New Directions

in the
Management of Insomnia

Balancing
Pathophysiology
and Therapeutics

Proceedings From an Expert Roundtable Discussion

Release date: October 10, 2013

Expiration date: October 31, 2014
Estimated time to complete activity: 1.5 hours

Jointly sponsored by Postgraduate Institute for Medicine

and MedEdicus LLC

This activity is supported by an educational grant from Merck & Co.

Distributed with
2 Target Audience
This activity has been designed to meet the educational needs
of physicians involved in the management of patients with
insomnia disorder.
Statement of Need/Program Overview
An estimated 40 to 70 million Americans are affected by
Faculty insomnia. According to these estimates, twice as many Americans
suffer from insomnia than from major depression. However, the
Larry Culpepper, MD, MPH—Co-Chair true prevalence of insomnia is unknown because it is
underdiagnosed and underreported. Recent updates in the
Professor and Chairman of Family Medicine
nosology and diagnostic criteria for insomnia have occurred as
Boston University School of Medicine well as advances in understanding pathophysiology, which, in
Boston University Medical Center turn, has led to the development of potential new treatments.
Boston, Massachusetts The burden of medical, psychiatric, interpersonal, and societal
consequences that can be attributed to insomnia and the
Tom Roth, PhD—Co-Chair prevalence of patients with insomnia disorder treated in primary
Director of Research care underscore the importance of continuing medical education
Sleep Disorders and Research Center (CME) that improves the clinical understanding, diagnosis, and
Henry Ford Hospital treatment of the disorder by primary care providers. This
continuing education activity is based on an expert roundtable
Detroit, Michigan
discussion and literature review and provides an update in
insomnia disorder.
Sonia Ancoli-Israel, PhD
Professor Emeritus of Psychiatry and Medicine Educational Objectives
Professor of Research After completing this activity, the participant should be better
University of California, San Diego able to:
• Perform a rapid assessment that leads to a diagnosis of
La Jolla, California
insomnia disorder
• Summarize the proposed pathophysiology of
Andrew Krystal, MD insomnia disorder
Director, Insomnia and Sleep Research Program • Evaluate current and emerging nonpharmacologic and
Professor of Psychiatry and Behavioral Sciences pharmacologic therapies for insomnia disorder
Duke University Medical Center • Appropriately select therapy for individual patients
Durham, North Carolina with insomnia disorder
Accreditation Statement
Phyllis Zee, MD, PhD This activity has been planned and implemented in accordance
Benjamin and Virginia T. Boshes Professor in Neurology with the Essential Areas and policies of the Accreditation Council
Director, Sleep Disorders Center for Continuing Medical Education through the joint sponsorship
Northwestern University of Postgraduate Institute for Medicine and MedEdicus LLC. The
Chicago, Illinois Postgraduate Institute for Medicine is accredited by the ACCME
to provide continuing medical education for physicians.
Credit Designation
The Postgraduate Institute for Medicine designates this enduring
material for a maximum of 1.5 AMA PRA Category 1 Credit(s)™.
Physicians should claim only the credit commensurate with the
extent of their participation in the activity.
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Faculty Disclosures
The faculty reported the following financial relationships or
relationships to products or devices they or their spouse/life
partner have with commercial interests related to the content of
this CME activity:
Sonia Ancoli-Israel, PhD, had a financial agreement or affiliation
during the past year with the following commercial interests in
the form of Consultant Fees: Ferring Pharmaceuticals; Merck &
Co.; and Prudue Pharma L.P.
Larry Culpepper, MD, MPH, had a financial agreement or
affiliation during the past year with the following commercial
interests in the form of Consultant Fees: Boehringer Ingelheim
Pharmaceuticals Inc.; Forest Labs; Janssen Pharmaceuticals, Inc.;
Jazz Pharmaceuticals plc; H. Lundbeck A/S; Merck & Co.;
Pfizer Inc.; Reckitt Benckiser Pharmaceuticals Inc.; Sunovion
Pharmaceuticals Inc.; and Takeda Pharmaceuticals Inc.
Speakers Bureau: Merck & Co. Ownership Interest: M3
(My Mood Monitor).
Andrew Krystal, MD, had a financial agreement or affiliation
during the past year with the following commercial interests in
the form of Consultant Fees: Abbott Laboratories; AstraZeneca;
Bristol-Myers Squibb; Eisai Inc.; Jazz Pharmaceuticals plc;
Johnson & Johnson; Merck & Co.; Neurocrine Biosciences, Inc.;
Novartis; Respironics, Inc.; Roche; Sunovion Pharmaceuticals
Inc.; and Teva Pharmaceutical Industries Ltd. Contracted
Research: Abbott Laboratories; Astellas Pharma; Brainsway;
National Institutes of Health; NeoSynch; Pfizer Inc.; St. Jude
Medical (for Advanced Neuromodulation Systems [ANS]); and
Teva Pharmaceutical Industries Ltd.
Tom Roth, PhD, had a financial agreement or affiliation during
the past year with the following commercial interests in the form
of Consultant Fees: Jazz Pharmaceuticals plc; Merck & Co.;
Neurocrine Biosciences, Inc.; Novartis; Pfizer Inc.; Purdue
Pharma L.P.; Speakers Bureau: Purdue Pharma L.P. Contracted
Research: Impax Laboratories, Inc.; Valeant Pharmaceuticals
(for CeraVe).
Phyllis C. Zee, MD, PhD, had a financial agreement or affiliation
during the past year with the following commercial interests in
the form of Consultant Fees: Ferring Pharmaceuticals; Jazz
Pharmaceuticals plc; Merck & Co.; Purdue Pharma L.P.; Takeda
Pharmaceuticals Inc.; Vanda Pharmaceuticals Inc.; and UCB, Inc.
Contracted Research: Philips Respironics. Ownership Interest: Teva
Pharmaceutical Industries Ltd.
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content of this CME activity:
The following PIM planners and managers, Laura Excell, ND,
NP, MS, MA, LPC, NCC, Trace Hutchison, PharmD, Samantha
Mattiucci, PharmD, CCMEP, and Jan Schultz, RN, MSN,
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MBA, CCMEP, hereby state that they or their spouse/life partner
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products or devices with any commercial interest related to the
content of this activity of any amount during the past 12 months.
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Monograph
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3
4 Pathophysiology of Insomnia
Introduction
An estimated 40 to 70 million Americans have insomnia.1
According to these estimates, twice as many Americans suffer from
insomnia than from major depression.2 Patients with insomnia
frequently report physical and emotional health problems,
compromised social functioning, and daytime distress. Common
risk factors for insomnia include female gender, advanced age,
comorbid disease, and occupations involving shift work.
Importantly, comorbid medical disorders are becoming more
appreciated as risk factors for insomnia.
Work productivity is negatively impacted by insomnia. In the 2009
US Workers America Insomnia Survey, presenteeism (low on-the-job
work performance defined in the metric of lost workday equivalents)
accounted for nearly 8 days of annual lost work performance per
worker, equating to $2280 in individual-level human capital value.
When extrapolated to the entire US workforce over the course of a
year, insomnia causes 252.7 million days of lost work performance,
resulting in a loss of $63.2 billion.3
The magnitude of insomnia-related problems has spurred research,
resulting in an improved understanding of the disorder. Over the
past decade, several changes have been made with regard to the
nosology of insomnia, most notably the recent realization that
insomnia is a disorder. In the past, insomnia was thought to be
secondary to another medical condition. The Diagnostic and
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5),
has recently renamed the diagnosis as insomnia disorder,
emphasizing that insomnia is a disorder in its own right even
though it typically coexists with other comorbid medical
conditions, including depression, anxiety, chronic pain, and
cardiovascular diseases.4 In addition, the Diagnostic and
Statistical Manual of Mental Disorders, Fourth Edition, Text
Revision, diagnostic criteria have been updated in the DSM-5 to
include more stringent measures regarding the chronicity of
insomnia-related symptoms. For the purpose of this monograph,
the term insomnia will be used as a disorder that meets the
DSM-5 criteria, which include the following: (1) difficulty falling
and/or staying asleep; (2) the sleep difficulty is accompanied by
next-day symptoms of distress/impairment; (3) sleep-related
symptoms occur at least 3 times per week for a minimum of
3 months; and (4) symptoms persist despite adequate
opportunities and circumstances to sleep.4
Insomnia is a prevalent and costly public health concern that is
associated with significant long-term effects on physical,
psychological, and occupational functioning. In order to minimize
the societal impact of insomnia and the burden it creates on the
healthcare system, families, and patients, clinicians need to
improve their recognition and treatment of insomnia as well as
coexisting medical conditions. This approach starts with having an
initial discussion with patients regarding the quality of their sleep.
Despite its prevalence, insomnia remains undertreated and
underreported. Patients are reluctant to seek medical treatment,
and sleep is not commonly discussed during office visits. This
continuing medical education/continuing education (CME/CE)
activity is designed to update readers on the pathophysiology of
insomnia, the interrelationships of insomnia and comorbid
disease, and new directions in the management of insomnia.
Current research suggests that insomnia is a disorder of
“hyperarousal” that is present 24 hours each day. The
pathophysiology of insomnia is multifactorial and may be thought
of in terms of dysregulation involving the following 3 components:
neurophysiologic hyperactivation of the sympathetic nervous
system; neuroendocrine dysregulation of hormones associated with
arousal; and cognitive/behavioral responses directed toward sleep
that perpetuate arousal. Expert insights on the pathophysiology of
insomnia from the roundtable discussion will be presented. Figure 1
presents a schematic diagram of the 24-hour sleep-wake cycle.5
Dr Tom Roth: For years we had this idea that insomnia is an
abnormality of the sleep system. Increasingly, we have learned that
insomnia is not an abnormality of the sleep system, but it is an
abnormality of the wake/arousal system. Over a decade ago, Saper
and colleagues proposed the flip-flop switch model of sleep-wake
regulation,6 which contains 2 sets of mutually inhibitory neural
elements: wake-promoting influences on 1 side and sleep-promoting
influences on the other. The monoaminergic nuclei (MN) are a
major influence of the wake-promoting system, and sleep is
influenced by the ventrolateral preoptic nucleus (VLPO), which is a
group of cells that generate non-rapid eye movement (NREM) and
rapid eye movement (REM) stages of sleep (Figure 2).5 In patients
with normal sleep, the flip-flop switch makes sudden transitions
between sleep and wakefulness, which explains why a limited
amount of time is spent in these transitional states throughout the
course of a 24-hour day (Figure 3).6 In patients with insomnia,
however, their ability to turn off the wake-promoting influences of
the flip-flop switch is weakened, resulting in extended periods of
time in transitional states and a prolonged state of wake.
For years we had this idea that insomnia is
an abnormality of the sleep system. Increasingly, we
have learned that insomnia is not an abnormality
of the sleep system, but it is an abnormality of the
wake/arousal system. —Dr Tom Roth
Dr Andrew Krystal: There are a number of objective measures that
support this model of hyperarousal, including elevations in heart
rate and heart rate variability. For example, Bonnet and Arand
performed a 36-hour study that showed the heart rate increased and
the mean heart rate variability decreased in all stages of sleep in the
group of people with insomnia compared to the control group of
people who have normal sleep.7 Studies have also found that
patients with insomnia, when compared to controls, have higher
metabolic rates throughout the course of a 24-hour day, further
suggesting arousal in the wake-promoting regions in the brain.8
Dr Larry Culpepper: There appears to be a neuroendocrine
component to this condition as well. Vgontzas and colleagues
found that levels of adrenocorticotropic hormone and cortisol
were significantly elevated in patients with insomnia compared to
matched controls, which results in increased arousal and
associated sleeplessness. In addition, patients with a higher degree
of sleep disturbance secreted more cortisol compared to those
with less sleep disturbance.9
Test Questions
 Hour 0 Hour 24

NREM REM

Wake ~ 16 hrs Sleep~ 8 hrs

2/3 of Sleep-Wake Cycle 1/3 of Sleep-Wake Cycle

Figure 1. A schematic diagram of the sleep-wake cycle. When transitioning into sleep, an individual begins in non-rapid eye movement (NREM) and
remains in this stage for approximately 85 minutes. After this initial stage of NREM, the brain switches to rapid eye movement (REM) for approximately
5 to 10 minutes before switching back to NREM. This 90-minute pattern continues throughout the night, with REM intervals becoming longer and
NREM intervals becoming shorter until wakefulness occurs. Disruptions in this defined pattern of sleep and wakefulness result in disturbances in sleep.
Adapted from Rogers and Holmes, 2012.5

Dr Phyllis Zee: Stepanski and colleagues compared

polysomnography and multiple sleep latency test data from
patients seeking evaluation for chronic insomnia with data from
patients without sleep problems.11 The insomnia group slept
significantly less than the control group, yet they were
significantly less sleepy the next day compared with matched
controls. This study found that if given the chance to sleep during
the day, patients with insomnia take longer than the general
population to fall asleep. Insomnia is a 24-hour disorder of
hyperarousal associated with difficulty sleeping at any time of day.

Insomnia is a 24-hour disorder of

hyperarousal associated with difficulty sleeping
at any time of day. —Dr Phyllis Zee
Figure 2. A schematic of the sleep-promoting and wake-promoting areas of the
human brain. There are multiple cell groups in the brain that contribute to the
sleep-wake system. The monoaminergic nuclei (MN) are responsible for promoting
wakefulness, while the ventrolateral preoptic nucleus (VLPO) promote sleep.
Monoaminergic nuclei of the arousal pathway include noradrenergic, serotonergic, Dr Sonia Ancoli-Israel: This inability to sleep during the day
dopaminergic, and histaminergic neurons located in the pedunculopontine and
laterodorsal tegmental nucleus (PPT/LDT), locus coeruleus (LC), dorsal and highlights why the initial assessment of sleep-related symptoms
median raphe nucleus (RN), and tuberomammillary nucleus (TMN), respectively. is so important. If patients indicate they’re having difficulty
Every 24 hours the arousal system is overtaken by inhibitory neurons of the VLPO, sleeping at night but they sleep well during the day, it is less
resulting in the transition from wakefulness to sleep.
likely to be insomnia. Someone with insomnia has difficulty
falling asleep during the day as much as they do at night.
Dr Andrew Krystal: Positron emission tomography has shown
that patients with insomnia exhibit greater brain glucose Someone with insomnia has difficulty
metabolism during sleep and wake periods compared to people falling asleep during the day as much as they
who have normal sleep, indicating the inability of patients with
insomnia to appropriately transition from wake to sleep.10 Table 1
do at night. —Dr Sonia Ancoli-Israel
lists elevated physiologic factors that have been observed in
patients who have insomnia, which are suggestive of hyperarousal.

Table 1. Physiologic Factors Increased During Sleep in Patients

With Insomnia Dr Phyllis Zee: There are primarily 3 different ways to promote
wakefulness: (1) blocking the sleep promoting neurons in the
Body temperature VLPO; (2) exciting the monoaminergic nuclei associated with
Brain glucose metabolism the wake system; and (3) stimulation of the orexin neurons.
Resting heart rate
Cortisol level Dr Tom Roth: I think all of you bring up a great point. When
Electroencephalogram beta wave activity patients with insomnia get out of bed at 7 o’clock in the morning,
their insomnia has not gone away. For patients who have
5

Test Questions
6 24 hours a day that expresses itself periodically. The criteria for
insomnia disorder specify that sleep disturbances must occur at
least 3 days a week for a minimum of 3 months for us to consider
a diagnosis of insomnia.4
Dr Larry Culpepper: What do we know about the underlying
brain activity or factors that contribute to this hyperarousal?
Dr Andrew Krystal: I don’t think we know all that much about it.
We know the wake system is more active during sleep in patients
with insomnia, at least to some degree. Additionally, the
psychopathological and behavioral patterns of sleep appear to play
a significant role in some patients with sleep problems. For
example, when people experience multiple nights of bad sleep and
frustration within their sleeping environment, they begin to
develop the expectation of poor sleep. This expectation becomes a
perpetuating factor that creates stress and increased activity of the
sympathetic nervous system. In addition to the neuroendocrine
and physiologic components of hyperarousal, there appears to be
a behavioral/psychopathological element to this condition.

Updates in the Diagnostic Criteria and

Figure 3. A schematic drawing of the flip-flop switch model of sleep-wake
regulation. The interaction between the ventrolateral preoptic nucleus (VLPO)
and the arousal pathways (Orexin [ORX], locus coeruleus [LC], dorsal and median
raphe nucleus [Raphe], and tuberomammillary nucleus [TMN]) is mutually
inhibiting, functioning like an on-off (flip-flop) switch. This flip-flop switch ensures
stability between sleep and wakefulness, which results in normal sleep patterns.
Insomnia causes dysregulation of the switch, resulting in irregular transitioning
between sleep-wake states and fragmented sleep. Reprinted with permission,
Saper et al, 2005.6
myocardial ischemia, we find that just because they don’t have
angina 24 hours a day doesn’t mean their cardiovascular function
is normal all of a sudden. People who have insomnia are not
symptomatic 24 hours a day, 7 days a week. They have insomnia
Nosology of Insomnia
The diagnostic criteria for insomnia have undergone recent
changes with the finalization of the DSM-5, most notably with the
chronicity of sleep-related disturbances, which the faculty will
discuss. In addition, insomnia has been renamed insomnia disorder,
emphasizing the point that while insomnia typically coexists with
other medical conditions, it requires separate clinical attention.
Becoming more aware of the numerous comorbid conditions
associated with insomnia is important and may assist clinicians in
better recognizing and managing insomnia. The following
discussion provides insight into the clinical implications of recent
changes in the diagnostic criteria and the significance of comorbid
conditions associated with insomnia.

Table 2. Insomnia Severity Index13

Please circle the number that best describes your CURRENT severity level of sleep problem(s).

Please rate this past week’s severity of the None Mild Moderate Severe Very severe
following insomnia problems:
1. Difficulty falling asleep 0 1 2 3 4

2. Difficulty staying asleep 0 1 2 3 4

3. Waking up too early 0 1 2 3 4

Very Satisfied Moderately Dissatisfied Very dissatisfied

satisfied satisfied
4. How satisfied/dissatisfied are you with your 0 1 2 3 4
current sleep pattern?
Not at all A little Somewhat Much Very much

5. How noticeable to others do you think your 0 1 2 3 4

sleep problem is in terms of impairing the
quality of your life?
6. How worried/distressed are you about your 0 1 2 3 4
current sleep problem?
7. To what extent do you consider your sleep 0 1 2 3 4
problem to interfere with your daily functioning
(mood, concentration, work)?

Scoring: 0-7 No clinically significant insomnia; 8-14 Sub-threshold insomnia; 15-21 Moderate clinical insomnia; 22-28 Severe clinical
insomnia. Adapted from Morin et al, 2001.13

Test Questions
Table 3. DSM-5 Insomnia Disorder Criteria 780.52 (G47.00)

A. A predominant complaint of dissatisfaction with sleep quantity

I think it’s important for primary care clinicians to,
or quality, associated with one (or more) of the following first of all, ask their patients about sleep.
symptoms:
—Dr Sonia Ancoli-Israel
1. Difficulty initiating sleep. (In children, this may manifest as
difficulty initiating sleep without caregiver intervention.)
2. Difficulty maintaining sleep, characterized by frequent
awakenings or problems returning to sleep after awakenings.
(In children, this may manifest as difficulty returning to Dr Tom Roth: I think it’s also important for clinicians to
sleep without caregiver intervention.) differentiate sleep disturbance from insomnia because they are
3. Early-morning awakening with inability to return to sleep. not the same thing. When there are inadequate opportunities or
B. The sleep disturbance causes clinically significant distress or circumstances to sleep, sleep disturbances typically occur. But
impairment in social, occupational, educational, academic,
behavioral, or other important areas of functioning.
that is not insomnia. An insomnia diagnosis is made when a
C. The sleep difficulty occurs at least 3 nights per week.
patient meets the following 4 criteria (Table 3): (1) nighttime
D. The sleep difficulty is present for at least 3 months. symptoms of difficulty falling asleep and/or staying asleep;
E. The sleep difficulty occurs despite adequate opportunity (2) next-day symptoms of distress/impairment; (3) symptoms
for sleep. occur at least 3 times per week for a minimum of 3 months; and
F. The insomnia is not better explained by and does not occur (4) symptoms persist despite adequate opportunity and
exclusively during the course of another sleep-wake disorder circumstances to sleep.4
(e.g., narcolepsy, a breathing-related sleep disorder, a circadian
rhythm sleep-wake disorder).
G. The insomnia is not attributable to the physiological effects of a Comorbid Conditions Associated
substance (e.g., a drug of abuse, a medication).
H. Coexisting mental disorders and medical conditions do not
With Insomnia
adequately explain the predominant complaint of insomnia. Dr Phyllis Zee: I would add that insomnia is now listed as
Specify if: insomnia disorder in the DSM-5 and the International
• With non–sleep disorder mental comorbidity, including Classification of Sleep Disorders, Third Edition (ICSD-3)
substance use disorders diagnostic manuals. In the past, insomnia was labeled as primary
• With other medical comorbidity (the absence of an adjunct comorbid condition) or secondary
• With other sleep disorder (insomnia arising in the context of another disorder). Although
• Coding note: The code 780.52 (G47.00) applies to all three insomnia is often associated with other conditions, such as pain,
specifiers. Code also the relevant associated mental disorder, depression, anxiety, and cardiovascular diseases, insomnia is its
medical condition, or other sleep disorder immediately after
own distinct disorder (Table 4).14
the code for insomnia disorder in order to indicate the
association.
Table 4. Prevalence of People With Insomnia and
Specify if:
Comorbid Medical Conditions14
• Episodic: Symptoms last at least 1 month but less than
3 months. Prevalence of insomnia
• Persistent: Symptoms last 3 months or longer. In the presence In the absence of
• Recurrent: Two (or more) episodes within the space of comorbid comorbid
of 1 year. condition condition
Comorbid condition % %
Note: Acute and short-term insomnia (i.e., symptoms lasting less than 3 months
but otherwise meeting all criteria with regard to frequency, intensity, distress, Cardiovascular disease
and/or impairment) should be coded as other specified insomnia disorder. Hypertension 26.1 22.8
Reprinted with permission from the Diagnostic and Statistical Manual of Mental
Disorders, Fifth Edition, (Copyright ©2013). American Psychiatric Association. Heart disease 30.1 23.7
All Rights Reserved.
Musculoskeletal disease
Dr Larry Culpepper: In terms of how you define and diagnose Arthritis 30.6 21.5
insomnia, what are some key principles that primary care Back or neck pain 34.2 17.7
clinicians should know?
Digestive disorders
Dr Sonia Ancoli-Israel: I think it’s important for primary care Diarrhea, constipation, or gas 42.2 20.2
clinicians to, first of all, ask their patients about sleep. Research
Gastroesophageal reflux disease 39.2 20.7
has shown that 70% of the clinicians don’t ask their patients about
(GERD)
sleep, and more than 50% of the patients don’t talk about it.12
Thus, the first step is to determine the overall sleep-wake status of Sleep disorders
the patient. If the patient responds that he or she is experiencing Sleep apnea 40.9 22.0
sleep problems, then it takes a little more in-depth questioning Restless leg syndrome 50.6 22.6
regarding the specific symptoms of insomnia and their frequency
Emotional disorders
and severity. There are several questionnaires—including the
Insomnia Severity Index (Table 2)13 and the Epworth Sleepiness Major depressive disorder 55.7 21.1
Scale—that clinicians can use to facilitate sleep-related discussion
Generalized anxiety disorder 65.6 21.2
with their patients.
7

Test Questions
8 Dr Sonia Ancoli-Israel: And since insomnia is its own disorder,
you treat it once you’ve made a diagnosis.
And since insomnia is its own disorder, you treat it
once you’ve made a diagnosis. —Dr Sonia Ancoli-Israel
Dr Larry Culpepper: I think what Dr Ancoli-Israel mentioned is
the single most important message to relay to primary care
clinicians. In the past, we clinicians have been under the false
impression that when an existing comorbid condition resolves—
for instance, depression—insomnia would go away as well. And
that, quite often, is not the case.
Dr Tom Roth: If you look at people with depression when they
go into remission, the most common residual symptom is
difficulty sleeping. It is important to understand that the number
of residual symptoms linearly predicts time to relapse of
depression. The Sequenced Treatment Alternatives to Relieve
Depression (STAR*D) trial described the types and frequency of
residual depressive symptoms and their relationship to
depressive relapse after treatment with citalopram.15 More than
90% of the patients with depression who went into remission had
at least 1 residual depressive symptom, and the most common
residual symptom domain was sleep-related disturbance
(71.7%).15 The study revealed that having a greater number of
residual symptoms was associated with a higher probability of
relapse. The point is that treating insomnia enables you to better
manage coexisting disorders.
Dr Andrew Krystal: As mentioned earlier, the error clinicians
have made in the past is undertreating insomnia, expecting
insomnia to get better once the symptoms of a comorbid
condition improved. Moreover, clinicians should consider the
possibility of underlying comorbid conditions when patients
present with symptoms suggestive of insomnia. Research shows
that insomnia is a known risk factor for other disorders, most
notably depression and anxiety. One of the classic studies, the
Johns Hopkins Precursors Study, evaluated the associations
between self-reported sleep disturbances and subsequent clinical
depression among medical students (classes 1948-1964; mean
follow-up period of 34 years).16 Patients who reported insomnia
symptoms during medical school were twice as likely to develop
clinical depression compared to those without insomnia
symptoms. Clinicians need to assess whether or not there are
underlying comorbid conditions, such as depression, which may
be intensifying the symptoms of insomnia.
Dr Phyllis Zee: There is also research to suggest that insomnia
may serve as a risk factor of cardiometabolic disease. A recent
study that evaluated the impact of sleep on levels of fasting
glucose, fasting insulin, and estimated insulin resistance showed
that insomnia was associated with a 23% higher fasting glucose
level and a 48% higher fasting insulin level in patients with type 2
diabetes.17 In addition, Vgontzas and colleagues evaluated the
joint effects of insomnia and short sleep duration on diabetes
risk.18 They showed that patients with insomnia and sleep
duration of less than 5 hours were at significantly higher risk of
developing diabetes compared to people who have normal sleep.
Dr Larry Culpepper: It’s also important to remember that the
very treatment of the comorbid condition itself may lead to
insomnia-related symptoms. Respiratory stimulants, selective
serotonin reuptake inhibitors, beta blockers, and many other drug
classes are associated with reports of disturbed sleep (Table 5).19
Table 5. Common Medications That Contribute to Insomnia19
Drug class Medications
Antidepressants Selective serotonin reuptake inhibitors
(fluoxetine, citalopram, sertraline, paroxetine),
venlafaxine, duloxetine
Decongestants Pseudoephedrine, phenylephrine
Cardiovascular Beta blockers, alpha-receptor antagonists, diuretics
Respiratory Theophylline, albuterol
Stimulants Methylphenidate, ephedrine, amphetamines
Opioids Codeine, oxycodone
Differentiating Circadian Rhythm
Disorders From Insomnia
Insomnia is occasionally comorbid with other sleep conditions,
including disorders in circadian rhythm. Table 6 lists common
circadian rhythm sleep disorders (CRSDs) that may occur in
conjunction with insomnia20; however, the effective treatments
for CRSDs are very different, emphasizing the importance of
differentiating sleep-related symptoms of CRSDs from insomnia.
Table 6. Circadian Rhythm Sleep Disorders20
Irregular sleep-wake rhythm disorder (ISWD) occurs when a person’s
sleep pattern is undefined, which typically includes a series of naps
throughout the 24-hour sleep-wake cycle. ISWD is common in elderly
patients with comorbid medical disorders, such as Alzheimer’s disease.
Delayed sleep phase disorder (DSPD) is a pattern of going to bed late in
the evening/early morning and sleeping until late in the afternoon. DSPD
is common in teenagers.
Advanced sleep phase disorder (ASPD) is a pattern of early
evening sleepiness and early morning awakening. ASPD is common
in elderly patients.
Shift work disorder occurs when a person’s work hours are scheduled
during the normal sleep period.
Non-24-hour sleep disorder occurs when the suprachiasmatic nucleus
does not receive light from the external environment, resulting in a
sleep-wake cycle that shifts later each day. Non-24-hour disorder is
common in patients who are totally blind.
Adapted from Sack et al, 2007.20
Current and Emerging Treatment
for Insomnia
The Role of Behavioral Treatment Interventions in
Insomnia Disorder
It is widely accepted that psychological and behavioral factors
play significant roles in hyperarousal. Interventions that target
these factors play an important part in the management of
insomnia disorder (Table 7).21 Several studies have reported the
effects of behavioral treatment methods administered to patients
with chronic insomnia.22 Patients reported significant increases in
sleep time as well as improvements in sleep latency, total wake
time, and sleep efficiency after behavioral interventions. The
Test Questions
Table 7. Common Evidence-Based Cognitive and Behavioral Therapies
for Insomnia21
Cognitive behavioral therapies target these
Sleep hygiene therapy involves teaching healthy lifestyle practices to negative learned responses and essentially reteach
improve sleep. Sleep hygiene is recommended to be used in conjunction
with other cognitive and behavioral therapies. Patients are instructed to an individual how to sleep. —Dr Sonia Ancoli-Israel
(including but not limited to): avoid napping, maintain a regular exercise
program and healthy diet, sleep in a quiet, dark environment, and avoid
stimulants such as caffeine and nicotine at least 6 hours before bedtime.

Stimulus control therapy is designed to re-associate the bedroom with the
rapid onset of sleep. Once in bed, if the patient is unable to fall asleep in
what seems to be about 20 minutes (without looking at a clock), he or she
is instructed to leave the bedroom to engage in a relaxing activity and return
to bed when sleepy (repeat this as necessary). The objective of stimulus
control therapy is to limit wake time in bed. Patients should be cautioned
about the possibility of daytime sleepiness during the course of therapy.
Sleep restriction therapy limits time in bed to the amount of time actually
spent sleeping (normally derived from a sleep log). This approach is
designed to improve sleep continuity by using sleep restriction to enhance
sleep drive (the ability to sleep). Once sleep efficiency improves, the
allowed time in bed is gradually increased by 15 to 30 minutes over a period
of several weeks until optimal sleep duration is achieved. The objective of
sleep restriction therapy is to limit wake time in bed. Patients should be
cautioned about the possibility of daytime sleepiness during the course of therapy.
Dr Larry Culpepper: Even a short course of behavioral therapy can
be very effective. In a study involving nurse practitioners trained to
provide behavioral therapy, individuals with chronic insomnia
either received a short course of behavioral therapy, consisting of
2 intervention sessions and 2 telephone calls, or they received
printed educational materials.24 A total of 67% of the individuals
treated with behavioral therapy showed a clinical response, compared
to 25% in the control group. In addition, 55% of those in the
behavioral treatment group no longer met the criteria for insomnia
at study completion, compared to 13% in the control group.
Behavioral therapy is achievable in the primary care setting and
can be performed by a physician or another clinician.

Relaxation training is a technique that uses muscle relaxation, guided Behavioral therapy is achievable in the primary
imagery, and/or abdominal breathing exercises to lower arousal states that
interfere with sleep.
care setting and can be performed by a physician or
another clinician. —Dr Larry Culpepper
Cognitive Behavioral Therapy for Insomnia (CBT-I) is a combination
of behavioral therapy (eg, sleep restriction, stimulus control) and
psychotherapeutic methods, which involve identifying dysfunctional
beliefs about sleep and replacing them with more positive alternatives.

Adapted from Schutte-Rodin et al, 2008.21

following discussion addresses different types of behavioral
interventions and their impact on insomnia disorder.
Dr Sonia Ancoli-Israel: Before we discuss behavioral therapy, we
should first discuss Spielman and colleagues’ “3P” model because
it is the basis of a lot of what we do when administering cognitive
behavioral therapies.23 The key words in the “3P” model are
predisposing, precipitating, and perpetuating (Table 8).23
Predisposing factors include conditions such as personality type
or hyperarousal. These factors predispose patients to sleep-related
difficulties, but that does not mean they have insomnia. Then
there are precipitating factors, such as stress, that may cause
patients to lose sleep for a few nights. Getting married, having a
new baby, or visiting the in-laws may cause acute sleep-related
problems, but those typically resolve on their own after the
triggering event has disappeared. However, some individuals
experience persistent sleep difficulties, eventually spending more
time in bed in an attempt to get more sleep, which makes their
sleep worse and leads to negative conditioning. These types of
behaviors feed into and perpetuate insomnia, making it more
difficult to sleep. Cognitive behavioral therapies target these
negative learned responses and essentially reteach an individual
how to sleep.
Table 8. Contributing Factors to Insomnia23
Predisposing Precipitating Perpetuating
factors factors factors
Personality traits Arthritis pain Napping
Genetic traits Psychiatric illness Excessive time in bed
Social factors Stressful event Negative learned behaviors
Dr Tom Roth: There are some data that suggest cognitive
behavioral therapy for insomnia (CBT-I) not only improves
insomnia symptoms but also augments the remission of
depression. Manber and colleagues evaluated the addition of
CBT-I to escitalopram (cotherapy) in patients with coexisting
insomnia and depression, compared to escitalopram plus
control.25 Cotherapy resulted in a higher rate of remission from
depression as compared to the control group (61.5% vs 33.3%,
respectively) and was associated with a greater rate of remission
from insomnia as compared to the control group (50.0% vs 7.7%,
respectively). This study emphasizes the point we made earlier:
Treating both disorders improves patient outcomes.
Dr Phyllis Zee: We studied the impact of a 16-week afternoon
aerobic exercise program plus sleep hygiene measures in patients
with insomnia 55 years and older. The control group consisted of
patients involved in nonaerobic activity plus sleep hygiene.26 The
physical activity group improved significantly in sleep quality, sleep
latency, sleep duration, daytime dysfunction, and sleep efficiency.
The physical activity group also had significant reductions in
depressive symptoms and daytime sleepiness. Not only does
routine long-term exercise improve sleep quality in people with
insomnia, but better sleep the night before predicts your capacity
to exercise the next day.
Not only does routine long-term exercise improve
sleep quality in people with insomnia, but better
sleep the night before predicts your capacity to
exercise the next day. —Dr Phyllis Zee

Test Questions
10 Dr Phyllis Zee: Some patients have tried exercising in the late
evening, but that has shown to actually phase shift (delay)
circadian rhythms. Not only does exercising late in the evening
enhance symptoms of sympathetic arousal but, at the same time,
you’re giving the wrong signal to the circadian clock.
Dr Tom Roth: I do not think these insights are unique to sleep
medicine. For example, there are several different methods to
treat obesity, but they are all roads to the same outcome. The
exact same thing is true for behavioral therapy. There is no secret
road to the goal of improving sleep, and it is up to the clinician, his
or her resources, the patient’s interest, and the patient’s
sophistication as to what the best road to that goal might be.
Prescription Medications
Table 9 lists medications approved by the US Food and Drug
Administration (FDA) for the treatment of insomnia. There are
myriad medications that are used to treat insomnia, including
tricyclic antidepressants, antipsychotics, and herbal medications,
which have not received regulatory approval for insomnia. Within
each medication class, there are differences in pharmacokinetic/
pharmacodynamic indices, which allow clinicians to prescribe
patient-specific interventions. Clinicians should consider the
following factors when selecting a pharmacologic agent:
(1) symptom patterns; (2) comorbid conditions; (3) concurrent
medications; (4) contraindications; (5) side effects; and (6) cost.
With the exception of low-dose doxepin, the most recently FDA-
approved medications have short half-lives and work during the
first few hours of sleep, without significant sleep maintenance
effects. In contrast, emerging therapies have longer half-lives and
will presumably have improved effects on sleep maintenance.
Expert guidance in the pharmacologic treatment of insomnia and
sleep-related disorders will be presented.
Dr Andrew Krystal: The older sleep agents are the
benzodiazepines, which potentiate inhibition mediated by
GABAA receptors through binding to a benzodiazepine site on the
GABAA receptor complex. Benzodiazepines work on the sleep
side of the flip-flop switch. Different subtypes of the GABAA
receptor are located throughout the central nervous system, and
benzodiazepines bind to these receptors without specificity;
therefore, not only do they enhance sleep but they also shut down
different parts of the brain that we might not want them to,
leading to unwanted side effects, including balance and memory
problems.27 Medications that potentiate GABAA receptor activity
by binding to the benzodiazepine binding site appear to have
some degree of abuse potential, but the abuse seems to be limited
to a subgroup of the population prone to substance abuse.
Generally speaking, the majority of people take these medications
for therapeutic purposes. Compared to benzodiazepines,
nonbenzodiazepines demonstrate greater selectivity in terms of
preferential binding to a subset of GABAA receptors, affecting
specific subunits that have regional effects in brain function. To
date, 6 subunits have been identified, and, with the exception of
eszopiclone, the nonbenzodiazepines preferentially bind the alpha
1 subunit, which is primarily associated with sedation.28 Because
the mechanism of action for nonbenzodiazepines is limited to the
alpha 1 subunit, they do not appear to relax muscles or provide
anxiolysis to the same degree as benzodiazepines.
Dr Tom Roth: A major difference between the classic
benzodiazepines and nonbenzodiazepines relates to
pharmacokinetics. The nonbenzodiazepines tend to have much
shorter half-lives, which typically minimizes next-day sedation.
However, female gender and concomitant medications, such as
clarithromycin, have been shown to influence the rate at which
some of these medications are metabolized.
Dr Andrew Krystal: There appears to be differences among
agents within the nonbenzodiazepine drug class itself. When
escitalopram plus zolpidem controlled-release (CR) were
administered to patients with insomnia and comorbid anxiety,
sleep-related parameters improved but anxiety scores did not.29
However, when escitalopram plus eszopiclone were administered
to a similar patient population, both insomnia and anxiety scores
improved significantly. This difference appears to be related to the
effects on additional GABAA receptor subunits, which are
associated with anxiolysis.30 The point is that these medications
seem to differ clinically, and if you want to help people in terms of
insomnia with comorbid anxiety, eszopiclone is probably a better
adjunctive therapy than zolpidem CR.
Dr Larry Culpepper: Studies have also found that eszopiclone
improves insomnia and depression scores when coadministered
with fluoxetine.31 In addition to improvements in sleep parameters
at each time point in the study, the eszopiclone cotherapy group
showed significantly greater changes in 17-item Hamilton Rating
Scale for Depression (HAM-D-17) scores, and a significantly
greater number of patients achieved remission from depression.
Dr Phyllis Zee: There are some medications, including
eszopiclone and low-dose doxepin, that are indicated for sleep
maintenance insomnia, whereas other medications, such as
zaleplon, are not (Table 9).
Dr Sonia Ancoli-Israel: I think that is a major point. An
important aspect of selecting insomnia medications is matching
the medication with the patient’s sleep complaint. If a patient is
having difficulty staying asleep, but not falling asleep, you have to
think about a medication in which the action is going to be
maintained during the second half of the night, as opposed to just
the first half of the night.
An important aspect of selecting insomnia
medications is matching the medication with the
patient’s sleep complaint. —Dr Sonia Ancoli-Israel
Dr Tom Roth: When you look at the existing treatment options that
work on the sleep system, none of the GABAA receptor agonists
really have major sleep maintenance effects. They actually have sleep
maintenance effects for 3, 4, and 5 hours at the max. The reason for
that is very simple. If you have effects that last for 6, 7, and 8 hours
with medications that potentiate the GABA system, you are going to
have significant next-day impairment. This, in part, explains why a
lot of clinicians tend to use off-label medications, including atypical
antipsychotics and antidepressants. Among approximately 900
million office visits that took place in 2006, an estimated 30 million
visits included a prescription for insomnia without depression listed
as comorbidity; nearly half of these prescriptions were for
antidepressants.32 Compared to medications that work on the
GABA system, the majority of off-label medications have longer
Test Questions
Table 9. Commonly Prescribed FDA-Approved Insomnia Medications
Brand name Generic name Half-life FDA-approved indications Available doses
Histamine receptor antagonist (H1)
Silenor® Doxepin 15 hrs Sleep maintenance 3 mg, 6 mg
Melatonin receptor agonist (M1 and M2)
Rozerem® Ramelteon 2.6 hrs Sleep onset 8 mg
GABAA-receptor agonists: nonbenzodiazepines
*For all zolpidem products, the lowest available dose is recommended when initiating treatment in women
Sonata® Zaleplon 1 hr Sleep onset 5 mg, 10 mg
Edluar® Zolpidem 2.5 hrs Sleep onset 5 mg, 10 mg
(Sublingual tablet)
Ambien® Zolpidem 2.5 hrs Sleep onset 5 mg, 10 mg
ZolpiMist® Zolpidem 2.5 hrs Sleep onset 1 spray = 5 mg
(Oral spray)
Intermezzo® Zolpidem 2.5 hrs Middle-of-the-night awakenings 1.75 mg, 3.5 mg
(Sublingual tablet)
Ambien CR® Zolpidem 2.5 hrs Sleep onset 6.25 mg, 12.5 mg
(Controlled-release) Sleep maintenance
Lunesta® Eszopiclone 5-7 hrs Sleep onset 1 mg, 2 mg, 3 mg
Sleep maintenance

GABAA-receptor agonists: benzodiazepines

Halcion® Triazolam 2-4 hrs Sleep onset 0.125 mg, 0.25 mg
Restoril® Temazepam 8-20 hrs Sleep onset 7.5 mg, 15 mg, 22.5 mg, 30 mg
Sleep maintenance
Doral® Quazepam 39-73 hrs Sleep onset 7.5 mg, 15 mg
Sleep maintenance

half-lives, resulting in sleep maintenance effects in 6, 7, and 8 hours.
These medications are effective because they target receptors
involved in the wake system, including histamine, dopamine, and
serotonin. The wake systems are very important with regard to the
pathophysiology of insomnia, and that may be why these
medications are frequently prescribed in practice.
Dr Larry Culpepper: Since a number of clinicians prescribe
off-label medications for the treatment of insomnia, the role of
the FDA in the United States should be mentioned. The FDA has
clearly stated that hypnotic medications should be started at the
lowest possible dose and then titrated to the desired effect,
provided the titration can be performed safely and the lower dose
was ineffective.
Dr Tom Roth: The best example of this is low-dose doxepin. In
the past, doxepin had been prescribed at doses as high as 25 mg to
100 mg for the treatment of insomnia. After a dose-response
study was performed, the hypnotic dose of doxepin was
determined to range from 3 mg to 6 mg.34 It’s not whether
doxepin is a good drug or a bad drug. The point is the drug’s
effects are dose dependent. At doses higher than 6 mg, doxepin
has significant anticholinergic effects. At doses ranging from 3 mg
to 6 mg, doxepin has limited anticholinergic effects and works
primarily on the histamine receptor. So again, the problem with
using off-label medications is our lack of knowledge with regard
to the dose-response relationships between safety and efficacy.
I think doxepin provides us with a clear example of that.

The FDA has clearly stated that hypnotic
medications should be started at the lowest possible
dose and then titrated to the desired effect,
provided the titration can be performed safely and
the lower dose was ineffective. —Dr Larry Culpepper
Nonprescription Medications
Dr Larry Culpepper: Nonprescription therapies are frequently
used by patients to treat insomnia-related symptoms, but there is
limited safety and efficacy data to support these therapies. For
instance, people occasionally use alcohol as a sleep aid, thinking
this will improve their sleep. While alcohol has been reported to
help people fall asleep more quickly, this effect is offset by having
more disrupted sleep in the second half of the night.35

Dr Phyllis Zee: And then there is the issue of anticholinergic side

These recommendations will become part of product labeling,
and we have already seen this with the recent changes to
zolpidem.33 For medications that are used off-label, this
information is not readily available because the medications
haven’t been studied systematically.
effects, especially in the elderly, with many of the over-the-counter
(OTC) sleep medications. Elderly patients may already have
some cognitive impairment and balance issues, and medications
with anticholinergic side effects only worsen many of their
coexisting conditions.
11

Test Questions
12 Dr Sonia Ancoli-Israel: These side effects need to be avoided in
this population. Diphenhydramine, for example, has increased
rebound effects in the elderly (worsening of sleep compared to
pretreatment symptoms).36 Yet, the elderly are some of the
highest users of OTC sleep medications.37
Dr Andrew Krystal: A significant number of OTC sleep
medications contain either diphenhydramine or doxylamine,
which have substantial anticholinergic effects. Consumers who
see OTC sleep medications in the drug store frequently assume
they are safer than prescription medications, but this is not
necessarily the case.
Dr Phyllis Zee: In addition to OTC antihistamines, there are
numerous other medications that patients use to self-medicate,
rather than seeking medical attention. The 2002 National Health
Interview Survey data showed that more than 1.6 million US adults
use complementary and alternative medicine for sleep-related
symptoms.38 A total of 65% of those patients used biologically
based therapies, including herbal remedies, which have limited
safety and efficacy data and are not regulated by the FDA.
Dr Tom Roth: Falls and the risk for falling are important issues
with regard to insomnia and its treatments. The majority of data
seem to indicate that the causative factor, with regard to
medications, is total sedative load.39,40 If a patient is taking
medications with significant anticholinergic side effects while also
taking a sleep agent, there is a risk for falling. It is not linked to any
single medication. Additionally, there are studies that show
insomnia is more of a risk factor than sleep agents.41 If you give a
medication for insomnia to patients and they sleep for 8 hours
and do not get out of bed, they do not fall. However, if you have
patients who have to get up 3 or 4 times a night because of an
underlying medical condition, then sleep agents are a risk.
Differentiating Treatments for Insomnia
From Treatments for Circadian
Rhythm Disorders
CRSDs occur when the timing of the endogenous circadian
rhythm and the normal 24-hour sleep-wake cycle are offset.
Circadian rhythms are coordinated by the suprachiasmatic
nucleus (SCN), which is reset by light through the
retinohypothalamic tract.42 Although less potent than light,
melatonin, which is released by the pineal gland during the dark
cycle, resets circadian rhythm as well.43 Because they play key
roles in stabilizing circadian rhythm, timed exposure to melatonin
and light are effective treatment methods in patients with CRSDs.
Dr Tom Roth: I would like to take a minute and have Dr Zee
briefly explain the roles of melatonin and light in CRSDs.
Dr Phyllis Zee: Light is the strongest entraining agent for the
circadian clock. Exposure to bright light in the early morning
induces phase advances, whereas light exposure in the evening
delays the phase of circadian rhythms.44 In patients with CRSDs,
the timing of light exposure (as a treatment intervention) is
targeted toward the patient’s presenting symptoms. For example,
elderly patients often present with an advanced phase disorder,
which means they go to bed early at night and wake up early in the
morning. In this circumstance, increasing light exposure in the
evening (to keep them up later) and limiting light exposure in the
morning (to entrain a later wake time) would be an initial
intervention in this type of patient. In patients with a delayed
phase disorder, the exact opposite would be prescribed. With
regard to melatonin, it has demonstrated clinical benefit in
patients with CRSDs. Melatonin does not have a major role in the
treatment of insomnia disorder45; however, in a patient who only
has trouble falling asleep, one should consider the possibility of a
delayed circadian rhythm. If an underlying circadian
misalignment is present, a trial of low-dose melatonin may be
useful. A low dose of melatonin would be 0.3 mg to 1 mg. It’s not
approved by the FDA for the treatment of insomnia disorder.
Dr Andrew Krystal: I think it’s important to emphasize that
melatonin should not be taken right before going to bed.
I think it’s important to emphasize that melatonin
should not be taken right before going to bed.
—Dr Andrew Krystal
Dr Phyllis Zee: I agree. Many patients with delayed sleep phase
disorder come to me indicating that they’ve tried melatonin, but
it didn’t work. They usually have taken it right before bedtime,
which is too late to advance the phase of circadian rhythms. To
advance the timing of the sleep-wake cycle, the ideal time to take
melatonin is 5 to 6 hours before the patient’s natural sleep time.
Dr Sonia Ancoli-Israel: To add to what Dr. Zee was mentioning a
moment ago with regard to light, the best way for the advanced
phase patients to avoid morning light is by wearing sunglasses
when they go outside because the mechanism is through the eyes.
The light-dark cycle information is relayed from the retina to the
SCN primarily by the retinohypothalamic tract.
Dr Tom Roth: Many elderly people are terrified of falling during
the night, so they keep a night light on. It is very important that
elderly people keep a night light by their bathroom but outside of
the line of vision. We need light during the day, but we also need
darkness at night.
Dr Phyllis Zee: If the patient needs a night light, recommend
a red filter because melatonin does not get suppressed very
easily with long-wavelength light, such as red. In contrast,
short-wavelength light, such as blue, is more effective in
suppressing the secretion of melatonin from the pineal gland.
Short wavelength light also activates the sympathetic nervous
system, resulting in increased arousal.46
Emerging Therapies for Insomnia
Two separate research groups discovered orexin (also referred to
as hypocretin) neuropeptides, which are wake-promoting
neurotransmitters produced by a cluster of neurons in the
hypothalamus.47,48 Orexin peptides influence the patient’s
sleep-wake cycle, appetite, and autonomic nervous system,
including effects on metabolic rate and behavioral responses to
stress.47 The brain contains 50,000 to 80,000 orexin producing
Test Questions
 neurons, which have extensive projections to many different regions
in the brain. The strongest projections appear to target wake-
promoting regions that regulate arousal, including noradrenergic
neurons of the locus coeruleus, histaminergic neurons of the
tuberomammilary nucleus, dopaminergic neurons of the ventral
tegmental area, and serotonergic neurons of the raphe nuclei.49
The orexin neurons are predominantly active during periods of
wakefulness and become less active during NREM and REM
sleep. Patients who have narcolepsy experience chronic sleepiness
and have an approximately 90% loss of functioning orexin
neurons, further suggesting the wake-promoting role of orexin
neuropeptides.50 Because orexin plays a significant role in the
wake cycle, recent research has exploited the clinical benefits of
antagonizing this receptor.
In phase III clinical trials, suvorexant, a dual orexin receptor
antagonist, significantly improved sleep onset and sleep
maintenance compared to placebo.51,52 However, while the
efficacy of suvorexant was established, next-day impairment
was a concern, warranting further evaluation of select doses. In
addition, research has shown that antagonizing serotonin
receptors (5HT-7) significantly improves sleep maintenance,
suggesting a potential role for agents with this effect in the
treatment of insomnia.53 In this final section, the roundtable
panelists discuss emerging therapies and their potential roles in
the management of insomnia.
Dr Larry Culpepper: Turning the discussion toward emerging
treatments, how do the orexin receptor antagonists and serotonin
receptor antagonists affect the sleep-wake system?
Dr Tom Roth: For the past 30 years, we’ve had medications that
work primarily on the sleep system through GABA mechanisms.
However, with the emergence of low-dose doxepin, orexin
receptor antagonists, and serotonin receptor antagonists, there are
more medications focused on reducing arousal associated with
the wake system, rather than simply pushing sleep harder. Orexin
receptor antagonists are probably the medications that are closest
to the finish line, and orexin is a major transmitter system that is
involved in the arousal system. It feeds into the noradrenergic,
histaminergic, and serotonergic systems.
Dr Phyllis Zee: In addition, when orexin neurons are firing during
wakefulness, they inhibit the VLPO, which is the sleep-promoting
center in the brain. It’s not only activating the wake promoting
regions in the brain, but it’s also inhibiting the sleep center.6
Therefore, if you antagonize the orexin system, you can promote
sleep by affecting both sleep and wake.
Dr Tom Roth: When you give a patient zolpidem, you want it to go
to the VLPO, but it binds receptors in the cerebellum as well, which
causes ataxia. It does these things because the GABA system is so
widespread. In contrast, orexin is produced by a small group of cells
that are located in the lateral hypothalamus, with significant
projections to regions of the brain that promote arousal.49 When
these medications are administered, they cause regional effects on
the brain versus the widespread effects we typically see with
medications that potentiate the GABA system, which has a lot to do
with receptor density.
Test Questions Take CME Test
Dr Larry Culpepper: We will need to adjust our thinking with
regard to these newer agents because they’re drastically different,
at least from a pharmacokinetic perspective. For example,
suvorexant, an orexin receptor antagonist, has a half-life of
12 hours.52 If this was a benzodiazepine that was affecting the
GABA system, the sleep side of the switch, you could not use
these medications because of the significant next-day impairment.
We will need to adjust our thinking with regard
to these newer agents because they’re drastically
different, at least from a pharmacokinetic
perspective. —Dr Larry Culpepper
Dr Tom Roth: If you look at low-dose doxepin, it has profound
effects on sleep at the end of the night. If you look at the orexin
and serotonin receptor antagonists, they have profound effects on
sleep at the end of the night. That is a very important time
because in those later hours you have already slept for 4 or
5 hours, and your homeostatic drive (the increased need for sleep
due to extended periods of wakefulness) is way down. Most
people experience wake time in the last 3 hours of the night, and
these medications are targeting those final hours of sleep. The
other factor you have to remember is benzodiazepine receptor
agonists work by simply shutting the brain down, and that makes
you fall asleep very, very quickly, which is what Dr Culpepper was
alluding to earlier. When transitioning patients from
benzodiazepine receptor agonists to these newer medications,
patient education will become very important because the
pharmacokinetic/pharmacodynamic indices of these medications
are profoundly different. The onset of action of these newer
compounds is not as fast as the medications that work on the
GABA system; conversely, the duration of action of these newer
agents appears to be longer.
Dr Sonia Ancoli-Israel: These medications may not help patients
get to sleep as fast as medications affecting the GABA system
because orexin receptor antagonists, for example, are more
focused on extending sleep. Education will be necessary to reduce
the patient’s expectation of rapidly falling asleep.
Final Thoughts
Research suggests that insomnia is a condition of hyperarousal
caused by a relative shift in the balance of activity of the
sleep-promoting and wake-promoting systems towards an increase
in activity in wake-promoting systems. Insomnia is not a symptom
of other disorders, but it’s comorbid with other medical conditions,
requiring its own intervention. Several studies, which have
evaluated behavioral and pharmacologic therapy, support this
direction in treatment. In addition, clinicians will not only need to
inquire about insomnia when comorbid conditions are present but
they will also need to inquire about comorbid conditions when
insomnia is present.
13
14 References
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13. Morin CM, Belleville G, Bélange L, Ivers H. Insomnia severity
index: psychometric indicators to detect insomnia cases and
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32. Lai LL, Tan MH, Lai YC. Prevalence and factors associated with
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33. FDA Drug Safety Communication: FDA approves label
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44. Czeisler CA, Richardson GS, Coleman RM, et al. Chronotherapy:
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15
 New Directions
in the
Management of Insomnia

Balancing Pathophysiology
and Therapeutics

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 New  Directions  in  the  Management  of  Insomnia  
Balancing  Pathophysiology  and  Therapeutics    
Proceedings  From  an  Expert  Roundtable  Discussion  
 
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1. BR,  a  48-­‐year-­‐old  female,  circles  the  number  “3”  for  each  question  on  the  Insomnia  Severity  
Index.  BR’s  total  score  indicates  which  level  of  insomnia?  
a. No  clinically  significant  insomnia  
b. Sub-­‐threshold  insomnia  
c. Moderate  clinical  insomnia  
d. Severe  clinical  insomnia  
 
2. Which  of  the  following  medications  is  least  likely  to  contribute  to  insomnia?  
a. Pseudoephedrine  
b. Methylphenidate  
c. loratadine  
d. Theophylline  
 
3. Which  of  the  following  comorbid  conditions  is  the  most  prevalent  with  insomnia?  
a. Hypertension  
b. Arthritis  
c. Gastroesophageal  reflux  disease  (GERD)  
d. Depression  
 
4. According  to  DSM-­‐5  diagnostic  criteria,  insomnia-­‐related  symptoms  must  occur  3  times  per  
week  for  which  duration  of  time?  
a. At  least  1  month  
b. At  least  2  months  
c. At  least  3  months  
d. At  least  6  months  
 
5. During  a  normal  sleep  cycle,  which  statement  is  true  with  regard  to  NREM  and  REM  stages  of  
sleep?  
a. NREM  becomes  longer  and  REM  becomes  shorter  through  the  night  
b. The  amount  of  time  in  REM  and  NREM  does  not  change  through  the  night  
c. REM  becomes  longer  and  NREM  becomes  shorter  through  the  night  
d. REM  and  NREM  cycles  occur  every  30  minutes  through  the  course  of  the  night  
 

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6. Approximately  what  percentage  of  patients  does  not  discuss  sleep-­‐related  disturbances  with  
their  primary  care  provider?  
a. 20%  
b. 30%  
c. 10%  
d. 55%  
7. With  regard  to  insomnia,  all  of  the  following  statements  are  true  EXCEPT:  
a. Insomnia  is  highly  comorbid  with  other  medical  conditions  
b. Insomnia  has  been  renamed  insomnia  disorder  
c. Insomnia  patients  exhibit  decreased  brain  glucose  metabolism  during  sleep  
d. Insomnia  is  a  condition  of  hyperarousal  
 
8. Which  of  the  following  is  a  sleep-­‐promoting  neurotransmitter?  
a. GABA  
b. Histamine  
c. Serotonin  
d. Acetylcholine  
 
9. All  of  the  following  statements  are  true  with  regard  to  the  ventrolateral  preoptic  nucleus  
(VLPO)  EXCEPT:  
a. The  VLPO  is  inhibited  by  the  wake-­‐promoting  regions  of  the  brain  
b. The  VLPO  contains  the  inhibitory  neurotransmitter  GABA    
c. The  VLPO  facilitates  NREM  and  REM  sleep  
d. The  VLPO  contains  the  excitatory  neurotransmitters  histamine  and  dopamine  
 
10. According  to  research,  the  condition  of  hyperarousal  is  all  of  the  following  EXCEPT:    
a. A  result  of  excessive  cortisol  production  
b. A  result  of  increased  sympathetic  nervous  system  stimulation  
c. A  12-­‐hour  syndrome,  occurring  frequently  at  nighttime    
d. A  result  of  perpetuating  negative,  learned  behaviors  
 
11. With  regard  to  suvorexant,  all  of  the  following  statements  are  true  EXCEPT:  
a. It  is  an  orexin  receptor  antagonist  
b. It  improves  sleep  maintenance  
c. It  improves  sleep  onset  
d. It  has  a  half-­‐life  of  3  hours  
 
12. Which  of  the  following  statements  is  true  with  regard  to  melatonin  for  the  treatment  of  
insomnia?  
a. Melatonin  is  FDA-­‐approved  to  reduce  sleep  onset    
b. Melatonin  is  FDA-­‐approved  to  improve  sleep  maintenance  
c. Melatonin  is  not  FDA-­‐approved  for  the  treatment  of  insomnia      
d. Melatonin  is  most  effective  when  taken  at  bedtime  
 
13. Based  on  current  literature,  which  of  the  following  medications  is  the  best  treatment  option  for  
a  patient  with  insomnia  and  comorbid  anxiety?  
a. Zolpidem  CR  
b. Eszopiclone  

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 c. Ramelteon  
d. Diphenhydramine  
 
 
 
14. Which  agent’s  primary  mechanism  of  action  involves  antagonizing  the  histamine  (H1)  receptor?  
a. Temazepam  
b. Doxepin  
c. Ramelteon  
d. Zaleplon  
 
15. Which  of  the  following  medications  has  product-­‐specific  labeling  that  indicates  the  lowest  
available  dose  is  recommended  when  initiating  treatment  in  women?  
a. Doxepin  
b. Zaleplon  
c. Eszopiclone  
d. Zolpidem  
 
16. Circadian  rhythms  are  coordinated  by  the:  
a. Tuberomammilary  nucleus  
b. Monoaminergic  nucleus  
c. Suprachiasmatic  nucleus  
d. Ventrolateral  preoptic  nucleus  
 
17. Persistent,  negative  learned  behaviors  that  people  associate  with  sleep  are  considered  which  
type  of  behavioral  factor?  
a. Predisposing  
b. Precipitating  
c. Perpetuating  
d. Participating  
 
18. Sleeping  in  a  quiet  room,  avoiding  daytime  napping,  and  maintaining  a  regular  exercise  
program  are  examples  of:  
a. Sleep  hygiene  therapy  
b. Stimulus  control  therapy  
c. Biofeedback  therapy  
d. Sleep  restriction  therapy  
 
19. Which  of  the  following  medications  does  not  have  an  FDA-­‐approved  indication  for  sleep  
maintenance?  
a. Zolpidem  CR  
b. Eszopiclone  
c. Zaleplon  
d. Quazepam  
 
20. Orexin  neuropeptides  are  produced  by  a  cluster  of  neurons  located  in  the:  
a. Ventrolateral  preoptic  nucleus  
b. Hypothalamus  

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 c. Tuberomammilary  nucleus  
d. Locus  coeruleus  
 
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PIM  supports  Green  CME  by  offering  your  Request  for  Credit  online.    If  you  wish  to  receive  
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On  the  navigation  menu,  click  on  “Find  Post-­‐test/Evaluation  by  Course”  and  search  by  course  ID  9496.  
 
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