recommendation reflects a lower degree of certainty in the outcome and appropriateness of the patient-care strategy for
all patients, but should not be construed as an indication of ineffectiveness. GRADE recommendation strengths do not refer to the magnitude of treatment
effects in a particular patient, but rather, to the strength of evidence in published data. Downgrading the quality of evidence for these treatments is predictable
in GRADE, due to the funding source for most pharmacological clinical trials and the attendant risk of publication bias; the relatively small number of eligible
trials for each individual agent; and the observed heterogeneity in the data. The ultimate judgment regarding propriety of any specific care must be made by
the clinician in light of the individual circumstances presented by the patient, available diagnostic tools, accessible treatment options, and resources.

1. We suggest that clinicians use suvorexant as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK)
2. We suggest that clinicians use eszopiclone as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK)
3. We suggest that clinicians use zaleplon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK)
4. We suggest that clinicians use zolpidem as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK)
5. We suggest that clinicians use triazolam as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK)
6. We suggest that clinicians use temazepam as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults. (WEAK)
7. We suggest that clinicians use ramelteon as a treatment for sleep onset insomnia (versus no treatment) in adults. (WEAK)
8. We suggest that clinicians use doxepin as a treatment for sleep maintenance insomnia (versus no treatment) in adults. (WEAK)
9. We suggest that clinicians not use trazodone as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK)

10. We suggest that clinicians not use tiagabine as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK)
11. We suggest that clinicians not use diphenhydramine as a treatment for sleep onset and sleep maintenance insomnia (versus no treatment) in adults.

(WEAK)
12. We suggest that clinicians not use melatonin as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK)
13. We suggest that clinicians not use tryptophan as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK)
14. We suggest that clinicians not use valerian as a treatment for sleep onset or sleep maintenance insomnia (versus no treatment) in adults. (WEAK)

Keywords: insomnia, treatment, pharmacologic, guideline
Citation: Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. 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;13(2):307–349.

S P E C I A L A R T I C L E S

Clinical Practice Guideline for the Pharmacologic Treatment of
Chronic Insomnia in Adults: An American Academy of Sleep Medicine
Clinical Practice Guideline
Michael J. Sateia, MD1; Daniel J. Buysse, MD2; Andrew D. Krystal, MD, MS3; David N. Neubauer, MD4; Jonathan L. Heald, MA5

1Geisel School of Medicine at Dartmouth, Hanover, NH; 2University of Pittsburgh School of Medicine, Pittsburgh, PA; 3University of California, San Francisco, San Francisco, CA;
4Johns Hopkins University School of Medicine, Baltimore, MD; 5American Academy of Sleep Medicine, Darien, IL

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308Journal of Clinical Sleep Medicine, Vol. 13, No. 2, 2017

MJ Sateia, DJ Buysse, AD Krystal, et al. Clinical Practice Guideline: Insomnia

TA B L E O F C O N T E N T S

Introduction 308
Background 309
Methodology 312
Clinical Practice Recommendations 315
Orexin receptor agonists
Suvorexant 317

Benzodiazepine receptor agonists
Eszopiclone 318
Zaleplon 321
Zolpidem 323

Benzodiazepines
Triazolam 326
Temazepam 327

Melatonin agonists
Ramelteon 329

Heterocyclics
Doxepin 331
Trazodone 332

Anticonvulsants
Tiagabine 333

Over-the-counter preparations
Diphenhydramine 334
Melatonin 335
L-tryptophan 337
Valerian 338

Literature Reviews 338
Estazolam 338
Quazepam 339
Flurazepam 340
Oxazepam 341
Quetiapine 341
Gabapentin 341
Paroxetine 341
Trimipramine 342

Discussion and Future Directions 342

I N T R O D U C T I O N

Aims
This clinical practice guideline was initiated at the request
of the Board of Directors of the American Academy of Sleep
Medicine (AASM), who also reviewed this document and
provided feedback. No formal clinical practice guidelines for
the pharmacological treatment of insomnia have previously
been issued by the AASM, despite the fact that this remains,
by far, the most common approach to therapy, after treatment
of comorbidities. Pharmacotherapy is one of two major ap-
proaches to treatment, the alternative being cognitive behav-
ioral therapies for insomnia (CBT-I), already identified as a
standard of treatment. This paper does not directly address the
relative benefits of these two approaches. Rather, the conclu-
sions and recommendations regarding pharmacotherapy must
be considered within the context of specific treatment goals,
comorbidities, prior treatment responses, availability, safety,
patient preference and cost considerations. Despite the clearly

favorable benefit to risk ratio of CBT-I, not all patients with an
insomnia disorder can and will derive benefit from this treat-
ment alone. This failure may result from inability to access
such treatment (due to availability, cost restraints, etc.), inabil-
ity or unwillingness to participate in the therapy, or treatment
non-responsiveness. Thus, pharmacotherapy, alone or in com-
bination with CBT-I, must continue to be considered a part of
the therapeutic armamentarium, as it currently is for perhaps
25% of the population.1 Unfortunately, many individuals use
medications or substances (e.g. over-the-counter sleep aids or
alcohol) which are not demonstrated to be effective in manag-
ing insomnia and/or have significant potential for harm. For
the estimated 3.5% to 7% of individuals receiving prescrip-
tion medication for sleep disturbance,2–4 significant knowledge
gaps and anxieties about the proper usage of these agents ex-
ists among the prescribers.

This paper includes a systematic review and meta-analyses
which provides the basis of the initial AASM clinical practice
guideline for pharmacological management of insomnia. The
aims of the present analysis are: (1) to determine the efficacy
of individual prescription and non-prescription medications
for treatment of insomnia; (2) to assess the efficacy of indi-
vidual medications for specific sleep complaints (i.e. difficulty
initiating sleep/difficulty maintaining sleep); (3) to evaluate the
potential for adverse effects of these drugs; (4) to consider the
evidence concerning efficacy and adverse effects in delineat-
ing evidence-based guidelines for the use of pharmacotherapy
in the management of chronic insomnia; and (5) to offer rec-
ommendations for optimizing quality and uniformity of future
investigations.

This clinical practice guideline is intended to serve as one
component in an ongoing assessment of the individual patient
with insomnia. As discussed elsewhere,5–7 a comprehensive
initial evaluation should include a detailed history of sleep
complaints, medical and psychiatric history, and medication/
substance use. These factors, together with patient preferences
and treatment availability, should be used to select specific
treatments for specific patients. This clinical practice guide-
line is not intended to help clinicians determine which patient
is appropriate for pharmacotherapy. Rather, it is intended to
provide recommendations regarding specific insomnia drugs
once the decision has been made to use pharmacotherapy. This
guideline is also not intended to recommend one drug over an-
other. Very few comparative efficacy studies have been con-
ducted among these agents. Rather, the guideline provides a
recommendation and evidence base for each individual drug.
The selection of a particular drug should rest on the evidence
summarized here, as well as additional patient-level factors,
such as the optimal pharmacokinetic profile, assessments of
benefits versus harms, and past treatment history.

This guideline should be used in conjunction with other
AASM guidelines on the evaluation and treatment of chronic
insomnia. These guidelines indicate that CBT-I is a standard
of treatment and that such treatment carries a significantly fa-
vorable benefit:risk ratio. Therefore, based on these guidelines,
all patients with chronic insomnia should receive CBT-I as a
primary intervention. Medications for chronic insomnia dis-
order should be considered mainly in patients who are unable Do

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to participate in CBT-I, who still have symptoms despite par-
ticipation in such treatments, or, in select cases, as a temporary
adjunct to CBT-I.

Clinical Guidelines and Practice Parameters
The AASM has issued several guidelines, reviews, and prac-
tice parameters related to the assessment and management of
insomnia. A 2000 review and practice parameter paper ad-
dressed the comprehensive evaluation of chronic insomnia.5,6
Non-pharmacological management of insomnia has been
the subject of two practice parameter papers.8–11 No formal,
evidence-based standards of practice for pharmacological
treatment of insomnia have been published, although clinical
guidelines addressing this topic have been issued by various
groups. The Standards of Practice Committee of the AASM
addressed non-prescription treatments for insomnia in a 2006
paper12 which concluded that there is sparse or little evidence to
support use of these agents for insomnia. Preliminary but con-
flicting evidence was noted for valerian and first-generation
H1 antagonists for short-term use. A 2005 National Institutes
of Health consensus conference13 on manifestations and man-
agement of chronic insomnia found moderate-to-high-grade
evidence to support the efficacy of both cognitive-behavioral
therapies and benzodiazepine agonists in the short-term man-
agement of insomnia, but noted a relative paucity of data
concerning long-term usage of such treatments, despite the
chronicity of the condition. Little evidence supporting efficacy
of other widely used treatments (sedating antidepressants and
non-prescription agents) was found.

A 2008 AASM clinical guideline paper on the evaluation
and management of chronic insomnia defined psychological
and behavioral therapies as a standard of treatment (the high-
est level of recommendation at that time).7 No specific level
of recommendation was offered for pharmacological therapies,
but the consensus recommendation was that such treatment,
when used, should be accompanied by cognitive-behavioral
therapies whenever possible. Short/intermediate acting benzo-
diazepine receptor agonists (benzodiazepines [BZDs] or newer
BZD receptor agonistic modulators [BzRAs]) or ramelteon
were recommended as first-line pharmacotherapy. Other drugs,
such as sedating antidepressants or anticonvulsant medications
were recommended as second- or third-line agents, particu-
larly when comorbidities (e.g. mood disorder or epilepsy) are
present. Other, non-prescription drugs such as over-the counter
antihistamine sleeping aids and herbal/nutritional agents were
not recommended due to lack of demonstrated efficacy as well
as safety concerns.

A consensus statement from the British Association for
Psychopharmacology14 assessed evidence related to chronic
insomnia, including management issues, and came to similar
conclusions. CBT interventions were recommended as first-
line treatment. BzRAs were found effective for short-term use,
although degradation of improvement following discontinua-
tion of hypnotic was noted to be of concern. Limited evidence
and toxicity concerns were cited for other prescription and
non-prescription agents, although prolonged-release melato-
nin was recommended as a first-line treatment for insomnia in
persons over 55 years.

In May 2016, the American College of Physicians published
its own clinical practice guideline for the management of
chronic insomnia.15 This guideline makes two major recom-
mendations. The first is that all patients with chronic insomnia
receive CBT-I as the initial treatment intervention. This is a
strong recommendation based on moderate quality evidence.
The second is that a shared decision-making approach be em-
ployed by clinicians in determining whether pharmacotherapy
should be employed for those patients who did not achieve
adequate response with CBT-I (weak recommendation based
on low quality evidence). The guideline notes that there was
insufficient evidence to draw conclusions regarding the overall
efficacy of pharmacotherapy in the insomnia population. More
specifically, there was also insufficient evidence to determine
the efficacy of benzodiazepines, trazodone and melatonin in
the management of chronic insomnia. Studies of more recent
generation sleep aids such as BzRAs, doxepin and suvorexant
found improvement in a number of sleep outcome variable but,
as is the case with our own guideline, much of the evidence
was of low quality. Although evidence is presented for indi-
vidual drugs, there were no specific recommendations made
for single agents. Finally, there was insufficient evidence found
to determine the balance of benefits versus harms.

B A C K G R O U N D

Insomnia disorder is defined in the International Classification
of Sleep Disorders, Third Edition16 as a complaint of trouble
initiating or maintaining sleep which is associated with day-
time consequences and is not attributable to environmental cir-
cumstances or inadequate opportunity to sleep. The disorder
is identified as chronic when it has persisted for at least three
months at a frequency of at least three times per week. When
the disorder meets the symptom criteria but has persisted for
less than three months, it is considered short-term insomnia.

Occasional, short-term insomnia affects 30% to 50% of the
population.17 The prevalence of chronic insomnia disorder in
industrialized nations is estimated to be at least 5% to 10%.18,19
In medically and psychiatrically ill populations, as well as in
older age groups, the prevalence is significantly higher. Chronic
insomnia is associated with numerous adverse effects on func-
tion, health, and quality of life. Epidemiologic studies dem-
onstrate marked impairment in functional status among those
with chronic insomnia.20,21 Increased rates of work absentee-
ism,22 and occupational and motor vehicle accidents have also
been widely reported.23,24 Persistent insomnia has been identi-
fied in multiple studies as a significant risk factor for the devel-
opment of psychiatric disorders, especially mood disorder.25,26
This condition is also associated with increased risk of relapse
for depression and alcoholism, as well as adverse effects in
chronic pain populations. More recent investigations suggest
that chronic insomnia is associated with increased risk for car-
diovascular disease. In particular, insomnia with objectively
short sleep time is a significant risk factor for the development
of hypertension.27,28

Chronic insomnia imposes substantial economic burdens
on society.29–31 Estimation of the direct and indirect costs Do

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of chronic insomnia are complicated by many confounding
variables, but virtually all analyses of these costs indicate
substantially higher economic burden for an insomnia popu-
lation. Direct cost analysis demonstrates significantly higher
utilization of emergency and office health care visits as well
as greater cost for prescription drugs.32 Likewise, indirect
costs in the form of work absenteeism, loss of productivity,
and insomnia-related accidents contribute significantly to
the economic burden of the disorder. In the United States, a
2009 study33 found that direct and indirect costs for insom-
nia patients were in excess of $2,000/year greater than those
of a matched non-insomnia group. Total direct and indirect
cost estimates for insomnia in the United States differ sub-
stantially due to variability in methodologies. Nevertheless,
estimates suggest direct costs of $2–16 billion per year and
indirect costs of $75–100 billion. The latter are accounted
for in large part by worker absenteeism, presenteeism (lower
productivity due to daytime impairment), and work-related
accidents.29

General treatment measures for insomnia include the
treatment of comorbid medical and psychiatric conditions,
modifying sleep-interfering medications and substances, and
optimizing the sleep environment. Specific treatments for in-
somnia fall into two primary categories. Non-pharmacological
therapies, largely cognitive behavioral in nature, have been
the subject of numerous meta-analyses and practice guide-
lines.10,34–37 Pharmacological therapy, including over-the-coun-
ter sleep aids and alcohol, is the most widely used treatment for
insomnia, yet no evidence-based clinical practice guidelines
have been published to date by the AASM. This paper includes
a systematic review and meta-analyses which provide the basis
of the initial AASM clinical practice guideline for pharmaco-
logical management of insomnia.

History of Hypnotic Usage
Pharmacological agents have been used for the treatment of in-
somnia throughout much of recorded history. Prior to the 20th
century, opioids, various herbal preparations, bromide salts,
and alcohol were the primary hypnotic alternatives. Through
the first half of the 20th century, barbiturate and related com-
pounds became the most commonly used agents for manage-
ment of anxiety and sleep disturbance, as well as epilepsy. By
mid-century, however, the adverse side effects and lethal over-
dose potential of these agents became recognized, contributing
to curtailment of use.

The first BZD, chlordiazepoxide, was introduced to the
United States market in 1963, followed shortly by diazepam.
Flurazepam, the first benzodiazepine approved by the Food
and Drug Administration (FDA) as a hypnotic, became avail-
able in 1970 and rapidly supplanted the use of barbiturates
and similar compounds for treatment of insomnia. Zolpidem,
the first United States nonbenzodiazepine, benzodiazepine
receptor agonist (non-BZD, or BzRA) hypnotic, became
available in 1992 and remains the most widely prescribed
hypnotic medication, accounting for 87.5% of all BzRA pre-
scriptions in a recent survey of hypnotic use.38 Since 2005,
a melatonin agonist (ramelteon), a low dose form of the se-
dating tricyclic medication (doxepin), and, most recently,

an orexin receptor antagonist (suvorexant) have entered the
United States market.

Current Hypnotic Usage
Hypnotic prescribing practices have varied in recent decades
as availability of various agents and safety concerns have
evolved. Despite the development of numerous BZD hypnotic
medications of varying durations of action, the overall fre-
quency of hypnotic prescriptions for insomnia declined dur-
ing the two decades from 1970–1990, from 3.5% to 2.5%.39
Due to apparent concerns regarding the potential for toler-
ance and dependency with BZD use, physicians increasingly
prescribed sedating antidepressants “off label,” especially
trazodone, despite the absence of efficacy studies for this or
any other sedating antidepressants for treatment of insomnia.
Survey of office-based physician prescribing practices for the
period 1987–1996 revealed an over 50% decline in BZD hyp-
notic prescriptions accompanied by a nearly 150% increase
in trazodone prescriptions.40 Overall prescriptions for insom-
nia declined by about 25% during this period. A more recent
study,38 utilizing the National Health and Nutrition Examina-
tion Survey (NHANES) data from 1999–2010, analyzed the
frequency of usage of medications commonly used for insom-
nia. This includes BZDs approved for treatment of insomnia,
BzRAs, ramelteon, trazodone, doxepin and quetiapine. The au-
thors report that just under 3% of the sample population used
one of these agents within the past month. In contrast to the
apparent trends of preceding decades, frequency of usage of
any medication commonly used for insomnia increased over
the decade, from 2.0% in the first year sampled to 3.5% in the
final year (2009–2010). BzRAs, predominantly zolpidem, were
most commonly prescribed (1.23% of the population), followed
by trazodone (0.97%), BZDs (0.4%), quetiapine (0.32%) and
doxepin. However, it should be noted in this and other studies
that other agents—especially BZDs not approved for insomnia,
other antidepressants, antipsychotics, and analgesics—are not
included in these data. It seems likely that the true prevalence
of medication use for sleep disturbance is higher than these
figures suggest. In fact, a subsample analysis of the NHANES
data from 2005–2008 found that approximately 19% of re-
spondents reported use of at least one pill or medication for
sleep in the past month. The 2005 National Sleep Foundation’s
(NSF) survey of sleep habits found that 7% of respondents re-
port using a prescription medication to improve sleep at least a
few nights per month.41

Physicians and other health care providers have consistently
expressed reservations about the use of medication, particu-
larly BZDs and BzRAs, to treat insomnia. They cite concerns
regarding safety and dependency as key issues. However, they
also note a lack of awareness and/or availability of alternative
treatments.42 Many favor an initial approach of treating asso-
ciated comorbidities and advising good sleep hygiene.43 An
ever-increasing amount of data makes it clear that the latter
approach is very often unsuccessful, leaving providers feeling
compelled to prescribe medications. Most of those surveyed
recognize the need for additional, non-pharmacological treat-
ment for their patients, but cite a number of barriers to acquir-
ing such treatment.44Do

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Data concerning use of non-prescription agents for sleep
promotion are limited. The aforementioned NSF survey re-
ported that nearly one in four respondents used some form of
sleep aid “at least several times per month.” Eleven percent
stated that they used alcohol to help sleep, 9% used over-the
counter sleep aids, and 2% used melatonin.

Previous Meta-Analyses
Several meta-analyses of pharmacotherapy for insomnia have
been conducted. Nowell and colleagues45 conducted a meta-
analysis of 22 randomized controlled trials (RCTs) of BZDs and
zolpidem for treatment of primary insomnia published from
1966 to 1996. They found moderate effect sizes (d = 0.56 to 0.71
for key sleep variables) for improvement with these agents, but
noted limitations in the duration of trials and lack of follow-up
study regarding outcome. A 2000 study commissioned by the
Canadian Medical Association46 evaluated 45 RCTs (n = 2,672)
of BZDs for treatment of primary insomnia. This investigation
found reduction in sleep latency (non-significant in objective
[polysomnography; PSG] assessment but significant in subjec-
tive reports) and a somewhat larger and significant increase in
total sleep time by both objective and subjective reports. The
authors also note an increase in adverse events with BZDs
(pooled odds ratio for any adverse event = 1.8) and call into
question the risk/benefit ratio for these agents.

A comparative evaluation of the efficacy of hypnotic drugs
was conducted by the National Centre for Clinical Excellence
of the UK.47 In summary, the analysis found little difference
among the numerous BZDs and BzRAs among the 24 studies
which directly compared more than one drug. Some small dif-
ferences were noted, such as shorter sleep latency but less total
sleep time with zaleplon when compared to zolpidem. On the
whole, major differences in adverse effects were not observed
between drugs. Meta-analyses in this report were few due to
limitations of data reporting.

Glass and colleagues48 compared benefits versus risks for
all sedative hypnotic agents in a meta-analysis of RCTs of ac-
tive agent versus placebo or other active compound in popula-
tions > 60 years of age and free of contributing comorbidities.
They reported a small effect size for improvement in sleep
quality (d = 0.14). Separate analysis of BZDs alone yielded
a somewhat more robust improvement in quality (d = 0.37).
Significant but modest increase in total sleep time (TST) and
reduction in number of awakenings (NOA) was also found for
all sedative-hypnotics and for the BZD group alone, although
effect sizes are not reported for these variables. Cognitive
side effects were more common with sedative-hypnotics. The
authors note that, with respect to the sleep quality measures
reported for all sedative hypnotics, the number needed to
treat is 13, while the number needed to harm is 6, thereby
indicating an unfavorable risk/benefit ratio for this popula-
tion. Independent analysis of this ratio for BZDs alone was
not conducted.

A 2007 meta-analysis49 evaluated 105 RCTs of BZDs, Bz-
RAs and antidepressant medications for treatment of chronic
insomnia in the adult populations regardless of comorbidi-
ties. In summary, the analysis indicates moderate and sig-
nificant improvement in major sleep parameters with both

BZDs and BzRAs in both objective (PSG) and subjective
(sleep diary) assessments, with the exception of PSG results
for wake after sleep onset (WASO) and TST, which yielded
results just below the range of significance. Far fewer stud-
ies were available for antidepressants. These showed signifi-
cant reduction in sleep latency and a non-significant trend
toward reduced WASO. Four studies utilizing PSG mea-
sures showed substantial improvement in TST (79.6 min)
while single subjective data set suggested reduction in TST
compared to placebo. The authors note substantial hetero-
geneity of data which was reduced in subgroup analyses by
type of drug. Between-groups comparisons showed no sig-
nificant efficacy differences between BZDs and non-BZDs.
All three groups demonstrated significantly higher rates of
adverse events versus placebo. BZDs exhibited a higher rate
of adverse events than BzRAs.

Huedo-Medina and colleagues50 conducted systematic re-
view and meta-analysis of data on BzRAs submitted to the
United States Food and Drug Administration from 15 studies.
They found that BzRAs produce significant reduction of sleep
latency by both objective and subjective measures with effect
sizes of 0.36 and 0.33, respectively. Other sleep variables did
not show significant differences but limited data reporting on
these variables precluded definitive conclusions.

Winkler and Doering51 analyzed data from 31 randomized
controlled trials of sleep-promoting substances used for treat-
ment of primary insomnia. Studies included BZDs, BzRAs,
melatonin agonists, antidepressants and other sedating com-
pounds. Only studies which included objective (PSG) data
were considered. The meta-analysis revealed that both BZDs
and BzRAs were significantly more effective than antide-
pressants. Both demonstrated small to moderate effect sizes
for major sleep variables. BZDs were somewhat superior to
BzRAs for subjective sleep latency (SL). No analysis of treat-
ment-emergent adverse events was reported.

Finally, Wilt and colleagues52 conducted a systematic re-
view and meta-analyses of 35 randomized, controlled trials of
at least 4 weeks duration, and harms information from 11 long-
term observational trials. Their review found that eszopiclone,
zolpidem, and suvorexant improved short-term outcomes,
with small effect sizes and low-to-moderate strength evidence.
They also found that evidence for BZDs, melatonin agonists,
and antidepressants was insufficient or of too-low strength.
Finally, they concluded that there is insufficient evidence to
determine the comparative effectiveness or long-term efficacy
of pharmacotherapies for insomnia.

In summary, these meta-analyses suggest small to moderate
effect sizes for most major sleep outcome variables with both
BZDs and BzRAs. However, some of these analyses report
significant increases in treatment-emergent adverse events and
raise concerns regarding their relative risk:benefit ratio. Data
supporting the use of sedating antidepressants in the treatment
of insomnia are scant. Overall, the studies are limited by lack
of availability of high quality evidence and considerable vari-
ability in design and methodology across investigations. All of
these analyses addressed efficacy only for major drug groups
(e.g., BZDs, BzRAs), failing to address issues of safety or ef-
ficacy for individual agents.Do

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M E T H O D O L O G Y

Expert Task Force
In order to develop this clinical practice guideline, the AASM
commissioned a task force composed of content experts in the
field of insomnia, an AASM Board of Directors liaison, and
AASM Science and Research Department staff members. Prior
to appointment, the content experts were required to disclose
all potential conflicts of interest according to the AASM’s

policy. In accordance with the AASM’s conflicts of interest
policy, task force members with a Level 1 conflict were not
allowed to participate. Task force members with a Level 2
conflict were required to recuse themselves from any related
discussion or writing responsibilities. All relevant conflicts of
interest are listed in the Disclosures section.

PICO Questions
A PICO (Patient, Population or Prob lem, Intervention, Com-
parison, and Outcomes) question template was developed to be
the focus of this guideline:

“ In adult patients diagnosed with primary chronic insomnia,
how does [intervention] improve [outcomes], compared to
placebo?”

The PICO question template was approved by the AASM
Board of Directors. The task force identified the pharmaco-
logical interventions of interest, based on FDA approval status
and common off-label usage. Based on their expertise, the task
force developed a list of patient-oriented clinically relevant
outcomes that are indicative of whether a treatment should be
recommended for clinical practice. The task force then rated
their relative importance and selected the top six outcomes.
The following outcomes were determined to be “critical” or
“important” for clinical decision making across all interven-
tions: sleep latency, wake after sleep onset, total sleep time,
quality of sleep, number of awakenings, and sleep efficiency
(Table 1). The task force then determined which outcomes
were “critical” for clinical decision making for each individual
intervention (Table 2). Lastly, clinical significance thresholds,
used to determine if a change in an outcome was clinically sig-
nificant, were defined for each outcome by task force clinical
judgement, prior to statistical analysis (Table 3). These deci-
sions were made by nominal consensus of the task force, based

Table 1—PICO question parameters.
Population Intervention Comparison Outcomes
Adult patients diagnosed with
primary chronic insomnia

1. Diphenhydramine †
2. Doxepin*
3. Eszopiclone*
4. Melatonin †
5. Ramelteon*
6. Suvorexant*
7. Temazepam*
8. Tiagabine**
9. Trazodone**

10. Triazolam*
11. Tryptophan †
12. Valerian + hops †
13. Zaleplon*
14. Zolpidem*

Placebo control Sleep latency (SL)
Total sleep time (TST)
Wake after sleep onset (WASO)
Quality of sleep (QOS)
Sleep efficiency (SE)
Number of awakenings (NOA)

* = FDA-approved, indicated for the treatment of insomnia. ** = FDA-approved, off-label usage for the treatment of insomnia. † = Over-the-counter
medication. Sleep latency is defined as the time to fall asleep following bedtime. PSG sleep latency may be reported as time to onset of first epoch of
N1 (Stage 1) sleep, or, in more recent studies, as latency to persistent sleep (LPS), or time to onset of first 10 consecutive min of sleep. Total sleep time
is defined as the total time spent in bed, minus sleep latency and wake after sleep onset. Wake after sleep onset is defined as the sum of wake times
from sleep onset to the final awakening. Quality of sleep is a patient-reported measure, the definition of which varies by measurement tools and patient
perceptions. Sleep efficiency is defined as the percentage of time spent in bed during which sleep occurs; it is calculated as (TST / time in bed) × 100.
Number of awakenings is defined as the number of awakenings after sleep onset, excluding the final awakening.

Table 2—“Critical” outcomes by intervention.
TST SL WASO QOS
Diphenhydramine    
Doxepin    
Eszopiclone    
Melatonin  
Ramelteon  
Suvorexant    
Temazepam    
Tiagabine   
Trazodone    
Triazolam  
Tryptophan   
Valerian-hops  
Zaleplon   
Zolpidem    

TST = total sleep time, SL = sleep latency, WASO = wake after sleep
onset, QOS = quality of sleep.

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on their expertise and familiarity with the literature and clini-
cal practice.

Literature Searches, Evidence Review and Data
Extraction
Multiple literature searches were performed by the AASM
research staff using the PubMed database throughout the
guideline development process (see Figure 1). Keywords and
Medical Subject Headings (MeSH) terms were:

• insomnia OR sleep initiation and maintenance disorder
NOT transient AND

• clinical trial OR randomized controlled trial
• NOT editorial, letter, comment, case reports, biography,

review

The full literature search string can be found in the supple-
mental material. Searches were performed on April 26, 2011
(search 1), May 12, 2014 (search 2), October 15, 2014 (search 3),
and January 25, 2016 (search 4). Based on their expertise and
familiarity with the insomnia literature, task force members
submitted additional relevant literature and screened reference
lists to identify articles of potential interest. This served as a

“spot check” for the literature searches to ensure that important
articles were not missed.

Abstracts from all retrieved articles were individually as-
sessed by two task force members to deter mine whether the
publication should be included or excluded from further consid-
eration in the project. Exclusion criteria can be found in Figure 1.
A total of 129 publications were approved for inclusion.

Full texts of accepted articles were reviewed and data per-
taining to GRADE53 for the outcomes of interest were extracted
into spreadsheets by AASM staff. All data pertaining to ad-
verse events were extracted into separate spreadsheets. Arti-
cles that met inclusion criteria but did not report outcomes of
interest were rejected from the final evidence base. If outcome
data were not presented in the format necessary for statistical
analysis (i.e., mean, standard deviation, and sample size), the
authors were contacted in an attempt to obtain the necessary
data. Finally, clinicaltrials.gov was used as a final resource
for attempting to obtain data necessary for completing statis-
tical analyses. If the necessary data were not available from
the publication, the author, or clinicaltrials.gov, the paper was
included in the evidence base as supporting evidence, but was

not used for statistical analysis or for determining quality of
evidence. Of the 129 accepted publications, 46 were included
in the statistical and meta-analysis.

For some drugs, none of the accepted publications provided
data that could be used for statistical analysis. In these cases,
the task force did not make a recommendation, but provided a
literature review of these accepted papers instead. These pub-
lications are not included in Figure 1.

Statistical and Meta-Analysis
For outcomes of interest, data from baseline and last-treatment
time points were used for all statistical and meta-analyses.
Data from crossover trials were treated as parallel groups.
Change-from-baseline values were also used for statistical
and meta-analyses, when the change-from-baseline standard
deviation was provided or could be calculated from the pro-
vided statistic. Standardized mean difference (SMD) was used
for meta-analyses of quality of sleep (QOS) when data were
reported using variable scales. Analyses were limited to FDA-
approved doses. For adverse events, all data presented in the
accepted papers were used for statistical and meta-analysis. All
calculations and meta-analyses were performed using Review
Manager 5.3 software. Whenever possible, meta-analyses were

Figure 1—Evidence base flow diagram.

Table 3—Clinical significance threshold.
Measurement Tool a

Outcome Polysomnography Actigraphy Subjective
Sleep latency (SL), min 10 10 20
Total sleep time (TST), min 20 20 30
Wake after sleep onset (WASO), min 20 20 30
Quality of sleep (QOS), varies b Varies Varies Varies
Sleep efficiency (SE), % 5 5 10
Number of awakenings (NOA), n 2 2 0.5

a Clinical significance was judged to be present when a specific agent led to a mean change in the outcome of this magnitude, compared to placebo.
b For standardized mean difference (SMD), an effect size of 0.5 is considered clinically significance (based on Cohen’s d).

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performed by pooling data across studies for each outcome and
adverse event. The evidence was grouped for analysis based on
the drug, dosage, clinical outcome of interest, and methodol-
ogy used to obtain the data (e.g., data obtained by PSG were
analyzed separately from data obtained by sleep diary).

All meta-analyses were performed as per-treatment analyses
using the random effects model. For most interventions, abso-
lute effects of drug treatments are represented by the mean dif-
ference (MD) ± standard deviation (SD) of post-treatment drug
versus post-treatment placebo. Meta-analyses for adverse events
are presented as risk difference. The result of each meta-analysis
is displayed as a forest plot. Pooled results are expressed as the
total number of patients, MD and 95% confidence interval (CI)
between the experimental treatment and placebo.

Interpretation of clinical significance for outcomes of inter-
est was conducted by comparing the absolute effects of drug
treatment to the clinical significance threshold previously de-
termined by the task force for each outcome of interest. Inter-
pretation of adverse events was based upon the risk difference
and clinical expertise of the task force.

Strength of Recommendations
The GRADE approach (Grades of Recommendation, Assess-
ment, Development and Evaluation) was used for the assess-
ment of quality of evidence. For details on how the AASM
uses GRADE to develop its clinical practice guidelines, refer
to Morgenthaler et al.53 The task force assessed the following
three components to determine the direction and strength of
a recommendation: quality of evidence, balance of beneficial
and harmful effects, and patient values and preferences.

For the determination of the quality of evidence for an inter-
vention, the task force used objective data whenever possible
(e.g., PSG). When only subjective data were available (e.g.,
sleep diaries), this evidence was used to determine the over-
all quality of evidence. The decision to use objective data as
the primary determinant of quality of evidence was based on
the preference for an objective measure of physiologic changes
for determining clinically significant efficacy, the standard-
ization of sleep parameter measurements and reporting, and
the current requirements of PSG data for FDA approval of
hypnotic medications. The results of this assessment are pre-
sented as summary of findings tables for each intervention (see
Tables S1–S24 in the supplemental material).

The task force developed recommendation statements con-
sistent with GRADE methodology based on the balance of the
following factors:

1. Quality of evidence. Quality of evidence was based
exclusively on the studies that could be included
in meta-analyses. The task force determined their
overall confidence that the estimated effect found in
the literature was representative of the true treatment
effect that patients would see, based on the following
criteria: overall risk of bias (randomization, blinding,
allocation concealment, selective reporting, and
author disclosures); imprecision (when 95% CI cross
the clinical significance thresholds); inconsistency (I2
cutoff of 75%); indirectness (study population); and
risk of publication bias (funding sources). The task

force also considered the consistency of the supporting
evidence (i.e. data the met inclusion criteria, but could
not be included in the meta-analyses). However such
evidence did not impact judgments regarding the
quality of evidence or final recommendations.

2. Benefits versus harms. The task force determined if the
beneficial outcomes of the intervention outweighed any
harmful side effects based on the following criteria:
meta-analysis (if applicable); analysis of any harms/
side effects reported within the accepted literature; and
the clinical expertise of the task force.

3. Patient values and preferences. The task force
determined if patient values and preferences would
be generally consistent, and if patients would use the
intervention based on the body of evidence reviewed.
These judgments were based on the clinical expertise
of the task force members and any data published on
the topic relevant to patient preferences.

Taking these major factors into consideration, and adhering to
GRADE recommendations, the task force assigned a direction
(for or against) and strength (STRONG or WEAK) for each
recommendation statement.

Additional information is provided in the form of “Remarks”
immediately following the recommendation statements, when
deemed necessary by the task force. Remarks are based on the
evidence evaluated during the systematic review, and are in-
tended to provide context for the recommendations.

Approval and Interpretation of Recommendations
A draft of the guideline was made available for public comment
for a two-week period on the AASM website. The task force took
into consideration all the comments received and made revisions
when appropriate. Based on recommendations from public com-
ments, the task force decided to include data from clinicaltrials.
gov, which allowed the development of a recommendation for the
use of suvorexant. Due to a conflict of interest, Andrew Krys-
tal did not participate in the development of the suvorexant rec-
ommendation. The final guideline was submitted to the AASM
Board of Directors who approved these recommendations.

The recommendations in this guideline define principles of
practice that should meet the needs of most adult patients, when
pharmacologic treatment of chronic insomnia is indicated. This
guideline should not, however, be considered inclusive of all
proper methods of care or exclusive of other methods of care
reasonably used to obtain the same results. A STRONG rec-
ommendation is one that clinicians should, under most circum-
stances, always be following when pharmacological treatment
is indicated (i.e., something that might qualify as a quality
measure). A WEAK recommendation reflects a lower degree
of certainty in the appropriateness of the patient-care strategy
and requires that the clinician use his/her clinical knowledge
and experience, and refer to the individual patient’s values and
preferences to determine the best course of action. The ultimate
judgment regarding propriety of any specific care must be made
by the clinician, in light of the individual circumstances pre-
sented by the patient, available diagnostic tools, accessible treat-
ment options and resources, as well as safety considerations.Do

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of findings tables are presented in the supplemental material. A
summary of the recommendations and GRADE determinations
is presented in Table 4. A summary of the recommendations,

“critical” outcomes, and side effects is presented in Table 5.
It is essential that the recommendations which follow be

interpreted within the appropriate context of clinical prac-
tice. Readers will note that all specific recommendations fall
within the “weak” (for or against) classification of the GRADE
system. This should not be construed to mean that no sleep-
promoting medications are clearly efficacious or indicated
in the treatment of chronic insomnia. Hypnotic medications,
along with management of comorbidities and non-pharmaco-
logical interventions such as CBT, are an important therapeutic

The AASM expects this guideline to have an impact on
professional behavior, patient outcomes, and, possibly, health
care costs. This clinical practice guideline reflects the state of
knowledge at the time of publication and will be reviewed and
updated as new information becomes available.

C L I N I C A L P R A C T I C E R E C O M M E N D AT I O N S

The following clinical practice recommendations are based on
the systematic review and evaluation of evidence following the
GRADE methodology. Remarks are intended to provide con-
text for the recommendations. All meta-analyses and summary

Table 4—Summary of clinical practice recommendations and GRADE components of decision-making.

Treatment

Recommendation

Direction and
Strength of

Recommendation

Quality
of

Evidence

Benefits
and Harms

Assessment
Patients’ Values and Preferences
Assessment

Orexin receptor agonists

Suvorexant
This recommendation is based on trials of 10, 15/20,
and 20 mg doses of suvorexant.

We suggest that clinicians use suvorexant as a
treatment for sleep maintenance insomnia (versus no
treatment) in adults.

WEAK Low
Benefits

outweigh

harms

The majority of patients would use this
treatment (over no treatment), but many
would not.

BZD receptor agonists

Eszopiclone
This recommendation is based on trials of 2 mg and
3 mg doses of eszopiclone.

We suggest that clinicians use eszopiclone as a
treatment for sleep onset and sleep maintenance
insomnia (versus no treatment) in adults.

WEAK Very low
Benefits

outweigh

harms
The majority of patients would use this
treatment (over no treatment), but many
would not.

Zaleplon
This recommendation is based on trials of 10 mg
doses of zaleplon.

We suggest that clinicians use zaleplon as a
treatment for sleep onset insomnia (versus no
treatment) in adults.

WEAK Low
Benefits
outweigh
harms
The majority of patients would use this
treatment (over no treatment), but many
would not.

Zolpidem
This recommendation is based on trials of 10 mg
doses of zolpidem.

We suggest that clinicians use zolpidem as a
treatment for sleep onset and sleep maintenance
insomnia (versus no treatment) in adults.

WEAK Very low
Benefits
outweigh
harms
The majority of patients would use this
treatment (over no treatment), but many
would not.

Benzodiazepines

Triazolam
This recommendation is based on trials of 0.25 mg
doses of triazolam.

We suggest that clinicians use triazolam as a
treatment for sleep onset insomnia (versus no
treatment) in adults.

WEAK High
Benefits

approx equal
to harms

The majority of patients would use this
treatment (over no treatment), but many
would not.

Temazepam
This recommendation is based on trials of 15 mg
doses of temazepam.

We suggest that clinicians use temazepam as a
treatment for sleep onset and sleep maintenance
insomnia (versus no treatment) in adults.

WEAK Moderate
Benefits
outweigh

harms
The majority of patients would use this
treatment (over no treatment), but many
would not.

Melatonin agonists

Ramelteon
This recommendation is based on trials of 8 mg
doses of ramelteon.

We suggest that clinicians use ramelteon as a
treatment for sleep onset insomnia (versus no
treatment) in adults.

WEAK Very low
Benefits
outweigh
harms
The majority of patients would use this
treatment (over no treatment), but many
would not.

Heterocyclics

Doxepin
This recommendation is based on trials of 3 mg and
6 mg doses of doxepin.

We suggest that clinicians use doxepin as a treatment
for sleep maintenance insomnia (versus no treatment)
in adults.

WEAK Low
Benefits
outweigh
harms
The majority of patients would use this
treatment (over no treatment), but many
would not.

Trazodone
This recommendation is based on trials of 50 mg
doses of trazodone.

We suggest that clinicians not use trazodone as
a treatment for sleep onset or sleep maintenance
insomnia (versus no treatment) in adults.

WEAK Moderate
Harms

outweigh
benefits

The majority of patients would use this
treatment (over no treatment), but many
would not.

Anticonvulsants

Tiagabine
This recommendation is based on trials of 4 mg
doses of tiagabine.

We suggest that clinicians not use tiagabine as a
treatment for sleep onset or sleep maintenance
insomnia (versus no treatment) in adults.

WEAK Very low
Harms

outweigh
benefits

The majority of patients would not use
this treatment (over no treatment), but
many would.

Over-the-counter preparations

Diphenhydramine
This recommendation is based on trials of 50 mg
doses of diphenhydramine.

We suggest that clinicians not use diphenhydramine
as a treatment for sleep onset and sleep maintenance
insomnia (versus no treatment) in adults.

WEAK Low
Benefits
approx equal
to harms
The majority of patients would not use
this treatment (over no treatment), but
many would.

Melatonin
This recommendation is based on trials of 2 mg
doses of melatonin.

We suggest that clinicians not use melatonin as
a treatment for sleep onset or sleep maintenance
insomnia (versus no treatment) in adults.

WEAK Very low
Benefits
approx equal
to harms
The majority of patients would use this
treatment (over no treatment), but many
would not.

L-tryptophan
This recommendation is based on trials of 250 mg
doses of tryptophan.

We suggest that clinicians not use tryptophan as
a treatment for sleep onset or sleep maintenance
insomnia (versus no treatment) in adults.

WEAK High
Harms

outweigh
benefits
The majority of patients would use this
treatment (over no treatment), but many
would not.

Valerian
This recommendation is based on trials of variable
dosages of valerian and valerian-hops combination.

We suggest that clinicians not use valerian as a
treatment for sleep onset or sleep maintenance
insomnia (versus no treatment) in adults.

WEAK Low
Benefits
approx equal
to harms
The majority of patients would not use
this treatment (over no treatment), but
many would.

approx = approximately.

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Table 5—Summary of “critical” outcomes by indication.
Recommended for Treating Sleep Onset Insomnia

Eszopiclone
Sleep latency: Mean reduction was 14 min greater, compared to placebo (95% CI: 3 to 24 min reduction); Quality of sleep*: Moderate-to-Large a
improvement in quality of sleep, compared to placebo; Side effects: See Recommendation 2, “Harms”
This recommendation is based on trials of 2 mg and 3 mg doses of eszopiclone.

Ramelteon
Sleep latency: Mean reduction was 9 min greater, compared to placebo (95% CI: 6 to 12 min reduction); Quality of sleep*: No improvement b in
quality of sleep, compared to placebo; Side effects: See Recommendation 7, “Harms”
This recommendation is based on trials of 8 mg doses of ramelteon.

Temazepam
Sleep latency: Mean reduction was 37 min greater, compared to placebo (95% CI: 21 to 53 min reduction); Quality of sleep*: Small a improvement
in quality of sleep, compared to placebo; Side effects: See Recommendation 6, “Harms”
This recommendation is based on trials of 15 mg doses of temazepam.

Triazolam
Sleep latency*: Mean reduction was 9 min greater, compared to placebo (95% CI: 4 to 22 min reduction); Quality of sleep*: Moderate c improvement
in quality of sleep, compared to placebo; Side effects: See Recommendation 5, “Harms”
This recommendation is based on trials of 0.25 mg doses of triazolam.

Zaleplon
Sleep latency: Mean reduction was 10 min greater, compared to placebo (95% CI: 0 to 19 min reduction); Quality of sleep*: No improvement b in
quality of sleep, compared to placebo; Side effects: See Recommendation 3, “Harms”
This recommendation is based on trials of 5 mg and 10 mg doses of zaleplon.

Zolpidem
Sleep latency: Mean reduction was 5–12 min greater, compared to placebo (95% CI: 0 to 19 min reduction); Quality of sleep*: Moderate a
improvement in quality of sleep, compared to placebo; Side effects: See Recommendation 4, “Harms”
This recommendation is based on trials of 10 mg doses of zolpidem.

Recommended for Treating Sleep Maintenance Insomnia

Doxepin
Total sleep time: Mean improvement was 26–32 min longer, compared to placebo (95% CI: 18 to 40 min improvement); Wake after sleep onset:
Mean reduction was 22–23 min greater, compared to placebo (95% CI: 14 to 30 min reduction); Quality of sleep*: Small-to-moderate a improvement
in quality of sleep, compared to placebo; Side effects: See Recommendation 8, “Harms”
This recommendation is based on trials of 3 mg and 6 mg doses of doxepin.

Eszopiclone
Total sleep time: Mean improvement was 28–57 min longer, compared to placebo (95% CI: 18 to 76 min improvement); Wake after sleep onset:
Mean reduction was 10–14 min greater, compared to placebo (95% CI: 2 to 18 min reduction); Quality of sleep*: Moderate-to-Large a improvement in
quality of sleep, compared to placebo; Side effects: See Recommendation 2, “Harms”
This recommendation is based on trials of 2 mg and 3 mg doses of eszopiclone.

Temazepam
Total sleep time: Mean improvement was 99 min longer, compared to placebo (95% CI: 63 to 135 min improvement); Wake after sleep onset: Not
reported; Quality of sleep*: Small a improvement in quality of sleep, compared to placebo; Side effects: See Recommendation 6, “Harms”
This recommendation is based on trials of 15 mg doses of temazepam.

Suvorexant
Total sleep time: Mean improvement was 10 min longer, compared to placebo (95% CI: 2 to 19 min improvement); Wake after sleep onset:
Mean reduction was 16–28 min greater, compared to placebo (95% CI: 7 to 43 min reduction); Quality of sleep*: Not reported; Side effects: See
Recommendation 1, “Harms”
This recommendation is based on trials of 10, 15/20, and 20 mg doses of suvorexant.

Zolpidem
Total sleep time: Mean improvement was 29 min. longer, compared to placebo (95% CI: 11 to 47 min. improvement); Wake after sleep onset: Mean
reduction was 25 min greater, compared to placebo (95% CI: 18 to 33 min reduction); Quality of sleep*: Moderate a improvement in quality of sleep,
compared to placebo; Side effects: See Recommendation 4, “Harms”
This recommendation is based on trials of 10 mg doses of zolpidem.

Not Recommended for Treating either Sleep Onset or Sleep Maintenance Insomnia

Diphenhydra mine
Sleep latency: Mean reduction was 8 min greater, compared to placebo (95% CI: 2 min increase to 17 min reduction); Total sleep time: Mean
improvement was 12 min longer, compared to placebo (95% CI: 13 min reduction to 38 min improvement); Quality of sleep*: No improvement a in
quality of sleep, compared to placebo; Side effects: See Recommendation 11, “Harms”
This recommendation is based on trials of 50 mg doses of diphenhydramine.

Melatonin
Sleep latency: Mean reduction was 9 min greater, compared to placebo (95% CI: 2 to 15 min reduction); Quality of sleep*: Small a improvement in
quality of sleep, compared to placebo; Side effects: See Recommendation 12, “Harms”
This recommendation is based on trials of 2 mg doses of melatonin.

Tiagabine
Total sleep time: Mean improvement was 1–7 min longer, compared to placebo (95% CI: 7 min reduction to 15 min improvement); Wake after sleep
onset: Mean reduction was 1–9 min greater, compared to placebo (95% CI: 6 min increase to 25 min reduction); Quality of sleep*: No-to-Small a
improvement in quality of sleep, compared to placebo; Side effects: See Recommendation 10, “Harms”
This recommendation is based on trials of 4 mg doses of tiagabine.

Trazodone
Sleep latency*: Mean reduction was 10 min greater, compared to placebo (95% CI: 9 to 11 min reduction); Wake after sleep onset: Mean reduction
was 8 min greater, compared to placebo (95% CI: 7 to 9 min reduction); Quality of sleep*: No improvement d in quality of sleep, compared to
placebo; Side effects: See Recommendation 9, “Harms”
This recommendation is based on trials of 50 mg doses of trazodone.

L-tryptophan
Sleep latency: Not reported; Wake after sleep onset*: Mean reduction was 10 min greater, compared to placebo (95% CI: 4 to 15 min reduction);
Quality of sleep*: Small e improvement in quality of sleep, compared to placebo; Side effects: see Recommendation 13, “Harms”
This recommendation is based on trials of 250 mg doses of tryptophan.

Valerian
Sleep latency: Mean reduction was 9 min greater, compared to placebo (95% CI: 0 to 18 min reduction); Quality of sleep*: Not reported;
Side effects: See Recommendation 14, “Harms”
This recommendation is based on trials of variable dosages of valerian and valerian-hops combination.

Drugs are listed alphabetically. All reported measures are based on polysomnographic data, unless otherwise noted. *Based on subjective reporting. a Based
on Cohen’s d: 0.2 = small effect; 0.5 = moderate effect; 0.8 = large effect. b Based on a 7-point Likert scale (1 = excellent, 7 = very poor). c Based on a 4-point
scale (1 = good, 4 = poor). d Based on a 4-point scale (1 = excellent, 4 = poor). e Based on a 3-point scale (sleep quality index: 1 = low, 3 = high).

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option for chronic insomnia. The strength of recommendations
within the GRADE system are driven by the degree of confi-
dence in a variety of factors related to the intervention includ-
ing (1) the availability of specific data regarding efficacy; (2)
the quality of that data, and (3) other considerations such as
potential risks, impact of treatment, patient values and prefer-
ences, and perceived burden of treatment.

The existing data regarding sleep-promoting medications
imposes limits on the degree of confidence as a result of sev-
eral factors. These include: (1) a high degree of variability in
the statistical information presented. Many studies, especially
older studies, do not present results that meet the criteria for
meta-analysis within GRADE and are, by necessity, excluded
from formal analysis; (2) a significant degree of variability in
sleep outcomes within and across studies. Such variability
produces a “downgrading” of the quality of evidence within
GRADE; (3) industry sponsorship. Very few clinical trials with
adequate sample size have been sponsored by agencies outside
of industry. As a result, the quality of evidence for a vast ma-
jority of available data is downgraded due to potential publi-
cation bias associated with such sponsorship; (4) a paucity of
systematic data collection and analysis of treatment-emergent
adverse events. Absent such information, it is difficult to as-
sign a high degree of confidence to estimations of benefit:risk
ratio; and (5) absence of outcome data (such as functional sta-
tus or prevention of complications of chronic insomnia) that
would inform judgments regarding the impact of therapy.

The strength (or weakness) of these recommendations
speaks as much, or more, to the limitations of the data as it
does to the relative benefits and risks of the treatments per se.
Clinicians must continue to exercise appropriate judgement,
based not only on the recommendations presented herein, but
also on individual patient characteristics, comorbidities, and
patient preferences in the prescribing of sleep-promoting med-
ications and general management of chronic insomnia.

Finally, the literature review, meta-analyses, and recom-
mendations are based only on FDA-approved doses. This
should not be interpreted as a recommendation for the use of
a specific dose in clinical practice. Numerous factors, includ-
ing, but not limited to, age, sex, comorbidities, and concurrent
use of other medications may affect dosage recommendations.
Clinical judgment is necessary in determining appropriate
dosage, on a patient-by-patient basis.

Orexin receptor agonists

Suvorexant for the Treatment of Chronic Insomnia

Recommendation 1: We suggest that clinicians use
suvorexant as a treatment for sleep maintenance insomnia
(versus no treatment) in adults. [WEAK]

Remarks: This recommendation is based on trials of 10,
15/20, and 20 mg doses of suvorexant.

Summary
Two RCTs54,55 evaluated suvorexant for treatment of chronic
primary insomnia. The statistical analyses and recommen-
dation are based on data available on clinicaltrials.gov. The

overall quality of evidence was low due to imprecision and
risk of publication bias. The overall evidence for suvorexant
was weakly in favor of its effectiveness for the treatment of
sleep maintenance insomnia only. Objective reports of wake
after sleep onset (PSG) showed clinically significant reduction
at both 10 mg and 20 mg dosages. Subjective TST data dem-
onstrated improvement, but failed to meet clinical significance.
Objective reports (PSG) at the 10 mg and 15/20 mg dosages
showed minimal improvements in sleep latency that failed to
meet clinical significance. However objective reports (PSG) at
20 mg dose did show clinically significant reduction in sleep
latency, suggesting that suvorexant may improve sleep onset at
higher dosages. PSG sleep efficiency (SE) results demonstrate
improvements that are near or above the level for clinical sig-
nificance. PSG number of awakenings (NOA) was not statisti-
cally significantly reduced or increased in either study. Finally,
sleep quality ratings showed minimal change.

Adverse events were assessed in both studies. Overall fre-
quency of adverse events was not significantly increased ver-
sus placebo. There was no evidence of daytime residual or
withdrawal symptoms. Therefore the task force judged the
overall benefits to outweigh the potential harms. Based on their
clinical judgement, the task force determined that the majority
of patients would use suvorexant over no treatment.

See Tables S1–S3 in the supplemental material.

Discussion
Two RCTs54,55 evaluated suvorexant for treatment of chronic
primary insomnia. However, data were not presented in a way
that could be used for statistical analyses; therefore the statisti-
cal analyses and recommendation are based on data available
on clinicaltrials.gov. Additional outcomes data from Herring
2012 and 2016 are discussed below as supporting evidence.

Herring 201255 evaluated adults 18–64 years of age with
DSM-IV primary insomnia in a randomized placebo-con-
trolled crossover study which included two 4-week trial pe-
riods. Sixty-two subjects received 10 mg suvorexant and 61
received 20 mg. Subjects underwent PSG at the end of week
4. Sleep diary data were also obtained. The primary endpoint
was sleep efficiency; secondary endpoints included latency to
persistent sleep and wake after sleep onset. Inclusion criteria
were LPS > 20 min and WASO > 60 min.

Herring 201654 conducted two randomized placebo-con-
trolled parallel trials of 3 months each (i.e. trial 1 and trial 2).
Only data from trial 1 were available for statistical analyses.
Adults 18- to 64-years-old and adults > 65 with primary in-
somnia were included. Two-hundred fifty four and 239 patients
were randomized to suvorexant 15/20 mg in the two trials, re-
spectively. The dosages of interest for this analysis were 20
mg for younger adults and 15 mg for older adults. Data for
the two dosages were pooled for analysis. Inclusion criteria
were LPS > 20 min and WASO > 60 min. Sleep diary data was
collected for all patients and a subset underwent PSG. Both
studies reported data as difference between placebo and drug
change from baseline.

Sleep latency: Herring 201255 found a reduction of 2.3 min
(95% CI: 13.68 min lower to 9.08 min higher) for suvorexant Do

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10 mg when compared to placebo (not considered clinically
significant). The quality of evidence was low due to impre-
cision and potential publication bias. At the 20 mg dosage, a
clinically significant reduction versus placebo of 22.3 min was
reported (95% CI: 33.77 to 10.83 min lower). The quality of
evidence was MODERATE due to potential publication bias.
LPS in the first trial of Herring 201654 showed reductions of
8.1 min (95% CI: 13.85 to 2.35 min lower), and failed to meet
clinical significance. The quality of evidence was low due to
imprecision and potential publication bias. LPS in the second
trial of Herring 2016 was not available for statistical analyses.
However, published data show a reduction of 0.3 min, which
also fails to meet the clinical significance threshold.

Subjective latency, reported as TSO in Herring 201654 trial 1,
showed reductions at the pooled 15/20 mg dosages (−5.2 min;
95% CI: 0.3 to 10.1 min lower) that failed to meet the clini-
cal significance threshold. The quality of evidence was mod-
erate due to potential publication bias. Herring 201654 trial 2
reported reductions in TSO of 7.6 min, while TSO reported
in the Herring 201255 study was reduced at both dosages (−3.0
min and −4.3 min at 10 mg and 20 mg, respectively); none of
these changes met the clinical significance threshold.

total Sleep time: Herring 2016, trial 1, reported improve-
ments in subjectively reported total sleep time of 10.6 min with
15/20 mg dosages (95% CI: 1.79 to 19.41 min higher), which
did not meet the clinical significance threshold. The quality
of evidence for this outcome was moderate based on potential
publication bias.

PSG TST was reported only in the Herring 201255 inves-
tigation. At both 10 mg and 20 mg, clinically significant im-
provement was seen versus placebo (+22.3 min and +49.9 min,
respectively).

Neither suvorexant 10 mg (+5.5 min) nor 20 mg (−1.8 min)
produced statistically or clinically significant improvement in
subjective TST versus placebo at 4 weeks (Herring 2012). In
trial 2 of the 15/20 mg dosages (Herring 201654), subjective
TST was improved (+22.1 min), although the mean change falls
below the clinical significance threshold.

Wake after Sleep onSet: Both studies reported PSG
WASO. Herring 201255 found clinically significant reduction of
WASO at both 10 mg and 20 mg (−21.4 min; 95% CI: 6.66 to
36.34 min lower; −28.1 min; 95% CI: 13.13 to 43.07 min lower,
respectively). The quality of evidence was low due to impre-
cision and potential publication bias. Herring 2016,54 trial 1,
reported reductions of −16.6 min (95% CI: 8.33 to 24.87 min
lower) with low quality of evidence due to imprecision and po-
tential publication bias. Herring 201654 trial 2 reported a 31.1 min
reduction in WASO. Reductions of subjective WASO in the two
trials of 15/20 mg suvorexant in the Herring 201654 study did not
meet clinical significance thresholds (−2.4 min and −7.7 min).

Quality of Sleep: Sleep quality reductions were not statis-
tically significant in either study.

Sleep efficiency: Herring 201255 found PSG SE improve-
ment of +4.7% (95% CI: 0.97 to 8.43% higher) for 10 mg and

+10.4% (95% CI: 13.13 to 43.07 min lower) for 20 mg, with low
and moderate quality of evidence due to imprecision and po-
tential publication bias. These values approximate (10 mg) or
exceed (20 mg) the clinical significance threshold of 5%.

number of aWakeningS: Number of awakenings showed
no significant reduction in either study.

overall Quality of evidence: The overall quality of
evidence for these studies was low due to imprecision and po-
tential publication bias.

HarmS: Neither study found a significant increase in one
or more adverse events versus placebo for suvorexant in the
10–20 mg range. Rates of serious adverse events were negli-
gible and not significantly different between suvorexant and
placebo. Frequency of daytime somnolence was increased in
the 15/20 mg doses (Herring 201255: placebo 0.4%; 20 mg 4.9%.
Herring 201654: placebo = 3.4%; 15/20 mg = 5.1% [trial 1]; pla-
cebo = 3.1%; 15/20 mg = 8.4%). The degree of somnolence was
reported to be typically mild to moderate and did not often
result in discontinuation. Frequency of somnolence was noted
to increase significantly in dose-dependent fashion at dosages
exceeding FDA-recommended levels.

Assessments of withdrawal symptoms and daytime perfor-
mance decrements did not reveal clinically significant findings
in either domain. There was no evidence of the emergence of
narcolepsy symptoms.

patientS’ valueS and preferenceS: The task force de-
termined that a majority of patients would likely use suvorex-
ant compared to no treatment. This assessment reflects the task
force’s clinical judgment, based on suvorexant’s efficacy for
reduction of WASO and improvement in TST and SE and its
relatively benign side effect profile.

BZD receptor agonists

Eszopiclone for the Treatment of Chronic Insomnia

Recommendation 2: We suggest that clinicians use
eszopiclone as a treatment for sleep onset and sleep
maintenance insomnia (versus no treatment) in adults.
[WEAK]

Remarks: This recommendation is based on trials of 2 mg
and 3 mg doses of eszopiclone.

Summary
Six RCTs evaluated eszopiclone 2 mg for the treatment of
chronic primary insomnia.56–61 The overall quality of evidence
was downgraded to low due to imprecision and risk of publica-
tion bias. The evidence for eszopiclone 2 mg was weakly in
favor of its efficacy for improving sleep onset disturbance and
total sleep time. Meta-analysis data from three studies which
reported objective sleep latency showed a clinically significant
mean reduction in PSG sleep latency.58,60,61 Four studies which
evaluated subjective total sleep time demonstrated a significant
mean increase versus placebo.57–59,61 Assessment of PSG SE in Do

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two studies58,61 and subjective sleep quality in four studies57,59–61
revealed improvements which fell just below the threshold for
clinical significance. Measures of reduction in wake time after
sleep onset and number of awakenings revealed trends toward
improvement which fell below the defined level of clinical sig-
nificance. Meta-analysis of adverse effects, derived from all
six studies, indicated no significant differences versus placebo.

Six studies assessed the effects of eszopiclone 3 mg for
treatment of chronic primary insomnia.57,60–64 The quality of
evidence for these studies as a whole was downgraded to very
low due to significant heterogeneity, imprecision and poten-
tial publication bias. The collective evidence for eszopiclone 3
mg was weakly in favor of efficacy for improving sleep onset,
total sleep time, sleep efficiency, number of awakenings and
sleep quality. The meta-analysis data from three studies dem-
onstrated clinically significant reduction in objective sleep la-
tency.60–62 Four studies likewise revealed clinically significant
increase in mean subjective total sleep time.57,61,63,64 PSG sleep
efficiency, reported in two studies61,62 also exceeded the thresh-
old for clinically significant improvement, as did subjective
sleep quality, which was reported in all six studies included
in meta-analysis. A trend in the direction of reduced WASO
was observed, but did not reach clinical significance. Insuf-
ficient data were available for meta-analysis of eszopiclone 3
mg adverse effects.

Overall, the benefits of eszopiclone 2 mg and 3 mg were
judged to be greater than the potential harms. Based on clinical
judgment, the task force determined that the majority of well-
informed patients would use eszopiclone over no treatment.
This judgement is based on the evidence of improvement in
sleep latency, total sleep time, sleep efficiency and sleep qual-
ity, coupled with its low potential for adverse events.

See Figures S1–S7, S68–S69, and Tables S4 and S5 in the
supplemental material.

Discussion
A total of nine studies were included in the meta-analyses
for eszopiclone 2 mg and 3 mg.56–64 Three of these studies in-
cluded only older adults ( > 65 years).56,58,59 The remainder in-
cluded younger adults, typically 21–65 years of age. Inclusion
criteria for most of these studies required persistent subjective
sleep latency > 30 min and TST < 6.5 h.57–62 Ancoli-Israel and colleagues56 studied 388 older adults for 12 consecutive weeks of nightly eszopiclone 2 mg. Inclusion criteria for this study specified TST < 6 h and WASO > 45 min. Outcome data were
patient-reported. McCall and colleagues58 also reported on
two-week administration of 2 mg eszopiclone versus placebo
to 254 to older adults. In addition to sleep latency and TST
inclusion criteria, subjects were required to have WASO > 20
min. PSG was conducted on nights 1, 2, 13, and 14. Scharf
and colleagues59 administered 1 and 2 mg of eszopiclone or
placebo nightly to 231 older adults for two weeks, employing
nightly patient-reported data.

Erman and colleagues57 evaluated multiple dosages of
eszopiclone (1, 2, 2.5, and 3 mg versus placebo and an active
control (zolpidem 10 mg) in 65 adult subjects (age 21–65) who
received each intervention for two nights, followed by 3–7 day
washout, in randomized sequences. PSG was conducted for the

two nights on each treatment. The primary endpoint was la-
tency to persistent sleep, with secondary endpoints of SE and
WASO. Uchimura and colleagues60 employed a similar cross-
over design with eszopiclone doses of 1, 2, and 3 mg, zolpidem
10 mg and placebo in 65 patients. PSG was conducted during
each two-night intervention. Primary endpoints were objective
latency to persistent sleep (LPS) and subjective SL. Zammit
and colleagues61 examined eszopiclone 2 and 3 mg vs. placebo
for 44 consecutive nights, with PSG on nights 1, 15, 29. Patient-
reported data were collected for nights 1, 15, 29, 43, and 44.
Primary endpoint was PSG-defined LPS.

Krystal and colleagues63 investigated six-month nightly
use of eszopiclone 3 mg versus placebo in 788 adults. Patient-
reported data were collected at weekly intervals. Similarly,
Walsh and colleagues64 reported on nightly use of eszopiclone
3 mg in 830 adults, with weekly patient-reported data. Finally,
Boyle and colleagues,62 in a study designed primarily to as-
sess next-day driving skill, report subjective data from a single
night of eszopiclone 3 mg versus placebo.

Sleep latency: Three studies assessed LPS as determined
by PSG for eszopiclone 2 mg.58,60,61 The McCall investiga-
tion58 focused exclusively on older adults and demonstrated the
greatest reduction in LPS. The mean reduction in LPS versus
placebo for the three studies (−14.87 min; CI: −5.47 to −24.27
min) exceeded the threshold for clinical significance. The qual-
ity of evidence was LOW due to imprecision and potential pub-
lication bias.

All six trials of eszopiclone 2 mg reported subjective sleep
latency.56–61 As noted above, three of the six included only older
adults. Mean difference from placebo fell slightly below the
clinical significance threshold (−17.78 min; CI: −7.04 to −28.52
min). The quality of this evidence was low due to imprecision
and potential publication bias.

Three studies investigated PSG LPS with eszopiclone 3
mg.60–62 The mean difference in LPS (−13.63 min; CI: −3.7
to −23.56 min) fell below the clinical significance threshold.
The quality of evidence was VERY LOW due to heterogene-
ity, imprecision and potential publication bias. Subjective SL
with eszopiclone 3 mg was reported in four studies.57,61,63,64 The
mean difference exceeded the clinical significance threshold
(−25.00 min; CI: −13.94 to −36.07 min). The greatest reduc-
tions were reported in the extended 6-month trials of Krystal
and Walsh. Quality of evidence was low due to imprecision
and potential publication bias.

Two additional studies not included in the meta-analysis
reported subjective SL with eszopiclone 3 mg. Soares and
colleagues65 analyzed efficacy in perimenopausal/early meno-
pausal women with sleep onset complaints. Joffe et al.66 ex-
amined outcomes in perimenopausal/menopausal women who
exhibited hot flashes and manifested either sleep onset or main-
tenance problems. The reductions in sleep latency versus pla-
cebo for these two studies (−15.7 and −17.8 min, respectively)
were within the overall range found in the meta-analysis.

total Sleep time: Only one eszopiclone study reported
adequate objective total sleep time data. Therefore meta-anal-
ysis was not possible for this outcome at either dosage.58 Four Do

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studies included subjective TST for eszopiclone 2 mg.57–59,61
The meta-analysis revealed a mean increase in TST of 27.53
min versus placebo, just below the threshold for clinical sig-
nificance of 30 min. The quality of evidence was LOW due
to imprecision and potential publication bias. The only study,
noted above, which reported objective TST (in patients > 65
years) found an increase in TST of 28.6 min greater than pla-
cebo, consistent with the subjective results.

Four studies included adequate data for subjective TST
meta-analysis for eszopiclone 3 mg.57,61,63,64 These studies dem-
onstrate substantially greater increases in TST at this dosage
with a mean difference versus placebo of 57.1 min, exceeding
the clinical significance threshold. The quality of evidence was
moderate, due to potential publication bias.

The two studies of eszopiclone 3 mg in perimenopausal/
early menopausal women revealed mean increases in subjec-
tive TST (versus placebo) of +66.5 min and +23.0 min.65,66

Wake after Sleep onSet: Two studies were included in
the meta-analysis of objective WASO for eszopiclone 2 mg.58,61
The mean reduction in WASO was 10.02 min greater than pla-
cebo, below the clinical significance level of 20 min for PSG
data. The quality of evidence was rated as moderate due to
potential publication bias. The confidence interval (−2.77 to

−17.27 min) fell below the threshold.
Five studies reported adequate data for subjective WASO

meta-analysis.56–59,61 The mean difference versus placebo was
below the threshold for clinical significance (−4.74 min; CI

−11.87 to +2.39 min). The quality of evidence was moderate
due to potential publication bias.

The data for PSG and patient-reported WASO with eszopi-
clone 3 mg demonstrated greater reduction of WASO than with
2 mg, but below clinical significance levels. The two studies
including PSG WASO demonstrated a mean reduction of 14.69
min versus placebo (CI: −11.69 to −17.68 min).61,62 Quality of
evidence was moderate (potential publication bias). Subjective
WASO for 3 mg was reported in four studies with mean reduc-
tion of 15.14 min (CI: −8.16 to −22.11 min). Quality of evidence
was low due to imprecision and potential publication bias.

Krystal and colleagues63 published an independent sub-
group analysis of subjective WASO data from their 6-month
nightly trial of 3 mg, in order to evaluate the impact of base-
line WASO severity on outcome. They identified a positive
relationship between baseline WASO severity and degree of
improvement in WASO (as determined by eszopiclone/placebo
difference) at all time points. The two investigations of meno-
pausal women found eszopiclone-placebo mean differences for
subjective WASO of 37.3 and 14.9 min, respectively.65,66

Quality of Sleep: The meta-analysis for sleep quality with
eszopiclone 2 mg included four studies and found a moderate
effect size of +0.47 SMD (CI: +0.32 to +0.63 SMD).57,59–61 The
quality of evidence was moderate due to imprecision and po-
tential publication bias. Sleep quality ratings for 3 mg, based
on six studies, showed a large effect size of +0.82 SMD (CI:
+0.41 to +1.24 SMD), although quality of evidence was very
low due to imprecision, heterogeneity and potential publica-
tion bias.57,60–64

In addition to the studies included in meta-analysis, Soares
and colleagues65 reported statistically significant improvement
in quality for eszopiclone 3 mg in their study of perimeno-
pausal and postmenopausal women.

Sleep efficiency: Two studies reported PSG SE for eszopi-
clone 2 mg.58,61 The mean improvement in SE of 4.83% fell be-
low the significance threshold of 5%. (CI: 2.21 to +7.46%). For
the 3 mg dosage, PSG SE exceeded the clinical significance
threshold at 5.61%.61,62 The quality of evidence for both doses
was low due to imprecision and potential publication bias.

In studies outside the meta-analysis, Joffe66 reported a 14.6%
improvement versus placebo in SE with 3 mg.

number of aWakeningS: The PSG NOA for 2 mg showed
an increase of 0.12 awakenings based on two studies.58,61 Evi-
dence quality was MODERATE. Subjective NOA was based
on four studies and likewise demonstrated no clinically signifi-
cant difference from placebo. Evidence quality was moderate
due to potential publication bias.57–59,61

overall Quality of evidence: The overall quality of
evidence in the meta-analytic data from these studies was
downgraded to very low for several reasons. Substantial het-
erogeneity across studies was noted for multiple outcomes.
The data were also downgraded for imprecision, due to the
relatively large confidence intervals, which cross the clinical
significance thresholds for several outcomes. All of these stud-
ies were industry sponsored, resulting in further downgrading
of evidence due to potential publication bias. The quality of ev-
idence for individual outcomes ranged from moderate to very
low. Therefore the overall quality of evidence was very low.

HarmS: Sufficient data for meta-analysis of side effects was
available only for the 2 mg eszopiclone dosage. Five side effects
(dizziness, dry mouth, headache, somnolence and unpleasant
taste) were included. Four studies examined dizziness with 2
mg eszopiclone and found no difference from placebo.57,58,60,61
Two studies reported adequate data for dry mouth.58,61 A +0.06
risk difference was reported for eszopiclone. For headache,
four studies found essentially no difference between eszopi-
clone and placebo.56,57,59,61 The same was true for next-day som-
nolence, based on five studies.57–61 Finally, five studies found a
+0.07 risk difference for unpleasant taste.56–59,61

Although meta-analysis was not possible for eszopiclone 3
mg, individual studies reported results which are consistent
with those of the 2 mg dosage. Krystal and colleagues63 re-
ported numerically higher adverse event rates for somnolence
(eszopiclone 9.1%; placebo 2.6%), unpleasant taste (26.1%
versus 5.6%), dry mouth (6.6% versus 1.5%), and dizziness
(9.8% versus 3.1%). Boyle62 studied braking reaction time and
other performance measures and found no difference between
eszopiclone 3 mg and placebo. Walsh64 reported significantly
greater frequencies of adverse events including somnolence
(eszopiclone: 8.8% versus placebo: 3.2%), unpleasant taste
(19.7% versus 1.1%) and myalgia (6.0% versus 2.9%). No dif-
ference was seen on the Benzodiazepine Withdrawal Scale
scores following discontinuation. Zammit61 demonstrated no Do

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impairment in digit symbol substitution at either 2 mg or 3 mg.
Joffe and colleagues66 reported a 15.2% risk for metallic taste,
but placebo rate for this side effect was not identified. Soares
and colleagues65 found a significant increase in unpleasant
taste with eszopiclone (17.6% versus 0.5%). Headache fre-
quency was no different and report of dry mouth was slightly
increased for eszopiclone (4.0% to 1.4%).

In summary, the task force found that there was weak ev-
idence of efficacy in the treatment of sleep onset and main-
tenance insomnia, with limited or no consistent evidence of
adverse events in excess of placebo, with the possible excep-
tion of unpleasant taste. Therefore, benefits were deemed to
marginally outweigh harms.

patientS’ valueS and preferenceS: The task force de-
termined that a majority of patients would likely use eszopi-
clone compared to no treatment. This assessment reflects the
task force’s clinical judgment, based on eszopiclone’s efficacy
for sleep onset and maintenance, and its relatively benign side
effect profile.

Zaleplon for the Treatment of Chronic Insomnia

Recommendation 3: We suggest that clinicians use
zaleplon as a treatment for sleep onset insomnia (versus no
treatment) in adults. [WEAK]

Remarks: This recommendation is based on trials of 10 mg
doses of zaleplon.

Summary
Two RCTs meeting inclusion criteria investigated the use of
zaleplon 5 or 10 mg in the treatment of chronic primary in-
somnia.67,68 One of these reported only subjective outcomes67,
and one reported subjective and PSG outcomes.68 No meta-
analysis was possible for these studies, due to the manner of
reporting results. The overall quality of evidence from these
studies was downgraded to low due to imprecision and po-
tential publication bias; both studies were industry supported.
The overall evidence for zaleplon 10 mg support its efficacy
for the treatment of sleep onset insomnia. At the 10 mg dose,
one objective (PSG) study demonstrated a reduction in sleep
latency from baseline that met the criterion for clinical signifi-
cance, with an approximately 9.5 min difference from placebo.
Subjective sleep latency, reported in one study, showed a non-
significant change of −11.4 min. Subjective TST increased by
approximately 21.5 min, but the difference from placebo was
not statistically significant. WASO was not significantly dif-
ferent from placebo. Similarly, subjective sleep quality showed
minimal differences from placebo. The overall evidence for
zaleplon 5 mg did not support its efficacy for treatment of any
insomnia symptoms, based on self-report studies only. No
PSG studies at the 5 mg dose met inclusion criteria. Treatment-
emergent adverse events showed no significant difference from
placebo for zaleplon 10 mg or 5 mg, and only one study sug-
gested a small increase in rebound using self-reported TST as
the outcome.

Data from three additional studies of zaleplon 5–10 mg met
our inclusion criteria but could not be included in meta-analyses

because key outcome data were presented in insufficient de-
tail.69–71 However, the results of these three studies were con-
sistent with those of the two studies presented above, in finding
differences from placebo in subjective SOL but no significant
differences in subjective TST or sleep quality.

Overall, the evidence for efficacy of zaleplon 10 mg is
marginal, and the evidence for harm appears equivalent to
placebo; therefore potential benefits minimally outweigh po-
tential harms. The lack of evidence for efficacy of zaleplon 5
mg makes any potential benefits equivalent to its minimal po-
tential harms.

Based on clinical judgment, the task force determined that
the majority of well-informed patients would use zaleplon
over no treatment. This judgement is based on the minimal
evidence of improved sleep latency across PSG and self-report
domains, coupled with a low potential for adverse events.

See Tables S6 and S7 in the supplemental material.

Discussion
Evidence from two RCTs which investigated the use of za-
leplon 5 or 10 mg in the treatment of chronic primary insomnia
was included in the main analysis of outcomes, although meta-
analysis could not be performed because data were presented
as medians, or as means with no standard deviation.67,68,70
Subjects in each study met criteria for primary insomnia or
insomnia associated with nonpsychotic mental disorder by ei-
ther DSM-III-R or DSM-IV criteria, together with quantitative
criteria for self-reported sleep disturbance (SOL > 30 min, plus
either subjective TST < 6.5 h, WASO > 30 min, or > 3 awaken-
ings) and associated daytime complaints. Walsh 200068 also re-
quired PSG LPS of > 20 min on two screening nights. Patients
were 18–65 years of age68,70 or 65 years and older.67 Study de-
signs included randomized, double-blind, placebo run-in with
zaleplon 5–20 mg or placebo for 14–35 nights, followed by a
2–7 night placebo substitution. Walsh68 used PSG outcomes,
whereas the other two studies used self-report only. Data for
zaleplon 20 mg were not considered here because this is not an
FDA-approved dose.

Sleep latency: One study evaluated the impact of zaleplon
10 mg versus placebo on PSG sleep latency (SL).68 This study
showed a clinically significant 9.5 min reduction in mean sleep
latency versus placebo (difference in median of 8.5 min) that
approached the 10 min value considered clinically significant,
and was judged by the task force to be sufficient evidence
for making a recommendation. The CI (−0.19 to −18.80 min)
crossed the clinical significance threshold, and therefore the
quality of evidence was downgraded for imprecision. It was
downgraded further due to the risk of publication bias since
the study was industry-funded. The resultant quality of evi-
dence is low.

Self-reported sleep latency was reported in one study,68
which showed a reduction compared to placebo at the end of
treatment (−11.40 min; CI: −26.36 to +4.56 min), which failed
to meet the criterion for clinical significance. Hedner67 also
reported reductions in subjective sleep latency; however, the
results could not be subject to meta-analysis, since the mean
values were presented only in graphic form.Do

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Additional studies not included in the primary analysis
yield similar findings. Ancoli-Israel69 conducted a randomized,
double-blind, multi-center study of the efficacy of zaleplon 5
and 10 mg versus placebo in older adults with DSM-IV insom-
nia, using a similar study design to Hedner,67 with self-report
outcomes. This study reported significant differences between
zaleplon 10 mg and placebo at both treatment weeks, and be-
tween zaleplon 5 mg and placebo at week 2 only. Elie 199970
reported significant differences on placebo at weeks 1–3 of
treatment, with differences in the range of −8 to −15 min. Fry71
reported a 28-day double-blind, placebo run-in and run-out
study of adults with DSM-III-R insomnia. Median subjective
sleep latency was signficantly different from placebo at weeks
1, 3, and 4 for zaleplon 10 mg, and at week 1 for zaleplon 5 mg.
Because mean and standard deviation data were not reported,
data from these two studies could not be formally evaluated in
our meta-analysis.

total Sleep time: The effects of zaleplon 10 mg on subjec-
tive TST were evaluated in one study.68 Over the course of a
five-week study, TST differed significantly from placebo only
in week one, with a difference of 21.5 min between groups (CI:
−5.6 to +48.6 min); this difference failed to meet the criterion
for clinical significance. Quality of the evidence was down-
graded to low due to imprecision and potential publication bias.

Objective TST was evaluated in 2 studies.67,68 However,
meta-analysis of these studies was not possible due to the man-
ner of data reporting. These studies showed no consistent evi-
dence of a zaleplon − placebo difference at the 10 mg or 5 mg
dose of zaleplon. Mean/median differences in subjective TST
at the end of treatment were in the range of +7 to +22.4 min
in favor of zaleplon. The results of studies not included in our
formal analysis69–71 showed very similar findings for subjec-
tive TST, with inconsistent differences between placebo and
zaleplon 10 mg.

The effects of zaleplon 5 mg versus placebo on subjective
total sleep time were reported in one study.67 No significant
differences in median sleep time were found between zaleplon
5 mg and placebo across 2–4 weeks of treatment. The results of
studies not included in our formal analysis69–71 showed similar
findings for subjective TST, with no differences between pla-
cebo and zaleplon 5 mg.

Wake after Sleep onSet: Objective WASO was evaluated
in one study,68 but failed to meet the criterion for clinical sig-
nificance (−2.10 min; CI: −10.23 to +6.03 min). The quality of
evidence was moderate, due to potential publication bias. Sub-
jective WASO was not reported in any of the studies.

Quality of Sleep: Subjective sleep quality, evaluated on
an ordinal 1–7 scale (1 = good, 7 = bad) was reported in one of
the formally evaluated studies for both 5 mg and 10 mg.67 At
both dosages sleep quality improved (−0.10 points; CI: −0.27
to +0.07 points), but failed to meet the criterion for clinical
significance. The quality of evidence for both doses was down-
graded to moderate due to potential publication bias.

In three additional studies,69–71 subjective sleep quality dif-
fered from placebo inconsistently at either dose; the majority of

study weeks showed no difference between groups. Quality of
evidence was downgraded for publication bias. Precision and
heterogeneity could not be formally evaluated.

Sleep efficiency: Neither PSG nor subjective sleep effi-
ciency were formally evaluated in any of the studies reviewed
here.

number of aWakeningS: Number of awakenings were
evaluated in the sole PSG study.68 However, formal evaluation
of findings was not possible. No data were presented in the
paper, but NOA was reported not to differ between zaleplon 10
mg and placebo at any treatment week. Subjective NOA was
evaluated in the two studies formally included in our evalua-
tion but data were presented as median values and could not
be included in meta-analyses. Hedner67 reported a difference
of uncertain clinical significance only at week 1 and Walsh68
reported a difference only at week 3. Data from three addi-
tional studies not included in our formal analysis69–71 showed
no significant differences in NOA for either zaleplon 10 mg or
zaleplon 5 mg at any study week.

overall Quality of evidence: As noted above, no meta-
analyses could be conducted on data from studies of zaleplon.
Some studies reported median data only, or mean values with
no standard deviation, for some of the key outcomes. Still other
studies presented data for key outcomes only in graphical form.
The quality of evidence was downgraded for imprecision, due
to the relatively large confidence intervals which cross the clin-
ical significance thresholds for multiple outcomes. All of these
studies were industry sponsored, resulting in further down-
grading of evidence due to potential publication bias. The qual-
ity of evidence for individual outcomes ranged from moderate
to low, therefore the overall quality of evidence was low.

HarmS: No meta-analysis was conducted on harms. Each
of the individual studies showed no significant difference in
the overall rate of treatment-emergent adverse events between
zaleplon and placebo. Several symptoms related to the cen-
tral nervous system were more frequent numerically among
zaleplon treated patients, although these differences were not
statistically significant due to the low overall incidence of ad-
verse events. The most common adverse events in studies of
zaleplon versus placebo included headache, asthenia, neuras-
thenia, pain, fatigue, and somnolence. There was no clear evi-
dence of dose-dependent effects.

Several of the reviewed studies reported data from double-
blind placebo runout periods. No significant withdrawal symp-
toms were noted on the Benzodiazepine Withdrawal Symptom
Questionnaire.70,71 The single PSG study noted no evidence
of withdrawal upon discontinuation for the 10 mg dose. Evi-
dence of discontinuation-related increases in subjective TST
were noted at the zaleplon 5 and 10 mg dose in older adults,
and for subjective SOL in older adults at the zaleplon 5 mg
dose.67,69 A small increase in NOA of the second discontinu-
ation night was also noted with zaleplon 5 mg.70 These dif-
ferences were small in absolute magnitude and of doubtful
clinical significance. Other studies did not report evidence of Do

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rebound insomnia.71 Categorically-defined rebound insomnia
was not significantly different for zaleplon 5 mg or zaleplon 10
mg versus placebo.69,70

The task force found that there was weak objective evidence
of efficacy for zaleplon 10 mg in the treatment of sleep onset
insomnia that was just below criteria for clinical significance,
and no consistent evidence for efficacy in TST. Likewise, there
was no statistical evidence of adverse events in excess of pla-
cebo, although some treatment-emergent adverse events were
numerically more prevalent in zaleplon groups. Evidence for
withdrawal effects was weak, inconsistent, and unlikely to be
clinically important. On balance, benefits were deemed to mar-
ginally outweigh harms.

patientS’ valueS and preferenceS: The task force de-
termined that a majority of patients would likely use zaleplon
compared to no treatment. This assessment reflects the task
force’s clinical judgment, based on zaleplon’s efficacy for sleep
onset, and its relatively benign side effect profile.

Zolpidem for the Treatment of Chronic Insomnia

Recommendation 4: We suggest that clinicians use zolpidem
as a treatment for sleep onset and sleep maintenance
insomnia (versus no treatment) in adults. [WEAK]

Remarks: This recommendation is based on trials of 10 mg
doses of zolpidem.

N.B. Although 10 mg. was the recommended starting dos-
age for adults at the time of initial approval, the FDA has
subsequently lowered the recommended starting dosage of im-
mediate-release zolpidem products to 5 mg. Further, the FDA
has recommended a reduction of starting dosage for extended-
release forms of zolpidem from 12.5 mg to 6.25 mg.

Summary
Twelve RCTs evaluated zolpidem 10 mg for the treatment of
chronic primary insomnia.57,59,60,70,72–79 The overall quality
of evidence was downgraded to very low due to significant
heterogeneity, imprecision, and risk of publication bias. The
evidence for zolpidem 10 mg was weakly in favor of its effec-
tiveness for improving sleep onset, sleep maintenance, sleep
quality, SE and TST. In addition, one paper evaluated the ef-
fectiveness of zolpidem extended release 6.25 mg80 and one pa-
per assessed zolpidem extended release 12.5 mg.81

Five studies examined the effects of zolidem 10 mg on ob-
jective sleep latency.60,73,76,77,82 The mean reduction (vs. placebo)
for PSG-determined latency to sleep exceeded the threshold
for clinical significance. Ten studies presented patient-reported
sleep latency data.57,60,70,72–76,78,82 The mean reduction in subjec-
tive latency fell approximately at the significance threshold.
Two studies73,76 reported adequate objective TST data for meta-
analysis and found that the mean improvement in TST also
exceeded the clinical significance threshold. The same was
true for subjective TST, based on eight studies.57,70,73–76,78,82 Two
studies73,76 found that PSG-determined reduction in WASO was
clinically significant. Six studies included adequate data for
meta-analysis of subjective WASO57,72,75,76,78,82; the mean reduc-
tion fell below the clinical significance threshold. Six studies

evaluating sleep quality reported moderately large improve-
ment in this parameter based on SMD.57,60,76,78,79,82 Improve-
ment in PSG SE in the four studies included also exceeded the
clinical significance threshold.73,76,77,82 Number of awakenings
(objective) fell below the clinical significance threshold.77,82 Re-
duction in subjective number of awakenings also failed to meet
the clinical significance threshold.

The single paper reporting on extended-release zolpidem
6.25 mg80 found moderate reduction in PSG-determined
WASO (based on only the first 6 h of sleep) and minimal im-
provement in LPS and SE at end-treatment in an elderly popu-
lation. Overall quality of evidence from this report was LOW
due to imprecision and potential publication bias. Data from
the one study81 on zolpidem extended-release 12.5 mg found
moderate reduction in PSG LPS. Reduction in WASO was also
moderate, while SE was not significantly different from pla-
cebo. Overall quality of evidence was LOW due to imprecision
and potential publication bias.

Meta-analysis was conducted for amnesia, dizziness, head-
ache, nausea, somnolence and “taste perversion” (altered or
unpleasant taste) in studies employing zolpidem 10 mg. Small,
but potentially significant increases in amnesia, dizziness and
somnolence were reported with zolpidem.

Overall, the benefits of zolpidem 10 mg and extended-
release zolpidem 12.5 mg were judged to be greater than the
minimal potential harms. Benefits and harms were judged to
be approximately equal for extended-release zolpidem 6.25 mg.
It was determined by clinical judgement of the task force that
the majority of well-informed patients would use zolpidem and
extended-release over no treatment. This judgement is based
on the evidence of improvement in sleep latency, total sleep
time, WASO, sleep efficiency, and sleep quality, coupled with
relatively low potential for adverse events. The data for ef-
ficacy of zolpidem extended-release 6.25 mg is minimal and
inconclusive at best.

See Figures S18–S27, S70–S75 and Tables S8–S10 in the
supplemental material.

Discussion
Twelve studies were included in the meta-analysis for zolpidem
10 mg.57,60,70,72–79,82 Dorsey and colleagues72 studied 141 meno-
pausal or perimenopausal women who exhibited both insomnia
(TST < 6 h or WASO > 1 h) and nocturnal hot flashes or sweats.
Subjects received zolpidem 10 mg or placebo in a 4-week trial.
Outcomes included patient-reported TST, SL, WASO, and
NOA. Elie70 investigated three dosages of zaleplon versus zol-
pidem 10 mg or placebo. The study included 615 adults with
SL > 30 min and either TST < 6.5 h or WASO > 30 min or > 3
awakenings per night. Subjects received one of three zaleplon
dosages, zolpidem 10 mg or placebo for 28 nights. Outcome
data included subjective SL, QOS, TST and NOA. Erman57
assessed 65 adults with reported sleep-onset insomnia and
baseline PSG SL > 20 min and TST < 7 h or WASO > 20 min.
Enrollees were administered eszopiclone at 4 dosages, zolpi-
dem 10 mg and placebo in a randomized treatment sequence
of 2 nights per intervention with intervening washout. Primary
outcome was PSG-determined LPS with secondary measures
including SE, WASO and NOA. Hermann73 administered Do

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zolpidem 10 mg or placebo for two weeks to 21 adults with
difficulty initiating or maintaining sleep. PSG was conducted
on the final treatment night with reported outcomes including
SL, TST, SE and WASO.

Perlis75 evaluated 199 subjects with primary insomnia
(SL > 45 min or TST < 6 h) with zolpidem 10 mg or placebo. Subjects were instructed to take the medication 3–5 times per week as needed over a twelve-week period. Sleep diary out- comes included SL, TST, WASO and NOA. Jacobs74 compared zolpidem 10 mg, cognitive behavior therapy and placebo in 63 adults with primary sleep-onset insomnia (SL > 1 h on > 3
nights/week). Subjects received zolpidem for 28 days, followed
by taper. Primary outcome was patient-reported sleep latency
with secondary outcomes of SE and TST. Randall76 investi-
gated the efficacy of zolpidem 10 mg (5 mg for subjects 65–70
years) over an eight-month period in 91 subjects (age 23–70
years) with screening PSG SE < 85%. Patient-reported out- comes and PSG data at one and eight months included SL, TST, WASO and SE. Scharf82 evaluated 75 adults for five weeks with zolpidem 10 mg, 15 mg or placebo. Inclusion criteria included SL > 30 min or TST < 6 h. Subjects underwent sleep studies on the first two nights of each treatment week. Primary outcomes were defined as LPS and SE.

Staner79 assessed the effects of three drugs, including zol-
pidem 10 mg, in a driving simulation study of 23 adults with
recurrent SL > 30 min or WASO > 60 min. Sleep quality data
was reported. Uchimura60 compared zolpidem, eszopiclone
and placebo in a crossover design as described in the eszopi-
clone section. Walsh78 compared the efficacy of zolpidem 10 mg
to trazodone 50 mg and placebo in 278 adults with insomnia
characterized by frequent SL > 30 min and TST 4–6 h. Sub-
jective sleep latency and TST were reported. Ware77 assessed
rebound insomnia in zolpidem 10 mg, triazolam 0.5 mg and
placebo. Ninety-nine subjects with baseline PSG-determined
LPS > 20 min and TST 4–7 h took zolpidem 10 mg, triazolam
or placebo for 28 consecutive days. PSG LPS, SE, TST, and
WASO were evaluated.

Two studies reported on extended-release (ER) zolpidem.
Roth81 assessed zolpidem ER 12.5 mg in 212 adults with in-
somnia who reported > 1 h WASO at least 3 nights per week.
Patients received zolpidem or placebo nightly for 3 weeks in a
parallel group design. Walsh80 studied 205 elderly adults with
insomnia with the same inclusion criteria and design, employ-
ing a 6.25 mg dose of zolpidem ER versus placebo.

Fourteen additional studies met inclusion criteria but could
not be included in meta-analysis due to inadequate data
sets.71,83–95 Pertinent results from these studies are noted inde-
pendently of meta-analysis results.

Sleep latency: Five studies included adequate data for PSG
SL meta-analysis.60,73,76,77,82 The mean difference from placebo
of −11.65 min exceeded the clinical significance threshold. The
95% CI of −4.15 to −19.15 min crossed the clinical significance
threshold and was therefore considered imprecise. Heterogene-
ity was high. With potential publication bias as well, the qual-
ity of evidence was rated as very low.

Ten of the twelve studies used in meta-analysis reported
subjective SL.57,60,70,72–76,78,82 The improvement in sleep latency

versus placebo was at the significance threshold (mean differ-
ence: 19.55 min; CI: −14.2 to −24.9 min). Evidence quality was
very low due to imprecision, heterogeneity and potential pub-
lication bias.

Six additional studies assessed sleep latency outcomes with
zolpidem.88–90,92,94,95 These studies varied significantly with re-
gard to drug preparation, dosage, mode of administration and
methodology, rendering comparisons between them or to the
meta-analytic data difficult. Four of the six evaluated sublin-
gual zolpidem, primarily for treatment of middle-of-the-night
(MOTN) awakenings. Roth and colleagues88 reported results
of a three-way crossover study of zolpidem sublingual 1.75 mg,
3.5 mg and placebo. Zolpidem reduced both objective (latency
to persistent sleep) and subjective latency to sleep (SL) follow-
ing MOTN awakenings (PSG: 1.75 mg: −11.2 min versus pla-
cebo; 3.5 mg: −18.4 min/subjective: 1.75 mg: −11.83 min versus
placebo; 3.5 mg: −15.23 min). Roth89 also reported reduced sub-
jective latencies following MOTN awakenings with sublingual
zolpidem 3.5 mg over a 28-day trial. Zammit95 administered
immediate release oral zolpidem 10 mg, zaleplon 10 mg or pla-
cebo to subjects with sleep maintenance insomnia following
induced MOTN awakenings Zolpidem reduced PSG latency to
persistent sleep following the awakenings (−30.5 min versus
placebo). Staner90 compared the effects of sublingual zolpidem
10 mg to immediate release oral zolpidem on PSG initial sleep
latency and reported shorter latency to persistent sleep with
the sublingual preparation (−10.28 min) versus the oral prepa-
ration. Walsh94 investigated subjective SL in an 8-week trial
of as-needed zolpidem 10 mg (3–5 times per week). For medi-
cation nights only, end treatment SL for the zolpidem 10 mg
group was 12.6 min less than the placebo group.

Walsh80 investigated the effects zolpidem ER 6.25 mg and
found reduction of PSG LPS of 13.0 min. Roth81 reported a
decrease in PSG LPS of 8.2 min versus placebo at end of treat-
ment with zolpidem ER 12.5 mg.

total Sleep time: Two studies73,76 were included in the
meta-analysis of PSG-determined TST. Mean reduction in
TST met the clinical significance threshold at +28.91 min, how-
ever the 95% CI crossed the threshold (CI: +10.85 to +46.97
min). The quality of evidence was downgraded to LOW due
to imprecision and potential publication bias. Eight studies
reported adequate data for meta-analysis of patient-reported
TST.57,70,73–76,78,82 The mean difference for subjective TST from
these studies exceeded the significance threshold (+30.04 min;
CI: +15.12 to +44.96 min). Quality of evidence was low due to
imprecision and potential publication bias.

Six additional studies presented TST data which was not
sufficient to be included in the analysis.71,83,84,88,92,95 Allain and
colleagues83 evaluated zolpidem 10 mg administered on an as-
needed basis over a four week period. When only drug nights
were included in analysis, zolpidem produced a statistically
significantly greater increase in subjective TST versus placebo
(+19.9 min). Cluydts84 and Hajak85 found no difference in sub-
jective TST with nightly versus intermittent (5/7 nights) use of
zolpidem 10 mg, both of which produced numerical improve-
ment (+11.3 and +16.9 min, respectively). In a study designed
primarily to address potential rebound insomnia following Do

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four weeks of treatment with zaleplon, zolpidem or placebo,
Fry71 reported substantially greater improvement in patient-
reported TST with zolpidem 10 mg versus placebo (+28.2 min).
In another study of rebound insomnia, Voshaar92 compared
zolpidem 10 mg to temazepam 20 mg (without placebo con-
trol) administered nightly for four weeks. The two drugs pro-
duced improved TST without significant difference between
the two. Finally, in two studies Roth89 and Zammit95 investi-
gated effects of zolpidem following MOTN awakenings. Roth
and colleagues compared sublingual zolpidem 1.75 mg and 3.5
mg to placebo. Both dosages produced greater TST following
awakening as compared to placebo (+14.7 min and +25.9 min,
respectively). Zammit administered zolpidem 10 mg following
MOTN awakening and reported TST after awakening 30 min
greater than placebo.

TST data were not reported in the extended-release studies.

Wake after Sleep onSet: Two studies reported adequate
data for meta-analysis of PSG WASO.73,76 These studies yielded
a mean difference from placebo of −25.46 min (CI: −17.94 to

−32.99 min). This exceeds the threshold for clinical signifi-
cance. The quality of evidence was LOW due to imprecision
and potential publication bias.

Zolpidem ER 12.5 mg reduced WASO by 20 min greater
than placebo at treatment conclusion, although this was based
on only the first 6 h of sleep.81 Comparison of changes from
baseline in this study, however, suggested smaller differences
between drug and placebo. Walsh,80 using the same selective
sample of 6 h, found WASO 13.0 min less in the zolpidem ER
6.25 mg group than in the placebo group. Given the sampling
of only 6 h, it is difficult to clearly determine whether or not
these agents would fulfill the criterion for clinical significance,
which is based on an entire night of sleep.

Six studies assessed patient-reported WASO.57,72,75,76,78,82 The
mean difference fell below the level of clinical significance at

−13.57 min (CI: −7.30 to −19.84 min). Quality of evidence was
low due to heterogeneity and potential publication bias.

Quality of Sleep: Six studies included sleep quality
data.57,60,76,78,79,82 The meta-analysis produced a standardized
mean difference of +0.64 (CI: +0.03 to +1.26 SMD), suggest-
ing moderate overall improvement in patient-reported sleep
quality. Quality of evidence was very low due to imprecision,
heterogeneity and potential publication bias.

Sleep efficiency: PSG sleep efficiency was reported in
four studies.73,76,77,82 The mean difference favored zolpidem
(+6.12%; CI: +4.39 to +7.85%), but did not exceed the clinical
significance threshold. Quality of evidence was low.

In the Roth81 study of zolpidem ER 12.5 mg, PSG SE was
3.9% better with zolpidem than placebo. Walsh80 found a dif-
ference of 2.4% on favor of zolpidem ER 6.25 mg. Neither
value exceeds the clinical significance threshold.

number of aWakeningS: PSG-determined number of
awakenings was reported by Scharf82 and Ware.77 The mean
difference from placebo was −0.95 awakenings (CI: −0.49 to

−1.41 awakenings), which fails to meet the clinical significance

threshold. Quality of evidence was moderate. Subjective awak-
ening was reported in six studies.70,72,73,75,78,82 Mean reduction
versus placebo was −0.31 awakenings (CI: −0.17 to −0.45
awakenings), which also fails to achieve clinical significance.
Evidence quality was low due heterogeneity and potential pub-
lication bias.

overall Quality of evidence: The overall quality of
evidence in the meta-analytic data from these studies was
downgraded to very low for several reasons. Substantial het-
erogeneity across studies was noted for multiple outcomes.
The data were also downgraded for imprecision, due to the
relatively large confidence intervals which cross the clinical
significance thresholds for several outcomes. All of these stud-
ies were industry sponsored, resulting in further downgrading
of evidence due to potential publication bias. The quality of ev-
idence for individual outcomes ranged from moderate to very
low, therefore the overall quality of evidence was very low.

HarmS: Meta-analysis for adverse effects of zolpidem was
possible for six side effects: amnesia, dizziness, sedation,
headache, nausea, and taste perversion (altered or unpleasant
taste). Two studies70,82 included data on amnesia and found a
minimal difference from placebo (0.03 risk difference). A
small increase in risk (0.06 risk difference) was identified for
dizziness, based on analysis of four investigations.57,60,72,82 Risk
for headache was mildly increased in the zolpidem group (0.07
risk difference).57,72,78 Minimal difference was observed in the
risk for nausea (0.02 risk difference),57,82 and somnolence had a
slightly higher risk (0.04), based on six studies.57,60,70,72,78,82 Risk
for taste perversion was low and approximately equal in both
groups.60,70

Numerous studies have evaluated rebound insomnia after
discontinuation of zolpidem.68,70,71,73,75,77,80,82,86,92 Some of these
studies found no evidence of rebound after varying durations
of nightly or intermittent use, for up to six months.68,73 Other
investigations reported evidence of rebound, limited primarily
to night 1 following discontinuation.70,71,80,81

Evaluation of daytime improvement and impairment was
limited. Dorsey72 reported improvement in sleep-related dif-
ficulty with daytime function. Hajak85 described marked
improvement in quality of life ratings with both nightly and
intermittent use. Morning alertness and performance impair-
ment were tested in several studies. Roth81 and Walsh80 found
no evidence of impairment on digit symbol substitution test
(DSST) or Rey auditory-verbal learning test (RAVLT) after
zolpidem modified-release 12.5 mg. Scharf82 reported no im-
pairment on DSST or digit symbol copying. Staner79 found
no indication of impairment in a driving simulation study
after seven consecutive nights of zolpidem 10 mg. Zammit95
formally assessed sleepiness following administration of zol-
pidem 10 mg following MOTN awakening. Subjects showed
significantly reduced PSG latencies versus placebo at 4, 5, and
7 h following administration. This was accompanied by im-
pairment on DSST at 4 and 5 h.

In summary, the task force found that there was weak evi-
dence of efficacy in the treatment of sleep onset and mainte-
nance insomnia, with limited evidence of mild adverse events Do

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in excess of placebo, with the possible exception of excessive
sleepiness following administration of higher dosages (10 mg)
less than 8 h prior to awakening. Therefore, benefits were
deemed to marginally outweigh harms.

patientS’ valueS and preferenceS: The task force de-
termined that a majority of patients would likely use zolpidem
compared to no treatment. This assessment reflects the task
force’s clinical judgment, based on zolpidem’s efficacy for
sleep onset and maintenance, and its relatively benign side ef-
fect profile.

Benzodiazepines

Triazolam for the Treatment of Chronic Insomnia

Recommendation 5: We suggest that clinicians use
triazolam as a treatment for sleep onset insomnia (versus
no treatment) in adults. [WEAK]

Remarks: This recommendation is based on trials of 0.25
mg doses of triazolam.

Summary
Because only one study96 contained data of sufficient quality,
meta-analysis was not performed. The quality of evidence for
this study was high. This study, consisting of patient-reported
data, showed a modest decrease in subjective SL, which fell
below the clinical significance threshold. Two additional stud-
ies, which did not contain data suitable for meta-analysis, re-
ported statistically significant reductions in subjective SL with
triazolam 0.25 mg versus placebo.97,98 Roehrs96 found an in-
crease in TST, although the mean change fell below the range
of clinical significance. WASO was not reported, while sleep
quality showed mild to moderate reduction versus placebo.
Number of awakenings was insignificantly decreased.

No meta-analysis of harms was possible. Given the mar-
ginal evidence for efficacy in improving sleep onset, coupled
with limited evidence regarding harms, the task force judged
the harms to be approximately equal to the benefits. Based on
its clinical judgement, the task force determined that, in light
of the evidence for efficacy for sleep onset and the absence of
information regarding harms, the majority of patients would
be likely to use triazolam compared to no treatment.

See Table S11 in the supplemental material.

Discussion
Roehrs96 studied 32 adults with insomnia in a complex design
which began with 11 days in which subjects received either tri-
azolam or placebo nightly, “as needed” or every third night. This
was followed by 14 nights in which subjects chose to self-admin-
ister treatment, with placebo (week 1) or triazolam 0.25 (week 2).

Thirteen additional studies met general inclusion and exclu-
sion criteria.97–109 These studies were highly varied in design,
many utilizing interval scales (as opposed to specific numeric
values) for reporting of sleep outcome variables. Some did not
include a placebo comparison. Many included dosages which
are higher than current recommended dosages. Therefore, only
those studies which contained pertinent data are discussed.

Bowen100 compared triazolam 0.5 mg, flurazepam 30 mg and
placebo in 120 insomnia outpatients. The two-night crossover
comparison of triazolam 0.5 mg and placebo included only 18
subjects, who completed morning sleep questionnaires. Elie97
evaluated triazolam 0.125 mg (with upward dosage adjustment
to 0.25 mg during the study period, as indicated) versus zopi-
clone and placebo in 48 elderly (60–90 years) subjects. Subjects
received one of three interventions nightly for three weeks in
a parallel group design. Outcome variables were patient-
reported. Greenblatt103 reported an RCT of 6 nights baseline
placebo administration followed by triazolam 0.5 mg for 7–10
nights in a total of 60 subjects with sleep onset or maintenance
insomnia. Outcome data were derived from subjective reports.
Hajak104 treated 1,507 subjects with sleep onset or maintenance
insomnia with triazolam 0.25 mg, zopiclone or placebo. The
triazolam versus placebo comparison groups totaled 605 sub-
jects, who received drug or placebo for 28 consecutive nights
and reported sleep variables on visual analog scales.

Monti106 assessed 24 chronic insomnia subjects with tri-
azolam 0.5 mg, zolpidem and placebo in a 27-night trial, with
PSG on nights 4/5 and 15/16 and 29/30. Reeves98 evaluated 37
geriatric subjects ( > 60 years) with triazolam 0.25 mg, fluraz-
epam or placebo in a 28 day trial. The triazolam and placebo
groups included 28 subjects who completed daily sleep diaries.
Rickels107 studied 50 subjects with sleep onset or maintenance
insomnia who received either triazolam 0.5 mg or placebo for 7
days. Outcome data were subjective ratings and interval scales.
Scharf108 administered triazolam 0.5 mg, quazepam or placebo
to 65 chronic insomnia subjects. After placebo run-in, partici-
pants received nightly drug or placebo for 9 nights, followed by
14 nights of every-other-night administration. Outcomes were
patient reported rating scales.

Sleep latency: In the only study with adequate data for
meta-analysis, Roehrs96 found a small reduction in subjective
SL (−9.2 min; CI: −22.3 to +3.9 min) which fell below clinical
significance. Quality of evidence for these data was high.

Monti106 found no significant differences between triazolam
0.5 mg and placebo for PSG SL at any time point.

Elie97 found larger reductions in subjective ratings of SL
for triazolam 0.125–0.25 mg versus placebo. Hajak104 found
no significant difference from placebo in SL “response rate”
(SL reduction of > 15 min) for triazolam 0.25 mg. In contrast,
Reeves98 found triazolam 0.25 mg statistically superior to pla-
cebo for SL in a geriatric population on subjective ratings of

“how much [the drug] helped.” Bowen100 found triazolam 0.5
mg to be statistically significantly better than placebo on in-
terval ratings for reduction of sleep onset time. Greenblatt103
reported sleep diary reductions from baseline placebo levels
of 55 min and 24 min in two separate triazolam 0.5 mg groups.
Rickels107 reported similar subjective improvement on ratings
of sleep induction for triazolam 0.5 mg.

total Sleep time: Roehrs96 observed a moderate increase
in subjective TST (+25.20 min; CI: −9.12 to +59.52 min). This
fell below the clinical significance threshold of 30 min and was
not statistically different from placebo. Quality of evidence
was moderate due to imprecision.Do

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In additional studies, Hajak104 found no significant differ-
ence between triazolam 0.25 mg and placebo in “percentage
of responders” for TST (defined as > 20% increase in TST).
Ratings for improvement in TST were significantly better
for triazolam 0.25 mg than placebo in the Reeves98 geriatric
study.

Monti106 observed a statistically significant increase in ob-
jective TST with triazolam 0.5 mg (+16 min versus placebo).
Bowen100 found that triazolam 0.5 mg was significantly pre-
ferred to placebo for sleep duration. In two separate triazolam
0.5 mg groups, Greenblatt103 noted increases in subjective TST
of 1.02 and 0.76 h. Rickels107 reported that triazolam 0.5 mg
was rated as significantly superior to placebo for sleep dura-
tion. Scharf108 noted significantly greater subjective improve-
ment in interval ratings of TST with both daily and every other
night administration of triazolam 0.5 mg.

Wake after Sleep onSet: No studies reported data on
WASO.

Quality of Sleep: Roehrs,96 using a 4-point scale (1 = good,
4 = poor), found small improvements in QOS ( −0.37 points; CI:
−0.66 to −0.07 points), which was not considered to be clini-
cally significant. Quality of evidence was high.

Elie97 found no significant difference between triazolam
(0.125/0.25 mg) and placebo in an elderly population with
respect to QOS. Likewise, Hajak104 reported no statistically
significant difference between triazolam 0.25 and placebo.
Reeves98 demonstrated significant improvement in QOS for
triazolam 0.25 mg versus placebo in a geriatric population.

Sleep efficiency: Sleep efficiency was not reported by any
study.

number of aWakeningS: Roehrs96 reported a reduction in
NOA of 0.37 (CI: −1.7 to +0.96 awakenings), which did not
meet the clinical significance threshold. Quality of evidence
was LOW due to significant imprecision.

Hajak104 noted no significant difference from placebo in
the percentage of “responders” (reduction of NOA to < 3) with triazolam 0.25 mg. However, Reeves98 did find a statisti- cally significant reduction at this dosage in ratings for NOAs. Bowen100 observed a statistically significant reduction in sub- jective ratings for NOA with triazolam 0.5 mg versus placebo. Greenblatt103 also reported reductions of 0.58 and 0.89 patient- reported awakenings from placebo baseline in two groups ad- ministered 0.5 mg triazolam.

overall Quality of evidence: The overall quality of
evidence for the triazolam data, based on the single study
meeting criteria for meta-analysis, was HIGH.

HarmS: Insufficient data were available for meta-analysis of
adverse events associated with triazolam 0.25 mg. Very little
systematic analysis of adverse effects is available. Hajak104
reported that “speech disorder” was the only adverse effect,
among many, to be significantly more frequent in the triazolam
group than in the placebo condition.

patientS’ valueS and preferenceS: The task force
determined that a majority of patients would be likely to use
triazolam compared to no treatment. This assessment reflects
the task force’s clinical judgment, based on weak evidence for
triazolam’s efficacy and the absence of information regarding
harms.

Temazepam for the Treatment of Chronic Insomnia

Recommendation 6: We suggest that clinicians use
temazepam as a treatment for sleep onset and sleep
maintenance insomnia (versus no treatment) in adults.
[WEAK]

Remarks: This recommendation is based on trials of 15 mg
doses of temazepam.

Summary
Three RCTs investigated the use of temazepam in the treat-
ment of chronic primary insomnia.110–112 These studies pro-
vide a limited assessment of temazepam in that they included
small sample sizes of 19, 20, and 34 subjects, respectively.
The overall quality of evidence from these studies is moder-
ate. Meta-analyses for temazepam 15 mg were conducted for
SL, TST and sleep quality. Two studies110,112 were included in
the meta-analysis of SL. These showed a reduction in subjec-
tive SL which exceeded the threshold for clinical significance.
Meta-analysis of TST showed improvement in subjective TST
which exceed the threshold for clinical significance. There
were insufficient data for meta-analysis of WASO. One study
of objective WASO revealed a clinically significant reduction.
Subjective and objective SE was significantly increased, based
on limited data from secondary studies. There was evidence
for marginal improvement in sleep quality of 0.25 standard de-
viations. This was not a clinically significant difference from
placebo and falls below the threshold for clinical significance.
There were minimal data on adverse effects, and the available
data do not suggest a high frequency of treatment-emergent
adverse events (TEAEs).

Meta-analysis for temazepam 30 mg was not possible for
any sleep outcomes. Data from individual studies are reported
below.

In summary, meta-analysis data are available for temaze-
pam 15 mg only. These data, coupled with data from secondary
studies not adequate for meta-analysis, demonstrate efficacy
for temazepam 15 mg in improving subjective and possibly ob-
jective sleep latency, subjective and objective TST, and objec-
tive WASO (the latter based on a single study). Temazepam 30
mg appears to have significant efficacy for improving subjec-
tive sleep latency and TST. The data also support a clinically
significant effect for both 15 mg and 30 mg on subjective NOA,
although data for objective NOA at 20 mg revealed no signifi-
cant effect.

Given the significant improvements in patient-reported SL
and TST, coupled with additional data derived from secondary
studies (see below), the task force judged that the benefits of te-
mazepam 15 mg appear to be greater than the potential harms.
Based on its clinical judgement, the task force determined that,
in light of the evidence for efficacy and minimal evidence for Do

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harms, the majority of well-informed patients would be likely
to use temazepam compared to no treatment.

See Figures S28–S30 and Tables S12 and S13 in the sup-
plemental material.

Discussion
Evidence from three RCTs which investigated the use of te-
mazepam in the treatment of insomnia was included in the sta-
tistical analysis.110–112

Glass110 evaluated 19 subjects 70 years of age or older who
met DSM-IV diagnostic criteria for primary insomnia. Sub-
jects underwent a crossover study of two weeks of treatment
with placebo, temazepam 15 mg, or diphenhydramine 50 mg
with randomized order of administration. Sleep was assessed
using diary-derived variables. Adverse effects were recorded
and daytime impairment was systematically assessed using
the digit symbol substitution task (DSST), the manual tracking
task (MTT), and the morning-after memory impairment, using
a free-recall procedure.

Wu112 assessed 71 patients with DSM-IV diagnosed insom-
nia who were randomized to one of four groups (CBT-I alone,
CBT-I plus pharmacotherapy with temazepam 15 mg, pharma-
cotherapy alone, or placebo). For the purpose of this analysis,
pharmacotherapy alone was compared to placebo (n = 34).
Subjects received 8 weeks of treatment. End-of-treatment PSG
and patient diary data for SL, TST and SE were compared.

Hindmarch111 studied 20 individuals with “a history of
nighttime medication for insomnia.” No additional diagnostic
information was provided. Subjects were randomized to re-
ceive temazepam 15 and 30 mg or placebo for a single night
using a within-subjects crossover design. Outcome was as-
sessed using the Leeds Sleep Evaluation Questionnaire which
consisted of Visual Analogue Scale (VAS) ratings of “Ease of
Falling Asleep” and “Quality of Sleep.” Adverse effects were
not reported, but daytime sedation was assessed with a Choice
Reaction Time task, the Critical Flicker Fusion Test, and “Ease
of Awakening” and “Integrity of Behavior Following Wakeful-
ness” items from the Leeds scale.

Six additional studies which included temazepam-placebo
comparisons were reviewed.92,113–117 Cuanang113 studied 60
adult “outpatients with insomnia.” Parallel group design in-
cluded three groups: temazepam 20 mg, temazepam 10 mg
and placebo. Subjects received treatment or placebo for five
nights. Patient-reported data including sleep quality (“better,
same or worse”), SL, and TST were collected each morning.
Fillingim114 evaluated 75 adult patients with difficulty initiat-
ing (SL > 30 min) and maintaining ( > 1 awakening with diffi-
culty returning to sleep) sleep and TST < 6 h. Subjects received temazepam 30 mg, glutethimide or placebo in parallel group design for four nights. Outcomes included patient-reported estimates of SL, TST, NOA and QOS. Heffron115 reported on 55 “insomnia outpatients” who received temazepam 30 mg or placebo in parallel groups for four nights. Subjects reported SL, TST, NOA and QOS. Tuk116 studied 21 “primary sleep- onset insomnia” patients in a within-patient crossover study. Subjects received a single night of placebo and a single night of temazepam 20 mg with one-week intervening washout. PSG was conducted on each of the two nights. SL, TST, WASO and

SE were reported. Voshaar92 assessed 85 individuals with
DSM-III-R primary insomnia in a within-subjects crossover
design including temazepam 20 mg, zolpidem and placebo. A
single-blind placebo period of four days was followed by 28
days of active treatment with zolpidem or temazepam. Data
are presented as means for the placebo period and active treat-
ment period for each sleep outcome. Wilson117 conducted an
actigraphic evaluation of 38 subjects with “complaints of poor
sleep.” Subjects were randomized to one of two crossover de-
signs, each of which included two weeks of placebo and two
weeks of temazepam 20 mg. Subjective results from patient
diaries as well as actigraphic results were averaged over the
respective periods.

Sleep latency: The meta-analysis for subjective SL, based
on two studies110,112 of temazepam 15 mg revealed a mean re-
duction of 20.06 min (CI: −1.07 to −39.05 min). Quality of evi-
dence was moderate due to imprecision.

One additional study assessed subjective SL at the 15 mg
dosage. Hindmarch111 found no effect on the VAS scale rating
for “ease of getting to sleep.”

Three studies114,115 evaluated the effects of temazepam 30 mg
on subjective sleep latency from patient diaries. Fillingham114
reported a reduction of SL of 40 min versus placebo. Hef-
fron115 found a 45 min reduction versus placebo. Hindmarch111
reported a statistically significant effect on a VAS for “ease of
getting to sleep” with temazepam 30 mg.

Tuk116 found no difference between temazepam 20 mg and
placebo in PSG SL. However, it is noteworthy that in this
sample of “primary sleep onset insomnia” patients, both te-
mazepam and placebo produced a reduction from baseline
of approximately 53 min (to SL of about 24 min). Wilson117
demonstrated a SL derived from actigraphy which was only
7 min less than that of placebo. However, of note, the end-of-
treatment SL for temazepam (by actigraphy) was only 15 min,
suggesting a possible floor effect for these results.

Three studies assessed subjective SL with temazepam 20
mg.92,113,117 Cuanang113 reported a reduction from baseline
which was 34.2 min greater than placebo reduction. Voshaar92
found end-of-treatment SL for temazepam 20 mg which was 29
min less than placebo. Similarly, Wilson117 found subjective SL
was 23 min less than placebo.

total Sleep time: Two studies110,112 were included in the
meta-analysis for subjective TST at 15 mg. The analysis re-
vealed a mean increase in TST of 64.4 min (CI: +8.1 to +120.8
min). Quality of evidence was moderate due to imprecision.
No additional studies evaluated subjective TST at this dosage.
Wu112 reported a PSG TST of 99.1 min greater than placebo for
15 mg.

Two studies114,115 reported subjective TST at the 30 mg dos-
age. Fillingim114 demonstrated TST which was 53 min greater
than placebo, while Heffron115 noted a 54.6 min greater TST
versus placebo. There were no investigations of objective TST
for this dosage.

At the 20 mg dosage, three trials92,113,117 reported subjective
TST. Cuanang113 found a 78 min greater TST increase from
baseline than placebo. Voshaar92 demonstrated a 46 min greater Do

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TST than placebo at end-of-treatment. Wilson117 also found an
18 min greater TST with temazepam 20 mg than with placebo.
One study117 assessed objective TST at 20 mg. Actigraphy re-
vealed a 12 min greater TST at this dosage versus placebo.

Wake after Sleep onSet: Meta-analysis for WASO was
not possible. One investigation116 evaluated PSG WASO at the
20 mg dosage and reported WASO time which was 28.1 min
less than placebo. Of note, the subjects in this study were de-
scribed as exhibiting “sleep onset insomnia.” At the same dos-
age, subjective WASO was 15 min less than placebo.92 This
was below the threshold for clinical significance.

Quality of Sleep: Meta-analysis was conducted for sleep
quality ratings from two studies110,111 for temazepam 15 mg.
The SMD was 0.25, below the range for clinical significance.
However, it should be noted that the Hindmarch111 study was
underpowered to detect all but extremely large effects in that it
only included 20 subjects. The quality of evidence was moder-
ate due to imprecision.

Two studies found statistically significant improvement in
sleep quality ratings for temazepam 30 mg.114,115 Cuanang113
reported statistically significant improvement for temazepam
20 mg on a quality rating comparing “better quality” to “same
or worse quality.”

Sleep efficiency: Meta-analysis was not achievable for SE
at any dosage.

At 15 mg, Wu112 found a PSG SE which was 13.3% greater
than placebo (CI: +3.9 to +22.6%). Subjective SE was +14.1%
versus placebo (CI: +5.8 to +22.3%). The quality of evidence
for both was moderate due to imprecision. At 20 mg, Tuk116
reported a +5.9% PSG SE versus placebo.

number of aWakeningS: No meta-analysis of NOA was
possible. One study110 reported data for subjective NOA at the
15 mg dosage (−0.5 awakenings; CI: −1.29 to +0.29 awaken-
ings). Quality of evidence was moderate due to imprecision.

Two studies114,115 reported subjective NOA at 30 mg. They
found −1.0 and −1.24 awakenings, respectively, compared to
placebo.

Tuk116 found no significant reduction in PSG NOA at 20 mg.
One study117 reported data for subjective NOA at 20 mg (−0.2
awakenings compared to placebo).

overall Quality of evidence: The overall quality of
evidence in the meta-analytic data from the two available stud-
ies was moderate for temazepam 15 mg due to imprecision.

HarmS: Limited data on adverse effects of temazepam 15
and 30 mg are available. Meta-analysis could not be performed.
Glass110 found no notable increase in adverse effects with te-
mazepam 15 mg versus placebo and no significant effects
were found on measures of daytime impairment. Cuanang113
reported “no marked difference in adverse events,” although
temazepam 20 mg was associated with a modest increase in
headache, blurred vision, depression and confusion. However,
the frequency of these events was low overall. Heffron115 found

no difference in overall frequency of adverse events but noted
that drowsiness, lethargy and vertigo were more commonly
reported with temazepam 30 mg. There is some evidence that
temazepam 30 mg is associated with daytime impairment
on tests such as the Choice Reaction Time Test and Critical
Flicker Fusion Test.111

In summary, the task force found that there was weak evi-
dence of efficacy of temazepam in terms of therapeutic effects
on sleep onset, total sleep time, awakenings, sleep efficiency,
and possibly WASO with limited or no consistent evidence of
adverse events in excess of placebo. However, there was also
limited evidence for daytime impairment with temazepam
30 mg. Over, benefits were deemed to outweigh harms for te-
mazepam 15 mg.

patientS’ valueS and preferenceS: Based on its clini-
cal judgement, the task force determined that a majority of pa-
tients would be likely to use both temazepam 15 mg and 30 mg
compared to no treatment.

Melatonin agonists

Ramelteon for the Treatment of Chronic Insomnia

Recommendation 7: We suggest that clinicians use
ramelteon as a treatment for sleep onset insomnia (versus
no treatment) in adults. [WEAK]

Remarks: This recommendation is based on trials of 8 mg
doses of ramelteon.

Summary
Four RCTs investigated the use of ramelteon in the treatment
of chronic primary insomnia.118–121 The overall quality of evi-
dence from these studies was downgraded to very low due to
substantial heterogeneity across studies, imprecision and po-
tential publication bias. The overall evidence for ramelteon 8
mg. was weakly in favor of its effectiveness for the treatment of
sleep onset disturbance only. Meta-analysis of the three stud-
ies meeting inclusion criteria that reported objective (PSG)
sleep latency demonstrated marginal reduction of sleep latency.
The analysis revealed minimal increase in PSG-determined to-
tal sleep time which fell well below the defined threshold for
clinical significance. Measures of sleep efficiency and sleep
quality showed no clinically significant improvement. There
was no evidence of significant difference from placebo for any
adverse events, based on available side effect data. Although
the evidence for efficacy is marginal, the benefits appear to be
greater than the minimal potential harms. Based on clinical
judgment, the task force determined that the majority of well-
informed patients would use ramelteon over no treatment. This
judgement is based on the evidence of improved sleep latency,
coupled with its apparently low potential for adverse events.

See Figures S31–S38, S76 and S77 and Table S14 in the
supplemental material.

Discussion
Evidence from four RCTs which investigated the use of ramelt-
eon in the treatment of chronic primary insomnia was included Do

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in the statistical analysis.118–121 Subjects in all studies demon-
strated chronic primary insomnia with associated daytime
complaints. All studies required mean objective LPS of > 20
min on two nights of PSG screening. All studies except Mayer
and colleagues119 also required mean objective WASO > 60
min. Kohsaka and colleagues118 studied 65 chronic insomnia
patients for two nights each at ramelteon doses of 4, 8, 16, and
32 mg. Roth and colleagues120 studied 100 older adults (age > 65
years) with chronic primary insomnia. Subjects were adminis-
tered two consecutive nights each of placebo, ramelteon 4 mg,
and ramelteon 8 mg in a three-phase crossover protocol, with
randomization of the treatment sequence and sustained wash-
out time between each two night sequence.

Zammitt121 studied the effects of nightly ramelteon in adults
at dosages of 8 and 16 mg. PSG was conducted at baseline, and
weeks 1, 3, and 5. The Mayer paper119 reported on six-month
nightly use of ramelteon in 451 adults with chronic insomnia
from 46 multinational sites. Two nights of PSG were conducted
in week 1 and at approximately one month intervals thereafter.

Sleep latency: The impact of 8 mg ramelteon on PSG-as-
sessed SL was evaluated in three studies.118,120,121 Objective sleep
latency data in the study by Mayer and colleagues119 were not
adequate for meta-analysis and therefore could not be included.

Meta-analysis of the grouped evidence demonstrated mar-
ginal improvement in this critical outcome. However, the mean
difference between the treatment and control groups was not
clinically significant (−9.57 min; CI: −6.38 to −12.75 min). The
confidence interval crossed the clinical significance threshold,
and therefore the quality of evidence was downgraded for im-
precision. It was downgraded further for the high degree of
heterogeneity across studies (I2 = 96%), and due to the risk of
publication bias since all these studies were funded by indus-
try. The resultant quality of evidence is very low.

Mean differences in objective sleep latency varied from −7.6
min to −13.1 min. Of note, the Roth investigation included ex-
clusively older adults and found the smallest improvement in
sleep latency. Subjective sleep latency from these investiga-
tions was comparable to objective latencies with mean differ-
ence (−11.44 min; CI: −3.31 to −19.56 min) falling below the
clinical significance threshold.

Several additional papers which met inclusion criteria, but
did not contain data suitable for this analysis, have addressed
the efficacy and side effect profile of ramelteon.122–126 The ob-
jective and subjective sleep latency from these results were
consistent with the meta-analysis findings. This was likewise
the case for sub-group analysis of subjects with primary sleep
onset complaints.124 A post-hoc analysis of the data from Zam-
mitt by Mini and colleagues123 found a significantly greater
percentage of ramelteon 8 mg patients with > 50% reduction in
sleep latency at week 1 (63.0% versus 39.7% for placebo), week
3 (63.0% versus 41.2%), and week 5 (65.9% versus 48.9%).

total Sleep time: All four studies included in the meta-
analysis evaluated objective total sleep time for ramelteon 8
mg.118–121 Although small improvements in TST were observed
in some individual studies, ranging from 1.2 to 12.5 min lon-
ger, the meta-analysis reveals minimal increase (+6.58 min; CI:

+1.36 to +11.80 min) which falls well below the threshold for
clinical significance. The quality of evidence was downgraded
to LOW due to the high degree of heterogeneity across stud-
ies, and due to the risk of publication bias since all these stud-
ies were funded by industry. Meta-analysis results of reported
subjective TST were consistent with the objective finding (+5.7
min; CI: −7.65 to +19.04 min). Additional studies not included
in meta-analysis supported these results.122,125,126

Wake after Sleep onSet: Meta-analysis of objective WASO
from the two studies reporting adequate data118,121 show a clini-
cally insignificant increase (+3.5 min; CI: +2.77 to +4.23 min)
in WASO for the ramelteon group, well below the significance
threshold of 20 min. The quality of evidence was downgraded
to moderate due to potential publication bias. One study not in-
cluded in meta-analysis122 found no difference in PSG WASO.

Zammitt and Mayer reported subjective WASO data for
meta-analysis.119,121 The ramelteon group demonstrated a clini-
cally insignificant increase in WASO of 5.2 min (CI: −6.77 to
+17.24 min). The quality of evidence was low due to heteroge-
neity and potential publication bias. The only additional study
which assessed subjective WASO found no difference between
placebo and ramelteon 8 mg.126

Quality of Sleep: Sleep quality ratings showed virtually
no difference from placebo in any of the studies assessed.119–121
Meta-analysis suggests no difference between ramelteon and pla-
cebo, with a pooled mean difference of −0.04 points (CI: −0.13 to
+0.05 points) on a 7-point Likert scale. The quality of evidence
was downgraded to low due to heterogeneity and the risk of pub-
lication bias since all these studies were funded by industry. Ad-
ditional studies which assessed subjective sleep quality found no
difference between ramelteon and placebo groups.122,125,126

Sleep efficiency: Three studies reported sleep efficiency
data included in meta-analysis.118,120,121 Minimal improvements
in sleep efficiency were reported (+1.93%; CI: +1.00 to +2.87%),
falling well below the clinically significance threshold for ob-
jective sleep efficiency of 5%. The quality of evidence was low
due to heterogeneity and potential publication bias. Additional
studies did not report sleep efficiency data.

number of aWakeningS: No meta-analysis for PSG num-
ber of awakenings was conducted as only one study reported
adequate data for analysis.119 This investigation found no clini-
cally significant difference between ramelteon 8 mg and pla-
cebo (+0.1 awakenings; CI: +0.08 to +0.15 awakenings). The
quality of evidence was moderate due to potential publication
bias. Other studies which evaluated NOA reported no signifi-
cant differences as well.120,125,126

In summary, these studies show very weak evidence for re-
duction of sleep latency at the recommended prescribed dosage
(8 mg), with mean decrease of 9.57 min (CI: −6.38 to −12.75
min), and no consistent evidence of improvement in other ob-
jective or subjective parameters.

overall Quality of evidence: The overall quality of
evidence in the meta-analytic data from these studies was Do

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downgraded to very low for several reasons. Substantial het-
erogeneity across studies was noted for multiple outcomes.
The data were also downgraded for imprecision, due to the rel-
atively large confidence intervals, which cross the clinical sig-
nificance thresholds for multiple outcomes. All of these studies
were industry sponsored, resulting in further downgrading of
evidence due to potential publication bias. The quality of evi-
dence for individual outcomes ranged from moderate to very
low; therefore, the overall quality of evidence was very low.

HarmS: Meta-analytic data on adverse effects showed a rela-
tively low frequency of adverse effects overall and none which
were significantly different than placebo. This analysis included
headache, nausea, upper respiratory infection and nasopharyn-
gitis. A single case of leukopenia, which was judged possibly
related to medication, was noted in the Mayer study.119 Both
Zammitt121 and Mayer119 found no evidence of rebound insom-
nia or withdrawal effects following discontinuation (notably,
the Mayer et al. study was based on six months of nightly use).

The studies not included in the meta-analysis found no in-
dication of a significant difference in adverse events between
ramelteon and placebo. Commonly reported adverse events
in these studies included fatigue, headache, dizziness and
somnolence.

Three studies assessed for next-day impairment associated
with ramelteon. Roth and colleagues reported on next-day re-
sidual pharmacological effects of ramelteon in an older adult
population.120 Observations of DSST, immediate and delayed
recall, subjective alertness, and concentration showed no sig-
nificant residual as compared to placebo on any outcomes.
Employing the same residual effect measures, Zammitt et al.121
reported small but statistically significant impairment with
ramelteon 8 mg. in immediate recall at week 3 only, delayed
recall (week 1 only), level of alertness (week 5), and ability to
concentrate (week 1). Mayer119 found no consistent evidence
of next-day impairment in alertness, recall, DSST or visual
analogue scales of mood, energy, or cognition. Overall, the
available data suggest no consistent evidence of next-day im-
pairment associated with the use of ramelteon.

In summary, the task force found that there was weak evi-
dence of efficacy in the treatment of sleep onset insomnia, with
limited or no consistent evidence of adverse events in excess
of placebo. Therefore, benefits were deemed to marginally out-
weigh harms.

patientS’ valueS and preferenceS: Based on its clini-
cal judgement, the task force determined that in light of its
efficacy for sleep onset and its relatively benign side effect
profile, a majority of patients would be likely to use ramelteon
compared to no treatment.

Heterocyclics

Doxepin for the Treatment of Chronic Insomnia

Recommendation 8: We suggest that clinicians use doxepin
as a treatment for sleep maintenance insomnia (versus no
treatment) in adults. [WEAK]

Remarks: This recommendation is based on trials of 3 mg
and 6 mg doses of doxepin.

Summary
Four studies addressed the efficacy of doxepin 3 mg.127–130 Four
studies also investigated the 6 mg dosage.128–131 The overall
quality of evidence for both dosages was low due to poten-
tial publication bias and imprecision. The evidence suggests
minimal improvement in SL but clinically significant im-
provements in WASO, TST and SE. The overall evidence was
graded as weakly in favor of doxepin’s efficacy in improving
sleep maintenance.

Meta-analysis shows that PSG and patient-reported SL
at 3 mg and PSG SL at 6 mg fell below the clinical signifi-
cance threshold. Both PSG and subjective TST at 3 mg, as
well as PSG TST at 6 mg, were above significance thresholds,
although subjective TST at 6 mg fell short of this criterion.
PSG data for reduction of WASO exceeded the clinical sig-
nificance threshold at both dosages, although patient diary
data for WASO at the 6 mg dosage fell below threshold, based
on two studies. The SMD in sleep quality for doxepin 3 mg
suggests moderate improvement, while the SMD for the 6 mg
dosage suggests mild improvement. The objective SE for both
dosages exceeded the clinical significance level, while objec-
tive NOA fell short.

Meta-analysis of side effects included headache, diarrhea,
somnolence and upper respiratory infection at 3 mg, and head-
ache and somnolence at the 6 mg dose. Results suggest mild
increase in somnolence at 6 mg. Given the demonstrated im-
provements in WASO, TST and SE, with limited adverse ef-
fects, the task force judged the benefits to outweigh the harms.
The clinical judgement of the task force was that the majority
of well-informed patients would use doxepin over no treatment.
This judgement is based on the evidence for clinically signifi-
cant improvement in WASO, TST and SE.

See Figures S39–S53, S78–S83 and Tables S15 and S16 in
the supplemental material.

Discussion
Five studies investigated the effects of doxepin at 3 mg and/or
6 mg.127–131 Krystal127 conducted a 12-week RCT of nightly dox-
epin 1 and 3 mg versus placebo in 240 elderly ( > 65 years) sub-
jects with predominant sleep maintenance insomnia. Subjects
were randomized to one of three treatment groups. Outcome
variables included both PSG and sleep diary data. Krystal128
investigated doxepin 3 mg and 6 mg in a five week trial which
included 221 adults with sleep onset and maintenance insom-
nia who were randomized to one of the two doxepin doses or
placebo. PSG data and sleep diaries were included. Roth129 em-
ployed a crossover design with randomized assignment to one
of four treatment sequences which consisted of two nights each
of doxepin 1 mg, doxepin 3 mg, doxepin 6 mg and placebo,
with intervening washout. PSG and sleep diary data were col-
lected. The study included 67 adults who met both baseline
PSG-defined sleep onset and maintenance criteria. Scharf130
employed the identical crossover design and dosages in 76 el-
derly insomnia subjects. Lankford131 reported data on a four
week nightly trial of doxepin 6 mg or placebo in 254 elderly Do

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subjects with sleep onset and sleep maintenance insomnia.
Outcome variables were patient-reported and clinician rated.

Hajak132 also conducted a RCT of doxepin, but the dosages
(25–50 mg) were significantly higher that FDA-approved hyp-
notic dosages. For this reason, this study was not included in
the current analysis.

Sleep latency: Four studies127–130 reported PSG SL data
for the 3 mg dosage. The mean difference from placebo
(−2.30 min; CI: −6.22 to +1.62 min) was below the defined
significance threshold. Evidence quality was moderate due to
potential publication bias. Likewise, patient-reported SL127,130
did not meet clinical significance (−9.35 min; CI: −21.89 to
+3.19 min). Quality was low due to imprecision and poten-
tial publication bias. Three studies included adequate data
for meta-analysis at the 6 mg dosage,128–130 showing a mean
difference for objective SL of −5.29 min (CI: −1.34 to −9.25
min) with moderate quality of evidence due to publication
bias. No sleep diary data were available for meta-analysis of
SL at this dosage.

total Sleep time: Four investigations127–130 reported PSG
data for TST at 3 mg. The analysis reveals a clinically signifi-
cant increase in TST at this dosage (+26.14 min; CI: +18.49 to
+33.79 min). Quality was low due to imprecision and potential
publication bias. Subjective reports for 3 mg127,130 were also
in the range of clinical significance (+43.57 min; CI: +5.16 to
+81.98 min) with very low quality of evidence due to hetero-
geneity, imprecision and potential publication bias. At the 6
mg dosage, PSG-determined TST,128–130 also met the clinical
significance criterion (+32.27 min; CI: +24.24 to +40.30 min)
with moderate quality of evidence due to potential publication
bias. However, subjective TST at this dosage130,131 fell short
of significance (+18.84 min; CI: −1.65 to +39.34 min) with
LOW quality of evidence due to imprecision and potential
publication bias.

Wake after Sleep onSet: WASO was considered a key
outcome variable in all of the doxepin studies noted. The PSG
data for 3 mg doxepin showed a clinically significant mean dif-
ference from placebo of −22.17 min (CI: −14.72 to −29.62 min),
based on four trials.127–130 Quality of evidence was low due to
imprecision and potential publication bias. Only one study
reported subjective WASO, with a reduction of 20.0 min ver-
sus placebo. Quality of these data was low due to imprecision
and potential publication bias. At 6 mg, PSG WASO showed
a clinically significant reduction of 23.14 min (CI: −16.36 to

−30.34 min)128–130 with LOW quality of evidence due to impre-
cision and potential publication bias. Patient diary results did
not meet clinical significance (−14.39 min; CI: −3.93 to −24.86
min)130,131 with moderate quality of evidence due to potential
publication bias.

Quality of Sleep: Quality of sleep ratings for the 3 mg
dosage suggest substantial improvement (SMD: +0.57; CI:
+0.26 to 0.88 SMD) with low quality of evidence,127,130 due to
imprecision and potential publication bias. More modest im-
provement was noted at 6 mg (SMD +0.28; CI +0.06 to 0.49

SMD)130,131 with moderate quality of evidence due to potential
publication bias.

Sleep efficiency: PSG SE was reported in three studies
for the 3 mg dosage.127,129,130 Evidence quality was low due to
imprecision and potential publication bias. The improvement
in SE was clinically significant at +6.78% (CI: +4.50 to 9.07%).
SE at the 6 mg dose, based on two investigations129,130 was also
significantly improved (+7.06%; CI: +5.12 to 9.01%) with mod-
erate quality of evidence due to potential publication bias.

number of aWakeningS: PSG-determined NOA was
mildly increased (+0.53 awakenings; CI: −0.37 to +1.42 awak-
enings) for 3 mg127,129,130 and the 6 mg dose (+0.44 awakenings;
CI: −0.57 to +1.44 awakenings), with moderate quality for both,
due to potential publication bias.

overall Quality of evidence: The quality of evidence
in the meta-analytic data for the majority of variables was mod-
erate to low due to industry sponsorship and, in some cases,
imprecision (due to relatively large confidence intervals for
numerous variables that cross clinical significance thresholds).
Quality was further downgraded to very low for subjective
TST at 6 mg as a result of the above factors plus heterogene-
ity of data. As a result, the overall quality of evidence for the
doxepin data is considered very low.

HarmS: Meta-analysis was available for both the 3 mg127–129
and 6 mg128,129,131 dosages and revealed no increase in head-
ache frequency with doxepin. Somnolence showed no sig-
nificant increase versus placebo (+0.01 risk difference) at the
3 mg level127–129 and a small increased risk at 6 mg (+0.04
risk difference).128,129,131 Data were also available for meta-
analysis of risk for diarrhea and upper respiratory infection.
Neither showed significantly greater risk than placebo. With
respect to next-day residual effects, no difference was ob-
served between doxepin 3 mg or 6 mg and placebo on DSST,
Symbol Copying Test, or visual analogue scales for morning
sleepiness.127–130

In summary, the task force found weak evidence for efficacy
in the treatment of sleep maintenance insomnia, with mini-
mal evidence of adverse events in excess of placebo. Therefore,
benefits were deemed to be greater than harms.

patientS’ valueS and preferenceS: Based on its clini-
cal judgement, the task force determined that in light of the
data supporting efficacy for reducing WASO, and improving
TST, SE and sleep quality, a majority of patients would be
likely to use doxepin compared to no treatment.

Trazodone for the Treatment of Chronic Insomnia

Recommendation 9: We suggest that clinicians not
use trazodone as a treatment for sleep onset or sleep
maintenance insomnia (versus no treatment) in adults.
[WEAK]

Remarks: This recommendation is based on one trial of a 50
mg dose of trazodone.Do

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See Table S17 in the supplemental material.

Summary
A single study78 of trazodone 50 mg met inclusion criteria;
therefore, no meta-analysis is available. The overall qual-
ity of evidence for this study was moderate due to potential
publication bias. The patient-reported data from this study
demonstrated a modest reduction in SL which fell below the
threshold for clinical significance. Likewise, the moderate in-
crease in TST and the small reduction in WASO did not reach
the clinical threshold criteria. Quality of sleep was insignifi-
cantly improved and reduction in NOAs fell just below clinical
significance. In summary, none of the sleep outcome variables
improved to a clinically significant degree.

No meta-analysis of harms was possible. Given the absence of
demonstrated efficacy on numerous critical outcome variables,
coupled with limited evidence regarding harms, the task force
judged the harms to potentially outweigh the benefits. Based on
its clinical judgement, the task force determined that, despite
the absence of significant efficacy for trazodone 50 mg and the
paucity of information regarding harms, the majority of patients
would be likely to use trazodone compared to no treatment.

Discussion
Walsh78 investigated the efficacy of trazodone 50 mg versus
zolpidem 10 mg and placebo. The final sample for the trazo-
done and placebo groups included 187 adults with sleep on-
set insomnia. Subjects were administered either trazodone or
placebo in double-blind fashion for 14 consecutive nights. All
data were patient-reported.

Sleep latency: Subjective SL was reduced by 10.2 min (CI:
−8.95 to −11.44 min). This falls short of the clinical significance
threshold. The quality of evidence was moderate due to poten-
tial publication bias.

total Sleep time: Sleep diary TST was increased by a clin-
ically insignificant 21.8 min (CI: +20.10 to +23.49 min). The
quality of evidence was moderate due to potential publication
bias.

Wake after Sleep onSet: Sleep diary WASO was reduced
by 7.7 min (CI: −8.89 to −6.5 min), falling below the threshold.
The quality of evidence was moderate due to potential publica-
tion bias.

Quality of Sleep: On a 4-point scale (1 = excellent,
4 = poor) sleep quality was not significantly improved versus
placebo (−0.13 points; CI: −0.11 to −0.14 points). The quality of
evidence was moderate due to potential publication bias.

number of aWakeningS: This outcome was reduced by
0.4 (CI: −0.37 to −0.42 awakenings) compared to placebo, less
than the 0.5 subjective awakening threshold. The quality of
evidence was moderate due to potential publication bias.

overall Quality of evidence: The overall quality of
evidence for this study was moderate.

HarmS: There was no meta-analysis of harms. In the Walsh78
paper, the trazodone group experienced significantly more
side effects than the placebo group. Chief among these were
headache (trazodone 30%; placebo 19%) and somnolence (tra-
zodone 23%; placebo 8%). In all, 75% of trazodone subjects
reported some adverse event(s), compared to 65.4% of subjects
who received placebo.

patientS’ valueS and preferenceS: Based on its
clinical judgement, the task force determined that, despite
the absence of significant efficacy for trazodone 50 mg and
the paucity of information regarding harms, the majority of
patients would be likely to use trazodone compared to no
treatment. This is based on the perception of trazodone as a

“safer” sleep-promoting agent by many physicians and the re-
sulting recommendations and prescribing practices of those
physicians.

Anticonvulsants

Tiagabine for the Treatment of Primary Insomnia

Recommendation 10: We suggest that clinicians not use
tiagabine as a treatment for sleep onset or sleep maintenance
insomnia (versus no treatment) in adults. [WEAK]

Remarks: This recommendation is based on trials of 4 mg
doses of tiagabine.

Summary
Three studies addressed the efficacy of tiagabine 4 mg.133–135
The overall quality of evidence was very low due to potential
publication bias, heterogeneity, and imprecision. Meta-analy-
ses were conducted for SL (PSG and subjective), TST (PSG
and subjective), WASO (PSG and subjective), sleep quality,
SE (PSG), and NOA (PSG and subjective). These analyses
revealed that both objective and subjective measures of sleep
latency fell below the threshold for clinical significance. Mea-
sures of TST showed minimal change (PSG) and mild to mod-
erate reduction (sleep diary). WASO data demonstrated no
clinically significant change on either metric. Meta-analysis
of SMD for sleep quality suggested improvement which fell
below the clinical significance threshold. Neither objective nor
subjective NOAs were reduced by clinically significant levels,
while PSG SE was minimally reduced.

Meta-analysis of adverse effects showed no difference be-
tween tiagabine and placebo on headache or nausea. Given the
absence of demonstrated efficacy on numerous critical out-
come variables (with slight trending toward mild worsening
on some outcomes), coupled with limited evidence regarding
harms, the task force judged the harms to potentially outweigh
the benefits.

It was determined by clinical judgement of the task force
that the majority of well-informed patients would not use ti-
agabine over no treatment. This judgement is based on the lack
of evidence for efficacy and the limited systematic information
regarding adverse effects.

See Figures S55–S64, S84 and S85 and Tables S18–S20 in
the supplemental material.Do

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MJ Sateia, DJ Buysse, AD Krystal, et al. Clinical Practice Guideline: Insomnia

Discussion
Three studies were included in the meta-analyses of ti-
agabine.133–135 Roth133 studied 207 elderly primary insomnia
patients (65–85 years) with difficulty initiating and maintain-
ing sleep who received tiagabine 2, 4, 6, or 8 mg or placebo on
two consecutive study nights with PSG recordings in a paral-
lel group design. Walsh134 similarly evaluated 232 adults with
chronic sleep-onset and maintenance insomnia. Tiagabine 4, 6,
8, or 10 mg or placebo was administered on two consecutive
nights with PSG. Walsh135 conducted a crossover study of 58
adults (age 35–64) with chronic sleep onset and maintenance
problems. Subjects received 4, 8, 12, and 16 mg and placebo
for two consecutive nights of sleep recording. Medication-free
washout periods between doses ranged from 5–12 nights.

Sleep latency: The meta-analysis for SL included three
studies.133–135 PSG SL data showed a small increase in SL
(+3.65 min; CI: −8.00 to +15.31 min) with very low quality of
evidence due to heterogeneity, imprecision and potential pub-
lication bias. The subjective data133,135 showed a moderate in-
crease in SL (+13.31 min; CI: +7.54 to 19.37 min). Quality of
evidence was moderate due to potential publication bias.

total Sleep time: Objective data for TST133–135 demon-
strated a minimal reduction in TST (−1.21 min; CI: −7.44 to
+5.02 min) with LOW quality evidence due to heterogeneity
and potential publication bias. Patient-reported TST133,135 was
reduced by 19.95 min (CI: −25.35 to −14.54 min) with moder-
ate quality of evidence due to potential publication bias. Nei-
ther subjective nor objective findings met clinical significance.

Wake after Sleep onSet: The PSG WASO analysis133–135
revealed essentially no difference from placebo (−0.56 min; CI:

−6.77 to +5.65 min). Quality of evidence was low due to het-
erogeneity and potential publication bias. Sleep diary data133,135
indicated a small, clinically insignificant increase (+4.29 min;
CI: −0.22 lower to +8.79 min) with moderate quality of evi-
dence due to potential publication bias.

Quality of Sleep: The meta-analysis for QOS133,135 re-
sulted in a SMD of +0.48 (CI: −0.5 to +1.46 SMD), which falls
below the level of clinical significance. Quality of evidence
was very low due to heterogeneity, imprecision and potential
publication bias.

Sleep efficiency: The objective sleep efficiency was re-
duced (−0.53%; CI: −0.02 to −1.05%). Quality of evidence was
moderate due to potential publication bias.

number of aWakeningS: The PSG NOAs were mildly
increased (+0.5 awakenings; CI: −1.29 to +2.29 awakenings).
The subjective NOA was minimally reduced at −0.21 awaken-
ings (CI: −0.9 to +0.48 awakenings), falling below the thresh-
old for clinical significance. Level of evidence was low for both
measures due to imprecision and potential publication bias

overall Quality of evidence: The overall quality
of evidence for the meta-analytic data was very low due to

significant heterogeneity, imprecision and potential bias (in-
dustry sponsorship) for some critical outcomes.

HarmS: Meta-analysis was possible for two adverse effects
(headache and nausea). Neither showed any significant dif-
ference from placebo. None of the three studies found a sig-
nificant difference from placebo on morning-after DSST or
visual analogue scales for sleepiness/alertness at the 4 mg
dose.

patientS’ valueS and preferenceS: Based on its clini-
cal judgement, the task force determined that in light of the
absence of significant efficacy at this dose and the paucity of
information regarding harms, the majority of patients would
not be likely to use tiagabine compared to no treatment.

Over-the-counter preparations

Diphenhydramine for the Treatment of Primary
Insomnia

Recommendation 11: We suggest that clinicians not use
diphenhydramine as a treatment for sleep onset and sleep
maintenance insomnia (versus no treatment) in adults.
[WEAK]

Remarks: This recommendation is based on trials of 50 mg
doses of diphenhydramine.

Summary
Two RCTs evaluated diphenhydramine 50 mg for the treat-
ment of chronic primary insomnia.110,136 The overall quality of
evidence was downgraded to low due to imprecision and risk
of publication bias. The overall evidence for diphenhydramine
50 mg was weakly against its effectiveness for improving
sleep onset and TST. The mean reduction in patient-reported
sleep latency versus placebo fell below the level of clinically
significant improvement. The same studies found a small in-
crease in TST which also fell below the threshold for clinical
significance. The single paper136 which included PSG-deter-
mined SL and TST showed outcomes which also fell below
clinical significance thresholds. None of the other objective
or patient-reported outcome variables reached clinical sig-
nificance thresholds. In addition, one paper meeting inclusion
criteria137 but not including suitable data for meta-analysis
evaluated diphenhydramine 50 mg in mild to moderate in-
somnia patients.

No meta-analysis was possible for side effects. Since no
systematic data addressing harms is available, it is difficult
to make a clear determination regarding benefits versus
harms. However, in light of the absence of clear benefits, the
task force judged the benefits and harms to be approximately
equal. It was determined by clinical judgement of the task
force that the majority of well-informed patients would not
use diphenhydramine over no treatment. This judgement is
based on the absence of evidence for clinically significant
improvement.

See Figures S65 and S66 and Table S21 in the supplemen-
tal material.Do

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MJ Sateia, DJ Buysse, AD Krystal, et al. Clinical Practice Guideline: Insomnia

Discussion
Two studies of diphenhydramine 50 mg included adequate
data for meta-analysis. Glass110 studied 25 elderly subjects
(mean age = 73.9 years) with insomnia. Enrollees received
diphenhydramine, temazepam 15 mg and placebo in a cross-
over design with two weeks of nightly use for each interven-
tion, followed by washout. Primary outcomes measures were
sleep variables recorded in patient diaries. Morin136 compared
diphenhydramine (14 nights, followed by 14 nights of pla-
cebo) to a valerian-hops preparation (28 nights) and placebo
(28 nights) in a total population of 184 adults with occasional
insomnia (2–4 nights/week with SL > 30 min or WASO > 30
min). Patients were randomly assigned to the intervention
groups and PSG and patient-reported data were collected. A
third study,137 not included in meta-analysis, assessed mild to
moderate insomnia patients in family practice settings. Par-
ticipants received diphenhydramine 50 mg and placebo for one
week each in crossover fashion, without intervening washout.
Outcome assessment was based on patient-completed sleep
questionnaires.

Sleep latency: The single study employing PSG136 found
a 7.89 min reduction in SL (CI: −17.40 to +1.62 min). This fell
below the significance threshold. Quality of evidence was low
due to imprecision and potential publication bias. Two stud-
ies110,136 met requirements for meta-analysis of subjective SL.
This revealed a mean difference from placebo of −2.47 min (CI:
−8.17 to +3.23 min). The Rickels study137 found statistically sig-
nificant improvement in SL with diphenhydramine using a 0–4
patient-rating scale, but no specific quantitative data regarding
actual SL times were included.

total Sleep time: Morin136 reported a PSG TST increase
of 12.37 min (CI: −13.38 to +38.12 min). This fell below the
significance threshold of 20 min. Quality of evidence was
low due to imprecision and potential publication bias. Meta-
analysis of the two studies demonstrated a 17.86 min increase
(CI: −3.79 to + 39.51 min) in subjective TST versus placebo.
The Rickels study137 found “statistically significant improve-
ment” in patient-reported TST but, as noted above, it is un-
clear to what extent this represented clinically significant
improvement.

Wake after Sleep onSet: No data pertaining to wake af-
ter sleep onset were available.

Quality of Sleep: Glass110 found minimal difference in
sleep quality between diphenhydramine and placebo (mean
difference of +0.1 SD; CI: −0.45 to +0.65 SD). Quality of
evidence was downgraded to moderate due to potential pub-
lication bias. Rickels137 reported statistically significant im-
provement in sleep quality.

Sleep efficiency: The objective sleep efficiency data from
the single study reporting PSG analysis136 found no clinically
significant improvement (+2.59%; CI: −3.25 to +8.43%). In
this same study, subjective SE also fell below the threshold
(+4.61%; CI: +1.33 to +7.88%).

number of aWakeningS: The change in subjective number
of awakenings (−0.3 awakenings; CI: −1.03 to +0.43 awaken-
ings) was not clinically significant.110

overall Quality of evidence: The overall quality of
evidence in the meta-analytic data from these studies was
downgraded to low for imprecision, due to confidence inter-
vals which crossed the clinical significance thresholds for sub-
jective TST, a critical outcome. These studies were industry
sponsored, resulting in further downgrading of evidence due
to potential publication bias. The quality of evidence for indi-
vidual critical outcomes ranged from moderate to low, there-
fore the overall quality of evidence was low.

HarmS: No meta-analysis of adverse effects was possible.
Neither Morin136 nor Glass110 found significant differences
between diphenhydramine and placebo in adverse events.
Rickels137 reported higher numerical rates of drowsiness, diz-
ziness, and grogginess with diphenhydramine but no statistical
analysis was conducted.

Morin136 found no substantial rebound effects following dis-
continuation of diphenhydramine. Glass110 noted minimal dif-
ferences between diphenhydramine and placebo in the number
of subjects experiencing rebound for at least one sleep out-
come variable. Glass110 found no difference in morning-after
DSST or Manual Tracking Task (MTT) between interventions.

In summary, the task force found that there was weak evi-
dence demonstrating an absence of efficacy in the treatment of
sleep onset insomnia, with minimal evidence of adverse events
in excess of placebo. Therefore, benefits were deemed approxi-
mately equal to harms.

patientS’ valueS and preferenceS: Based on its clini-
cal judgement, the task force determined that, in light of the
paucity of data supporting efficacy for sleep onset and mainte-
nance, a majority of patients would not be likely to use diphen-
hydramine compared to no treatment.

Melatonin for the Treatment of Primary Insomnia

Recommendation 12: We suggest that clinicians not use
melatonin as a treatment for sleep onset or sleep maintenance
insomnia (versus no treatment) in adults. [WEAK]

Remarks: This recommendation is based on trials of 2 mg
doses of melatonin.

Summary
Three studies addressed the efficacy of melatonin 2 mg.138–140
These investigations included only older adults ( > 55 years).
The overall quality of evidence was very low due to poten-
tial publication bias, heterogeneity, and imprecision. Meta-
analysis was only achievable for sleep quality. This indicated a
SMD of +0.21 (CI: −0.36 to +0.77 SMD), which was not clini-
cally significant. The minimal overall evidence available was
weakly against melatonin’s efficacy in improving sleep onset,
maintenance, or quality.

No adequate data for meta-analysis of adverse effects was
available. Given the lack of evidence for efficacy in treating Do

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insomnia, and the unavailability of systematic data on side ef-
fects, the task force judged the benefits to be approximately
equal to harms. It was determined by the task force that the
majority of well-informed patients would use melatonin over
no treatment. This is based on its availability and the wide-
spread perception of melatonin as a benign sleep aid.

See Figure S67 and Table S22 in the supplemental material.

Discussion
Three studies included adequate data for melatonin meta-anal-
ysis.138–140 Lemoine138 studied 170 older adults (age > 55 years)
with primary insomnia. Subjects received either prolonged re-
lease melatonin (PRM) 2 mg or placebo nightly for 3 weeks.
Outcome data was patient-reported. Luthringer139 similarly
studied 40 older adults (age > 55 years) who received PRM 2
mg or placebo for 3 weeks. Outcomes included both PSG and
subjective data. Finally, Wade140 evaluated 354 patients of the
same age group with PRM 2 mg or placebo nightly for 3 weeks.
Outcome data was patient-reported.

In addition, seven trials which met inclusion criteria but
did not include adequate data for meta-analysis were identi-
fied.141–147 These investigations employed various dosages and
combinations with other agents, rendering meaningful com-
parisons to the 2 mg RCTs impossible. Pertinent features of
these studies are included within each outcome section.

Haimov143 conducted a randomized crossover study of el-
derly adults with insomnia consisting of one week on each of
three interventions (2 mg sustained-release melatonin, 2 mg
fast-release melatonin or placebo) with intervening washout,
followed by a 2-month extension of 1 mg slow-release melato-
nin. Data were derived from actigraphy. Zhdanova147 evaluated
three dosages of melatonin (0.1, 0.3, and 3 mg) versus placebo in
a randomized crossover study of 30 elderly ( > 50 years) adults
(15 normal sleepers and 15 insomnia subjects with reduced SE).
Subjects received each dosage or placebo for one week with
intervening washout. Wade146 administered prolonged-release
melatonin 2 mg or placebo to adults with primary insomnia
for 3 weeks, after which the melatonin group continued for 26
weeks, while the placebo group was re-randomized to mela-
tonin or placebo (1:1). Sleep outcome variables (from sleep
diary) were analyzed according by age group as well as by
melatonin deficiency status. Baskett141 conducted a random-
ized controlled crossover study of healthy elderly with sleep
maintenance problems. Subjects received 5 mg melatonin or
placebo for four weeks with intervening washout.

Sleep latency: Meta-analysis was not possible for sleep
latency. Luthringer139 reported a PSG SL reduction of 8.9 min
(CI: −2.35 to −15.45 min), which falls below clinical signifi-
cance (prolonged release 2 mg). The quality of evidence was
low due to imprecision and potential publication bias.

In the Haimov143 investigation, fast-release melatonin pro-
duced significantly shorter SL than placebo at one week. At 2
months, sustained release 1 mg resulted in significantly shorter
SL than placebo. Zhadanova147 reported no significant im-
provement in PSG SL at any dosage.

Wade146 found that the melatonin deficient group (includ-
ing all ages) showed no improvement with melatonin versus

placebo on SL at three weeks. However, the elder group (65–80
years) showed significant reduction of SL with melatonin, re-
gardless of melatonin deficiency status (SL: −19.1 min; pla-
cebo −1.7 min). This improvement held at 19 weeks for the
elder group (melatonin: −25.9 min; placebo: −8.3 min). Wade145
subsequently re-analyzed these data and reported that the sig-
nificant improvement in SL held when the age range for the

“elderly” group was expanded to 55–80 years, but not lower.
Baskett141 found no improvement in SL (as measured by sleep
diary) with melatonin 5 mg.

total Sleep time: There were inadequate data for meta-
analysis of TST. Luthringer139 found an increase of 2.2 min ver-
sus placebo (CI: −19.13 to +23.53 min) in objective TST with
melatonin 2 mg. The quality of evidence was very low due to
significant imprecision of the data, and potential publication
bias.

Zhdanova147 observed no increase in objective TST at any
dosage. Wade146 reported no improvement in patient-reported
TST in the low melatonin secretor population (regardless of
age) at 3 weeks but observed a small improvement (estimated
difference: +13.1 min) at 29 weeks. Analysis of the elderly
population revealed no significant improvement in TST at any
point. Baskett141 reported no improvement at the 5 mg dose as
measured by sleep diary.

Wake after Sleep onSet: No meta-analysis was possible
for WASO. Luthringer139 found a small increase in WASO
(+8.5 min: CI: −11.75 to +28.75 min) in the prolonged release
melatonin 2 mg group. The quality of evidence was very low
due to significant imprecision of the data, and potential publi-
cation bias.

Quality of Sleep: The meta-analysis of QOS demonstrated
a small improvement in quality of sleep (+0.21 SMD: CI: −0.36
to +0.77 SMD), which fell below the threshold for clinical sig-
nificance. The quality of evidence was very low due to hetero-
geneity, imprecision and potential publication bias.

Baskett141 found no improvement in quality of sleep with
5 mg melatonin. Wade146 reported no improvement with pro-
longed-release melatonin at 3 weeks and 29 weeks in the low
excretor and elderly groups.

Sleep efficiency: There were not adequate data for meta-
analysis of melatonin SE.

Haimov143 reported small to moderate increases in acti-
graphic SE versus placebo (placebo: 77.4%; fast-release 2 mg/1
week: 78.8%; sustained release 2 mg/1 week: 80.4%; sustained
release 1 mg/2 months: 84.3%). Both of the sustained release
dosages and durations were statistically significantly different
from placebo. Zhdanova147 also reported significant improve-
ment in PSG SE versus placebo in the multiple dose crossover
study (placebo: 78%; melatonin 0.1 mg: 84%; 0.3 mg 88%; 3
mg: 84%). Baskett141 found no difference between placebo and
melatonin 5 mg for subjective SE.

number of aWakeningS: Insufficient data precluded
meta-analysis of NOA. Luthringer139 found an increased (+1.4 Do

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awakenings; CI: −4.59 to +7.39 awakenings) NOA with mela-
tonin, as measured by PSG. The quality of evidence was very
low due to significant imprecision of the data and potential
publication bias.

Zhdanova147 and Baskett141 reported no difference in NOA
between melatonin and placebo by PSG or patient diary,
respectively.

overall Quality of evidence: The overall quality of
evidence in the single outcome meta-analytic data from these
studies was downgraded to very low due to heterogeneity, im-
precision, and industry sponsorship, resulting in potential pub-
lication bias.

HarmS: Meta-analysis for adverse events was not possible. Of
the included investigations, none reported clinically significant
differences in adverse events between melatonin and placebo
for any dosage or duration.138–140,146 With one possible excep-
tion, no rebound or withdrawal effects were reported.138,139,146
Haimov143 found marginally significant difference in SE be-
tween the active phase for two month, 1 mg sustained-release
melatonin and the withdrawal period.

In summary, the task force found that there was weak evi-
dence against clinically significant efficacy in the treatment of
sleep onset insomnia, with little systematic evidence regarding
harms. However, mixed evidence suggests possible improve-
ment in SL in an elderly population. Therefore, benefits were
deemed to be approximately equal to harms.

patientS’ valueS and preferenceS: Based on clinical
judgement, the task force determined that despite the paucity
of meta-analytic data, equivocal data regarding efficacy for
sleep-onset insomnia, and absence of data regarding sleep
maintenance, a majority of informed patients would be likely
to use melatonin compared to no treatment. As previously
noted, this is based on its availability and the widespread per-
ception of melatonin as a benign sleep aid.

L-tryptophan for the Treatment of Primary Insomnia

Recommendation 13: We suggest that clinicians not use
tryptophan as a treatment for sleep onset or sleep maintenance
insomnia (versus no treatment) in adults. [WEAK]

Remarks: This recommendation is based on trials of 250 mg
doses of tryptophan.

Summary
Only one study148 contained adequate data, so meta-analysis
was not possible. The quality of evidence for the critical out-
comes was high. This study, consisting of patient-reported
data, showed a modest decline in TST, which was not clinically
significant. WASO was decreased slightly, while sleep quality
was mildly increased; neither met thresholds for clinical sig-
nificance. Sleep efficiency was insignificantly decreased.

No meta-analysis of harms was possible. Given the absence
of demonstrated efficacy on numerous critical outcome vari-
ables, coupled with limited evidence regarding harms, the task
force judged the harms to potentially outweigh the benefits.

Based on its clinical judgement, the task force determined that,
despite the absence of significant efficacy for tryptophan 250
mg and the absence of information regarding harms, the ma-
jority of patients would be likely to use tryptophan compared
to no treatment.

See Table S23 in the supplemental material.

Discussion
Hudson148 investigated the effects of food source tryptophan
(250 mg), pharmacological tryptophan 250 mg, both with
carbohydrate, versus carbohydrate alone. Subjects (n = 31) re-
ceived one of the three interventions for one week. Outcome
data consisted of sleep diaries.

Two additional papers met inclusion criteria, but used much
higher dosages. Hartmann149 compared tryptophan 1 g to seco-
barbital, flurazepam, and placebo in a one week trial. Tryp-
tophan and placebo groups included 52 subjects with chronic
insomnia. Data were patient-reported. Spinweber150 studied
20 young men with sleep onset insomnia. Following placebo
run-in, ten subjects received tryptophan 3 g and ten received
placebo for six nights, with PSG recordings nightly.

Sleep latency: The Hudson148 study did not report sleep
latency data.

Spinweber150 noted improvement in PSG sleep latency only
on nights 4–6 of administration (11.2 min lower than placebo
for this period). Hartmann149 found no difference in subjective
sleep latency between tryptophan and placebo during active
treatment.

total Sleep time: Hudson148 reported a moderate reduc-
tion in subjective TST (−20 min; CI: −31.29 to −8.7 min). The
quality of evidence was moderate due to imprecision. Other
investigations did not report TST data.

Wake after Sleep onSet: Hudson148 noted a small reduc-
tion in subjective WASO (−9.7 min: CI −15.21 to −4.18 min),
that did not meet clinical significance. The quality of evidence
was high.

Quality of Sleep: On a 3-point scale (1 = low, 3 = high)
sleep quality was increased (+0.3 points: CI +0.22 to +0.37
points) in the Hudson study.148 The quality of evidence was
high. Hartmann149 found no significant difference between
tryptophan and placebo on a measure of “How well I slept.”

Sleep efficiency: Sleep efficiency was not reported by any
study.

number of aWakeningS: NOA was not reported by any
study.

overall Quality of evidence: The overall quality of
evidence for this the critical outcomes was high.

HarmS: There was no meta-analysis of harms. None of the
papers reported systematic information regarding adverse ef-
fects associated with tryptophan.Do

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patientS’ valueS and preferenceS: Based on clinical
judgement, the task force determined that, despite the absence
of significant efficacy for tryptophan 250 mg and the absence
of information regarding harms, the majority of patients would
be likely to use tryptophan compared to no treatment.

Valerian for the Treatment of Primary Insomnia

Recommendation 14: We suggest that clinicians not use
valerian as a treatment for sleep onset or sleep maintenance
insomnia (versus no treatment) in adults. [WEAK]

Remarks: This recommendation is based on trials of vari-
able dosages of valerian and valerian-hops combination.

Summary
Morin136 evaluated a combination of valerian (374 mg native
extract) and hops (83.8 native extract). The overall quality of
evidence for these data was low due to imprecision and po-
tential publication bias. PSG sleep latency was reduced to a
degree that fell below the clinical significance threshold. Other
measures, including subjective SL, as well as PSG and patient-
reported TST and SE were improved, but did not meet clinical
significance thresholds.

No meta-analysis of harms was possible. Given the ab-
sence of demonstrated efficacy on critical outcome variables
(with the possible exception of marginally improved PSG SL),
coupled with limited evidence regarding harms, the task force
judged the harms to be roughly equal to the benefits. Based on
its clinical judgement, the task force determined that, given
the lack of efficacy for valerian (with the possible exception of
small improvements in SL) and the limited information regard-
ing harms, the majority of patients would not be likely to use
valerian compared to no treatment.

See Table S24 in the supplemental material.

Discussion
Morin136 investigated the effects of a valerian-hops combina-
tion in dosages noted above. This combination was compared
to diphenhydramine and placebo. Subjects with mild difficulty
initiating or maintaining sleep were randomized to one of the
three interventions (valerian-hops n = 59; diphenhydramine
n = 60; placebo n = 65) with nightly administration for 28 days.
A subset (valerian n = 22; placebo n = 26) underwent PSG at
baseline and at the end of weeks one and two.

One additional paper151 met inclusion criteria, but employed
a higher dosage. Oxman conducted a randomized trial involv-
ing 405 adults of all ages with insomnia. Subjects were ran-
domized to two-week, nightly administration of valerian (3,600
mg) or placebo. Outcomes were patient-reported and captured
as ranges, therefore the data were not usable for meta-analysis.

Sleep latency: Morin136 found a reduction in PSG SL of
9.29 min (CI: −0.27 to −18.3 min). This approached clinical
significance. The quality of evidence was LOW due to impre-
cision and potential publication bias. Subjective SL, however,
was increased by +3.77 min (CI: −4.47 to +12.01 min), with
moderate quality of evidence due to potential publication bias.
Oxman151 found no statistically significant improvement in SL.

total Sleep time: In the Morin136 study, PSG TST was in-
creased, although not to a clinically significant degree (+10.96
min; CI: −21.67 to +43.59 min) (very low quality of evidence).
Patient-reported TST was higher (+3.12 min; CI: – 22.08 to
+28.32) with moderate quality of evidence. Oxman151 found no
significant improvement in subjective TST.

Wake after Sleep onSet: WASO data were not reported
in any study.

Quality of Sleep: Morin136 did not report quality of sleep
data and Oxman151 found no statistically significant difference
versus placebo in the percentage of patients meeting the de-
fined sleep quality improvement criterion (valerian 28.7%; pla-
cebo 21.2%; difference +7.5% [95% CI:15.9 to 20.9%]).

Sleep efficiency: Minimal increases in objective (+0.96%;
CI: −5.02 to +6.94%) and subjective (1.85%; CI: −1.9 to +5.6%)
SE were noted by Morin.136 Both outcomes were downgraded
due to potential publication bias, while PSG data was down-
graded further due to significant imprecision.

number of aWakeningS: Oxman151 observed a statistically
significant reduction in average change scores for NOA with
valerian.

overall Quality of evidence: Quality of evidence
for all outcomes ranged from very low to moderate. The only
critical outcome for which adequate data was reported dem-
onstrated low quality evidence, therefore the overall quality of
evidence was low.

HarmS: Morin136 observed no difference between valerian-
hops and placebo with respect to frequency of adverse events.
No serious adverse events were noted. Likewise, Oxman151
found no increase in adverse events at the higher valerian dose
compared to placebo.

patientS’ valueS and preferenceS: Based on its clini-
cal judgement, the task force determined that, given the lack
of efficacy for valerian (with the possible exception of small
improvements in SL) and the limited information regarding
harms, the majority of patients would not be likely to use vale-
rian compared to no treatment.

L I T E R AT U R E R E V I E W S

The following section contains literature reviews of drugs for
which clinical practice recommendations were not possible,
due to inadequate data for statistical analyses.

Estazolam
Summary
Three studies evaluated the efficacy of estazolam152–154 us-
ing similar patient sleep questionnaires, but none of the data
were suitable for meta-analysis. Likewise, it was not possible Do

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to evaluate these data with respect to the established clinical
significance thresholds. Therefore, no recommendations re-
garding efficacy of estazolam are possible. The data suggest
statistically significant subjective improvement versus placebo
at the 2 mg dosage for all parameters assessed.

Discussion
Cohn152 compared estazolam 1 mg and 2 mg to flurazepam and
placebo in approximately 100 adults with chronic sleep onset
and maintenance insomnia in a parallel group design. Subjects
were randomized to receive drug or placebo for seven consecu-
tive nights. Outcomes were measured by sleep questionnaires
(interval ratings and Likert scales). Dominguez153 evaluated a
similar population of 45 adults with estazolam 2 mg, fluraz-
epam or placebo for 7 nights. Sleep variables were assessed by
patient questionnaire. Scharf154 studied 243 outpatients with
complaints of sleep onset or maintenance difficulty. Subjects
were randomly assigned to one of three parallel groups: es-
tazolam 2 mg, flurazepam 30 mg or placebo. Medications were
administered for 7 nights. Subjects rated sleep latency, TST,
QOS and NOA on numerical interval questionnaires.

Three studies found statistically significant improvement
in SL on patient ratings with estazolam 2 mg. The only study
which included estazolam 1 mg reported no significant im-
provement on SL. All three studies reported significant im-
provement versus placebo in sleep duration at 2 mg. The 1 mg
dosage also produced significant improvement in sleep du-
ration. Sleep quality was likewise improved at both dosages
studied, as were NOA. No studies assessed WASO or SE.

Quazepam
Summary
Seven studies evaluated the efficacy of quazepam versus pla-
cebo in randomized, controlled trials.108,155–160 One of these
studies160 reported PSG findings while the remainder relied ex-
clusively on subjective data derived from sleep questionnaires.
Data analysis varies somewhat across these studies, rendering
comparisons difficult. Only one investigation160 met require-
ments for meta-analysis. Overall, the studies suggest efficacy
in reducing time to onset of sleep, increasing TST, and reduc-
ing NOA. The methodologies employed were not comparable
to the standard of data reporting required by GRADE and,
therefore, no specific recommendation was made. Quazepam
and its metabolites have long half-lives, raising concerns re-
garding accumulation and daytime impairment. Data regard-
ing daytime sleepiness from these studies suggests a higher
percentage of patients with somnolence in the active treatment
group versus placebo, particularly at the 30 mg dosage.

Discussion
Alden155 evaluated 57 insomnia subjects in a 5 night, parallel
group design with quazepam 30 mg as the active drug. This
study and all additional quazepam studies reported here (with
the exception of Roth160) utilized patient sleep questionnaire
data consisting of numerical interval and other rating scales.
Hernandez156 studied 36 insomnia outpatients with quazepam
15 mg and placebo in a similar five night design. Martinez157

assessed 41 older adults ( > 65 years) with insomnia in a con-
trolled trial with quazepam 15 mg or placebo administered
over 5 consecutive nights. Mendels158 assessed the same dos-
age in 60 adult insomnia outpatients for five nights. O’Hair159
reported results of a five night trial in 60 subjects with quaz-
epam 30 mg. Scharf108 studied quazepam 15 mg and triazolam
0.5 mg versus placebo over a five week period. During this
time, subjects received active drug or placebo for nine con-
secutive nights, followed by 14 nights of every other night ad-
ministration. Subjects were 65 insomnia outpatients. Finally,
Roth160 evaluated quazepam 7.5 mg and 15 mg versus placebo
in 30 older insomnia subjects ( > 60 years). PSG was conducted
for two nights in the early phase of treatment (nights 1 and 2
of active treatment) and during the late phase (nights 6 and 7).

Sleep latency: Utilizing a cutoff of sleep latency < 45 min to identify “responders,” Aden155 reported quazepam 30 mg to be statistically superior to placebo. O’Hair159 demonstrated quazepam 30 mg to be significantly better than placebo on an interval scale for sleep latency.

Hernandez156 found quazepam 15 mg significantly bet-
ter than placebo on sleep latency interval scales. Likewise,
Scharf108 reported significantly shorter latencies at this dos-
age on interval scales during active treatment nights in every-
other-night administration although this was apparently not
the case during the initial nightly administration. Using a 45
min sleep latency cutoff as described above,155 Martinez157
demonstrated a significantly higher percentage of responders
to 15 mg in a geriatric population. Roth160 did not report sig-
nificant differences between quazepam 7.5 mg or 15 mg and
placebo on PSG SL.

total Sleep time: Utilizing a cutoff of sleep duration > 6 h
to identify “responders,” Aden155 reported quazepam 30 mg
to be statistically superior to placebo. O’Hair159 demonstrated
quazepam 30 mg to be significantly better than placebo on an
interval scale for TST.

Hernandez156 found quazepam 15 mg to be significantly su-
perior to placebo on sleep duration interval scales. Likewise,
Scharf108 reported significantly longer duration at this dosage
on interval scales during active treatment nights in every-other-
night administration, except on the initial night of administra-
tion. Using a > 6 h sleep duration cutoff as described above,155
Martinez157 demonstrated a significantly higher percentage of
responders to 15 mg in a geriatric population. Roth160 reported
improvement in PSG TST during early (treatment nights 1 and
2) and late (nights 6 and 7) with quazepam 15 mg in a geriat-
ric insomnia population. A statistically significant effect with
quazepam 7.5 mg was seen only during nights 6 and 7.

Wake after Sleep onSet: No studies reported placebo
comparisons for WASO.

Quality of Sleep: The majority of studies of “sleep qual-
ity” with quazepam utilized a composite index for sleep qual-
ity (including questions on nightmares and overall evaluation
of the medication) which is not consistent with sleep quality
measures used in other studies; therefore these results are not Do

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discussed. Scharf108 reported a single measure of sleep quality
(“How would you describe your sleep”). Quazepam 15 mg was
significantly better than placebo on active treatment nights in
both the nightly and every other night administration.

Sleep efficiency: No studies reported placebo comparison
data for SE.

number of aWakeningS: Employing a threshold for “re-
sponse” of < 2 awakenings, Aden155 reported a significantly higher percentage of responders to quazepam 30 mg than pla- cebo. O’Hair159 also found significantly fewer awakenings at this dosage compared to placebo using interval scales. At the 15 mg dosage, two studies156,157 found a significantly greater number of “responders” (i.e. < 2 awakenings) compared to pla- cebo. No PSG data for NOA were reported.

adverSe effectS: Five studies reported specific data for
daytime somnolence. Aden155 found an approximately four-
fold higher rate of somnolence at 30 mg (quazepam 16/24; pla-
cebo = 4/26). At the same dose, O’Hair159 reported somnolence
in 12/30 quazepam and 5/30 placebo subjects. At 15 mg, Mar-
tinez157 noted no difference in adverse events. Hernandez156
reported somnolence in 9/30 quazepam subjects and 6/30 pla-
cebo subjects. Mendels158 found 7/30 quazepam subjects and
4/30 placebo subjects demonstrated daytime somnolence.

Flurazepam
Summary
Sixteen studies met general inclusion and exclusion crite-
ria.98,100,101,105,109,149,152–154,161–167 No studies contained data ad-
equate for meta-analysis. No meta-analysis of harms was
possible. These studies were highly varied in design. Of these,
three100,101,105 included no flurazepam/placebo comparison and
were excluded from discussion. All of the studies included one
or both of the standard flurazepam doses: 15 mg and 30 mg.

Studies of the efficacy of flurazepam had numerous method-
ological inconsistencies, including instruments for subjective
assessments of sleep outcomes that were highly variable across
these studies, which made valid comparisons across studies
impossible. Many studies incorporated interval scales with no
reports of specific values. In light of these inconsistencies, and
the related unavailability of meta-analyses, no recommenda-
tions regarding efficacy of flurazepam were made. The data
for sleep onset at both the 15 mg and 30 mg dosages are mixed.
The majority of studies did report increases in TST with the 30
mg dosage, but not at 15 mg. Data for WASO are limited to two
studies, one of which (a PSG study) showed improvement at 30
mg. Sleep quality reports uniformly indicated improvement at
both dosages, while reports for NOA suggest reduction at the
30 mg dosage only.

Discussion
Cohn152 compared flurazepam 30 mg and placebo in approxi-
mately 100 adults with chronic sleep onset and maintenance
insomnia in a parallel group design. The study, with a total
n = 223, also included two dosages of estazolam, discussed

elsewhere. Subjects were randomized to receive drug or pla-
cebo for seven consecutive nights. Outcomes were measured
by sleep questionnaires (interval ratings and Likert scales).
Dominguez153 evaluated a similar population of 45 adults with
flurazepam 30 mg or placebo for 7 nights. Sleep variables were
assessed by patient questionnaire. Elie161 studied 60 outpatient
insomnia patients using a cross-over study design in which
each patient received a single dose of five different drugs (or
drug dosages) or placebo on one night of the week over a five
consecutive week period. Study drugs included flurazepam
15 mg, three crossover dosages of loprazolam, and placebo.
Outcomes included an index for sleep-onset based on patient
questionnaires. Elie162 investigated efficacy of flurazepam 30
mg and zopiclone versus placebo over 4 weeks. Flurazepam
and placebo groups included 12 chronic insomnia patients per
group. Subjects reported sleep outcome variables on post-sleep
numerical rating questionnaires. Hartmann162 studied 96 adult
patients (n = 45 for flurazepam and placebo groups) with vari-
ous insomnia complaints. Subjects were randomly assigned to
receive flurazepam 30 mg, secobarbital, l-tryptophan, or pla-
cebo for one week of active treatment. Outcomes were assess
by sleep logs which included subjective estimates of SL, NOA,
duration of awakenings, and QOS.

Mamelak164 investigated the effects of flurazepam 30 mg
and zopiclone versus placebo in three groups of 10 insomnia
subjects per group, each of which received one of the three
treatment conditions for 12 consecutive nights. Subjective es-
timates of SL, TST and NOA were reported. Mamelak165 stud-
ied 36 elderly patients with chronic insomnia. Patients were
randomized to flurazepam 15 mg, brotizolam or placebo for
14 nights. Outcomes included patient-reported SL, NOA, TST
and wake time. Daytime performance measures were con-
ducted at the beginning of treatment and following conclusion.
Melo de Paula166 evaluated flurazepam 30 mg versus placebo
and two dosages of lormetazepam in 60 adults with sleep on-
set or maintenance problems. Subjects received one of the four
treatment conditions for two weeks. Outcome data included
subjective SL, NOA and TST.

Reeves98 investigated the efficacy of flurazepam 15 mg and
triazolam versus placebo in 61 geriatric subjects (n = 27 for
flurazepam and placebo groups) with sleep onset or mainte-
nance insomnia. Subjective sleep outcomes were assessed by
interval rating questionnaires. Salkind167 evaluated fluraz-
epam 15 and 30 mg versus placebo in 30 general practice
insomnia patients. Subjects received each dose of fluraz-
epam and placebo for one week in a crossover trial. Patient-
reported SL, TST and QOS were primary outcome variables.
Daytime residual effects were also reported. Scharf154 stud-
ied 243 outpatients (n = 163 for flurazepam versus placebo)
with complaints of sleep onset or maintenance difficulty.
Subjects were randomly assigned to one of three parallel
groups: flurazepam 30 mg, estazolam 2 mg or placebo. Treat-
ments were administered for 7 nights. Subjects rated sleep
latency, TST, QOS and NOA on numerical interval question-
naires. Sunshine109 investigated the effects of 15 mg and 30
mg flurazepam versus two dosages of triazolam and placebo
in a five-night crossover study, with subjects receiving each
intervention for one night. Subjects were 25 inpatients who Do

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complained of sleep onset and maintenance problems. Pa-
tients completed sleep questionnaires with interval ratings
for TST and NOA.

Kripke163 conducted the only identified PSG study of fluraz-
epam. In this study, 99 subjects with chronic insomnia were
randomized to one of four parallel groups (flurazepam 15 mg,
flurazepam 30 mg, midazolam or placebo). Subjects received
treatment for 14 consecutive nights, with PSG recordings on
nights 1, 2, 7, 13 and 14. Objective SL, WASO, TST, and SE
were reported.

Sleep latency: The only PSG study of 30 mg163 found no
significant reduction in SL versus placebo.

Five studies152,154,164,166,167 reported statistically significant im-
provement on subjective ratings of sleep onset for flurazepam
30 mg versus placebo. Kripke163 found improvement in patient-
reported SL for 30 mg only in the early period (nights 1 and
2) of administration. No significant difference from placebo
was evident at end of 14-day treatment. Four reports109,149,153,162
found no significant subjective improvement in sleep onset
with flurazepam 30 mg versus placebo.

Three studies98,161,167 reported subjectively improved onset at
the 15 mg dosage. Kripke163 found patient-reported improve-
ment at this dosage only on nights 1 and 2. Two investigations
demonstrated no improvement in sleep onset for flurazepam 15
mg versus placebo.

total Sleep time: Eight studies109,152–154,163,164,166,167 reported
statistically significant improvement for flurazepam 30 mg
versus placebo on various subjective scales for sleep duration.
One study162 reported no significant improvement in duration
at this dosage.

Two studies109,167 found significantly improved patient-re-
ported duration at the 15 mg dosage; Kripke163 reported sub-
jective improvement only on nights 1 and 2. Likewise, two
studies98,165 found no significant subjective improvement in
sleep duration for flurazepam 15 mg.

Wake after Sleep onSet: Two studies reported data for
WASO. Kripke163 found significantly reduced PSG WASO with
flurazepam 30 mg versus placebo. Mamelak165 reported no sig-
nificant reduction in subjective WASO with flurazepam 15 mg
in an elderly insomnia population.

Quality of Sleep: Utilizing a variety of self-report scales,
six studies98,152–154,161,167 reported improvement in sleep quality
with flurazepam versus placebo. Four studies152–154,167 found im-
provement at the 30 mg dosage and three studies98,161,167 at the
15 mg level.

Sleep efficiency: One study163 reported PSG sleep effi-
ciency. Flurazepam 30 mg significantly improved sleep effi-
ciency versus placebo.

number of aWakeningS: Six studies109,152–154,162,164 assessed
subjective NOA with flurazepam 30 mg. All found significant
reduction in NOA. Three studies98,109,165 found no significant
reduction in NOA with flurazepam 15 mg.

adverSe effectS: Cohn152 reported that 68% of flurazepam
30 mg subjects experienced an adverse event versus 43% of
subjects receiving placebo. Approximately 50% of the fluraz-
epam group reported somnolence, about twice the rate in the
placebo population. Dominguez153 found a significant increase
in side effects for flurazepam 30 mg compared to placebo and
stated that 73% of side effects described as “undetermined”
were reports of somnolence. Elie161 indicated that there was no
significant difference in adverse events between flurazepam 15
mg and placebo; likewise Elie162 found no difference in rates of
somnolence for flurazepam 30 mg versus placebo. Mamelak164
found significant performance impairment with flurazepam 30
mg. Mamelak165 reported significantly shorter latencies to sleep
on MSLT at the beginning and end of treatment. The authors
also found significant impairment on digit symbol substitution
and serial learning as well as a significantly slower rate of im-
provement on reaction, response and movement time. Divided
attention was also impaired at end of treatment. Reeves98 noted
that 6 of 13 flurazepam subjects reported somnolence (versus
4/14 in the placebo group). Salkind167 described impaired motor
performance in the flurazepam 30 mg group (although not in
the 15 mg group) and a significantly higher rate of “hangover
effect” at the higher dosage. In the cross-over design, 11 of
30 flurazepam group experienced morning drowsiness/hang-
over, which was reported by only 3 of 30 subjects during the
flurazepam 15 mg period and 2 of 30 while taking placebo.
Finally, Scharf154 found AEs in 73% of the flurazepam 30 mg
group versus 43% on placebo subjects. Somnolence was the
most common event, reported by 57% of flurazepam subjects
and 23% of the placebo group.

Oxazepam
Götestam168 studied the efficacy of oxazepam 25 mg vs. pla-
cebo with a crossover design in 28 patients with “insomnia.”
Subjective reports using interval ratings showed a significant
reduction in SL and significant improvement in QOS.

Quetiapine
One study169 investigated the efficacy of quetiapine versus pla-
cebo control in primary insomnia. However, the study included
only 13 subjects. Numerical increase in subjective TST and de-
crease in subjective SL were found, but these differences were
not statistically significant, possibly due to small sample size.

Gabapentin
One study170 evaluated gabapentin for treatment of primary in-
somnia. This was an open-label investigation with 18 subjects,
variable dosages, and no placebo control. Therefore, the trial
was excluded.

Paroxetine
Two studies assessed paroxetine for treatment of primary in-
somnia. Nowell171 reported a trial of variable dosage in 15 pa-
tients, without placebo control. As a result, this investigation
was excluded.

Reynolds172 evaluated paroxetine 10 mg/20 mg in 27 older
adults with primary insomnia who were randomized to drug
or placebo. The two doses were pooled for statistical analysis. Do

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PSG data showed a modest but significant increase in SL, de-
crease in WASO and no difference in SE versus placebo. Sleep
quality was improved.

Trimipramine
Hohagen173 studied the effects of trimipramine in 15 adults
with primary insomnia. No placebo control was included and,
as a result, the study was excluded. Riemann174 evaluated 55
adults with primary insomnia in a placebo-controlled double
blind study. Dosage was variable (50–200 mg; mean 109.4 mg),
but pooled for analysis. No significant difference was observed
between trimipramine and placebo for PSG TST or SL, but
SE was significantly improved with trimipramine. Subjective
sleep quality also showed significant improvement.

D I S C U S S I O N A N D F U T U R E D I R E C T I O N S

Defining “Efficacy”
Assessment of the efficacy of a given agent for the treatment of
chronic insomnia is a complex and challenging task. It remains
unclear which are the most important variables for defining ef-
ficacy. Older studies, particularly the majority of investigations
of benzodiazepine efficacy, utilized a variety of predominantly
subjective scales and questionnaires. These are highly diverse
and did not often include specific numerical patient estimates
for sleep outcomes. Since the advent of newer benzodiazepine
receptor agonists, more specific and uniform outcomes for both
patient-reported and objective outcomes (e.g., self-reported
and PSG sleep onset latency, wake time after sleep onset, and
total sleep time) have been employed, although continued sub-
stantial variability in data reporting has not been uncommon.

In addition to the variability in outcome measures reported,
there are a number of critical unresolved issues regarding eval-
uating the efficacy of treatments for chronic insomnia. One
is the relative importance of subjective versus objective data.
Another is whether metrics of sleep quality, whether they be
subjective or objective (e.g. analysis of the microstructure of
sleep or related physiological parameters), are perhaps more
pertinent than measures of SL, TST or WASO. An additional
issue of importance is whether efficacy is better reflected by
measures of daytime alertness and cognitive, emotional, and
psychomotor function than by measures of sleep. Recent be-
havioral treatment studies in chronic insomnia have taken
yet another direction: measuring response or remission of the
insomnia syndrome as the most clinically-relevant outcome.
This approach makes sense from a patient-centered approach,
since most patients complain of “difficulty” falling asleep or
staying asleep, rather than tying their complaints to any spe-
cific numerical value. Indeed, several studies have identified a
group of “non-complaining poor sleepers” whose quantitative
sleep measures are similar to those with insomnia. Examining
the insomnia syndrome is also useful because it addresses both
sleep-related and wake-related symptoms.

Absent clear answers to these questions, the present analysis
relies on conventional subjective and objective measures of
major sleep variables (sleep onset latency, total sleep time or
wake time after sleep onset). The meta-analyses conducted

yield recommendations for use of a limited number of drugs
for a limited number of specific indications (i.e. sleep onset
and/or sleep maintenance). In all cases, the recommendations
are “weak,” in that they are based on relatively limited and
low quality evidence. The majority of medications included
in these analyses are FDA-approved drugs for treating insom-
nia. This is not surprising, given that FDA approval rests on
the demonstration of statistically significant changes in both
subjective and objective outcomes. Furthermore, FDA ap-
proval is based on standards of significant improvement versus
placebo for one or more indications (i.e. sleep onset or sleep
maintenance insomnia). Many agents, including some which
are not FDA-approved hypnotics, have been shown in one or
more studies to be “statistically significantly superior” to pla-
cebo for a given outcome(s), but are nonetheless not recom-
mended for treatment of chronic insomnia in this guideline. It
is important to understand the discrepancy between (1) FDA
approval and/or demonstration of “statistically significant su-
periority” to placebo and (2) the recommendations included
in this publication. The discrepancy results from different cri-
teria employed by the FDA and individual studies, on the one
hand, and the GRADE approach to clinical guidelines, on the
other. The GRADE approach establishes evidence quality rat-
ings and clinical significance thresholds that are not employed
in individual research studies and FDA assessment for ap-
proval. The thresholds were determined by clinical judgement
of the task force and represent best estimates of the degree of
improvement which the “typical patient” would find signifi-
cant. Although these thresholds are consistent with numerical
values that have been recommended as thresholds in contem-
porary publications, these standards entail a certain amount
of subjectivity on the part of the task force, as there are no
data which suggest absolute standards for clinical significance.
Without question, there may be divergent opinions regarding
what constitutes clinical significance and efficacy. Indeed, the
task force assumed that their recommendations are not abso-
lute indications of the presence or absence of clinical utility of
a given medication, but reflect their best judgment based on
the available data. Each prescriber bears the responsibility for
making treatment determinations with this in mind.

Patient selection and inclusion criteria for studies are vari-
able and may substantially impact results for a given outcome
(e.g. see Krystal, 2012). Studies not requiring a minimum in-
clusion criterion for a specific outcome (e.g. inclusion thresh-
olds for SL or WASO) may be underpowered to identify
significant change for that outcome. On the other hand, studies
with stringent PSG criteria for inclusion may not represent the
larger population of insomnia patients.

Understanding the Methodology
The recommendations of the task force were developed with
the use of GRADE, a state-of-the-art methodology for assess-
ment of clinical data. This approach has distinct strengths, as
well as certain limitations. GRADE is a rigorous, detailed, and
transparent system for evaluation of the relative strengths of
evidence for a given intervention. It incorporates several con-
siderations which may impact the quality of evidence for a
treatment approach. These factors include the heterogeneity of Do

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MJ Sateia, DJ Buysse, AD Krystal, et al. Clinical Practice Guideline: Insomnia

data (i.e. the degree of inconsistency of results across studies),
imprecision of the data (i.e. 95% CI which cross the clinical
significance threshold) and potential publication bias (as a re-
sult of industry sponsorship). Quality of evidence grades for
randomized clinical trials begin at HIGH and are downgraded
progressively for heterogeneity, imprecision, and/or potential
publication bias. Since the vast majority of studies in this field
are industry sponsored, the quality of evidence for nearly all
of these studies is, therefore, reduced from HIGH to MODER-
ATE. This is to be expected for clinical trials for many drugs
(i.e. not only hypnotics), since the vast majority are industry-
sponsored FDA registration studies. The extent to which this
downgrading of evidence is warranted due to actual publica-
tion bias is unknown, but under the GRADE system we have
chosen to adopt the conservative approach and assume risk of
bias. When heterogeneity and imprecision are accounted for,
the quality of evidence for many treatments considered is LOW
or VERY LOW. These latter two factors are not uncommon,
as there is substantial variability in sleep outcome variables
across studies and confidence intervals frequently overlap the
clinical thresholds for significance.

Meta-analysis requires specific data (numerical data for a
given outcome, presented as mean and standard deviation).
Many studies, particularly older investigations, do not report
data in the required format. Some newer publications do not
report data in this format because some sleep variables, par-
ticularly sleep onset latency, are not normally distributed. In
this case, the preferred measure of central tendency is not the
mean but the median, the standard deviation may not be a valid
measure of the degree of dispersion, and the statistical analy-
ses carried out are not based on the mean and standard devia-
tion. The result of this is exclusion of substantial amounts of
data from the formal meta-analyses. While these studies are
discussed in the paper and (secondarily) considered in formu-
lation of recommendations, the inability to include such data in
meta-analysis represents a distinct limitation.

As described in the methodology section, GRADE requires
a recommendation “for” or “against” use of each treatment.
When the evidence for efficacy is clear-cut, with (1) relatively
high quality of evidence; (2) a high degree of confidence that
benefits clearly outweigh harms; and (3) evidence that the
effects of treatment are of substantial magnitude, without
imposition of significant burden to the patient, a “strong” rec-
ommendation is delivered in the form of, “we recommend cli-
nicians use X for the treatment of chronic insomnia.” When
evidence for benefit is less clear and the quality lower, a

“weak” recommendation is made in the form of, “We suggest
that clinicians use (or not use)…” However, it is important for
clinicians to understand that a recommendation against use,
particularly when associated with low quality evidence, is not
equivalent to a demonstration of ineffectiveness. Rather, it
is often an indication that the available evidence is simply in-
sufficient and fails to provide convincing support in favor of
usage by GRADE standards. In the case of drugs (most com-
monly older drugs) for which none of the data were reported
in a format amenable to meta-analysis, we refrain from mak-
ing any recommendation. The specific indications for use of a
hypnotic employed in this report are limited to “sleep onset”

and “sleep maintenance.” insomnia. We chose these since,
from a practical clinical consideration, these are the primary
complaints with which chronic insomnia patients present, and
for which clinicians prescribe medication. Moreover, these are
the subtypes of insomnia that were actually studied in many
investigations, consistent with FDA approval strategies and the
matching of drugs to particular types of sleep disturbance.

Hence, some medications may show substantial improve-
ment in TST or sleep quality, yet demonstrate no or insig-
nificant reduction in SL, WASO or NOA to qualify for a
recommendation in favor of use.

As described, we established thresholds for clinically sig-
nificant improvement for each objective and subjective major
sleep outcome. Nevertheless, some degree of judgment was in-
troduced in formulating final recommendations. For example,
a medication may not have exceeded significance thresholds
for both subjective and objective evidence but, when the to-
tality of evidence (including those investigations which could
not be included in the meta-analysis) was considered, the
task force concluded that a reasonable standard had been met.
These considerations also include the role of adverse effects in
the decisions made.

Beyond the quality of evidence for or against use of a given
drug for sleep onset or maintenance insomnia, the task force
also considered the relative benefit:harm ratio and the likeli-
hood that an informed patient would use a specific agent. To a
great extent, these decisions are based on clinical judgement.
With respect to the benefit:harm consideration, the data on ad-
verse events is often limited or non-existent. This may reflect
the fact that treatment-emergent adverse events (TEAEs) are
typically not collected using specific assessment forms, but
rather, rely on spontaneous reporting by research participants.
In addition, the frequency of some TEAEs is so low that the re-
ported studies are underpowered to find a difference from pla-
cebo. This also implies that the effect size for a TEAE would
be very small, and hence, it is unlikely that the clinical sig-
nificance of TEAEs has been underestimated. However, some
TEAEs are very infrequent but very serious when they do oc-
cur (e.g. sleep-related behaviors with BzRA). Clinical trials are
likely to underestimate such risks due to the limited number
of patients treated and the limited duration of treatment. As a
result of these considerations, assessment of potential harms is
largely derived from clinical experience and theoretical con-
siderations, rather than well-documented evidence. This is
clearly a limitation of the analysis and further, more systematic
investigation of adverse effects is necessary.

Prior to formulation of the specific recommendations, the
task force—based on its clinical judgement and experience—
indicated what medications well-informed patients would or
would not choose to use. These judgments do not reflect the
input of actual patients, but only the task force’s judgment. In
most cases, these judgments were in agreement with recom-
mendations (i.e. an informed patient is likely to use a drug that
is recommended and not likely to use one that is not). In cer-
tain cases (e.g. melatonin), the task force considered that, given
widespread use and apparently benign side effect profiles, in-
formed patients may be likely to use a specific drug even when
data do not clearly support a recommendation for use.Do

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MJ Sateia, DJ Buysse, AD Krystal, et al. Clinical Practice Guideline: Insomnia

Clinical Application
Administration of sleep-promoting medication for chronic
insomnia is one possible component of what must be a com-
prehensive approach to evaluation and treatment of chronic
insomnia. This approach must include adequate assessment of
cause and characteristics of the disorder as well as evaluation
and treatment of contributing comorbidities. The latter may in-
clude any one or more of numerous medical, neurological and
mental disorders, as well as other primary sleep disorders.

Numerous investigations have demonstrated that hypnotic
medications are comparably efficacious to CBT-I during acute
treatment.11,112,175 However, these studies also make clear that
the gains associated with CBT-I are durable following comple-
tion of treatment, whereas those associated with medication
tend to dissipate following discontinuation of the drug. The
vast majority of investigations which are included in the cur-
rent analysis address relatively short-term use (e.g. one day to
five weeks). Some studies have shown that long-term treat-
ment with at least newer generation BzRA hypnotics can be
safe and effective under properly controlled conditions. How-
ever, chronic use should be reserved for those individuals for
whom CBT is either inaccessible or ineffective, who have been
appropriately screened for contraindications to such treatment,
who maintain long-term gains with medication, and who are
followed regularly. Patient preference must also be considered
in the determination of treatment approach.

The investigations which are included in this analysis were
focused on “primary” chronic insomnia, with the exception of
some older studies (e.g. zaleplon) which included some patients
with “mild” mental disorders, The extent to which these find-
ings apply to chronic insomnia associated with major comor-
bidities is uncertain, although a limited number of comparative
studies suggest at least some degree of efficacy in such cases.
It should also be emphasized that the findings presented in this
report apply only to adults. None of the agents discussed in this
report are approved for use in children and none of the find-
ings presented apply to children or adolescents. There is very
little information concerning pharmacotherapy for childhood
insomnia. Although independent analyses of efficacy in older
adults were not conducted, examination of the findings suggests
comparable efficacy across the adult age range. Pharmacoki-
netic and pharmacodynamic properties of many medications,
including benzodiazepine receptor agonist drugs, differ among
older and younger adults, necessitating lower starting dosages.
The limited information from these studies regarding adverse
effects in older adults does not allow meaningful conclusions
about the frequency of such events in older patients compared
to a younger population. The American Geriatric Society Beers
criteria recommend that benzodiazepines be avoided for treat-
ment of insomnia in older patients, due to risk of cognitive
impairment, falls, and motor vehicle accidents. The criteria fur-
ther recommend that newer generation benzodiazepine receptor
agonists be limited to shorter-term use (< 90 days).

The data on adverse effects derived from these clinical tri-
als, in general, do not suggest a high frequency of serious side
effects. However, the data are scant and inconsistent, suggest-
ing that caution should be applied in the assessment of rela-
tive risks associated with use of hypnotic medications. Other

reported adverse effects include—but are not limited to—de-
pendency/withdrawal, cognitive impairment, falls/fractures,
parasomnias, and driving impairment and motor vehicle ac-
cidents. Epidemiological studies have also suggested a pos-
sible link between hypnotic use and infection, depression and
overall mortality risk. These complications are observed most
frequently in older populations, who are among the most fre-
quent users of these drugs. Risks of dependency and serious
withdrawal complications are of greatest concern with true
benzodiazepine agents, particularly in the setting of escalat-
ing, long-term usage and insufficient monitoring. However,
although much concern has understandably been raised about
potential tolerance and addiction to these drugs, there is lim-
ited information regarding the true incidence of these com-
plications. The risks associated with use of these agents are
clearly increased not only in the elderly but also when they
are used in dosages in excess of those recommended, or when
combined with other psychoactive agents.38 Given the known
sedative effects of these agents, particularly those with longer
half-lives, clinicians must be diligent in cautioning patients re-
garding potential complications related to sedation. Such com-
plications are most likely to occur with longer-acting agents
and during morning hours following bedtime administration.
Use of shorter-acting agents and the lowest effective dosage
may help to reduce sedation-related complications. Appropri-
ate patient counseling and careful monitoring will also serve
to minimize risk. Complete avoidance of these medications
should also be considered in those who may be particularly
susceptible to adverse outcomes.

Future Directions
In an attempt to develop meaningful clinical practice recom-
mendations for the use of sleep-promoting medications, it be-
came increasingly clear to the task force that this endeavor is
fraught with multiple limitations. While existing data (espe-
cially more recent data) provide a reasonable foundation for
certain recommendations contained in this study, the overall
quality of evidence is relatively low in the vast majority of
cases. For numerous drugs, there is simply insufficient evi-
dence available to draw on in determining whether or not a
compound is efficacious. Data reporting, especially that of
older studies, is highly variable and idiosyncratic. As a re-
sult, comparing data from one study to another, or conducting
meta-analyses of data, is not possible. Virtually all studies of
prescription hypnotic agents are industry-funded. While the
reasons for this are understandable, the potential for publica-
tion bias, particularly lack of publication of negative results,
compromises the quality of evidence to a significant degree.
Moreover, the role of industry in study design and data analysis
may further compromise uniformity of data reporting.

With these limitations in mind, the task force recommends
the following for future investigations:

1. Clear definitions of inclusion and exclusion criteria;
2. Adequately powering studies to detect significant

differences for key sleep variables;
3. Development and utilization of uniform data collection

instruments which will promote improved cross-study
analysis and comparisons;Do

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MJ Sateia, DJ Buysse, AD Krystal, et al. Clinical Practice Guideline: Insomnia

4. Standardized statistical analysis and data presentation.
The majority of newer investigations now present
means + SD for specific PSG or sleep diary data. For
those variables that are not normally distributed, a
transformation can be sought which converts the
probability distribution to the normal distribution and
the transformed mean and SD can then be reported. An
effort to report means and SD data should be made for
all studies;

5. Although specific numerical data for individual sleep
are useful in assessing the efficacy of pharmacological
treatment for insomnia, other approaches to such
evaluation may be more clinically meaningful.
Specifically, determination of the efficacy of a drug
in achieving remission of chronic insomnia disorder
has been employed in cognitive behavioral treatments
for insomnia and should be considered as a clinically
relevant outcome in pharmacological trials. This may
include not only subjective and objective outcome data
for major sleep outcomes, but also sleep quality and
daytime functional outcomes;

6. To the extent possible, encourage funding for
independent, non-industry investigation of the efficacy
and effectiveness of hypnotic medications;

7. Data for adverse events associated with hypnotic
medications are not collected and analyzed in standard
ways. This is a widespread problem common to studies
of all types of medications. Continued efforts should
be made to standardize and systematize the reporting
of adverse effects data;

8. Daytime sedation, with concomitant risk of motor
vehicle or occupational accidents, is a significant
potential risk. Further efforts to include objective
assessments of performance impairments which may
be associated with daytime sedation is encouraged;

9. Virtually no data exists regarding the use of sleep-
promoting agents in children. Yet, such medications
are not infrequently used in this age group. As such,
studies of the efficacy and safety of sleep-promoting
medications in children and adolescents should be
required.

Summary
This analysis is, to the best of our knowledge, the most compre-
hensive assessment of efficacy of individual sleep-promoting
agents published to date. It relies heavily on rigorous evalua-
tion of the quality of evidence for efficacy, based on GRADE,
as well as determination of potential adverse effects, to the
extent possible. It is intended to serve as a useful guide for cli-
nicians in prescribing medications for the treatment of chronic
insomnia. This analysis, however, also makes it abundantly
clear that the availability and quality of the data which serve
as the foundation for such recommendations are sorely lim-
ited. The result is that many commonly used drugs, including
some which carry FDA approval for treatment of insomnia, are
not recommended. Further data are required to formulate any
reasonable conclusion regarding their efficacy or lack thereof.
As a result, clinicians must continue to exercise sound clinical

judgment, based not only on these recommendations, but also
on clinical experience, prior patient response, patient prefer-
ences, and potential adverse effects.

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A C K N O W L E D G M E N T S
The task force thanks and acknowledges the contributions of Karl Doghramji, MD,
who served as a critical reviewer of this guideline.

S U B M I S S I O N & C O R R E S P O N D E N C E I N F O R M AT I O N
Submitted for publication September, 2016
Submitted in final revised form September, 2016
Accepted for publication September, 2016
Address correspondence to: Michael J. Sateia, MD, Geisel School of Medicine at
Dartmouth, Hanover, NH 03755; Tel: (603) 650-7534; Fax: (603) 650-7820; Email:
research@aasmnet.org

D I S C L O S U R E S TAT E M E N T
The development of this clinical practice guideline was funded by the American
Academy of Sleep Medicine. Dr. Neubauer is a member of the Board of Directors for
the National Sleep Foundation; and he has been a consultant for Purdue Pharama.
Dr. Krystal serves on a scientific advisory board for Merck, and therefore did not
participate in the development of the suvorexant recommendation; he has received
research support from the NIH, TEVA and Sunovion; and he has been a consultant
for Flamel, Atentiv, Ostuka, Neurocrine, Lundbeck, Pernix, Janssen, Jazz and
Merck. Dr. Buysse has been a consultant for Cereve, Inc, Emmi Solutions, Philips
Respironics, BeHealth; he has received research support from the NIH; and he owns
intellectual property rights in the Pittsburgh Sleep Quality Index (PSQI). Mr. Heald
is employed by the American Academy of Sleep Medicine. The other authors have
indicated no financial conflicts of interest.

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SLEEP,Vol. 29, No. 10, 2006 1277

1.0 INTRODUCTION

BEDTIME PROBLEMS AND FREQUENT NIGHT WAKINGS
ARE HIGHLY PREVALENT IN YOUNG CHILDREN, OCCUR-
RING IN APPROXIMATELY 20% TO 30% of infants, toddlers,
and preschoolers. Bedtime problems include bedtime struggles
and bedtime refusal (e.g., verbal protests, crying, getting out of
bed, attention-seeking behaviors). These sleep behaviors usually
fall within the clinical diagnostic category of behavioral insom-
nia of childhood, limit-setting type, in which parents demonstrate
difficulties in adequately enforcing bedtime limits. Night wak-
ings are nocturnal awakenings that are viewed as problematic by
caregivers, generally because they are frequent and/or prolonged
and/or require parental intervention. In general, night wakings fall
within the diagnostic category of behavioral insomnia of child-
hood, sleep onset association type, in which children become
dependent upon specific sleep onset associations (e.g., rocking,
feeding, parental presence) to fall asleep at bedtime and to return

Practice Parameters for Behavioral Treatment of Bedtime Problems and Night
Wakings in Infants and Young Children
An American Academy of Sleep Medicine Report

Timothy I. Morgenthaler, MD1; Judith Owens, MD2; Cathy Alessi, MD3; Brian Boehlecke, MD, MSPH4; Terry M. Brown, DO5; Jack Coleman, Jr., MD6; Leah Friedman,
MA, PhD7; Vishesh K. Kapur, MD, MPH8; Teofilo Lee-Chiong, MD9; Jeffrey Pancer, DDS10; Todd J. Swick, MD11

1Mayo Clinic, Rochester, MN; 2Rhode Island Hospital, Providence, RI; 3VA Greater Los Angeles Healthcare System and University of California,
Los Angeles, Sepulveda, CA; 4University of North Carolina, Chapel Hill, NC; 5St. Joseph Memorial Hospital, Murphysboro, IL; 6Murfreesboro, TN;
7Stanford University, Stanford, CA; 8University of Washington, Seattle, WA; 9National Jewish Medical and Research Center, Denver, CO; 10Toronto,
Ontario, Canada; 11Houston Sleep Center, Houston, TX

Review of Bedtime Problems in Children—Morgenthaler et al

Disclosure Statment
This was not an industry supported study. Dr. Morgenthaler has received re-
search support from Itamar Medical Ltd. and ResMed Research Foundation;
and has received research equipment from Olympus. Dr. Owens is a consul-
tant for Eli Lilly, Sanofi-Aventis, Cephalon, and Shire; has received research
support from Eli Lilly, Cephalon, and Sepracor; and is a speaker for Eli Lilly,
Cephalon, Sanofi-Aventis, and Johnson & Johnson. Dr. Alessi is a consul-
tant for Prescription Solutions, Inc. Dr. Kapur has received research support
from the Washington Technology Center and Pro-tech Services, Inc.; and
has received research equipment from Respironics. Dr. Swick has received
research support from Sanofi-Aventis, Takeda Pharmaceuticals, Merck, Jazz
Pharmaceuticals, Pfizer, Somaxon, Astellas-Pharmaceuticals, and Cepha-
lon; and is on the speakers’ bureau of GlaxoSmithKline, Jazz Pharmaceu-
ticals, Sepracor, Cephalon, and Boehringer Ingelheim. Dr. Coleman has is
a consultant for Acclarent and Influent. Drs. Boehlecke, Brown, Friedman,
Lee-Chiong, and Pancer have indicated no financial conflicts of interest.

Address correspondence to: Timothy I Morgenthaler, MD, Mayo Sleep Disor-
ders Center, Mayo Clinic, 200 First Street SW, Rochester, MN 55905; Tel: (507)
284-3764; Fax: (507) 266-4372; E-mail: morgenthaler.timothy@mayo.edu

Summary: Bedtime problems and frequent night wakings are highly
prevalent in infants, toddlers, and preschoolers. Evidence suggests that
sleep disruption and/or insufficient sleep have potential deleterious ef-
fects on children’s cognitive development, regulation of affect, attention,
health outcomes, and overall quality of life, as well as secondary effects
on parental and family functioning. Furthermore, longitudinal studies have
demonstrated that sleep problems first presenting in infancy may become
chronic, persisting into the preschool and school-aged years. A solid body
of literature now exists supporting the use of empirically-based behavioral
management strategies to treat bedtime problems and night wakings in
infants, toddlers, and preschoolers. The following practice parameters
present recommendations for the use of behavioral (i.e., non-pharmaco-
logical) treatments of bedtime problems and night wakings in young chil-
dren (aged 0 – 4. years 11 months). A companion review paper1 on which
the recommendations are based was prepared by a taskforce appointed
by the Standards of Practice Committee (SPC) of the American Academy
of Sleep Medicine (AASM), and summarizes the peer-reviewed scientific
literature on this topic. The authors of the review paper evaluated the evi-
dence presented by the reviewed studies according to modified Sackett
criteria.2 Using this information and a grading system described by Eddy3
(i.e., standard, guideline or option), the Standards of Practice Commit-
tee and Board of Directors of the American Academy of Sleep Medicine
determined levels of treatment recommendation presented in the practice
parameters below. These practice parameters provide 3 types of recom-
mendations. First, recommendations are provided indicating that behav-
ioral interventions are effective in the treatment of bedtime problems and

night wakings in young children, producing reliable and significant clinical
improvement in sleep parameters. Second, recommendations are made
regarding specific behavioral therapies, including: (1) unmodified extinc-
tion, extinction with parental presence, and preventive parent education
are all rated as individually effective therapies in the treatment of bedtime
problems and night wakings (Standards), and (2) graduated extinction,
bedtime fading/positive routines and scheduled awakenings are rated as
individually effective therapies in the treatment of bedtime problems and
night wakings but with less certainty (Guidelines). There was insufficient
evidence to recommend standardized bedtime routines and positive rein-
forcement as single therapies. In addition, although behavioral therapies
for bedtime problems and night wakings are often combined, there was
insufficient evidence available to recommend one individual therapy over
another or to recommend an individual therapy over a combination of
therapies. Finally, recommendations are provided regarding the benefi-
cial effects of behavioral treatments on secondary outcomes, including
daytime functioning (child) and parental well-being.
Keywords: Practice guidelines; practice parameters; bedtime problems,
night wakings in young children; treatment, behavioral, non-pharmaco-
logical; unmodified extinction, graduated extinction, extinction with paren-
tal presence, parent education, positive routines, scheduled awakenings,
standardized bedtime routines, positive reinforcement.
Citation: Morgenthaler TI, Owens J, Alessi C et al. Practice parameters
for behavioral treatment of bedtime problems and night wakings in infants
and young children. SLEEP 2006;29(10):1277-1281.

SLEEP, Vol. 29, No. 10, 2006 1278

to sleep during the night.
The etiology of bedtime resistance and night wakings in child-
hood represents a complex combination of biological, circadian,
and neurodevelopmental factors that interact with environmen-
tal and behavioral variables. Thus, bedtime resistance and night
wakings in childhood, similar to psychophysiological insomnia
in adults, involve predisposing, precipitating, and perpetuating
factors. Bedtime problems and night wakings may be viewed as
representing some delay in the emergence of, or a regression in
behaviors associated with, the neurodevelopmental processes of
sleep consolidation and sleep regulation that evolve over the first
few years of life. Like most developmental processes, these are
shaped by both intrinsic (e.g., temperament) and extrinsic (e.g.,
sleeping environment, parenting practices) factors which, in turn,
may be modified by behavioral strategies.
It should be noted that bedtime problems and night wakings
in children, in contrast to the definition of insomnia in adults, are
defined as such primarily by caregivers, and do not necessitate a
subjective sleep complaint by the child himself. Thus, the defini-
tion of these sleep problems in young children is also highly influ-
enced by the developmental, environmental, and cultural context
in which they occur. Furthermore, although research definitions
of bedtime problems and night wakings generally include param-
eters related to some combination of frequency (e.g., number of
episodes per night or per week), severity (e.g., duration of epi-
sodes), and chronicity (e.g., weeks to months), there are currently
no standardized research criteria for defining these sleep problems
in the pediatric population. Finally, because of the nature of sleep
complaints in young children, outcomes may include parameters
related not only to daytime functioning in the child, but to paren-
tal variables (e.g., mental health, marital satisfaction) as well.

2.0 METHODS

The SPC of the AASM developed these practice parameters
based on the accompanying review paper.1 A task force of content
experts was appointed by the AASM in July, 2003 to review and
grade evidence in the peer-reviewed scientific literature regarding
the behavioral treatment of bedtime problems and night wakings.
Recommendations are based on evidence from studies evaluated
in this literature review.
The Board of Directors of the AASM approved these recom-
mendations. All members of the AASM SPC and Board of Direc-
tors completed detailed conflict-of-interest statements and were
found to have no conflicts of interest with regard to this subject.
These practice parameters define principles of practice that
should meet the needs of most patients in most situations. These
guidelines should not, however, be considered inclusive of all
proper methods of care or exclusive of other methods of care rea-
sonably expected to obtain the same results. The ultimate judg-
ment regarding appropriateness of any specific therapy must be
made by the healthcare practitioner and patient, in light of the
individual circumstances presented by the patient, available diag-
nostic tools, accessible treatment options, resources available and
other relevant factors.
The AASM expects these guidelines to have an impact on pro-
fessional behavior, patient outcomes, and, possibly, health care
costs. These practice parameters reflect the state of knowledge at
the time of publication and will be reviewed, updated, and revised

as new information becomes available. This practice parameter
paper is referenced, where appropriate, using square-bracketed
numbers to the relevant sections and tables in the accompanying
review paper,1 or with additional references at the end of this pa-
per. The AASM classification of evidence for evidentiary articles
is listed in Table 1. Definitions of levels of recommendations used
by the AASM appear in Table 2.

3. RECOMMENDATIONS

The recommendations in this paper are supported by Level I to
Level V evidence. Each of the 52 articles included in the accom-
panying review paper1 was evaluated using the evidence-based
approach outlined by the SPC in Table 1 of this paper. The evi-
dence was then evaluated by the SPC according to methodology
presented in Table 2 of this paper to establish a recommendation
level (Standard, Guideline, or Option). The following are recom-
mendations of the SPC and the Board of Directors of the AASM.
It should be noted that the age range of children included in these
recommendations is 0 – 4 years 11 months, and the target popu-
lation does not include children with known developmental dis-
abilities, or co-morbid medical or psychiatric conditions.

Table 1—AASM Classification Of Evidence

Evidence Study Design
Levels
I Randomized well-designed trials with low alpha and
beta error*
II Randomized trials with high alpha and beta error*
III Nonrandomized concurrently controlled studies
IV Nonrandomized historically controlled studies
V Case series

Adapted from Sackett2
*Alpha (type I error) refers to the probability that the null hypothesis
is rejected when in fact it is true (generally acceptable at 5% or less,
or p<0.05). Beta (Type II error) refers to the probability that the null hypothesis is mistakenly accepted when in fact it is false (generally, trials accept a beta error of 0.20). The estimation of Type II error is generally the result of a power analysis. The power analysis takes into account the variability and the effect size to determine if sample size is adequate to find a difference in means when it is present (Pow- er generally acceptable at 80-90%).

Table 2—AASM Levels Of Recommendations

Term Definition
Standard This is a generally accepted patient-care strategy, which
reflects a high degree of clinical certainty. The term
standard generally implies the use of Level I Evidence,
which directly addresses the clinical issue, or overwhelm-
ing Level II Evidence.
Guideline This is a patient-care strategy, which reflects a moderate
degree of clinical certainty. The term guideline implies
the use of Level II Evidence or a consensus of Level III
Evidence.
Option This is a patient-care strategy, which reflects uncertain
clinical use. The term option implies either inconclusive
or conflicting evidence or conflicting expert opinion.

Adapted from Eddy3

Review of Bedtime Problems in Children—Morgenthaler et al

SLEEP, Vol. 29, No. 10, 2006 1279

GENERAL RECOMMENDATION

3.1. Behavioral interventions are effective and recommended in the
treatment of bedtime problems and night wakings in young chil-
dren. [4.1] (Standard)

Of the 52 selected studies examining the effectiveness of be-
havioral interventions for the treatment of bedtime problems and
night wakings, 94% (49 of 52) reported that behavioral interven-
tions as a whole produced clinically significant improvements in
bedtime resistance and night waking, while the remaining three
studies reported equivocal findings. Nine of the 52 (17%) repre-
sented randomized treatment control trials that were classified as
Level I. Four studies (8%) were classified as Level II. The pri-
mary outcome measures in these thirteen studies were child sleep
parameters.

RECOMMENDATIONS FOR SPECIFIC THERAPIES

3.2 Unmodified extinction and extinction of undesired behavior with
parental presence are effective and recommended therapies in the
treatment of bedtime problems and night wakings. [4.2] (Standard)

Of the 23 separate studies involving the use of unmodified ex-
tinction, 21 found this behavioral strategy to be effective; four
were Level I randomized controlled trials and two were Level II.

The objective of unmodified extinction procedures for sleep prob-
lems is to reduce the undesired behavior (e.g., prolonged bedtime
protests) by eliminating any reinforcement (e.g., parental atten-
tion) of the behavior. This therapy usually involves having the
parents put the child to bed at a designated bedtime and then not
responding to the child’s undesired behavior;. It should be noted
that, although generally found to be effective, unmodified extinc-
tion has limited parental acceptance. Some parents find extinction
with parental presence, which involves a similar structure except
that the parents remain in the child’s room at bedtime during the
extinction procedure, more acceptable.

3.3. Parent education/prevention is an effective and recommended
therapy in the treatment of bedtime problems and night wakings.
[4.2] (Standard)

This recommendation is based on three randomized controlled tri-
als classified as Level I and one study classified as Level II. Parent
education programs may be targeted primarily towards prevention
of sleep problems, largely in the pre-natal period or first 6 months of
life, or towards intervention with a pre-existing sleep problem. Both
of these strategies focus on development of positive sleep habits,
and typically involve giving caretakers an education package that in-
cludes some combination of information on bedtime routines, sleep
schedules, and the acquisition of “self soothing” skills on the part of
the infant or child. Parental education also appears to be a highly cost-
effective treatment modality. Treatment format varies across studies
and includes individual therapist-parent sessions, group sessions, and
education booklets. Although there appears to be limited support for
the inclusion of clinical sessions in prevention/intervention educa-
tion programs, more research is needed to determine which of these
delivery models is most effective.

3.4. Graduated extinction of undesired behavior is an effective and
recommended therapy in the treatment of bedtime problems and
night wakings. [4.2] (Guideline)

This recommendation is based upon two randomized con-
trolled trials classified as Level I and one Level II study. The goal
of graduated extinction is to enable a child to develop the ability
to fall asleep independently, without requiring the intervention of
a parent. Parents are generally instructed to ignore bedtime crying
and tantrums for specified periods according to a fixed schedule
or progressively longer intervals, and to avoid reinforcing protest
behavior. This intervention is often referred to as “sleep training”.
Parental acceptance of graduated extinction techniques tends to
be greater than that of unmodified extinction.

3.5. Delayed bedtime with removal from bed/positive bedtime rou-
tines is an effective and recommended therapy in the treatment of
bedtime problems and night wakings. [4.2] (Guideline)

This recommendation is based on 1 Level I study. Delayed bed-
time involves temporarily delaying the child’s bedtime in order to
more closely approximate the actual sleep onset time; removal
from bed (also referred to as response cost) adds the requirement
for the parent to remove the child from bed for a specific time
period if sleep onset is not achieved within a prescribed time.
Positive bedtime routines involve the institution of a set sequence
of pleasurable and calming activities preceding bedtime in order
to establish a behavioral chain leading up to sleep onset. Both of

Table 3—Table of Treatment Terminology

Term Definition
Unmodified Involves parents putting the child to bed at a desig-
extinction nated bedtime and then ignoring the child until morn-
ing, although parents continue to monitor for issues
such as safety and illness. The objective is to reduce
undesired behaviors (e.g., crying, screaming) by elim-
inating parental attention as a reinforcer.
Graduated Involves parents ignoring bedtime crying and tantrums
extinction for pre-determined periods before briefly checking on
the child. A progressive (graduated) checking schedule
(e.g., 5 min., then 10 min.) or fixed checking schedule
(e.g., every 5 minutes) may be used. Like Unmodified
extinction, the goal is to enable a child to develop
“self-soothing” skills and be able to fall asleep inde-
pendently without undesirable sleep associations.
Positive Positive routines involve parents developing a set bed-
routines/ time routine characterized by enjoyable and quiet
faded activities to establish a behavioral chain leading up to
bedtime sleep onset. Faded bedtime involves temporarily de-
with laying the bedtime to more closely coincide with the
response child’s natural sleep onset time, then fading it earlier
cost as the child gains success falling asleep quickly. Re-
sponse cost involves taking the child out of bed for
prescribed brief periods if the child does not fall
asleep. These strategies rely on stimulus control as the
primary agent of behavior change and target reduced
affective and physiological arousal at bedtime.
Scheduled Involves parents preemptively awakening their child
awakenings prior to a typical spontaneous awakening, and provid-
ing the “usual” responses (e.g., feeding, rocking,
soothing) as if child had awakened spontaneously.
Parent Involves parent education to prevent the occurrence
education/ of the development of sleep problems. Behavioral in-
prevention terventions are incorporated into these parent educa-
tion programs.

Review of Bedtime Problems in Children—Morgenthaler et al

SLEEP, Vol. 29, No. 10, 2006 1280

these treatments are based upon stimulus control techniques, and
are targeted towards reducing affective and physiologic arousal at
bedtime.

3.6. The use of scheduled awakenings is an effective and recom-
mended therapy in the treatment of bedtime problems and night
wakings. [4.2] (Guideline)

The recommendation is based on 1 study classified as Level
I. Scheduled awakenings requires documentation of the pattern
of night wakings, followed by the institution of preemptive wak-
ing of the child by the parent prior to the expected time of those
awakenings, and subsequent fading out of the awakenings over
time. Studies suggest that this technique may be less acceptable to
parents, and may have less utility in very young children.

3.7. Insufficient evidence was available to recommend any single
therapy over another for the treatment of bedtime problems and
night wakings. Insufficient evidence was also available to recom-
mend combination, or multi-faceted, interventions for bedtime
problems and night wakings over single therapies. [4.2, 4.3, 4.4]
(Option)

Although several behavioral techniques were included as part
of a multi-component treatment package in a large number (14)
of studies, whether they are independently effective could not be
determined from the available data. [4.2] For example, insuffi-
cient evidence was available for standardized bedtime routines as
a stand-alone treatment to be evaluated and thus recommended as
a single therapy in the treatment of bedtime problems and night
wakings. Similarly, although positive reinforcement in the form
of token systems, verbal praise, etc was included as part of the
treatment package in 15 studies, there is currently insufficient
data to recommend it as a single intervention. [4.2]
There have been very few studies (5) that have conducted head-
to-head comparisons between different behavioral treatments. Al-
though these few studies suggest that there may be comparative
differences in degree and rapidity of treatment response, there is
currently not enough evidence to recommend the use of 1 treat-
ment over another. Similarly, although a total of 30 studies (5 of
which were classified as Level 1 or II, 16 as Level III, and 9 as
Level IV or V) included 2 or more types of behavioral interven-
tions (e.g., parent education, positive reinforcement, graduated
extinction, individually tailored treatment) in combination, there
was a great deal of variability in the treatment components includ-
ed in these studies. Therefore, no specific recommendations can
be made regarding the relative superiority of any combination vs.
single therapies. Only 1 study in children has compared the rela-
tive efficacy of combined behavioral-pharmacologic treatment vs.
behavioral treatment alone. [4.3, 4.4]

RECOMMENDATIONS FOR SECONDARY OUTCOMES

3.8. Behavioral interventions are recommended and effective in im-
proving secondary outcomes (child’s daytime functioning, parental
well-being) in children with bedtime problems and night wakings.
[4.6] (Guideline)

A total of 13 studies have assessed a number of secondary treat-
ment outcomes related to daytime functioning in the child (in-
cluding behavior, mood, self-esteem, parent-child interactions).
The majority of these studies reported positive effects on daytime

functioning; no adverse secondary effects were identified in any
of these studies. Parental (largely maternal) well-being (includ-
ing mood, overall mental health status, parenting stress, marital
satisfaction) has been included as an outcome measure in 12 stud-
ies; results have been consistent in demonstrating improvements
in perceived parenting efficacy, marital satisfaction, parenting
stress, and maternal mood.

4.0 AREAS FOR FUTURE RESEARCH

a) Standard research definitions of bedtime problems and night
wakings in young children need to be established. These def-
initions should include parameters such as frequency, sever-
ity, and duration of the sleep problem, and impact on daytime
functioning in both the child and the caregivers.

b) Criteria for primary subjective and objective outcome mea-
sures of child sleep parameters, and secondary outcome mea-
sures related to child daytime functioning (including mood,
neurobehavioral and neurocognitive function), and caregiver
well-being (including mood, functioning, sleep parameters)
need to be established.

c) Individual treatment components (e.g., extinction, positive
reinforcement, parent education) and delivery issues (includ-
ing format, duration, delivery mechanisms, etc) need to be
studied and compared in regards to efficacy, acceptance and
adherence, and cost-effectiveness.

d) The impact of potential confounding variables (e.g., child
temperament, parent education, cultural differences in sleep
practices) on treatment outcomes needs to be systematically
examined.

e) The role of alternative treatments, either alone or in com-
bination with behavioral therapies, such as the use of com-
plimentary and alternative medicine strategies (e.g., herbal
preparations, infant massage) should be studied.

f) The long-term impact of behavioral interventions for bed-
time problems and night wakings in children on persistence
of sleep problems into adulthood, later affective, cognitive,
and behavioral function, and the emergence of psychopathol-
ogy in adolescence and adulthood need to be evaluated.4

g) The use of behavioral treatment for bedtime problems and
night wakings in older (> 5 years) children and adolescents
needs to be explored. Additional studies are also needed to
examine the use of these strategies in children with special
needs (e.g., children with autism spectrum disorders, mental
retardation, neurodevelopmental disabilities) and in children
with chronic medical and psychiatric conditions.

ACKNOWLEDGEMENTS

The AASM and the SPC would like to thank Sara Seaquist and
Maria DeSena for coordinating the work on this practice param-
eter and Richard Rosenberg, PhD, Andrew L. Chesson, MD, Max
Hirshkowitz, PhD, and Susan Benloucif, PhD for their contribu-
tions to the preparation of the manuscript.

REFERENCES

1. Mindell JA, Kuhn B, Lewin DS, Meltzer LJ, Sadeh A. Behavioral
treatment of bedtime problems and night wakings in infants and
young children. An American Academy of Sleep Medicine Review

2. Sackett DL. Rules of evidence and clinical recommendations for
the management of patients. Canadian Journal of Cardiology. 1993;

Review of Bedtime Problems in Children—Morgenthaler et al

SLEEP, Vol. 29, No. 10, 2006 1281

9:487-9.
3. Eddy DM, (Ed.) A manual for assessing health practices and de-

signing practice policies: the explicit approach. Philadelphia, PA:
American College of Physicians; 1992

4. Ramchandani P, Wiggs L, Webb V, Stores G. A systematic review
of treatments for settling problems and night waking in young chil-
dren. BMJ. 2000 Jan 22;320(7229):209-13.

1179journal.publications.chestnet.org

Th e Pathophysiology of Insomnia

Jessica C. Levenson , PhD ; Daniel B. Kay , PhD ; and Daniel J. Buysse , MD

Insomnia disorder is characterized by chronic dissatisfaction with sleep quantity or quality

that is associated with diffi culty falling asleep, frequent nighttime awakenings with diffi culty

returning to sleep, and/or awakening earlier in the morning than desired. Although progress

has been made in our understanding of the

nature, etiology, and pathophysiology of

insomnia,

there is still no universally accepted model.

Greater understanding of the pathophysiology of

insomnia may provide important information regarding how, and under what conditions, the

disorder develops and is maintained

as well as potential targets for prevention and treatment.

The aims of this report are (1) to summarize current knowledge on the pathophysiology of

insomnia and (2) to present a model of the pathophysiology of insomnia that considers evi-

dence from various domains of research. Working within several models of insomnia, evidence

for the pathophysiology of the disorder is presented across levels of analysis, from genetic to

molecular and cellular mechanisms, neural circuitry, physiologic mechanisms, sleep behavior, and

self-report. We discuss the role of hyperarousal as an overarching theme that guides our concep-

tualization of insomnia. Finally, we propose a model of the pathophysiology of insomnia that

integrates the various types of evidence presented. CHEST 2015; 147� ( 4 ): 1179 – 1192

ABBREVIATIONS: GABA 5 g -aminobutyric acid ; MnPO 5 median preoptic area ; NREM 5 non-rapid eye
movement ; PEP 5 pre-ejection period ; PSG 5 polysomnography ; REM 5 rapid eye movement ; SNP 5
single-nucleotide polymorphism ; TMN 5 tuberomammillary nucleus of the posterior hypothalamus ; VLPO 5
ventrolateral preoptic area

[ Contemporary Reviews in Sleep Medicine ]

Manuscript received July 3 , 2014 ; revision accepted October 28 , 2014 .

AFFILIATIONS: From the Department of Psychiatry, University of
Pittsburgh School of Medicine, Pittsburgh, PA.

FUNDING/SUPPORT: Dr Buysse is supported by the National Institutes
of Health [Grants MH024652, MH102412, AG020677, and HL125103].
Drs Levenson and Kay are supported by the National Institutes of
Health [Grant HL082610, T32, PI Buysse].

CORRESPONDENCE TO: Daniel J. Buysse, MD, University of Pittsburgh,
3811 O’Hara St, WPIC E-1127, Pittsburgh, PA 15213; e-mail: buyssedj@
upmc.edu

© 2015 AMERICAN COLLEGE OF CHEST PHYSICIANS. Reproduction of
this article is prohibited without written permission from the American
College of Chest Physicians. See online for more details.

DOI: 10.1378/chest.14-1617

Insomnia disorder is characterized by

dissatisfaction with sleep quantity or quality,

associated with diffi culty falling asleep,

frequent nighttime awakenings with

diffi culty returning to sleep, and/or awak-

ening earlier in the morning than desired. 1 , 2

Th e disorder is also characterized by signifi –

cant distress or impairment in functioning,

and daytime symptoms including fatigue,

daytime sleepiness, impairment in cogni-

tive performance, and mood disturbances.

Insomnia is differentiated from sleep

deprivation by diffi culty sleeping despite

having adequate opportunity to sleep. 1

Prevalence estimates of insomnia vary,

with 30% to 43% of individuals reporting

at least one nighttime insomnia symptom. 3 – 6

Most reports suggest prevalence rates of

insomnia disorder at 5% to 15%. 4 , 5 , 7 , 8

Insomnia is a chronic problem in 31% to

75% of patients, 1 , 6 , 7 with more than two-

thirds of patients reporting symptoms for

at least 1 year. 9

Although progress has been made in recent

years regarding our understanding of the

nature, etiology, and pathophysiology of

1180 Contemporary Reviews in Sleep Medicine [ 1 4 7 # 4 C H E S T A P R I L 2 0 1 5 ]

insomnia, 6 , 10 – 12 there is still no universally accepted model.

Th is may be related to the heterogeneity of insomnia,

its highly comorbid nature, or diff erences in what level

of analysis the models use, from phenomenology to

physiology. To be comprehensive, an etiologic or

pathophysiologic model of insomnia should explain

features such as the heterogeneity of symptoms and the

risk insomnia confers for other comorbid conditions,

such as depression and cardiometabolic syndrome. It

should also explain the discrepancy between subjective

(self-report) and objective (polysomnography [PSG])

measures of insomnia symptoms reported by some

individuals with insomnia (see Reference 13 for a review).

Greater understanding of the pathophysiology of

insomnia may provide important information regarding

how, and under what conditions, the disorder develops

as well as potential targets for prevention and treatment.

Th e aims of this review are (1) to summarize current

breadth of knowledge on the pathophysiology of

insomnia and (2) to present a model of the pathophysi-

ology of insomnia that draws on evidence from various

domains. Our article is intended to provide a brief

overview of these topics for clinicians and researchers

whose main focus is not insomnia. More extensive

reviews of this topic can be found elsewhere. 12 , 14 , 15 Our

article is primarily informed by perspectives drawn from

psychology, psychiatry, and clinical neuroscience.

Levels of Analysis: An Approach to
Understanding Insomnia

Although evidence-based assessments and treatments

for mental disorders have been developed, diagnostic

criteria for these conditions—including insomnia—are

grounded in clinical consensus. 16 Further progress depends

on better understanding the etiology and pathophysiology

of mental health problems. One framework for doing

this has been off ered by the National Institute of Mental

Health’s “Research Domain Criteria” initiative. While

recognizing the value of current diagnostic categories,

the National Institute of Mental Health has begun to

emphasize observable “domains” of brain function

pertinent to mental health. Th ese research domains,

such as positive emotion, negative emotion, and arousal,

often show similar patterns of dysregulation across

traditional diagnostic categories and can be examined

across levels of analysis from genes to symptoms. Th ese

points pertain to insomnia as well. Th e fi rst two editions

of the International Classifi cation of Sleep Disorders

introduced . 25 diagnoses with “insomnia” as a

cardinal symptom, 2 , 17 but evidence for the reliability,

validity, and distinct pathophysiology of these insomnia

phenotypes has proved elusive. Partially as a conse-

quence of this, both the International Classifi cation of

Sleep Disorders , Th ird Edition 18 and Diagnostic and

Statistical Manual of Mental Health Disorders , Fift h

Edition , 1 now propose a single major category for

Insomnia Disorder or Chronic Insomnia Disorder.

Nevertheless, there remains an impetus for the fi eld to

develop an evidence-based model of insomnia that

accounts for heterogeneity in cause, symptoms, course,

comorbidities, and consequences. Th is review considers

evidence across seven levels of analysis based on the

Research Domain Criteria framework: genetic, molecular,

cellular, neuroanatomic, physiologic, behavioral, and

self-report.

Hyperarousal: An Overarching Th eme

Insomnia is often considered to be a disorder of

hyperarousal, 19 or increased somatic, cognitive, and

cortical activation. 20 , 21 Individuals with insomnia may

experience physiologic hyperarousal in both central

(cortical) and peripheral (autonomic) nervous systems

(see References 20 , 22 , 23 for full review). Hyperarousal

in insomnia can also refer to cognitive and emotional

processes, with several theories suggesting that cognitive

and aff ective hyperarousal at bedtime may contribute

to both acute and chronic insomnia. 24 , 25 Despite the

frequent attention to hyperarousal in the literature, it is

not frequently defi ned. In this report we conceptualize

hyperarousal as heightened physiologic, aff ective, or

cognitive activity, which interferes with the natural

“disengagement from […] the environment” 26 and

decreases the likelihood of sleep. Hyperarousal may be

detected using such measures as increased cortisol, heart

rate variability, EEG, or even self-report (eg, “I can’t turn

off my mind,” “I feel so keyed up”). One of the challenges

in identifying hyperarousal is that an individual always

has some level of arousal, and the exact threshold for

categorizing hyperarousal is not well defi ned. Th us, most

studies have identifi ed hyperarousal by noting diff erences

between insomnia and control groups, rather than

denoting a specifi c threshold. 27 We propose hyperarousal

as an overarching theme that, along with other contribu-

tory factors, enriches our understanding of the patho-

physiology of insomnia at each level of analysis and

across levels in an integrated model.

Genetics of Sleep and Insomnia

Sleep-wake traits, such as sleep duration and timing, are

heritable 28 and regulated by numerous genes. 29 Animal

and human studies also implicate genetic mechanisms

in the etiology of insomnia. Seugnet et al 30 isolated

1181journal.publications.chestnet.org

insomnia-like Drosophila fl ies (ins-1 fl ies) with rest-

activity traits that resemble human insomnia, includ-

ing decreased rest time, increased latency to a resting

state aft er lights out, greater fragmentation of rest periods,

and heightened activity levels. Whole-genome transcript

profi ling of ins-1 fl ies identifi ed 755 genes with human

homologs that were diff erentially expressed compared

with wild-type fl ies. Genes found to be conserved in

ins-1 flies are associated with sensory perception,

metabolism, cell surface signaling, and neuronal activity

and may have implications for understanding the

genetics of human insomnia.

Most genetic studies in humans have used a limited set of

self-report items to categorize insomnia symptom pheno-

types and yielded a wide range in heritability estimates

for insomnia (h 2 5 0-81%) across family history and

twin studies. 31 – 33 Studies using more stringent criteria to

defi ne insomnia have produced more realistic and reliably

modest h 2 estimates ranging from 31% to 58%. 32 , 34 , 35

Candidate gene studies have identifi ed gene variants that

may be involved in the pathophysiology of insomnia,

including Apo ε 4, 36 PER3 4/4 , 37 HLA DQB1 * 0602, 38
homozygous Clock gene 3111C/C Clock, 39 and short (s-)

allele of the 5-HTTLPR. 40 A genomewide association

study found numerous single-nucleotide polymor-

phisms (SNPs) signifi cantly associated with insomnia

symptoms. 41 Th e most signifi cant SNPs occurred

within genes involved in neuroplasticity (eg, ROR1,

PLCB1, EPHA4, and CACNA1A), stress reactivity

(eg, STK39, USP25, and MARP10), neuronal excitability

(eg, GABRB1 and DLG2), and mental health (eg, NPAS3). 41

Overall, current evidence suggests signifi cant heritability

and multigene involvement in the pathophysiology of

insomnia. Genes linked to brain functioning, arousal

regulation, and sleep-wake processes have been most

consistently found to be associated with insomnia. Th e

complex interplay of these genes may account, at least in

part, for the heterogeneity observed in insomnia

symptoms and consequences. Future genetic studies

with detailed assessment of sleep and health history of

patients with chronic insomnia disorder may further

refi ne our understanding of genetic factors involved in

the development and characteristics of insomnia.

Molecular Mechanisms of Sleep and Insomnia

Numerous sleep regulatory substances are linked to

circadian rhythmicity and sleep regulation. Although

recognizing the oversimplification, 42 we argue that

endogenous molecules can be categorized as primarily

wake-promoting/sleep-suppressing (eg, catecholamines,

orexin, and histamine) and sleep-promoting/wake-

suppressing substances (eg, g -aminobutyric acid [GABA],

adenosine, serotonin, melatonin, prostaglandin D2). 43

Very few molecular studies have been conducted in

insomnia and have focused on only a limited set of

molecules (eg, cortisol and GABA). Table 1 lists studies

linking various molecules to insomnia. 41 , 44 – 55 Findings

are mixed across studies, and no consistent pattern for a

specifi c type of molecule (sleep vs wake promoting) has

emerged. Despite contradictory evidence, 52 results have

largely been interpreted within the context of the

hyperarousal hypothesis. For example, increased 45 and

decreased 46 GABA in the occipital cortex of patients

with insomnia have been reported to be consistent with

the hyperarousal model of insomnia. However, sleep

regulatory molecules interact with each other in

complex ways (described in more detail later), and many

of their eff ects are dependent on the milieu of the brain

state; that is, they are state-dependent. Th ese factors

make it highly unlikely that all cases of insomnia can be

explained by alterations in any single type of molecule

(eg, hyperarousal-related). A more sophisticated

conceptualization holds that chronic insomnia results

from disintegration of the alternating rhythms

of wake-promoting and sleep-regulatory molecules

in the brain. 56 Constant routine, in-home PSG, and

sleep-deprivation studies, particularly those that

examine wake- and sleep-promoting molecules (or

their mRNA and associated micro-RNA) during

diff erent states across the 24-h day, may prove fruitful in

elucidating the molecular underpinnings of chronic

insomnia. In addition, studies that more fully link this

level of analysis with the genetic underpinnings are also

needed.

Cellular Mechanisms of Sleep and Insomnia

Many of the molecules involved in sleep-wake regula-

tion are produced by specifi c brain structures with

widespread projections throughout the brain. Th ere is,

however, mounting evidence that many sleep regulatory

molecules aff ect neurons locally, in the regions in which

they are produced. In local sleep theory proposed by

Krueger et al, 57 sleep is defined as a fundamental

emergent property of highly interconnected neurons, or

cortical columns. Local sleep propensity and slow wave

amplitude are posited to be dependent on accumulation

of sleep-regulatory substances (eg, tumor necrosis

factor- a and IL-1 b ) 58 , 59 resulting from prior neuronal

use. Synchronous firing within cortical columns is

postulated to propagate slow wave activity in adjacent

regions through humoral and electric interactions,

1182 Contemporary Reviews in Sleep Medicine [ 1 4 7 # 4 C H E S T A P R I L 2 0 1 5 ]

leading eventually to a “global” sleep state in the entire

organism.

From this perspective, insomnia may not be a “whole-

brain” event (ie, a simple matter of imbalance between

global amounts of sleep and wake). An animal model of

insomnia has demonstrated simultaneous localized Fos

activation in both sleep-promoting and wake-promoting

regions during global sleep. 60 In humans, spectral

EEG methods have identified heightened regional

electrical brain activity in patients with insomnia during

non-rapid eye movement (NREM) sleep. 61 , 62 Merica et al 61

proposed that the lack of objective sleep disruption in

many patients with insomnia may be due to isolated

neuronal groups remaining active during PSG-defi ned

sleep. Th is dynamic in the brain may be experienced as

wakefulness by many patients with insomnia and

miscategorized as “normal” sleep based on standard

PSG criteria. 63 Advances in neuroimaging technology

would be needed to determine whether insomnia is

associated with a distributed pattern of wakefulness

at the neuronal level or is better characterized by a

region-specifi c persistence of wake-like brain activity

during globally defi ned EEG sleep more consistent with

the next level of analysis. 64

Sleep-Wake Regulation and Neural Circuitry
of Sleep

On the global level, sleep is regulated by coordinated

wake and sleep brain networks. Insomnia may plausibly

involve dysregulation within these networks.

Wake Systems and Hyperarousal in Insomnia

Th e major wake-promoting systems of the brain

include the “bottom-up” reticular activating system,

limbic networks, and the “top-down” cognitive

systems. Neural systems originating in the brainstem,

thalamus, and hypothalamus 65 – 67 constitute the ascending

reticular activating system. Th is system projects to the

cortex via the thalamus and basal forebrain and

includes cholinergic pedunculopontine and laterodor-

sal tegmental nuclei, noradrenergic locus coeruleus

nuclei, serotoninergic dorsal and median raphe nuclei,

the parabrachial nucleus, the histaminergic tuber-

omammillary nucleus of the posterior hypothalamus

(TMN), and basal forebrain cholinergic nuclei.

Orexin/hypocretin neurons of the lateral hypothal-

amus project to all of the arousal-promoting centers in

the brainstem and hypothalamus and reinforce their

activity. Emotional and cognitive systems can enhance

TABLE 1 ] Insomnia Related Molecules (Neurotransmitters and Hormones)

Molecule Method Insomnia vs Control Subjects Reference

Calcium Blood serum levels ↑ 41

g -Aminobutyric acid Average brain spectroscopy ↓ 44

Occipital cortex spectroscopy ↑ 45

Anterior cingulate and occipital
cortex spectroscopy

↓ 46

Melatonin Evening wake/early sleep blood
serum levels

↓ 47

Urinary excretion Shifted 48

Noradrenaline Urinary excretion ↓ 49

Corticotropin-releasing hormone Blood serum levels ↑ 50

Adrenocorticotropic hormone Blood serum levels ↓ 50

24-h blood plasma levels ↑ 51

Cortisol Evening and morning salivary levels ↑ (Evening), ns (morning) 49

Blood serum levels ns 47

Salivary levels ns 52

Evening and morning salivary levels ns (Evening), ↓ (morning) 53

Evening and morning salivary levels ns 54

Evening wake/early sleep blood
plasma levels

↑ 55

Evening/early sleep blood plasma levels ↑ 51

Blood serum levels ↑ 50

↓ 5 insomnia less than control subjects; ↑ 5 insomnia greater than control subjects; ns 5 no signifi cant diff erence.

1183journal.publications.chestnet.org

monoaminergic expression and lead to suppression of

sleep-promoting regions such as the ventrolateral

preoptic area (VLPO). Inputs to the arousal system

may suppress the fi ring of VLPO neurons, disinhibit-

ing the orexin/hypocretin and TMN neurons and

thereby opposing sleep pressure.

During initiation of normal sleep, arousal systems are

down-regulated by inhibition from the VLPO and median

preoptic area (MnPO). Th e activation of arousal centers

at the end of the sleep period is suffi cient to terminate

sleep. Activity of arousal systems (eg, cortisol) respon-

sible for alertness is modulated by the circadian timing

system. 68 , 69 Insomnia is oft en considered a disorder of

excessive activation of the arousal systems of the brain

(ie, hyperarousal). 19 Hyperarousal in the physiologic,

emotional, or cognitive networks is believed to prevent

sleep regulatory processes from naturally occurring in

patients with insomnia (see References 20 , 22 – 25 ).

However, other evidence suggests that hyperarousal is

neither necessary nor suffi cient for the development

of chronic insomnia. For example, many patients with

insomnia show no signs of cardiovascular, body tempera-

ture, or cortisol marker of hyperarousal, 52 and not all

individuals with these common markers of hyperarousal

develop insomnia.

Sleep Systems: Two-Process Model of Sleep

Regulation

Th e activity of arousal and sleep centers described above

is modulated by two critical physiologic processes:

wake-dependent (homeostatic) sleep drive and circadian

rhythmicity. Th ese two processes have been described in

the two-process model and related conceptualizations,

such as the opponent-process model of sleep-wake

regulation. 70 According to the two-process model of sleep

regulation, 71 sleep propensity is regulated by the interac-

tion of a wake-dependent process (process S) and a

relatively wake-independent circadian process (process C).

Process S dictates that greater brain use during wakeful-

ness increases sleep need and is measured by greater u

activity in the waking EEG 72 , 73 and higher amplitude

EEG power in the d range (0.5-4.5 Hz) during NREM

sleep. 58 On the network level, sleep onset is driven by

activation of GABAergic and galanin neurons in the

VLPO and MnPO. 65 Accumulation of extracellular

adenosine during prior wakefulness has been posited as a

primary input to these systems. Axons from VLPO/MnPO

send outputs to arousal centers in the hypothalamus

and brainstem, inhibiting arousal-promoting neurons

of TMN, dorsal and median raphe nuclei, and locus

coeruleus while simultaneously promoting sleep.

Circadian sleep propensity is regulated by intrinsic

circadian oscillations governed by the suprachiasmatic

nuclei of the hypothalamus. Exogenous light, melatonin,

and social factors can infl uence the suprachiasmatic

nuclei-regulated circadian processes in the body, such

as REM sleep, body temperature, and endogenous

melatonin. Optimal sleep is believed to occur when

the S- and C-processes driving sleep are appropriately

coordinated.

One hypothesis based on the two-process model is that

insomnia results from insuffi cient sleep propensity

during the desired sleep period because of dysfunction

in the S- or C-process. Evidence is mixed on whether

patients with insomnia compared with control subjects

have less robust slow wave activity following sleep

deprivation suggestive of a defi ciency in process S. 74 – 76

Evidence linking insomnia to markers of circadian

dysfunction, including delayed or advanced core body

temperature rhythms, or increased mean nocturnal core

body temperature in diff erent insomnia phenotypes,

suggest dysregulation of process C. 77 However, some

studies failed to fi nd an association between core body

temperature and insomnia. 52

Sleep Switch

Th e mutually inhibitory circuitry of the VLPO and

arousal centers of the brain is oft en described as a

central “fl ip-fl op switch” regulating the activity of

wake and sleep promoting systems to produce bistable

sleep-wake states. 65 – 67 From this perspective, sleep and

wake states are achieved via reciprocal inhibition

between the VLPO/MnPO regions and monoamin-

ergic brainstem and hypothalamic arousal centers

(see Reference 67 for review). Overriding the fl ip-fl op

switch has been proposed as a mechanism of insomnia. 78

Although maintaining heightened awareness in the

presence of sleep debt may be necessary and benefi cial

in rare times of crisis, insomnia may result from chronic

coactivation of sleep and wake circuits during the

desired sleep period. This conceptualization of

insomnia is consistent with an animal study showing

that the reciprocal inhibitory innervation between the

VLPO and the arousal system can decouple under

stressful conditions, resulting in a unique state with

simultaneous sleep and wake features. 60 According to

this model, the core feature of insomnia is not reduced

sleep or excessive wakefulness but rather the simulta-

neous activation of brain structures responsible for each

state.

1184 Contemporary Reviews in Sleep Medicine [ 1 4 7 # 4 C H E S T A P R I L 2 0 1 5 ]

Other authors have proposed that insomnia is an

unstable state in which individuals rapidly transition in

and out of sleep-wake states (ie, a fl ickering switch).

Individuals with greater subjective-objective sleep

discrepancy may have more brief arousals from sleep

(eg, Reference 79 ) and more frequent sleep-wake

transitions during the sleep onset interval, 80 consistent

with rapid switching between sleep and wake states.

Structural and Functional Neuroimaging

Although slow wave activity during NREM sleep is

commonly believed to be global and homogeneous in

the cerebrum, numerous studies have demonstrated that

sleep is a dynamic process in space and time. Compared

with a resting wake state, NREM sleep is associated with

lower whole-brain metabolism, particularly in the cortical

association areas. 81 More specifi cally, increased slow wave

activity during NREM sleep corresponds with reduced

cerebral blood fl ow globally but most strongly correlates

with decreases in brain regions involved in adapting

behavior to environmental pressures (ventrolateral

prefrontal cortex), conscious processes (anterior cingulate,

precuneus/upper cuneus, mediotemporal cortex), action

selection (basal ganglia), and generation of slow oscilla-

tions during slow wave sleep (brainstem, midbrain, and

thalamic structures). 82 Principal components analysis of

PET scan data identifi ed two brain networks associated

with sleep: (1) reduced blood fl ow in frontal and parietal

association cortices and hippocampus, and increased

fl ow in the cerebellum; and (2) reduced blood fl ow in

the thalamus and a region that, on visual inspection,

overlaps with the precuneus and cuneus. 83

Lesion and structural neuroimaging studies also suggest

that specifi c brain regions may be associated with

insomnia. Animal studies demonstrated that lesions of

the thalamus, 84 raphe nucleus, 85 or mediobasal preoptic

area 86 result in insomnia. von Economo 87 observed the

sleep of patients aff ected by the encephalitis pandemic of

1918, and these observations revealed an association

between insomnia and lesions in the anterior hypothal-

amus. In addition, patients with traumatic brain injuries

who endorse insomnia symptoms had overlapping lesions

in the left dorsomedial frontal cortex. 88 Structural imaging

studies have identifi ed reduced gray matter volume in

left orbitofrontal, prefrontal, precuneus, and temporal

cortices in patients with insomnia. 89 – 93 Th ese structures

may represent dysfunctional nodes in networks of sleep/

wake regulation.

Functional imaging studies suggest that patients with

insomnia have smaller reductions in brain activity

during NREM sleep relative to resting wake. Specifi cally,

the frontoparietal cortex, medial temporal lobes, thalamus,

anterior cingulate, precuneus, and brain stem arousal

networks have been implicated. 94 , 95 Corsi-Cabrera et al 96

also examined the topographic distribu tion of brain

wave activity associated with wakefulness as an index

of cortical activation during the sleep onset period

among individuals with primary insomnia. Th ey found

higher b activity in left frontal and frontal midline

regions during W and N1 and higher levels of temporal

coupling linking the frontal, parietal, and posterior

midline regions during the sleep onset period in

primary insomnia as compared with control subjects.

One overarching hypothesis is that the regional patterns

of greater activation during sleep in patients with

insomnia refl ects impaired deactivation and disengage-

ment of brain regions involved in executive control,

attention, and self-awareness and may contribute to the

experience of insomnia. 96

Electrophysiologic and Physiologic
Dysregulation in Insomnia

Hyperarousal has been examined using various electro-

physiologic (EEG) and physiologic measures during

sleep and wakefulness. EEG indicators of hyperarousal

include increased high-frequency EEG activity ( b and g ),

decreased d activity, and increased REM EEG arousals.

As discussed later, physiologic measures include increased

body temperature, skin resistance, metabolic rate, and

heart rate, among others.

NREM Sleep Instability

Th e Neurocognitive Model of insomnia posits that acute

insomnia may be perpetuated by maladaptive behav-

ioral coping strategies and may develop into chronic

insomnia as a result of conditioned arousal. 21 Conditioned

arousal is the repeated association of sleep-related cues

with wakefulness and/or arousal, which, over time, results

in an arousal response when a sleep-related stimulus is

presented. 97 Th e neurocognitive model focuses specifi cally

on cortical arousal as the mechanism underlying

chronic insomnia, as indexed by high-frequency EEG

activity ( b and g , 16-50 Hz). Th is EEG activity is

hypothesized to increase around sleep onset as a result

of classic conditioning (ie, a learned response to cues

associated with sleep). Data to support this hypothesis

show diminished d and increased high-frequency NREM

EEG power among patients with insomnia, as well as an

association between high-frequency EEG activity and

subjective sleep complaints. 98 , 99 High-frequency EEG

1185journal.publications.chestnet.org

enhances sensory and information processing, which

may contribute to the subjective-objective discrepancy

that oft en characterizes insomnia. 21 Evidence is mixed

regarding insomnia-control diff erences in high-frequency

EEG activity during wakefulness. 72 , 100 However, high-

frequency waking EEG activity signifi cantly correlates

with high-frequency EEG activity during NREM 100 and

with self-reported hyperarousal symptoms. 72 Th ese

fi ndings support the hypothesis that high-frequency

EEG power in insomnia is a marker of CNS

hyperarousal. 101

REM Sleep Instability

Th e REM sleep instability model 102 hypothesizes that the

subjective experience of insomnia is related to decreased

REM sleep percent and increased REM EEG arousals. 103

In one study, arousals and awakenings during REM

more precisely distinguished patients with insomnia

from good sleepers than NREM parameters. 102 Fragmented

REM sleep may promote the perception of increased

wakefulness and nonrestorative sleep in insomnia,

which may contribute to subjective-objective sleep

discrepancies insomnia. 102

Physiologic Hyperarousal

Additional support for the involvement of hyperarousal

in the pathophysiology of insomnia comes from fi ndings

examining various measures of physiologic arousal

among individuals with insomnia. As early as 1967,

Monroe 104 showed that poor sleepers had increased

body temperature, vasoconstrictions, body movements,

and skin resistance as compared with good sleepers.

Insomnia has also been associated, in some studies, with

increased 24-h metabolic rate (as measured by oxygen

consumption), 27 , 105 24-h adrenocorticotropic hormone

and cortisol levels, 51 and heart rate. 106 Some investigators

have demonstrated greater inhibition of facial muscle

activity and increased cardiac vagal tone in response to

sleep-related emotional stimuli among individuals with

insomnia as compared with good sleepers. 107 Others

have specifically examined the sleep-onset period,

fi nding increased frontalis electromyogram, increased

heart rate, and decreased fi nger temperature among

subjects with insomnia as compared with control

subjects up to the point of sleep onset. 108 Findings have

also shown sympathetic activation among patients with

insomnia during sleep onset, as evidenced by consis-

tently lower cardiac pre-ejection period (PEP) values as

compared with good sleepers. 106 , 109 Cardiac PEP is the

time interval from the beginning of ventricular

depolarization (marked by the onset of the QRS

complex in the ECG) to the opening of the aortic valve.

PEP duration is inversely related to b -adrenergic tone. 106

Th us, lower PEP values indicate enhanced activation of

the sympathetic nervous system.

Many studies investigating physiologic arousal and

hyperarousal in insomnia have included small samples

and have not been consistently replicated. 52 For this

reason, it is not possible to specify diagnostic thresholds

for any single physiologic measure in insomnia. Noting

these findings, Varkevisser et al 52 cautioned against

overemphasizing hyperarousal in the conceptuali-

zation of chronic insomnia. Although hyperarousal is an

important heuristic concept in many models of insomnia,

several confl icting points remain to be resolved. First,

the extent to which hyperarousal is a cause or a conse-

quence of insomnia has not been elucidated. Second,

targeting hyperarousal in the treatment of insomnia

(eg, through relaxation training) is oft en less eff ective

than approaches that enhance sleep processes (eg, sleep

restriction and hypnotic medications). Th ird, markers

of hyperarousal can also be interpreted as insuffi cient

inhibition of arousal by sleep-promoting processes.

Behavioral and Cognitive Contributions to
Insomnia

Various biologic mechanisms regulate sleep and contrib-

ute to insomnia. Behavioral and cognitive mechanisms

(ie, beliefs that contribute to specifi c behaviors) can

also regulate sleep and contribute to, and exacerbate,

insomnia.

Perpetuating Factors

Th e “3P model,” 110 a diathesis-stress model, describes

a set of predisposing, precipitating, and perpetuating

factors that may contribute to the development and

maintenance of insomnia. Predisposing factors, such

as age or sex, make an individual more susceptible to

insomnia, and precipitating factors are events that

coincide with the onset of insomnia, such as major

stressors. 111 Perpetuating factors, the largest focus of

the 3P model, are behaviors and beliefs that maintain

insomnia, 111 such as increasing time in bed to “catch

up” on sleep. 110 However, extended time in bed

perpetuates insomnia because it leads to increased

wakefulness, fragmented sleep, variability in sleep

timing, 110 and associations between the sleep environ-

ment and wakefulness. Th us, initial attempts to reduce

symptoms of insomnia may evolve into perpetuating

factors themselves.

1186 Contemporary Reviews in Sleep Medicine [ 1 4 7 # 4 C H E S T A P R I L 2 0 1 5 ]

Stimulus Control

In 1972, Bootzin 112 proposed that stimuli associated with

sleep (eg, a quiet, dark bedroom) become discriminative

stimuli that reinforce sleep. Insomnia may result from

inadequate sleep-promoting stimuli or from the presence

of stimuli that are antithetical to sleeping, 112 such as

phone calls, reading, or worry. Stimulus control therapy

for insomnia aims to separate the stimuli associated with

sleep from the stimuli associated with other activities. 112

Cognitive Model

Th e cognitive model of insomnia 25 proposes that

individuals with insomnia are susceptible to excessive

worry and unpleasant intrusive thoughts, particularly

those related to getting enough sleep and the conse-

quences of sleep disturbance. Th is worry may develop

into sleep-related anxiety, lead to increased vigilance for

sleep-related threats (eg, watching the clock at night),

and ultimately result in an exaggeration of the magni-

tude of the actual sleep disruption. Cognitive therapy for

insomnia challenges these maladaptive cognitive

processes and limits the behaviors that maintain

unhelpful beliefs and insomnia. 113

In the psychobiologic inhibition model, 24 , 114 a variant of

the cognitive model, sleep is thought of as automatic, 24

whereas insomnia is thought of as a failure of automatic

sleep. Th e model specifi cally focuses on the attention-

intention-eff ort pathway as one sleep inhibitory process,

in which three processes occur: (1) increased selective

attention to sleep and symptoms of insomnia; (2) an

increase in the subjective value of sleep, which may

contribute to explicit “intention to sleep”; and (3) gradual

development of increased eff ort to sleep, described as

“sleep eff ort syndrome.” 114 Th us, treatment of insomnia

should focus on cognitive strategies that aim to reverse

sleep-related attentional bias 113 and behavioral strategies 115

aimed at reducing sleep eff ort.

Self-Report and Insomnia

Unlike many other sleep disorders, insomnia disorder

relies on self-report for diagnosis; physiologic markers

of sleep dysregulation (PSG) or hyperarousal are not

routinely indicated for the evaluation of insomnia. 116 – 118

Several groups have developed self-report measures

aimed at detecting insomnia and assessing insomnia-

related experiences and impairments. Focus groups that

captured patients’ subjective experience of insomnia

highlighted the pervasive impact of the disorder, the

perception that others do not fully understand the

impact of insomnia, and the importance of daytime

symptoms of insomnia. 119 Self-report measures that were

developed to assess presleep thought content 120 and

sleep-related quality of life impairment 121 in insomnia

demonstrated that (1) presleep cognitive activity among

patients with insomnia focuses on rehearsal/planning,

sleep and its consequences, and autonomic experiences,

among others, and (2) the most common impairments

pertain to energy/motivation, performance at work,

cognitive functioning, and emotion regulation. Th is

work has also shown that self-report symptom scales

reliably discriminate individuals with insomnia and

good sleepers. 120 , 122

Although PSG usually shows abnormalities in sleep

architecture and continuity among individuals with

insomnia, the magnitude of patient-control diff erences

is oft en small, and the severity of objective fi ndings is

oft en less than that obtained by self-report. 1 Neverthe-

less, diff erences among patients with insomnia in

subjective and objective measures may have important

clinical implications. For instance, a meaningful

discrepancy between subjective and objective mea sure-

ment of sleep is prevalent among patients with insomnia

with objective normal sleep duration but not among

patients with insomnia with objective short sleep. 123

Moreover, compared with patients with insomnia who

have normal overall sleep duration, patients with

insomnia with short objectively measured sleep duration

are at increased risk for adverse health outcomes,

including hypertension, diabetes, physiologic hyper-

arousal, cognitive diffi culties, and even mortality. 124 , 125

Th e magnitude and night-to-night variability of discrep-

ancy between self-reported and objectively measured

sleep may itself constitute a high-risk presentation that

may be informative for examining the etiology and

pathophysiology of insomnia. 126 , 127 Th us, objective

assessments of sleep may be useful adjunctive measures

in predicting the biologic severity and medical impact of

insomnia, and cost-eff ective objective measures of sleep

should be considered in the standard diagnostic

procedure for insomnia to diff erentiate phenotypes. 124 , 125

Integration and Treatment Implications

Our intent in this article has been to outline the mecha-

nisms by which insomnia develops and is maintained,

highlighting fi ndings in the literature at various levels of

analysis. Table 2 summarizes the evidence at each unit of

analysis, which indicates that evidence for the patho-

physiology has been generated using numerous

methodologies based on a range of theoretical scientifi c

perspectives. Integration of the evidence presented here

allows us to propose one possible model for the

1187journal.publications.chestnet.org

TABLE 2 ] Evidence for the Pathophysiology of Insomnia at Each Unit of Analysis

Unit of Analysis Evidence for This Perspective in Pathophysiology of Insomnia

Genes Elevated family risk for insomnia

Elevated genetic risk in twin studies

Insomnia phenotype in drosophila related to mutations in 755 genes with human homologs

Candidate gene studies support association between aspects of insomnia and Apo ε 4, PER34/4,
HLA DQB1 * 0602, 3111C/C Clock, short (s-) allele of the 5-HTTLPR

Numerous SNPs identifi ed in human genomewide association study studies

Molecules Mixed fi ndings regarding the role of wake- and sleep-promoting molecules in insomnia; no consistent
pattern for a specifi c type of molecule has emerged

Unlikely that all cases of insomnia can be explained by alterations in any single molecule type

See Table 1 for links between various molecules and insomnia

Cells Simultaneous localized Fos activation in both sleep-promoting and wake-promoting regions during
global sleep in rats. Individual cortical columns show sleep-like activity while other parts of the

brain show wake-like activity

Neuronal use results in modulation of gene expression in sleep regulatory substance, which acts locally
in the brain to promote sleep

Circuits In animals, lesions of the anterior ventral and the dorsomedial thalamus, raphe nucleus, or paramedial
preoptic area results in insomnia

Less robust slow wave activity following sleep deprivation among subjects with insomnia than control
subjects (process S); delayed and advanced core body temperature rhythms and heightened

nocturnal core body temperature linked to insomnia (process C)

Those reporting greater subjective-objective sleep discrepancy demonstrate sleep-related behaviors
consistent with rapid switching between sleep and wake states

Reduced gray matter volume in left ventromedial prefrontal cortex, precuneus, and temporal cortices in
patients with insomnia

Patients with insomnia have smaller reductions in brain activity during NREM sleep relative to resting
wake

Higher b activity in left frontal and frontal midline regions during W and N1, higher levels of temporal
coupling linking the frontal, parietal, and posterior midline regions during the sleep onset period in

insomnia as compared with control subjects

Physiology Diminished d and increased high-frequency NREM EEG power among patients with insomnia

Association between high-frequency EEG activity and subjective sleep complaints

High-frequency waking EEG activity correlates with high-frequency EEG activity during NREM, and with
self-reported hyperarousal symptoms

Arousals and awakenings during REM sleep more precisely distinguished subjects with insomnia from
good sleepers than the NREM parameters

Insomnia associated with increased body temperature, vasoconstrictions, body movements, skin
resistance, 24-h metabolic rate, 24-h ACTH, cortisol levels

Continuous sympathetic hyperactivation among subjects with insomnia during sleep onset

Behavior Some effi cacious treatments for insomnia focus on resolving the behavioral and cognitive factors
contributing to and exacerbating insomnia. These include:

Increasing the association between the bed and being asleep

Reestablishing a consistent sleep-wake schedule

Restricting time in bed to increase sleep drive and, subsequently, sleep effi ciency

Reducing somatic tension or intrusive thoughts that are antithetical to sleep

Psychotherapy targeting maladaptive beliefs about sleep

Self-reports Self-report measures discriminate subjects with insomnia from good sleepers

Presleep mentation among subjects with insomnia focuses on rehearsal/planning, sleep and its
consequences, and autonomic experiences

The areas of energy/motivation, performance at work, cognitive functioning, and emotion regulation
are the most commonly reported sleep-related impairments in insomnia

(Continued)

1188 Contemporary Reviews in Sleep Medicine [ 1 4 7 # 4 C H E S T A P R I L 2 0 1 5 ]

Figure 1 – Model of the pathophysiology of insomnia. GABA 5 g -aminobutyric acid; SNP 5 single-nucleotide polymorphism .

Unit of Analysis Evidence for This Perspective in Pathophysiology of Insomnia

Underestimation of sleep duration is prevalent among those with a subjective complaint of insomnia
but objectively normal sleep duration

The magnitude of discrepancy between self-reported and objectively measured sleep may itself
constitute a high risk factor for insomnia.

ACTH 5 adrenocorticotropic hormone; NREM 5 non-rapid eye movement; SNP 5 single-nucleotide polymorphism.

TABLE 2 ] (continued)

pathophysiology of insomnia. Figure 1 depicts this

model, in which insomnia is most likely to develop in

those who have increased genetic risk and who experi-

ence abnormalities in neurobiological processes. Th ese

trait-like vulnerabilities may lead to neurophysiologic

hyperarousal and to psychologic and behavioral

processes, which, individually or together, increase an

individual’s risk for developing insomnia and associated

downstream health consequences. Precipitating stressors

and other person-specifi c factors (eg, age, sex) moderate

these relationships. Th e extent to which an individual

with insomnia shows evidence of abnormalities in each

of the processes depicted may vary among diff erent

individuals.

Accordingly, interventions aimed at preventing or

resolving symptoms of insomnia may target various aspects

of the identifi ed pathophysiologic processes. Th e cur rent

gold standard psychologic treatment of insomnia is

Cognitive Behavioral Th erapy for Insomnia, 128 – 130 which

is typically composed of multiple treatment elements:

stimulus control therapy, sleep restriction therapy,

relaxation training, cognitive therapy, and sleep hygiene

education (see Reference 131 for a review). These

treatment elements focus on: (1) increasing the associa-

tion between the bed and being asleep; (2) reestab-

lishing a consistent sleep-wake schedule; (3) restricting

time in bed to increase sleep drive and, subsequently,

sleep effi ciency; (4) reducing somatic tension or intrusive

thoughts that are antithetical to sleep; (5) targeting

maladaptive beliefs about sleep; and (6) maintaining

good sleep practices. 131 As reviewed by Buysse 132 and

Morin and Benca, 7 the effi cacy of Cognitive Behavioral

Th erapy for Insomnia for the treatment of insomnia has

been demonstrated. Although these approaches make

eff orts toward reducing cognitive and emotional arousal,

there has also been a call for therapies that target

1189journal.publications.chestnet.org

physiologic hyperarousal across the night and day. 22

Some studies have documented changes in physiologic

measures with pharmacologic therapies, but much more

work is needed to draw conclusions about the effi cacy of

these approaches. 22

In addition, several effi cacious pharmacologic treatments

for insomnia target various aspects of the identifi ed

pathophysiologic processes (see References 133 , 134 for

review). For example, benzodiazepine receptor agonists

(eg, temazepam, zolpidem), which are generally eff ective

in the treatment of insomnia, promote sleep by enhancing

widespread inhibitory activity of GABA. Th e tricyclic

drug doxepin has shown effi cacy for sleep initiation and

maintenance insomnia; although not US Food and Drug

Administration-approved, trazodone is also widely used

for insomnia. Th e sedative eff ect of these drugs is mainly

achieved by targeting the histaminergic arousal system.

More recently, there has been progress in the develop-

ment of orexin receptor antagonists for the treatment of

insomnia (eg, almorexant, suvorexant); suvorexant was

recently approved by the Food and Drug Administra-

tion for this indication. Th ese drugs target the orexin

system that promotes arousal of brainstem/hypotha-

lamic arousal centers. Other medications have been

suggested for the treatment of insomnia, but additional

work is needed to demonstrate safety and effi cacy.

Future work on the pathophysiology of insomnia

may help to identify specifi c mechanisms in specifi c

patient groups, which may lead to more targeted

pharmacotherapy.

Conclusions

Evaluating evidence from a range of domains and across

various levels demonstrates not only the advances made

in understanding the pathophysiology of insomnia but

also the areas in which additional support is needed and

the type of analysis that might fi ll a gap in the literature.

For example, human genetic studies that include more

refi ned sleep measures (ie, clinical assessment, sleep

diaries, actigraphy, PSG) may provide greater power

needed to identify the role of genes in the pathophysiology

of insomnia. At the neural and physiologic levels, future

work should examine the potential role of impaired

“switching processes” and local and circuit-level sleep

dysregulation. Functional imaging, high-density EEG,

magnetoencephalography, and magnetic resonance

spectroscopy are useful tools for such studies. Last,

additional studies at all levels of analysis should more

deeply examine subjective-objective discrepancies as

one clue to insomnia pathophysiology. Greater under-

standing of the pathophysiology of insomnia may

provide important information regarding new targets

for prevention and treatment.

Acknowledgments
Financial/nonfi nancial disclosures: Th e authors have reported to
CHEST the following confl icts of interest: Dr Levenson receives
royalties from American Psychological Association books and receives
grant support from the American Psychological Foundation.
Dr Buysse has served as a consultant for Merck & Co, Inc; Medscape;
Purdue Pharma LP; Emmi Solutions, LLC; Eisai Co, Ltd; CME Outfi tters,
LLC; and Otsuka Pharmaceutical Co, Ltd . Dr Kay has reported that no
potential confl icts of interest exist with any companies/organizations
whose products or services may be discussed in this article.

Role of sponsors : Th e sponsor had no role in the design of the study,
the collection and analysis of the data, or the preparation of the
manuscript.

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