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Chapter 60. Treatment of Insomnia
TREATMENT OF INSOMNIA: INTRODUCTION
Our conceptualization of insomnia has undergone a dramatic shift during the past few years, from
an annoying but not particularly serious symptom to the recognition that 1) sleep loss from any
cause has serious consequences, 2) chronic insomnia and the impaired sleep it represents are
highly comorbid with (or indeed may cause) many other medical and psychiatric disorders, and 3)
chronic insomnia in some cases may represent a separate medical disorder in itself, with an
independent neurobiological basis. It has been suggested that certain chronic insomnias be
considered on a par with depression as a serious disorder with a tendency toward chronicity whose
treatment needs independent assessment and possibly long-term management (Jindal et al. 2004).
This increase in complexity is in part offset by improved treatment options, both pharmacological
and nonpharmacological. This chapter will review these areas in what we hope is a clinically useful
manner.
MORBIDITY OF INSOMNIA AND CONSEQUENCES OF SLEEP LOSS
The 2005 National Institutes of Health (NIH) Consensus Conference on Chronic Insomnia in Adults
estimated that 30% of the general population has symptoms or complaints consistent with
insomnia (http://consensus.nih.gov/2005/2005InsomniaSOS026html.htm). The symptoms of
insomnia may include complaints of not being able to get to sleep, not being able to stay asleep,
waking too early, or sleep that is not refreshing—and often a combination of the foregoing.
Individuals with insomnia report diminished quality of life, including impaired concentration and
memory, decreased ability to accomplish daily tasks, decreased ability to accomplish daily tasks,
and decreased ability to enjoy interpersonal relationships (Ancoli-Israel and Roth 1999). Untreated
insomnia is associated with increases in new-onset anxiety and depression, increased daytime
sleepiness, and increased health-related concerns (Richardson 2000), as well as increased use of
health-related services (Novak et al. 2004). Patients with primary insomnia demonstrate impaired
memory consolidation during sleep (Backhaus et al. 2006), and recent evidence suggests they may
have diminished hippocampal volumes (Riemann et al. 2007).
New data on the effects of sleep loss in otherwise healthy adults affirm the importance of adequate
sleep. Going without sleep for 17–21 hours, not uncommon in many occupations and life situations,
may lead to psychomotor performance decrements similar to those seen with legal alcohol
intoxication (Dawson and Reid 1997), which may not be apparent to the individual concerned.
Going without sleep for a single night following a hepatitis A immunization may lead to a 50%
reduction in hepatitis A antibody formation a month later (Lange et al. 2003). Relatively mild sleep
loss may result in significant decline in cognitive performance, and sleep restriction to 4 hours per
night for 2 nights in healthy males has been shown to decrease leptin and increase ghrelin
production, with potentially adverse effects on the potential to develop obesity (Spiegel et al.
2004). Both short-term total and partial sleep deprivation have been shown to increase C reactive
protein levels in otherwise healthy adults (Meier-Ewert et al. 2004). Although an insomnia
complaint is not isomorphic with sleep deprivation, individuals with insomnia have been shown to
get less sleep and therefore are at greater risk for the adverse events accompanying sleep
deprivation. Data are emerging suggesting a relationship between sleep loss and the development
of both insulin resistance and the individual components of the metabolic syndrome (Wolk and
Somers 2007), an issue of special concern in an American population thought to be generally mildly
sleep deprived and in which obesity and type 2 diabetes are serious public health issues.Print: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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We now recognize that the insomnia complaint may reflect dysfunction of several underlying
neurobiological systems supporting sleep, including the homeostatic Process S and circadian
Process C systems, as well as influences from comorbid medical and/or psychiatric conditions and
the effects of environmental stress and poor sleep habits. Quite often, several of these factors
interact to produce the insomnia-based symptom complex that patients present with, a
circumstance that serves to highlight the importance of accurate and comprehensive differential
diagnosis of an insomnia complaint before embarking on treatment.
This chapter advances the position that most patients with insomnia complaints can be helped if
sufficient attention is paid to accurate differential diagnosis, with recognition and appropriate
treatment of their underlying pathologies contributing to their complaints.
SLEEP ARCHITECTURE
Sleep architecture refers to the characteristic scalp electroencephalogram (EEG) patterns that
characterize the different waking and sleep states (wakefulness, rapid eye movement [REM] sleep)
and non-REM sleep stages (1 through 4). EEG rhythms are defined primarily by their frequency in
cycles per second (termed Hertz [Hz]), with the major frequency bands being delta (<4 Hz), theta
(>4 to <8 Hz), alpha (~8 to ~12 Hz), beta (~13 to ~20 Hz), and gamma (>20 Hz). Sometimes 12-
to 14-Hz “sleep spindle” activity is termed sigma activity.
Wakefulness is normally accompanied by what is termed a “low-voltage, fast” scalp-recorded EEG,
with frequencies usually greater than 8 Hz and amplitudes in the vicinity of 50 V or less. The most
prominent EEG rhythm of quiet, relaxed wakefulness is the so-called alpha rhythm, seen over the
top and back of the head (visual receptive regions) when the eyes are closed. Alpha rhythm
consists of rhythmical 8- to 12-Hz activity, usually about 50 V in amplitude.
The transition from wakefulness to sleep—normally Stage 1 non-REM sleep—is indicated by the
appearance in the EEG of slower 5- to 7-Hz theta activity of generally low voltage. The subject is
not responsive at this point but can be easily aroused. Stage 1 sleep usually constitutes only about
5%–7% of total sleep time.
After a few minutes, the typical subject transitions into Stage 2 sleep, characterized by further
slowing of the EEG and the appearance of sleep spindles and K complexes. Spindles are short
(usually <1 second) bursts of 12- to 14-Hz activity dominant over high central regions that wax and
wane in amplitude—hence the term spindle.
Stage 3 and Stage 4 sleep usually follow Stage 2 and are characterized by increased slowing and
increased amplitude of the EEG. Stage 3 sleep contains between 20% and 50% of high-voltage
(>75 mV) slow (<2 Hz) delta activity, and Stage 4 sleep contains >50% slow delta activity. Stage 3
and Stage 4 sleep are often grouped together and termed delta sleep or slow-wave sleep (SWS).
Stage 3 and 4 sleep constitute about 20%–25% of sleep time in adults, but that percentage is
higher in adolescents and lower in healthy elderly individuals as well as in many pathological
conditions, including depression, schizophrenia, and many insomnia disorders. Older individuals
may have slow-wave delta activity, but it is not of sufficient amplitude (75 V) to be formally
scored as Stage 3 or 4.
After the typical adult has been asleep (in non-REM sleep) for about 90 minutes, the EEG transitions
to a lower-voltage, faster pattern. The subject remains asleep, but the eyes can now be seen
rapidly moving beneath the closed lids. Consequently, this stage of sleep is called rapid eye
movement or REM sleep. If awakened during this stage, the subject will often report dreaming. The
time from sleep onset (i.e., Stage 1) to the onset of the first REM period is termed REM latency,
which has diagnostic implications. In some psychiatric disorders (e.g., major affective disorders,
schizophrenia, and eating disorders), and occasionally in narcolepsy, REM latency is shorter than
normal. REM latency tends to decrease with advancing age, but, as a rule of thumb, nocturnal REM
latency of less than 60 minutes in an adult should be considered unusually short and might suggest
a major affective disorder. REM sleep usually constitutes about 20% of total sleep time in adults.
Until very recently, conventional EEG sleep scoring was still largely based on the sleep atlas ofPrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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Rechtschaffen and Kales (1968), which dates from the time that sleep records were recorded on
paper EEG machines, usually run at a speed of 10–30 mm/second, and included only those EEG
frequencies easily visible to the naked eye (very low [<0.5 Hz] and very high [>50 Hz] frequencies
were usually not recorded). We can probably expect some significant revisions in scoring
techniques in the near future based on availability of computerized EEG recording and analytical
techniques. Altered sleep morphology not captured by conventional scoring includes the presence
of “cyclic alternating patterns” that appear during sleep and may be associated with daytime
fatigue (Guilleminault et al. 2006), computer quantification of slow-wave activity indexing sleep
drive and/or quality (Armitage et al. 2007), and the presence of very-high-frequency
(gamma-band) EEG activity (Perlis et al. 2001a, 2001b). Such issues have begun to be addressed in
“The AASM Manual for the Scoring of Sleep and Associated Events: Rules, Terminology and
Technical Specification,” recently published by the American Academy of Sleep Medicine (2007).
SLEEP PHYSIOLOGY AS IT RELATES TO INSOMNIA
It is necessary to have a basic understanding of the neurobiological mechanisms underlying sleep if
we are to understand insomnia.
Perhaps the most basic issue is that there are fundamentally two quite different types of sleep,
non-REM and REM, each with its own neuroanatomy, physiology, function, developmental course
across the life span, and pathologies. These differences are summarized in Table 60–1.
TABLE 60–1. Characteristics of non-REM and REM sleep
Non-REM sleep REM sleep
Neuroanatomy Basal forebrain, VLPO neurons Pontine tegmentum
Physiology
HR, RR, BP, BT, EMG
↕HR, ↕RR, ↕BP, poikilothermic,
EMG
Control mechanism Process S and Process C Independent pontine oscillator
Developmental course
across life span
Appears during first year, in early
adolescence, then stabilizes in adulthood
High at birth, decreases by age 6
years to adult levels
Function Neurometabolic restoration, synaptic pruning Early mammalian brain
development
Pathologies Insomnia, parasomnias, hypersomnias Nightmares, RBD, narcolepsy
Note. = increased; = decreased;
= very greatly decreased; ↕ = highly variable.
BP = blood pressure; BT = body temperature; EMG = electromyograph; HR = heart rate; REM = rapid eye
movement; RBD = REM sleep behavior disorder; RR = respiratory rate; VLPO = ventrolateral preoptic area.
At any single point in time, the brain will usually be in only a single “state”—that is, either awake,
in non-REM sleep, or in REM sleep. Admixtures of state, however, are possible and usually present
as unusual sleep pathologies. For example, “sleep paralysis” and cataplexy are admixtures of REM
sleep and awake. Sleepwalking is an admixture of partial (motor—not conscious) arousal and
non-REM sleep. The major indicator of what state we are in is the type of EEG patterns and related
physiological and behavioral activity present at the moment.
A second basic issue is that we usually conceptualize sleep as reflecting the balance of two
fundamental processes—Process S, a homeostatic process in which the tendency to go into
non-REM sleep is increased by previous time awake, and Process C, a circadian arousal process that
tends to offset Process S so that we don’t go to sleep until we are ready to—that is, when 1)
Process S has built up and 2) the Process C arousal tendency begins to decrease.
These different types of sleep and control processes should become clearer as we outline them in
the following sections.
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The neuronal systems that regulate our daily cycle of sleep and wakefulness, while quite complex,
are becoming better defined. Discovery of the ascending reticular activating system (ARAS), a
wakefulness-promoting neurophysiological circuit that originates in the lower and more central
parts of the brain, was based in part on von Economo’s observations of brain pathology in
individuals who died of the epidemic of sleeping sickness or encephalitis lethargica that was seen in
Europe and the United States in the early twentieth century. Mediated through two major pathways,
one to the thalamus and a second more direct one to the hypothalamus and cortex, these cell
groups when active promote wakefulness. The ARAS depends significantly on acetylcholine and
monoamines, as well as other neuropeptide neurotransmitter systems.
A second set of competing systems located primarily in hypothalamic and contiguous regions, and
emphasizing neuronal activity in the ventrolateral preoptic (VLPO) region of the hypothalamus,
promotes non-REM or slow-wave sleep and inhibits wakefulness. These neuronal systems depend
significantly on the inhibitory neurotransmitters galanin and -aminobutyric acid (GABA) (which
most hypnotics are thought to modulate). Cells in the VLPO system appear to be activated by a
buildup of adenosine secondary to duration of preceding wakefulness (Basheer et al. 2004). The
longer a person has been awake, the more likely it is that sleep will be triggered, and the adenosine
antagonist caffeine tends to prolong wakefulness.
Although the ARAS and the VLPO system are competing (increased activity in one decreases activity
in the other), normally only one system at a time is predominant, for as a rule we are either awake
or asleep and spend relatively little time in intermediate (and biologically less useful states) states.
This suggests from an engineering view a type of biological flip-flop switch. Recent research
indicates that such a switch may indeed exist, mediated by the lateral hypothalamic neuropeptides
orexin and hypocretin, serving the function of a stabilizing system to keep the brain in either a
wakeful or sleep state and preventing rapid oscillation from one state to the other (Saper et al.
2005). The role of orexin in modulating the sleep–wake system is not yet well understood, although
preliminary animal studies suggest orexin antagonists induce sleep in animals and humans
(Brisbare-Roch et al. 2007).
The REM State
REM sleep constitutes the third major physiological state (wakefulness and slow-wave sleep being
the others), with neuronal generating and control systems essentially independent of wakefulness
and non-REM or slow-wave sleep. The REM state is uniquely different from either wakefulness or
slow-wave sleep, may include elements of both, yet may be independent of both.
Brain stem neuronal systems that have independent oscillation frequencies appear to account for
the periodic generation of the REM state in all mammals, including humans. These systems largely
reside in the pontine tegmentum and may constitute a separate component of the ARAS. The
periods of these independent oscillations appear to be a function of body size, being approximately
2 hours in elephants, 90 minutes in humans, 60 minutes in Old World monkeys, 30 minutes in cats,
12 minutes in rats, and 6 minutes in mice. Cholinergic systems appear involved in activating REM
states, and monoamines in suppressing them. Agents that increase acetylcholine (ACh) activity,
such as the acetylcholinesterase inhibitor physostigmine, increase REM sleep, and agents that
increase monoamine activity, such as monoamine oxidase–inhibiting antidepressants, decrease
REM sleep. It has recently been suggested that a type of neurophysiological toggle switch also
exists for controlling transitions into and out of the REM state, consisting of mutually inhibitory
neuronal populations that are GABA-ergic in nature, with independent pathways mediating EEG and
atonia effects (Lu et al. 2006). This switch is thought to be subsidiary to the putative wake–sleep
toggle switch, preventing transitions into REM during wakefulness, absent pathologies such as
narcolepsy, which is thought to involve a weakened wake side of the wake–sleep switch due to loss
of orexin neurons. Such a model would help explain a number of disorders in which impaired REM
regulation is seen.
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A second major neurobiological system controlling the timing of sleep is termed Process C (for
circadian).
Like most living organisms, humans have prominent daily, or circadian, biological rhythms, which
have important implications for normal sleep regulation and sleep disorders. The body’s major
circadian oscillator is located in the suprachiasmatic nucleus (SCN) of the hypothalamus. The SCN
can oscillate independently, and animal studies suggest that separate genes control the phase,
period, and amplitude of its oscillations. Recent studies have linked specific human circadian clock
genes to circadian-based sleep disorders (Hamet and Tremblay 2006). The SCN controls many
biological rhythms, including those of body temperature, various hormones, and the sleep–wake
cycle, or perhaps more precisely the circadian alerting tendency, which is here termed Process C.
This rhythm appears coupled to the temperature rhythm, with higher body temperatures being
associated with an increased tendency to wakefulness, and vice versa.
The normal sleep–wake rhythm is a 24-hour rhythm that is usually synchronized to the circadian
temperature and cortisol rhythm. The sleep–wake rhythm may become desynchronized when the
sleep–wake schedule is abruptly changed (as occurs with a rapid time zone shift), during which the
circadian oscillator initially remains on its original schedule. This desynchrony between the
attempted sleep–wake schedule in the new time zone and the underlying circadian rhythm is one
cause of “jet lag.”
Human subjects who live in caves or other dimly lit, time cue–free environments will typically adopt
a sleep–wake rhythm of approximately 24.2 hours (Czeisler et al. 1999). This suggests that the
normal free-running circadian period is slightly longer than 24 hours and must be “phase advanced”
about 12 minutes each day to stay in synchrony with the 24-hour rhythm of the sun. Overall, it
appears easier to phase-delay than to phase-advance the body’s rhythms, since a phase delay is
going in the “direction” of a free-running rhythm. This has practical implications in the adaptation
to a new time zone. A phase delay, as in East-to-West travel (with a later bedtime), is generally
easier and more quickly adjusted to than a phase advance, such as when going West to East (with
an earlier bedtime).
Light is a major synchronizer of circadian rhythms, and it has become apparent that, as in most
other organisms, circadian rhythms in humans can be reset by appropriately timed exposure to
bright light (Czeisler et al. 1986). Recent evidence suggests that short-wavelength light (shifted
toward the blue end of the spectrum; wavelength ~460 nm) is more effective at modulating the
activity of the SCN compared to longer-wavelength light (Lockley et al. 2006). The phase–response
curve (PRC) plots how the timing of light exposure affects circadian rhythm timing. The human PRC
suggests that exposure to bright light immediately before or shortly after onset of the sleep period
(i.e., typically in the late evening) will tend to delay the circadian system, whereas exposure late in
the sleep period, shortly before or after awakening (i.e., early morning), will tend to advance the
circadian system. Light sensitivity may be related to the time of the lowest body temperature (the
“nadir” of the body temperature circadian rhythm), with light exposure just prior to the body
temperature nadir phase delaying the circadian rhythms and light exposure just after the nadir
phase advancing the circadian rhythms. The human PRC provides useful information for timing the
use of bright-light exposure as a therapeutic modality for treatment of jet lag or circadian rhythm
disorders resulting from shift work.
The hormone melatonin, secreted by the pineal gland at night, appears to influence circadian
rhythms. Its secretion is regulated by light information relayed to the pineal gland from the SCN.
Melatonin secretion can be blocked by exposure to bright light during normally dark times. There is
emerging evidence that melatonin can be used to reset the circadian system, to treat circadian
rhythm disorders, and possibly to treat jet lag and work shift change (Brzezinski 1997), although it
generally does not work well as a hypnotic agent. Although the therapeutic use of melatonin is
receiving considerable media attention, it has been classified as a food supplement and is available
over the counter.
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underpinnings, and pathologies in either or both can result in disturbed sleep and complaints of
insomnia. Part of the differential diagnosis of insomnia is attempting to separate the two systems
in terms of their independent contribution to the complaint, as this impacts treatment.
Functions of Sleep
Sleep is a function of the brain and is thought to support proper brain function. Emerging data
clearly suggest sleep has a major role in both memory consolidation and brain (synaptic) plasticity
(Walker and Stickgold 2006). Sleep spindle activity has been related specifically to improved
memory recall performance (Clemens et al. 2005; Schabus et al. 2004), and very localized increases
in very slow delta activity during sleep has been related to performance improvement in
sleep-dependent learning of motor tasks, supporting its role in synaptic “pruning and tuning”
(Huber et al. 2004).
Sleep is likely intimately related to regulation of overall energy metabolism as well, as suggested
by the effect of mild sleep restriction on changes in leptin (decreases) and ghrelin (increases)
production (Spiegel et al. 2004). Both sleep restriction and excessive sleep have been reported as
risk factors in the development of insulin resistance and type 2 diabetes (Yaggi et al. 2006), and it
has been postulated that chronic sleep loss may be a risk factor for obesity and insulin resistance,
as well as type 2 diabetes (Chaput et al. 2008; Gangwisch et al. 2007; Spiegel et al. 2005).
The role of REM sleep in adult animals remains to be clearly defined, but its role in the development
of the immature mammalian brain seems apparent, specific mechanisms notwithstanding. Human
newborns have about 50% REM sleep, and human premature infants 80%. Newborn infants of
altricial mammals like rats and cats have greater percentages of REM sleep than adult animals,
while newborn infants of precocial animals like guinea pigs have lower adultlike levels of REM sleep
at birth. It has been suggested that the periodic ascending brain activation associated with REM
sleep may be important in developing species-appropriate neuronal pathways in the developing
brain. Its role in adult animals has been postulated as involving learning and memory functions, but
studies to date are inconclusive in this regard.
THE INSOMNIA COMPLAINT
The duration of an insomnia complaint has a major impact on its differential diagnosis and
treatment. Transient and short-term insomnias are usually stress- or environmentally related, and
the cause is obvious. Although they rarely come to the attention of health care providers, their
treatment is also generally straightforward, and they should, as a rule, be treated when found to
prevent them from becoming more chronic. The chronic insomnia complaint requires a more
systematic differential diagnosis procedure, also fortunately usually fairly straightforward. We first
consider the transient and short-term complaint and then move on to a discussion of the chronic
insomnia complaint.
Transient and Short-Term Insomnias
Transient (several days) and short-term (several weeks) insomnias are quite common. Most
individuals experience short-term trouble with sleep latency or sleep maintenance at times of
stress, excitement, or anticipation; during an illness; after going to high altitudes; or accompanying
sleep time changes (e.g., shift work, jet lag). Such problems rarely come to the attention of the
clinician in the early stages, although, of course, clinicians will experience these problems
themselves. Symptoms of insomnias can nonetheless be decreased, and daytime functioning
improved, if certain guidelines are followed. Stress-related insomnia, or temporary trouble sleeping
in response to excitement or worry (e.g., anticipating a trip or a forthcoming interview or
examination), may appropriately be treated with a night or two of a short-half-life hypnotic agent
(e.g., zolpidem 5 or 10 mg at bedtime). This medication need not necessarily be taken in
anticipation of trouble sleeping; it can be placed at the bedside and taken only after the patient has
been unable to fall asleep for 30–60 minutes, because it has a rapid onset and relatively short
duration of action. Awakening in the middle of the night with inability to fall asleep again can be
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available for sleep.
Short-term insomnias are due to more serious and prolonged stressful situations and may last up to
several weeks. The concern is that, if not treated, a conditioned or learned insomnia may develop in
response to concerns about not being able to go to sleep that can result in a more chronic insomnia.
The appropriate treatment of transient and short-term insomnia not only improves daytime
performance but also may prevent the insomnia from developing into a chronic problem. There is no
reason that responsible patients who know they are susceptible to transient insomnia in relation to
predictable stressful events cannot have a hypnotic agent available to use prophylactically.
Bereavement is often associated with a short-term insomnia, which has been reported to respond
favorably to sedative tricyclic agents (Pasternak et al. 1991).
Altitude-Related Insomnia
Altitude-related insomnia may occur when individuals rapidly travel to higher altitudes, such as
skiing and mountain climbing trips. High-altitude insomnia results primarily from periodic breathing
with increases in sleep-related central apneas and hypopneas, which can be diminished by several
days’ administration of acetazolamide (125 mg once or twice a day). Acetazolamide also appears to
decrease risk of developing altitude sickness. A short-acting hypnotic may also be useful for several
nights. It has been demonstrated that both zaleplon (10 g) and zolpidem (10 mg) improve sleep
quality at altitude without adverse effects on respiration, attention, alertness, or mood (Beaumont
et al. 2007). Altitude-related insomnia normally improves spontaneously after several days, at least
at altitudes below 15,000 feet. Altitude-related sleep problems can also be seen in infants but
normally resolve spontaneously without specific treatment after the first night (Yaron et al. 2004).
Shift Work– and Jet Lag–Related Insomnia
Attempts to sleep at times substantially different from what one is accustomed to, commonly
associated with long-distance travel (jet lag) or shift work, often result in disrupted sleep and
insomnia complaints. In both cases sleep is being attempted when the Process C system may be in
the high arousal state, and wakefulness may be necessary when the Process C is in the low arousal
state. In both shift work– and jet lag–related insomnia, there can be significant problems with both
sleep and wakefulness.
Shift work is the more serious of the two since it is often prolonged and is known to be associated
with health and performance impairments. More than 6 million Americans work night shifts on a
regular or rotating basis, and shift work sleep disorder is common in this group, with increased
incidence of gastrointestinal and cardiovascular disorders and impaired family and social
functioning, as well as an increased risk of accidents (Schwartz and Roth 2006). When working
shifts is necessary, efforts must be made to preserve sleep as much as possible as well as to
maintain wakefulness during the work period. Such efforts can be both pharmacological and
behavioral. Modafinil (200 mg) has been shown to help maintain wakefulness during work hours,
but because it has a relatively long half-life (~12–15 hours), it should be taken early so as not to
interfere with later sleep. The use of hypnotics to improve sleep during the sleep period must be
considered in terms of the risk–benefit ratio. Bright light early during the work period, with
protection from bright light late in the work period and on the way home in the morning, can help
with subsequent sleep (Schwartz and Roth 2006).
Jet lag also involves travel-related rapid time zone changes such that waking activities are required
during the circadian sleep time and sleep is required during the circadian wake time. Symptoms are
due both to this circadian desynchrony and sleep loss. Paying proper attention to light exposure
following transoceanic travel and remembering that initially the circadian system responds to light
as though it is still on the time zone one departed from can facilitate rapid entrainment to the new
light–dark schedule. Protection of sleep with short-acting hypnotic agents during the new sleep
periods for the first few nights can be helpful, as is appropriate supplemental melatonin
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Chronic Insomnia
Chronic insomnia is of greater concern than short-term insomnia, as it is both common (the
National Sleep Foundation estimates that 10%–15% of adults experience chronic insomnia) and
results in substantial adverse effects on health, quality of life, and overall function, as reviewed by
Krystal (2007). Chronic insomnia in adults is a risk factor for the development of anxiety and
depression (Neckelmann et al. 2007; Richardson 2000). Chronic insomnia in adolescents is a risk
factor for development of early adult depression and substance abuse (Roane and Taylor 2008).
Chronic insomnia should be viewed not just as a sleep problem but also as a problem affecting the
individual 24 hours a day.
DIFFERENTIAL DIAGNOSIS OF THE CHRONIC INSOMNIA COMPLAINT: A
SIX-STEP DECISION PROCESS
The differential diagnosis and effective treatment of chronic insomnia can challenge the most
skilled clinician. With chronic insomnias, unlike transient and short-term insomnias, the primary
cause is rarely immediately apparent, and the likelihood of more than one cause is high. Accurate
diagnosis is important because different causes of insomnia can present in a similar fashion, and
the appropriate treatment for one may aggravate another. Failure to systematically pursue a
complete differential diagnosis may yield misdiagnoses, treatment failures, and dissatisfied
patients. Most patients with chronic insomnia present with a straightforward complaint of insomnia;
however, it is important to realize that a substantial disturbance in nocturnal sleep can present as
complaints of chronic fatigue, impaired daytime performance, and excessive daytime sleepiness
(EDS), which raises the question of a possible excessive sleep disorder. A careful history should
identify such patients so that a more appropriate inquiry into nocturnal sleep habits and patterns
can be undertaken. Similarly, a large variety of medical and psychiatric disorders (and sometimes
their treatments) are accompanied by insomnia complaints.
First in order in any patient is a detailed sleep history, which will include the type of insomnia
problem (sleep onset, sleep maintenance, early awakening), when it began (childhood, recently, at
time of major stress or life event), when it occurs (every night, weeknights only, at times of
stress), what has been done when and by whom, previous response to treatment, how the insomnia
affects daytime functioning, and similar issues. Family history is important since there are
substantial genetic contributions both to basic sleep control mechanisms and to sleep pathologies
(Hamet and Tremblay 2006). Development of atypical sleep-related habits counter to those of good
sleep hygiene should be inquired about. A sleep diary kept for 1–2 weeks may be helpful in
establishing the type, perceived severity, and periodicity of the insomnia.
For this group of insomnias, the clinician should first establish that the patient has a true insomnia
and is not just a typical short sleeper. Short sleepers, although not common, do exist and may get
along fine on 4–5 hours of sleep a night. They do not complain of EDS or fatigue, and usually they
have no sleep complaints. Their families, however, see the patient up until midnight and then out of
bed again at 4:00 A.M. and assume that he or she has a sleep problem and convince him or her to
seek professional help. Such individuals need no specific treatment, although an explanation is
helpful for family members.
It is also important to decide whether the insomnia reflects a problem with non-REM or slow-wave
sleep (more often) or REM sleep (less often). REM sleep–related insomnia complaints can result
from frequent awakenings from frightening dreams or nightmares or from REM sleep behavior
disorder (RBD). RBD is most often seen in older males and results from failure of proper skeletal
muscle inhibition during REM such that patients can act out their dreams, often resulting in very
disturbed sleep. Memory of dream content during the episode suggests RBD, which can be
confirmed by polysomnography (Schenck and Mahowald 2005).
With this information on hand, the differential diagnosis is facilitated by a systematic approach
such as that outlined in the schematic decision tree in Figure 60–1.
FIGURE 60–1. Differential diagnosis decision tree for chronic insomnia.Print: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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Note. SMSS = sleep state misperception syndrome.
Step 1—Medical Conditions Affecting Sleep
Medical conditions, as well as the pharmacological treatments of medical conditions, can result in
insomnia complaints. The endocrinopathies are notorious for being associated with sleep-related
complaints, as are conditions associated with chronic pain, breathing difficulties, cardiac
arrhythmias, arthritis, renal failure, and central nervous system (CNS) disorders, especially the
dementias. Evaluation may include a complete medical history and, if appropriate, a physicalPrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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examination with relevant laboratory tests. Keep in mind the fact that the incidence of medical
disorders accompanied by sleep complaints increases with age. Some of the more common medical
disorders associated with impaired sleep are listed in Table 60–2.
TABLE 60–2. Medical conditions commonly associated with impaired sleep
Cardiovascular disorders
Angina
Congestive heart failure
Ischemic heart disease
Pulmonary disorders
Chronic obstructive pulmonary disease
Cystic fibrosis
Asthma
Sleep apnea
Dyspnea from any cause
Neurological disorders
Dementias
Parkinson’s disease
Central nervous system degenerative disorders
Traumatic brain injury
Central nervous system neoplasms
Endocrinological disorders
Hyperthyroidism
Hypothyroidism
Cushing’s syndrome
Addison’s disease
Gastrointestinal disorders
Gastroesophageal reflux
Peptic ulcer disease
Genitourinary disorders
Nocturia
Renal failure
Immunological and rheumatic disorders
Rheumatoid arthritis
Osteoarthritis
Fibromyalgia
Pain and fever from any cause
Metabolic disorders such as diabetes
Sleep-related breathing disorders are frequently associated with insomnia complaints. ObstructivePrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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and mixed apneas are usually accompanied by other symptoms, such as snoring, excessive daytime
sleepiness, and possibly cognitive problems. Central apnea is an occasional, albeit uncommon,
cause of chronic insomnia, especially in older patients and at higher altitudes. The clinician should
inquire whether the patient has had any subjective sense of trouble getting his or her breath or
feeling like his or her breathing is interfered with, especially during the transition from wakefulness
to sleep. Also ask the bed partner whether the patient has irregular breathing or pauses in his or
her breathing during sleep. Snoring may be another clue (although it is more likely related to an
obstructive component). Frequent apneas cause sleep fragmentation, which results in insomnia
complaints and often complaints of increased daytime sleepiness (Bonnet and Arand 1997). Central
sleep apnea is frequently associated with medical and neurological disorders (Thalhofer and Dorow
1997), but it may also occur in otherwise healthy individuals. It is more frequently encountered in
older individuals (Ancoli-Israel et al. 1997). Both oxygen and continuous positive airway pressure
(CPAP) can be used in the treatment of central apnea in patients with medical disorders (Franklin
et al. 1997; Granton et al. 1996). The pharmacological treatment of central sleep apnea is less than
optimal. Therapeutic options might include protriptyline (5–20 mg at bedtime), fluoxetine (10–20
mg/day), or theophylline (300–600 mg/day) (Ancoli-Israel et al. 1997), although their efficacy has
yet to be clearly established in well-controlled studies.
Also, a number of prescription drugs may result in insomnia complaints (prescription drug use also
tends to increase with age). Commonly used medications that can produce insomnia complaints in
some patients are listed in Table 60–3.
TABLE 60–3. Commonly used drugs with insomnia as a side effect
-Blockers
Corticosteriods
Adrenocorticotropic hormone
Monoamine oxidase inhibitors
Phenytoin
Calcium channel blockers
-Methyldopa
Bronchodilators
Stimulating tricyclics
Stimulants
Some selective serotonin reuptake inhibitors
Thyroid hormones
Oral contraceptives
Antimetabolites
Some decongestants
Thiazides
No specific sleep abnormalities are usually associated with most medical disorders other than
usually a decrease in total sleep, an increase in awakenings, and perhaps decreases in REM sleep.
Fibromyalgia and chronic fatigue syndrome are very frequently associated with sleep complaints.
On occasion, fibromyalgia is associated with an alpha–delta type of sleep abnormality, in which
alpha frequency activity is accentuated in the slow-wave-sleep background, with a complaint of
nonrestorative sleep. This pattern suggests a state of CNS hyperarousal. Sleep complaints are very
common in chronic fatigue syndrome and can include insomnia, hypersomnia, nonrestorative sleep,
and sleeping at the wrong time of the 24-hour period (circadian rhythm abnormalities).
Conventional polysomnographic findings are generally nonspecific and include decreased sleepPrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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efficiency, decreased slow-wave sleep, increased sleep latency, and alpha–delta sleep EEG patterns
(VanHoof et al. 2007). Chronic fatigue–related disturbances in regulation of underlying sleep
control mechanisms are supported by several studies. One recent study found an increase in the
cyclic alternating pattern in polysomnograms of chronic fatigue patients complaining of
nonrestorative sleep (Guilleminault et al. 2006), and there is also evidence of decreased sleep drive
(Process S) in chronic fatigue syndrome (Armitage et al. 2007).
Treatment of insomnia associated with medical conditions involves first isolating and appropriately
treating the medical condition and then, if the insomnia complaint persists, evaluating the
possibility of a separate additional sleep disorder. Conditioned insomnia can complicate insomnia
complaints in this population, and it must be separately addressed (as outlined below). Similarly, it
is quite possible for a patient with primary insomnia also to have a medical condition that further
disrupts sleep. A study by Rybarczyk et al. (2005) indicated that cognitive-behavioral therapy (CBT)
may be effective in older patients with insomnia comorbid with other medical conditions, such as
osteoarthritis, coronary artery disease, or pulmonary disease, suggesting that CBT should be
considered in these conditions.
Insomnia associated with acute medical conditions is appropriately treated with short-half-life
hypnotic agents (e.g., zolpidem 5–10 mg, triazolam 0.125–0.25 mg, or eszopiclone 2–3 mg at
bedtime) if no other contraindication to their use exists. Insomnia complaints associated with
fibromyalgia and chronic fatigue syndrome are frequently resistant to treatment, although small
doses of amitriptyline (10–50 mg at bedtime) or cyclobenzaprine (10 mg three times a day) have
been reported to be helpful, and occasionally zolpidem (5–10 mg) will help with the associated
insomnia complaints.
Scharf et al. (2003) reported that treatment with sodium oxybate (Zyrem) improved both sleep
abnormalities and symptoms of pain and fatigue in patients with fibromyalgia. Edinger et al. (2005)
found that CBT was effective in treating sleep complaints in patients with fibromyalgia. Modafinil
has been reported to decrease daytime fatigue and sleepiness in fibromyalgia patients, but its
impact on sleep has not yet been reported (Schaller and Behar 2001). If a medical disorder is
suspected of causing or contributing to the sleep complaint, a change of or alterations in treatment
that might improve sleep should be considered. It is important, however, to remember that the
differential diagnosis of a chronic insomnia complaint does not stop here—the remainder of the
differential diagnosis should be completed.
Dementing illnesses such as Alzheimer’s disease are often associated with severe insomnia
complaints that are quite disruptive to patients and families and often are the factors precipitating
institutional care. Disease-associated neuropathological changes in the sleep and circadian rhythm
control centers in the hypothalamus and SCN may contribute to these symptoms. Patients with
Alzheimer’s disease demonstrate phase-delayed body temperature and activity rhythms, with
delayed sleep onset, increased nocturnal activity, and fragmented sleep, likely related to
disease-associated SCN lesions. Some evidence suggests that a melatonin deficiency may be
present in some patients with Alzheimer’s disease (Liu et al. 1999). Sleep is also disturbed in
dementia with Lewy bodies (DLB), which has been found in up to 20% of dementia cases referred
to autopsy (McKeith 2000); this disturbance is often in the realm of increased motor activity
suggestive of an REM behavior disorder (Boeve et al. 1998; Ferman et al. 1999). Clearly, then, sleep
and activity abnormalities associated with dementia may result from very different
pathophysiologies and thus might respond to different treatments. Until such specific treatments
can be based on specific pathophysiology, we should adhere to optimal environmental circadian
principles (quiet, dark nocturnal environment; bright, socially stimulating daytime environment).
Possible supplementation with evening melatonin and additional morning bright light may prove
useful, in addition to the appropriate use of sedative-hypnotic agents, with the proviso that CNS
lesions may significantly impact the response to hypnotic agents. There is evidence that behavioral
treatment methods may benefit some Alzheimer’s patients (McCurry et al. 2004).
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The presence of significant anxiety, dysphoric or cyclic mood, or frank depression with sleep
complaints should alert the clinician to a possible psychiatric-related insomnia. Nocturnal panic
attacks can result in insomnia complaints, even in individuals who do not have typical panic
episodes during the day. Accordingly, the clinician should pay special attention to evidence of
nocturnal arousals accompanied by autonomic symptoms such as tachycardia, rapid breathing, and
the sense of anxiety or fearfulness. Insomnias related to psychiatric causes usually covary with the
degree of psychiatric symptoms. The fear of not being able to get to sleep seen in patients with
conditioned insomnia (“I can’t turn off my thoughts”) sometimes can be difficult to distinguish from
anxiety, but treatments may differ (e.g., CBT for conditioned insomnia, anxiolytics for anxiety).
Psychiatric disorders, especially disorders associated with anxiety or depression, frequently include
insomnia as an associated symptom. Chronic anxiety is not infrequently associated with sleep-onset
insomnia or sleep-maintenance insomnia, whereas depression is not infrequently associated with
early-morning awakening. These associations are not specific enough to be diagnostic, however,
and a systematic psychiatric evaluation is necessary. Many depressive disorders appear to be
accompanied by shortened REM latency, increased REM density during the first REM period of the
night, and deficient slow-wave sleep. To date, however, such findings are not sufficiently specific to
merit the cost of a polysomnogram.
Antidepressant agents, although effective for the patient’s depression, may have significantly
different effects on sleep—a possibility that is useful to bear in mind. Table 60–4 shows
sleep-related effects of the major antidepressant groups.
TABLE 60–4. Overview of the effects of antidepressants on sleep
Drug
Continuity SWS REM sleep Sedation
TCAs
Amitriptyline (Elavil)
++++
Doxepin (Sinequan)
++++
Imipramine (Tofranil)
++
Nortriptyline (Pamelor)
++
Desipramine (Norpramin)
+
Clomipramine (Anafranil)
±
MAOIs
Phenelzine (Nardil)
Tranylcypromine (Parnate)
SSRIs
Fluoxetine (Prozac)
±
Paroxetine* (Paxil)
±
Sertraline (Zoloft)
Citalopram (Celexa)
Fluvoxamine (Luvox)
+
Others
Bupropion (Wellbutrin)
Venlafaxine (Effexor)
++
Trazodone (Desyrel)
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Drug
Continuity SWS REM sleep Sedation
Mirtazapine (Remeron)
++++
Duloxetine (Cymbalta)
Note. = increased; = decreased; = no change; + = slight effect; ++ = small effect; +++ = moderate
effect; ++++ = great effect; ± = no significant effect. EEG = electroencephalogram; MAOIs = monoamine
oxidase inhibitors; REM = rapid eye movement; SSRIs = selective serotonin reuptake inhibitors; SWS =
slow-wave sleep; TCAs = tricyclic antidepressants.
*When taken at bedtime, paroxetine potentially decreases sleep continuity less than other SSRIs.
Source. Adapted from Winoker A, Reynolds C: “Overview of Effects of Antidepressant Therapies on Sleep.”
Primary Psychiatry 1:22–27, 1994. Used with permission.
The choice of an antidepressant agent for a specific patient, all other things being equal, might well
take into account the type of accompanying sleep complaint and the therapeutic effect on sleep
desired. Typically, resolution of the depression will be accompanied by reduction in the sleep
complaints. If, for a patient already complaining of insomnia, an antidepressant with a known high
incidence of insomnia side effects is chosen, it may be useful to augment it with a hypnotic agent
early in the course of treatment.
Treatment of insomnia associated with anxiety can incorporate a benzodiazepine with
sedative-hypnotic properties with a sufficient bedtime dose to augment sleep. Many antianxiety
agents, such as sedative tricyclics, have sedative-hypnotic properties as well, which facilitate the
management of the insomnia component. Panic attacks can occasionally arise exclusively from
sleep (Rosenfeld and Furman 1994); treatment in such cases should probably follow conventional
panic attack treatment strategies. Mirtazapine, an antidepressant with antianxiety properties
(Anttila and Leinonen 2001), may be helpful in the management of some cases of anxiety with
insomnia.
Bipolar disorder may be accompanied by prominent sleep disruption. Manic and hypomanic
episodes may be accompanied by marked decreases in sleep, although not necessarily insomnia
complaints. Sedative antidepressants have been shown to increase the risk of a shift to mania in
treating insomnia complaints in bipolar depressed patients (Saiz-Ruiz et al. 1994), and the use of
other hypnotic agents would therefore be more advisable in these patients. Milder cyclic mood
disorders also may have associated insomnia complaints, which can be mistaken for a primary
insomnia or a conditioned arousal insofar as the patients find it difficult to turn off their thinking at
sleep onset or after awakening during the night. If these patients are questioned carefully,
evidence of a cyclic mood component will suggest that treatment with a mood stabilizer might be
appropriate for the chronic insomnia complaint in these patients.
Posttraumatic stress disorder (PTSD) is a psychiatric disorder in which sleep disturbances are a
hallmark. Patients with PTSD may exhibit increased sleep latency, decreased sleep efficiency,
recurrent traumatic dreams, and evidence of increased REM density (Mellman et al. 1997), as well
as evidence of impaired skeletal muscle inhibition during REM sleep (Ross et al. 1994). Chronic
nightmares in PTSD have been successfully treated with CBT (Davis and Wright 2007). Recent
reviews suggest that a variety of medications may be useful for insomnia problems associated with
PTSD, including the atypical antipsychotic olanzapine and the 1-adrenoreceptor antagonist
prazosin, and possibly serotonin 2 (5-HT2) receptor antagonists (van Liempt et al. 2006), and
residual insomnia in PTSD patients has been treated with CBT (Deviva et al. 2005). Overall,
however, satisfactory treatment of sleep problems in PTSD remains elusive.
Step 3—Substance Misuse
A careful drug history will help to identify those patients who have used sedatives or hypnotics,
including alcohol, nightly for many months to years in order to fall asleep and who have developed
a chronic insomnia secondary to substance misuse. Similarly, a history of stimulant use or other
inappropriate drug use may result in a sleep disorder. A history of chronic or excessive drug orPrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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alcohol use recounted by the patient or, equally important, by a family member or friend suggests
that further workup in this area is required. Psychotropic dependence—the perceived need to “take
a pill” to diminish anxiety about potentially not being able to sleep—is not always easy to
distinguish from physical dependence—the actual need for the physiological effects of medication in
order to maintain sleep.
Alcohol remains a significant problem, as do stimulants and other drugs of abuse.
Alcohol-dependent sleep disorder occurs in those who habitually “self-medicate” with alcohol to
induce sleep. Alcohol does tend to decrease sleep latency and wakefulness during the first 3–4
hours of sleep. It also suppresses REM sleep and leads to REM rebound (with the possibility of vivid
dreams or nightmares), with fragmented sleep during the latter part of the night. Treatment
includes withdrawal of alcohol, with long-term abstinence as the goal. When necessary, sedation
can be provided by judicious use of antihistamines (e.g., diphenhydramine [25–50 mg] or
cyproheptadine [4–24 mg]).
Chronic use of stimulants leads to prolonged sleeplessness, and their withdrawal is followed by a
period of hypersomnolence. A chronic insomnia complaint is often seen in long-term stimulant
abusers even when they are not actively abusing the agents. Treatment is similar to that of
alcohol-induced sleep disorder. Antikindling agents such as carbamazepine (100–600 mg/day) or
divalproex (250–1,500 mg/day) may help when CNS hyperarousal/kindling is evident, as is
sometimes seen in postcocaine panic disorder in polysubstance abusers.
Habituation to benzodiazepine agents does not usually result in insomnia unless they are too
rapidly withdrawn, in which case the withdrawal syndrome may include insomnia. Doses should be
tapered by one therapeutic dose per week.
In all cases of substance abuse sleep disorders, the insomnia complaint should emphasize
behavioral treatment strategies to the fullest extent possible because psychoactive agents have
already proved to be a problem.
Step 4—Circadian Rhythm Disorders
Circadian rhythm disorders often present as sleep complaints. The most common is the delayed
sleep phase syndrome (DSPS), which presents as sleep-onset insomnia. Typically, individuals with
DSPS cannot get to sleep until 3:00–4:00 A.M. If they can then sleep until 10:00 A.M. or noon the
next day, they can do fine, indicating that they may have no trouble initiating or maintaining sleep,
but if they are required to arise early to get to school or work, they complain of insomnia, and they
are, of course, sleep deprived. Individuals with DSPS typically sleep in on weekends to recoup lost
sleep. They often have already tried hypnotics, which are generally ineffective other than in
inducing drowsiness, and their complaints are usually long-standing. DSPS typically appears in
adolescence or early adulthood, and it is frequently familial. Often first-degree relatives have a
history of similar sleep patterns.
In DSPS patients, evidence indicates that temperature rhythms and sleep rhythms are delayed and
that possibly sleep persists for a longer time following the body temperature low point, suggesting
that these patients may continue to sleep through the period when bright light would be most
effective in phase-advancing their circadian system (Ozaki et al. 1988). Melatonin rhythms also
may be phase-delayed in DSPS (Shibui et al. 1999).
Other forms of circadian rhythm disorders presenting as sleep complaints include advanced sleep
phase syndrome (ASPS) and non-24-hour sleep–wake syndrome, also known as hypernychthemeral
syndrome (Richardson and Malin 1996). ASPS is accompanied by retiring very early in the evening
and correspondingly arising very early in the morning, a schedule that sometimes mimics that of
terminal insomnia. Patients with the hypernychthemeral syndrome experience a failure of the
circadian clock to entrain normally to the 24-hour day, and they sometimes experience a
free-running 25-hour rhythm. This disorder is especially prevalent in blind persons, for whom light
is unable to synchronize the circadian system. Some blind persons, however, are sensitive to light
as an entrainer of the circadian system so long as the retina and retinohypothalamic tract arePrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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functioning normally.
Treatment of circadian rhythm–based sleep disorders now most often includes both bright light and
melatonin. Early-morning bright-light exposure administered after the body temperature low point,
with restriction of light exposure in the evening, has been found to be effective for
phase-advancing the circadian system in DSPS (Regestein and Pavlova 1995; Rosenthal et al.
1990). Evening bright-light treatment has been found to be effective in phase-delaying the
circadian system and in effectively treating ASPS (Chesson et al. 1999). Melatonin has also been
used successfully in the treatment of DSPS (Dahlitz et al. 1991; Lamberg 1996; Szeinberg et al.
2006), and a case report indicated its successful use in entraining the circadian system in a blind,
mentally retarded child who was unresponsive to bright light (Lapierre and Dumont 1995).
Melatonin is also effective in synchronizing the free-running circadian rhythm in blind persons
(Lewy et al. 2006).
Step 5—Movement Disorders: Restless Legs Syndrome and Periodic Leg
Movements in Sleep
Restless legs syndrome (RLS) is not a true sleep disorder but rather a movement disorder that
interferers with sleep. RLS is characterized by uncomfortable sensations in the calves at sleep
onset that require that the patient get up and “walk them out.” RLS symptoms are often maximal
between the hours of 10 P.M. and 2 A.M., thus interfering with sleep. Severe untreated cases can be
associated with significant sleep impairment and even skeletal injury (Kuzniar and Silber 2007).
RLS is increased in pregnancy, iron deficiency, renal disease, and diabetic neuropathy. There are
genetic contributions to RLS, and several candidate gene loci have been identified (Winkelmann et
- 2007). While its pathophysiology remains unclear, some evidence suggests that RLS is
associated with increased intracortical excitability that can be reversed by the dopamine D2
receptor agonist cabergoline (Nardone et al. 2006).
Treatment for RLS should take into account severity, and division of patients into three groups has
been suggested: 1) those with intermittent RLS symptoms, 2) those with daily RLS symptoms, and
3) those with symptoms refractory to common treatments. Both behavioral and pharmacological
strategies should be employed, and treatment algorithms are available (Hening 2007). Dopamine
agonists have been used for treatment of RLS. Carbidopa or levodopa was used initially but
frequently led to augmentation, or worsening of symptoms, with time. Ropinirole 0.5–6 mg/day in
divided doses, and pramipexole 0.125–0.75 mg have been shown to be effective in treating RLS.
Gabapentin 300–1,200 mg has also been found helpful (Happe et al. 2003)
Because iron deficiency can be a cause of RLS, iron supplementation can often be helpful, especially
if serum ferritin levels are below 45 g/L (O’Keeffe 2005). Some evidence suggests a deficiency of
iron transport into the CNS in RLS (Connor et al. 2003), and the use of intravenous iron has been
reported to be helpful in severe cases but is not yet an approved treatment modality.
Periodic leg movements in sleep (PLMS; formerly termed nocturnal myoclonus) consist of periodic
leg jerks occurring during sleep. Physiologically they appear to consist of extensions of the great
toe and dorsiflexion of the ankle, knee, and hip, and they may represent the release of
Babinski-type reflexes due to enhanced spinal cord excitability during light sleep. Associated
muscle contractions are usually short (0.5–1.0 second) in duration and periodic (every 20–40
seconds), with recurrent episodes. They may be associated with EEG arousals or with
cyclic-alternating-pattern discharges in the EEG. There is disagreement as to whether PLMS
constitutes a form of sleep pathology that should be evaluated for treatment (Hogl 2007) or a
normal variant with little clinical significance and not requiring treatment (except perhaps for the
bed partner experiencing the kicking activity) (Mahowald 2007). In any case, dopaminergic agents
as used for RLS are the treatments of choice, but the issue remains unresolved, and individual
cases should be evaluated in the context of the latest medical literature.
Step 6—Conditioned Insomnia, Primary Insomnia, and Sleep State
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Finally, after the foregoing causes have been ruled out, a persistent chronic insomnia complaint
likely falls into what we term the conditioned insomnia/primary insomnia/sleep state
misperception syndrome category. This group has often been characterized as “psychophysiological
insomnia” (American Academy of Sleep Medicine 2005), a term recently resurrected in the latest
International Classification of Sleep Disorders (ICSD) that, while likely correct in that insomnia has
both psychological and physiological components, is not of great help in separating independent
causes that may respond to separate treatments. Primary insomnia is a DSM-IV-TR (American
Psychiatric Association 2000) diagnostic with emerging information on the pathophysiology
underlying its apparent chronic physiological hyperarousal. Conditioned insomnia is, as the name
suggests, a “learned insomnia” in which a susceptible individual, after having trouble sleeping for a
few nights, becomes fearful, with accompanying hyperarousal, about the very thought of going to
bed or even going into the bedroom. The sleep state misperception syndrome is an interesting if
still poorly understood condition that can be initially confusing, for these individuals appear unable
to recognize that they have been asleep. These three types (as used here) of chronic insomnia tend
to have a commonality of treatment approaches, which will likely continue to be the case until we
have more data on their specific independent pathophysiologies. From a statistical and
epidemiological standpoint, this category, in combination with the psychiatric causes of poor sleep,
represents overall the largest group of the chronic insomnias. We believe it useful to attempt to
separate the members of this category, even though they respond to the same treatment
approaches. We will consider these three syndromes independently, first defining each as best we
can and then discussing the common differential diagnosis and treatments options.
Conditioned Insomnia
The presenting symptoms for conditioned insomnia are as follows:
Insomnia complaint, in a susceptible individual, beginning at a time of stress but persisting after the
resolution of the stress
Fear of going to bed because of the difficulty getting to sleep
Racing thoughts when finally lying down and trying to sleep (must be differentiated from anxiety and
mood dysregulation)
May not be present in alternative sleep environment (couch, sleep lab, another home)
Conditioned insomnia is a learned arousal state. Typically beginning at a time of stress in
susceptible individuals (those with a history of fragile or easily interrupted sleep), a few nights of
trouble getting to sleep or staying asleep lead to development of a fear of going to bed because of
concern that sleep again will be difficult to initiate or maintain. This fear is associated with
increased cognitive and physiological arousal, and soon a vicious cycle is established in which
merely going into the bedroom to prepare for sleep results in a conditioned arousal response
sufficient to interfere with sleep. More specifically, these individuals develop a “conditioned
arousal” to the normal sleep environment.
The conditioned arousal can continue long after resolution of the initial stress, and the resulting
insomnia complaint can be quite chronic. Such individuals may be able to sleep on the living room
couch, because they are conditioned to arouse only in their own bedroom. They may be able to nap
during the day, and often sleep well on vacation or in a new environment. They may also sleep
normally in the sleep lab, which is a new environment in which they may not experience
conditioned arousal. Thus, a normal polysomnogram does not mean that the patient does not
experience insomnia at home. Frequently, such individuals complain of not being able to turn off
their thoughts at bedtime and recognize that they become fearful and aroused at the thought of
going to bed. The differential diagnosis includes anxiety disorders and racing thoughts associated
with a mildly hypomanic state, such as may accompany bipolar II disorder. Not surprisingly,
conditioned arousal can co-occur with and complicate other causes (e.g., medical, psychiatric) of
insomnia, having developed in response to the sleep difficulties associated with those disorders.
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The presenting symptoms for primary insomnia are as follows:
Complaint of chronic insomnia 1 month or more in duration (sometimes years), that may wax and wane
in intensity and appears independent of stressful or life events.
Little evidence of fear about going to bed or complaints of racing thoughts.
Other causes of chronic insomnia have been ruled out, or if present appropriately treated.
DSM-IV-TR criteria for primary insomnia are listed in Table 60–5.
TABLE 60–5. DSM-IV-TR diagnostic criteria for primary insomnia
- The predominant complaint is difficulty initiating or maintaining sleep, or nonrestorative sleep, for at least
1 month.
- The sleep disturbance (or associated daytime fatigue) causes clinically significant distress or impairment in
social, occupational, or other important areas of functioning.
- The sleep disturbance does not occur exclusively during the course of narcolepsy, breathing-related sleep
disorder, circadian rhythm sleep disorder, or a parasomnia.
- The disturbance does not occur exclusively during the course of another mental disorder (e.g., major
depressive disorder, generalized anxiety disorder, a delirium).
- The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a
medication) or a general medical condition.
Recent evidence suggests a state of hyperarousal may accompany and possibly be a cause of
primary insomnia. These patients evidence increases in brain metabolism using positron emission
tomography (PET) neuroimaging both while awake and during sleep compared with normally
sleeping control subjects (Nofzinger et al. 2004), and evidence of increased metabolism during
NREM sleep using single photon emission computed tomography (SPECT) imaging (Smith et al.
2002). They also evidence increased fast-EEG activity during sleep (Merica et al. 1998; Perlis et al
2001a, 2001b). There may be genetic contributions, although specifics remain to be determined
(Heath et al. 1990). The important point is that this may be a bona fide medical disorder requiring
long-term management, including possibly long-term medication for sleep.
Sleep State Misperception Syndrome
Sleep state misperception syndrome (SSMS), a somewhat confusing term and a still poorly
understood condition, characterizes individuals who may go to sleep, spend time asleep, and
awaken, and yet not be aware of having slept. If sleep lab studies are performed to investigate the
chronic insomnia complaint, findings may appear normal. However, despite evidence of normal or
near-normal sleep, SSMS patients may still have symptoms seen in other patients with chronic
insomnia, such as disturbed daytime vigilance (Sugerman et al. 1985). Interestingly, a “reverse
sleep state misperception syndrome” has also been reported, in which a patient reported having
slept normally while objectively awake (Attarian et al. 2004).
Physiological studies are sparse. One study reported evidence of increased basal metabolic rate in
patients with SSMS compared with control subjects, but not as high as in psychophysiological
insomnia (Bonnet and Arand 1997), and there is evidence of possible sleep EEG differences
(increased faster rhythms) in SSMS (Edinger and Krystal 2003).
The extent to which sleep misperception may constitute a clinically meaningful subtype of chronic
insomnia remains to be determined. Because the syndrome has yet to be objectively defined and
requires objective evidence of lack of awareness of being in a state of EEG-defined sleep, the issue
of etiology remains moot, although the usual suspects (genetics, impaired arousal regulation
(cause), conditioning or learning, stress responses) come to mind.
Differential Diagnosis for the Conditioned Arousal, Primary Insomnia, and Sleep
State Misperception Syndrome Group
Since other causes having already been eliminated, the major differential in the case of conditionedPrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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insomnia, sleep state misperception, and primary insomnia rests upon history, symptoms, and
perhaps a polysomnogram (may be helpful in SSMS). An important aspect of conditioned insomnia
is that it frequently complicates insomnias resulting from other causes, and requires independent
assessment and treatment.
In conditioned insomnia, the history will often disclose a stressful event as initiating the insomnia,
which continues after the event resolves. In conditioned insomnia, sleep complaints tend to be
fixed over time, but they may covary with the degree of daytime stress. These patients often tend
to be tense or “wired” individuals; thus, some individuals may be more prone than others to the
development of psychophysiological insomnia. Sleep-onset insomnia does not always characterize
this disorder. Some patients may be able to fall asleep rather easily, but then they may have
several hours of wakefulness later in the night, again unable to turn off their thoughts. Primary
insomnia tends to be more chronic without clear cut stressful initiating events. The separation of
primary insomnia from chronic mild anxiety is sometimes difficult. SSMS patients may complain of
getting absolutely no sleep at all—which of course is unlikely. The DSM-IV-TR criteria for primary
insomnia need to be met. SSMS may not be suggested until a laboratory study (actigraphy or
polysomnography) suggests a dissociation between subjective complaints and objective findings.
SLEEP LABORATORY STUDIES
Are sleep laboratory studies useful in any of the insomnias? In most cases—no. An all-night sleep
study or polysomnogram may be indicated in chronic insomnia patients who are suspected of
having either PLMS possibly causing insomnia or a SRBD, where identification and quantification is
useful. Some conditioned insomnia patients may have less trouble sleeping in the laboratory
environment than at home, which results in more normal-appearing polysomnographic findings.
Thus, the presence of a relatively normal polysomnogram result in the laboratory does not exclude
the possibility of real sleep difficulties in the patient’s regular sleep environment. A polysomnogram
can be helpful in the case of SSMS, where the findings may be within normal limits even though the
patient believes he or she has obtained little or no sleep. It is questionable, however, whether the
cost–benefit ratio merits a polysomnogram in the latter cases, unless there are other reasons for
the study (e.g., treatment nonresponsiveness).
Conventional polysomnography is designed primarily to quantify respiratory and related physiology
as well as muscle activity, but it does not typically sample brain activity with sufficient temporal
and spatial resolution to provide useful information about other insomnia conditions. A
polysomnogram in insomnia typically shows evidence of increased sleep latency, more frequent
awakenings, and lower-than-normal total sleep and sleep efficiency, but the patient has already
told you that. Functional neuroimaging studies (high-density EEG or magnetoencephalography, PET,
SPECT) are research tools of potential value in better understanding disturbances in brain function
underlying insomnia complaints, but they are not yet of routine diagnostic utility for most insomnia
patients.
Actigraphy, providing an objective measure of minute-to-minute activity over several days or
weeks, may be helpful in suggesting a circadian rhythm disorder and sometimes SSMS, but while
activity measures often correlate well with polysomnogram-determined sleep measures, actigraphy
alone has not yet been shown to be accurate for diagnosis (Littner et al. 2003).
TREATMENT OF CHRONIC INSOMNIA
It is very important to realize that more than one cause of chronic insomnia may be present—in
fact, it might be stated that comorbidity is the rule, not the exception. A patient may, for example,
have a medical cause and a psychiatric cause in addition to PLMS or another movement
disorder–related insomnia, and may then go on to develop a “conditioned” component. Patients
who are depressed with comorbid insomnia may also have a primary insomnia disorder. Thus a
complete differential diagnosis should be done for each patient, which should not stop when the
first likely cause is identified. Similarly, treatments should be designed to cover all appropriate
causes. The question of whether all appropriate treatments should be initiated together rather than
waiting to see if the first treatment modality works alone before adding another is an importantPrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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issue with no clear answer. Starting several at once risks overtreatment, whereas starting only one
modality to see if it works before starting the others can mean delay in obtaining relief, furthering
the belief that the insomnia is intractable and possibly even leading to the development or
aggravation of a conditioned component. In the absence of firm rules, good clinical judgment and a
good understanding of the patient are paramount.
Combined Treatment Approach for Chronic Insomnia
Recent years have seen major advances in both pharmacological and nonpharmacological
(behavioral) treatments for insomnia (Erman 2005). These treatments will often be supplementary
to the treatments designed specifically for medical, psychiatric, and other comorbidities, which may
also be concurrent. As a general rule, a combined approach—utilizing both behavioral and
pharmacological components—is preferable, recognizing that behavioral components may not
always be available.
The mainstay of nonpharmacological behavioral treatments is CBT, which has been well
documented as an effective strategy. Additional behavioral treatments include improved sleep
hygiene, biofeedback, sleep restriction, progressive relaxation, and various meditation techniques.
From the pharmacological standpoint, recent years have seen the development of a series of new
nonbenzodiazepine hypnotic agents that are both more effective and less troublesome than the
older benzodiazepine agents.
Nonpharmacological Treatments for Chronic Insomnia
Cognitive-Behavioral Therapy
CBT for chronic insomnia has proved effective in a number of recent studies (Morin 2004; Smith and
Perlis 2006). CBT has three components—education, behavioral modification, and cognitive therapy
(Morin 2004). The literature on CBT as an effective treatment for insomnia is extensive and
compelling and was nicely reviewed by Morin (2004). Smith and Perlis (2006) outline its use as a
first-line treatment for chronic insomnia, including insomnia comorbid with medical and psychiatric
disorders. One recent study using CBT in the treatment of insomnia associated with breast cancer
suggested improvement in both sleep and immunological function resulting from CBT (Savard et al.
2003). Two issues of concern are which patients are optimally suited (or not well suited) for CBT
(Smith and Perlis 2006) and whether therapists trained in CBT are available. Recent reports
indicate that CBT need not be a long-term and complex treatment program; indeed, a very brief
two-session form of CBT has recently been described that can be effective in primary care settings
(Edinger and Sampson 2003). Perlis et al. (2005) has published a manualized step-by-step
cognitive-behavioral treatment program for insomnia that clinicians should be able to implement
effectively.
Sleep Hygiene
Sleep hygiene should be emphasized in the treatment of any chronic insomnia, including
psychophysiological insomnia. Principles of good sleep hygiene are summarized in Table 60–6.
TABLE 60–6. Sleep hygiene
Regular sleep time
Establishing a regular sleep–wake schedule is very important, especially a regular time
to awaken in the morning, with no more than 1-hour deviation from day to day,
including weekends. Arousal time is perhaps the most important synchronizer of
circadian rhythms. Awakening at 6:00 A.M. on weekdays to go to work and then
sleeping until noon on weekends should be discouraged.
Proper sleep
environment
Sleep interruptions should be minimized. The bedroom should be cool, dark, and quiet.
The clinician needs to inquire specifically about noise, because patients may habituate
to a noisy sleep environment and may not remember the noise, even though it
continues to disrupt their sleep pattern. Patients who have convinced themselves thatPrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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they can sleep only with the radio or television on should be discouraged from this
practice. Attention to the radio or television may prevent their minds from wandering,
or may keep them from beginning to worry about other matters, and thus assist with
sleep latency, but the continuing noise will be a disruptive factor during the course of
the night. Clock radios that automatically turn off may be useful.
Wind-down time
Time to wind down before sleep is important. The clinician should advise patients to
stop work at least 30 minutes before sleep-onset time and to change their activities to
something different and non-stressful, such as reading or listening to music.
Stimulus control
This procedure, an important component of sleep hygiene, involves removing from the
bedroom all stimuli that are not associated with sleep. The bedroom should be used for
sleep and, of course, sexual activity (which is often conducive to sleep). Activities such
as eating, drinking, arguing, discussing the day’s problems, and paying bills should be
done elsewhere, because their associated arousal may interfere with sleep onset.
Avoidance of
poorly timed
alcohol and
caffeine
Caffeine is quite disruptive of nocturnal sleep in many patients, and it has a long
half-life. Thus, caffeine consumption should be limited to the forenoon and in some
individuals not be continued after noon. A glass of wine or beer in the evening may
help some individuals relax, but regularly having several drinks before bedtime for the
express purpose of using the alcohol as a sedative should be discouraged. Alcohol in
large doses can substantially disrupt and fragment sleep. Cigarette smoking may
produce or aggravate insomnia in some patients.
Late-night
high-tryptophan
snack
A bedtime snack such as a glass of milk, a cookie, a banana, or a similar
high-tryptophan food may help promote sleep onset in some patients.
Regular exercise
Periods of exercise for 20–30 minutes at least 3–4 days a week should be encouraged.
Improved aerobic fitness has been shown experimentally to promote slow-wave sleep.
Exercise should not occur within 3 hours of bedtime, however, because the autonomic
arousal accompanying the exercise may serve to delay sleep onset.
Biofeedback
Biofeedback treatment that directly teaches patients how to control autonomic functioning may be
a useful therapeutic strategy (Hauri et al. 1982). Biofeedback may serve the dual function of
enhancing a sense of self-control and reducing autonomic arousal. Although electromyography
(EMG) and skin temperature biofeedback systems are perhaps the most commonly available forms,
EEG biofeedback has been shown to be useful in some cases of chronic insomnia (Cortoos et al.
2006).
Sleep Restriction
Some patients with chronic insomnia (especially elderly patients) spend greater and greater
amounts of time in bed achieving less and less sleep, such that they may be in bed 10 hours or
more and sleep only 6 hours. Sleep tends to spread out among the hours spent in bed, and this
process further fragments nocturnal sleep. The principle of sleep restriction is to decrease
substantially the time spent in bed so that sleep will consolidate to that time (Spielman et al.
1987). Restricting time available for sleep results in enhanced consolidation (which has important
benefits in terms of improving actual and perceived sleep quality) and an improved subjective
sense of self-control over sleep habits. The steps involved include the following:
Have the patient maintain a sleep diary for at least 5 nights. This diary should include a) time to bed at
night, b) estimated time of sleep onset, c) number and estimated time of awakenings during the night,
- d) time of final awakening in the morning, and e) time out of bed. From this 5-night sleep diary data,
calculate the mean value for estimated total sleep time (TST) and percentage sleep efficiency: TST
divided by total time in bed.
- Set the beginning total time in bed to equal the mean TST. For example, if the patient’s estimate of hisPrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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or her TST per night averaged over 5 nights is 5½ hours, set the time in bed to no more than 5½ hours,
perhaps having the patient go to bed at 12:30 A.M. and get up again at 6:00 A.M. This restriction will
result in increased daytime sleepiness the first several days, so the patient may need encouragement to
continue with the program.
Instruct the patient to call in, usually to an answering machine, every morning while in the program and
report his or her sleep data for the previous night, including time to bed, time of awakenings during
sleep, time of final awakening, and time out of bed.
Calculate TST and sleep efficiency for each night. When mean sleep efficiency for 5 consecutive nights
reaches 85% or better, increase time in bed by 15 minutes, by allowing the patient to go to bed 15
minutes earlier. If mean sleep efficiency declines to less than 85%, decrease time in bed by 15 minutes
(but not within the first 10 days of treatment). Naps outside the prescribed time in bed are not allowed.
Repeat the above procedure until the patient is maintaining a sleep efficiency of 85% or better and
obtaining what he or she considers to be a subjectively adequate amount of nocturnal sleep.
Sleep restriction results in some unavoidable sleepiness at the beginning of the regimen, and not all
patients can complete this treatment. However, those who can have a substantial chance of
improving their sleep efficiency and achieving greater satisfaction with their sleep.
Pharmacological Treatment Options for Chronic Insomnia
The use of hypnotic agents in the treatment of insomnia has a long and checkered history. Early
sedative-hypnotic agents such as the barbiturates, and then agents such as Noludar, Placidyl,
Quaalude, and Doriden, with their potential lethality, disruption of sleep morphology, and addiction
and/or habit-forming tendencies, gave the word “hypnotic” a bad reputation, to a considerable
extent well deserved at the time. Such agents no longer have a place in the routine treatment of
insomnia. Although chloral hydrate (500–1,000 mg) is still available for hypnotic use, it is
associated with increased addiction potential and has a relatively limited range between effective
and lethal dose; thus, it might best be reserved for occasional use when indicated for other reasons.
Mendelson and Jain (1995) suggested that the ideal hypnotic would have a therapeutic profile
characterized by rapid sleep induction and no residual effects (including memory effects). Its
pharmacokinetic profile would include rapid absorption and optimal half-life, as well as specific
receptor binding and lack of active metabolites. Its pharmacodynamic profile would include lack of
tolerance or physical dependence and no CNS or respiratory depression. Although the ideal hypnotic
agent has yet to be developed, hypnotic agents are being systematically improved with respect to
most of the foregoing issues.
When the benzodiazepines came on the scene in the latter part of the twentieth century, with their
prominent and useful sedative, hypnotic, anxiolytic, and anticonvulsant effects, safety was
improved, but habituation, tolerance, and altered sleep morphology (decreased SWS) were side
effects of concern. Because these agents activate the multiple benzodiazepine receptors in the
brain and enhance CNS GABAergic inhibition, they have a role in insomnia related to anxiety, where
their anxiolytic and GABAergic hypnotic effects are useful. Benzodiazepine agents approved by the
U.S. Food and Drug Administration (FDA) for the treatment of insomnia are listed in Table 60–7.
TABLE 60–7. Benzodiazepine agents for treatment of insomnia
Drug Half-life (hours) Absorption Typical dose (mg) Active metabolite
Triazolam (Halcion) 2–5 Fast 2.5–10 No
Temazepam (Restoril) 8–12 Moderate 7.5–30 No
Estazolam (ProSom) 12–20 Moderate 1–2 Minimal
Quazepam (Doral) 50–200 Fast 7.5–15 Yes
Flurazepam (Dalmane) 50–200 Fast 15–30 Yes
The benzodiazepine compounds differ substantially in terms of half-life, and the clinician can
choose the agent with a half-life most appropriate for the clinical situation. A long-half-life hypnoticPrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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such as flurazepam (15–30 mg) or quazepam (7.5–15.0 mg) might be appropriate for an anxious
patient in whom daytime anxiolytic effects are helpful if the interference with psychomotor
performance is acceptable and tolerable and if both patient and physician realize that considerable
buildup in blood level can be expected. Patients with difficulty sleeping through the night might
benefit from intermediate-half-life agents such as temazepam (15–30 mg) or estazolam (1–2 mg).
Patients who must be alert in the morning without residual daytime sedation would best be
managed with a short-half-life agent such as triazolam (0.125–0.25 mg). Many other
benzodiazepines have been used for insomnia because of their sedative-hypnotic properties, but
current thinking suggests that these agents might best be reserved for those patients who have
significant anxiety or who have perhaps not responded to newer hypnotic agents.
Several new nonbenzodiazepine hypnotic agents have been developed that appear to act on the
omega1 benzodiazepine receptor but carry less potential for the problems that may accompany
benzodiazepine use, such as habituation, tolerance, and altered sleep patterns. These newer
nonbenzodiazepine agents generally have in common demonstrated efficacy in treating insomnia,
differing primarily in half-life and effective duration of action (Table 60–8).
TABLE 60–8. Nonbenzodiazepine agents for treatment of insomnia
Drug Half-life (hours) Absorption Typical dose (mg) Active metabolite
Zaleplon (Sonata) 1–1.5 Fast 5–20 No
Ramelteon (Rozerem) 1–2.6 Fast 4–8 Yes
Zolpidem (Ambien) 1.5–2.6 Fast 2.5–10 No
Zolpidem ER (Ambien CR) 2.8 Fast 6.12–12.5 No
Eszopiclone (Lunesta) 6 Fast 7.5–15 Yes
Zolpidem is an imidazopyridine agent active at the omega1 benzodiazepine receptor but without the
same degree of potential for tolerance or rebound seen with the benzodiazepines. Zolpidem has
shown no evidence of rebound insomnia after being used at 10 mg/day for up to 35 days (Monti et
- 1994; Scharf et al. 1994; Ware et al. 2007). An extended-release (XR) form of zolpidem is
available that extends duration of action about 1.5 hours. Its use over a 6-month period is
associated with minimal residual and rebound effects (Owen 2006a).
Zaleplon is a nonbenzodiazepine pyrazolopyrimidine sedative-hypnotic agent that also acts as a
benzodiazepine receptor agonist. With a short half-life of about 1.5 hours, this agent can be
administered during middle-of-the-night awakenings as long as the patient has 4 hours of possible
sleep time remaining (Zammit et al. 2006). Its short duration of action provides a somewhat more
favorable safety profile for adult and elderly patients (Israel and Kramer 2002).
Eszopiclone is a nonbenzodiazepine cyclopyrrolone agent with rapid absorption and a half-life of
about 6 hours. Eszopiclone is extensively metabolized by oxidation and demethylation, and the
cytochrome P450 (CYP) isozymes CYP3A4 are involved, thus agents that induce or inhibit these
enzymes may influence the metabolism of eszopiclone. Some individual report a bitter taste as a
side effect (Najib 2006).
As a group, these agents appear to be relatively safe and effective for insomnia complaints,
differing primarily in regard to half-life. With this increased safety and resulting increased
worldwide use has come potentially significant problems associated with their inappropriate use or
misuse, most often involving either 1) routine prescription without adequate preliminary
differential diagnosis (the clinician’s problem), and/or 2) taking the medication at an inappropriate
time such as before having retired to bed (most often the patient’s problem), resulting in
inappropriate and potentially dangerous drug-induced waking behaviors. This is an issue related to
proper differential diagnosis and proper treatment planning and monitoring, which needs to be
addressed by improved education (still unfortunately often relatively sparse in medical school
curricula). The 2005 NIH Consensus Conference on Chronic Insomnia in Adults recommended thatPrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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these newer nonbenzodiazepine hypnotic agents be considered as the first-line treatment for
insomnia rather than the traditional benzodiazepines. While not significantly altering sleep
morphology, these agents do not specifically increase SWS, an attribute thought to be possibly
desirable based on the role of SWS in memory function.
Additional recently developed agents include the melatonin MT1 and MT2 receptor agonist
ramelteon, approved for use in insomnia with no long-term-use restrictions (Owen 2006b).
Ramelteon is thought to promote sleep by influencing homeostatic sleep signaling mediated by the
suprachiasmatic nucleus (Pandi-Perumal et al. 2007). It was shown to be effective for treatment of
primary insomnia in elderly adults at a dose of 4 mg or 8 mg, with no evidence of adverse next-day
effects (Roth et al. 2007b).
Several agents that are not yet formally approved for the treatment of insomnia have been found to
selectively increase SWS. Sodium oxybate, a sedative-hypnotic agent that has been shown to
increase SWS, is currently FDA approved only for use in treating narcolepsy. Its potential for abuse
and limited availability are issues of concern. Tiagabine, a GABA reuptake inhibitor that increases
synaptic GABA through selective inhibition of the GABA transporter type 1 (GAT-1), has been shown
to increase SWS in a dose-dependent fashion in primary insomnia at doses up to 8 mg (Walsh et al.
2006). Gaboxadol, a selective extrasynaptic GABAA agonist, has been demonstrated to increase
SWS at a dose of 15 mg (Deacon et al. 2007) and to improve sleep in a phase-advance model of
insomnia (Walsh et al. 2007a). Lankford et al. (2008) reported results of two randomized,
placebo-controlled studies of the use of gaboxidal over a 30-night period in both young adult and
elderly patient with primary insomnia. Subjects treated with gaboxidal demonstrated enhancement
of PSG-measured sleep maintenance and SWS as well as improvement in subjective sleep
measures. The unique extrasynaptic mechanism of action of gaboxadol involves a GABAA receptor
well represented in the thalamus, suggesting a quite different mechanism of action than most other
GABA agents (Wafford and Ebert 2006).
The FDA has recommended limitations on quantities and duration of use for many hypnotic agents,
although several recently approved agents (e.g., eszopiclone, zolpidem ER, ramelteon) have no
such limitations.
There are a number of other sedative agents, many of them among the tricyclic antidepressant
arsenal, that have been used for insomnia, including amitriptyline, nortriptyline, trimipramine, and
doxepin (which are generally antihistaminic). Trazodone is also frequently prescribed. While clearly
indicated when insomnia complicates depression, their general use for insomnia has neither FDA
approval nor solid scientific backing. Special caution should be used in patients with increased risk
factors such as cardiac conduction defects, glaucoma, or seizure disorders. Similar considerations
exist for sedating atypical antipsychotic agents, which while often quite useful for insomnia
complaints, should remain in the domain of patients experiencing cognitive symptoms suggestive of
possible thought disorder. That being said, the author has had patients with chronic insomnia
nonresponsive to usual hypnotic agents that does respond well to very low bedtime doses of
sedative tricyclics such as nortriptyline. It should be noted that a recent placebo-controlled study
has found doxepin doses of 1, 3, and 6 mg to be effective for treatment of primary insomnia,
demonstrating improvement of both PSG-determined and patient-reported sleep measures.
Presumably at this dose the drug is acting primarily as an H1 selective antagonist (Roth et al.
2007a). FDA approval for doxepin in this dose range for insomnia is pending.
Over-the-counter sleep agents and various herbal remedies found in health food stores have
generally not been evaluated for hypnotic efficacy in well-controlled double-blind studies. Although
some have modest sedative effects, consumers should be cautious, especially as concerns regular
or excessive use of such agents.
The future may see the use of orexin-modulating agents in insomnia. Orexins are involved in
sleep–wake stabilization and are deficient in narcolepsy, which is accompanied by excessive
sleepiness. An orexin antagonist has been shown to induce sleep in both animals and humans, but
is not yet available for clinical use (Brisbare-Roch et al. 2007).Print: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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Long-Term Use of Hypnotic Agents for Chronic Insomnia
The long-term use of hypnotic agents employed in the treatment of chronic insomnia is a topic of
considerable concern. Short-term intermittent use is often recommended and remains a good
overall principle. If a specific etiology, such as a medical or psychiatric disorder, can be identified
and treated, the insomnia may resolve. Many, although not all, circadian rhythm disorders can be
effectively managed with bright-light or melatonin treatment. Many patients with primary
insomnia, however, may require long-term pharmacological management. In a recent study,
long-term (6-month) treatment of chronic primary insomnia with eszopiclone 3 mg led to enhanced
quality of life, reduced work limitations, and improved patient satisfaction with sleep without
evidence of rebound insomnia following medication discontinuation (Walsh et al. 2007b). Several
similar placebo-controlled studies reported that 12.5 mg zolpidem ER administered 3–7 nights per
week over a 6-month period resulted in improved daytime concentration and work performance as
well as improved satisfaction with nocturnal sleep (Erman et al. 2008; Krystal et al. 2008).
The use of the lowest dose of the most innocuous but most effective agent is a good rule.
Unnecessary withholding of treatment should be avoided, however. Considering the known adverse
effects of chronic sleep loss, in the context of the current availability of relatively safe and effective
hypnotic agents, there would appear to be no reason to withhold or to limit treatment in those
patients for whom a comprehensive and thorough diagnostic evaluation has established the
presence of a primary insomnia disorder that would benefit from long-term treatment. The
cost–benefit ratio of chronic pharmacological treatment must be carefully evaluated on an
individual patient basis.
Given the demonstrated effectiveness of CBT, it seems any patients being considered for long-term
hypnotic treatment should at least be given the option of trying CBT to see if it might decrease the
need for hypnotic use. The following three general rules might be useful to keep in mind when
considering the long-term use of hypnotics:
- Use the lowest effective dose and the shortest clinically indicated duration of use.
Do not put a patient on long-term hypnotic use for a chronic insomnia condition without including at the
very least a good trial of behavioral treatment for insomnia.
Do not hesitate to prescribe long-term use of one of the newer and safer hypnotic agents when clinically
indicated for an appropriately evaluated chronic insomnia condition (including but not limited to primary
insomnia).
INSOMNIA IN THE ELDERLY
Up to 50% of older Americans report chronic difficulties with their sleep (Foley et al. 1995), and
similar numbers have been reported from other cultures. In addition to resulting dissatisfaction
with sleep and aspects of daytime performance, those with sleep complaints use health services to
a greater extent (Novak et al. 2004). While the differential diagnosis and treatment strategies are
similar in elderly individuals, there are both physiological and behavioral aspects of aging that
impact sleep that require emphasis.
Normal Aging and Sleep Control Mechanisms
CNS changes associated with aging may adversely impact both Process S and Process C sleep
control systems. There is evidence that the number of non-REM-promoting VLPO neurons in the
hypothalamus decreases with age, beginning about after age 50 years, with the decrease being
more pronounced in women than men (Hofman and Swaab 1989). By age 85 years, there may be a
loss of 50% of VLPO neurons. To the extent that these VLPO neurons support the integrity of
non-REM sleep, or Process S, this cell loss could be related to the increase in insomnia complaints in
the elderly, especially women (Ancoli-Israel and Ayalon 2006). Additionally, the nocturnal
production of melatonin decreases with age, significantly so by age 60 years, which may lead to
impairment in the Process C circadian arousal control system (Cardinali et al. 2006). The possible
impact of such changes should be taken into account in evaluating sleep complaints in the
elderly—the use of hypnotics and/or melatonin supplementation may be especially useful (HaimovPrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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et al. 1995).
Those medical and psychiatric conditions adversely impacting sleep and sometimes comorbid with
insomnia increase in frequency in the elderly, and specific sleep disorders, such as RLS, sleep
apnea, and REM sleep behavior disorder, also increase in incidence with age. The comorbidity of
insomnia and sleep-related breathing disorders in the elderly is associated with significant
impairment (Gooneratne et al. 2006). Elderly people frequently take a variety of medications that,
for a variety of reasons, may either interact or act differently in the elderly person and result in
altered sleep patterns or sleep behavior.
Adverse Sleep Habits and Environments in the Elderly
Even the healthy elderly may live a lifestyle of restricted interests and decreased mental and
physical activities, which can contribute to poorer sleep. Process S appears to be stimulated by the
amount and intensity of the preceding day’s mental and physical activity, and reductions in such
can be expected to adversely impact Process S. Maintenance of a sleep-healthy lifestyle with
vigorous mental and physical as well as social activities can certainly help here. The impact of
exercise on sleep is still somewhat unclear (Driver and Taylor 2000; Kubitz et al. 1996); however,
the role of improved aerobic fitness in health and well-being generally is well established.
The less healthy elderly, who may reside in more restrictive environments or nursing homes, are at
special risk, not only because of the foregoing but because of the adverse impact of factors such as
irregular schedules, excessive nocturnal lighting, noise, and other issues adversely affecting sleep.
Efforts should be made to modify and improve the living and sleeping environment before routinely
moving to pharmacological interventions such as sedative-hypnotic agents.
Treatment of Insomnia in Elderly Patients
Strict attention to good sleep hygiene is important, including not spending excessive time in bed
and improving aerobic fitness if possible. Excessive use of caffeine, including that contained in
over-the-counter analgesics, should be curtailed.
Bright-light treatment has been useful in treating sleep disorders, including morning bright light for
certain cases of sleep-onset insomnia (possibly caused by a mild circadian phase delay), in elderly
patients. Evening bright light has been found to be effective in sleep-maintenance insomnia in
healthy elderly subjects (Campbell et al. 1995). It should be kept in mind that elderly individuals
may be less responsive to bright light and therefore might require a greater duration or intensity of
treatment (Duffy et al. 2007).
Use of pharmacological agents must be tempered by the awareness that half-lives may be
extended, that risk of multiple drug interactions may be increased, and that lower-than-usual doses
may be adequate. Zaleplon, because of its short half-life, may be a relatively safe agent in the
elderly, and indiplon (15 mg), a nonbenzodiazepine hypnotic active at the benzodiazepine alpha1
subunit, was shown to improve sleep in elderly patients with primary insomnia during a 2-week
treatment period with no significant side effects (Lydiard et al. 2006). Indiplon could potentially be
released as a hypnotic in the near future.
Some have suggested that use of hypnotics in elderly patients should be very conservative, with an
emphasis on nonpharmacological strategies (Bain 2006; Sivertsen and Nordhus 2007) and CBT,
which has been shown to be effective in elderly patients with insomnia. While concerns have been
expressed about a relationship between hypnotic use and falls in the elderly, a recent study found
that insomnia, but not hypnotic use, was associated with a greater risk of subsequent falls (Avidan
et al. 2005).
Considering the cognitive difficulties experienced by many elderly individuals possibly related to
sleep impairment, a recent study demonstrating improved cognitive function in an animal model of
genetically induced impaired sleep following treatment with a benzodiazepine to help improve
sleep might be important (Pallier et al. 2007). It has yet to be determined whether
nonpharmacological treatment of insomnia is as effective as pharmacological in reversing thePrint: Chapter 60. Treatment of Insomnia http://www.psychiatryonline.com/popup.aspx?aID=442065&print=yes…
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adverse cognitive effects of insomnia.
CONCLUSION
It is gratifying that the available treatment strategies for insomnia have improved coincidentally
with our recognition of the importance of protecting sleep and treating insomnia in recent years.
We are still left with an unclear understanding of the basic pathophysiology of many
insomnia-related syndromes, however, and until our knowledge base improves, we must depend on
systematic differential diagnosis and treatment planning using the information available.
Fortunately, with this approach, most patients with insomnia complaints can be significantly
helped.
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Copyright © 2009 American Psychiatric Publishing, Inc. All Rights Reserved.
Course Content
Introduction to Sleep and Insomnia
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Understanding Sleep Basics
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The Science of Insomnia
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Sleep and Insomnia Knowledge Check
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Historical Perspectives on Sleep
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The Role of Circadian Rhythms
Understanding Sleep Cycles and Patterns
Identifying the Causes of Insomnia
Effective Cognitive and Behavioral Strategies for Better Sleep
Developing a Personalized Sleep Plan and Conclusion
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