Numerous physiologic functions are altered during REM sleep. Breathing is
irregular, consisting of sudden changes in respiratory amplitude and frequency
corresponding to bursts of REM. Temperature control is lost and the body
temperature typically lowers. REM sleep brings on variability in heart rate, blood
pressure (BP), cerebral blood flow, and metabolism. Cardiac output and urine
volume decrease. Blood may become thicker as a result of autonomic instability and
REM duration varies throughout the night but increases each cycle. In the last half
of the night, REM becomes notably longer and more intense when body temperature
is at its lowest, around 5 AM. The human body clearly needs REM sleep, although the
reason it occurs is unknown. When deprived of REM sleep, whether through poor
sleep, drugs, or disease states, the brain and body try to catch up. REM rebound
occurs and may result in vivid dreams or an overall less restful sleep.
NEUROCHEMISTRY OF SLEEP–WAKE CYCLE
Wakefulness- and Sleep-Promoting Neurochemicals
A basic understanding of brain neurochemistry is essential in understanding sleep
disorders and the clinical use of hypnotics. Hypnotics exert their effects by
modulating brain neurotransmitters and neuropeptides (e.g., serotonin,
norepinephrine, acetylcholine, histamine, adenosine, and γ-aminobutyric acid
[GABA]). The neuronal systems in which neurotransmitters and neuropeptides act to
control the sleep–wake cycle lie in the brainstem, hypothalamus, and basal forebrain,
with connections in the thalamus and cortex. Noradrenergic, histaminergic, and
acetylcholine-containing neurons promote wakefulness as they modulate cortical and
18 Excitatory amino acids, such as glutamate and stimulating
neuropeptides (e.g., substance P, thyrotropin-releasing factor, corticotropin-releasing
factor) also promote wakefulness.
18 Hypocretin 1 and 2, also known as orexin A and
B, are neuropeptides that modulate the sleep–wake cycle. Hypocretin 1 and 2 are
deficient in people with narcolepsy and primary hypersomnia.
Wakefulness and sleep are antagonistic states competing for control of brain
activity. Sleep takes over as the wakefulness-maintaining neuronal systems weaken
and sleep-promoting neurons become active. Serotonin-containing neurons of the
brainstem raphe dampen sensory input and inhibit motor activity, promoting the
15,16,18 Opiate peptides (e.g., enkephalin, endorphin)
and GABA, an inhibitory neurotransmitter, also promote sleep.
Drug-Induced Effects on Neurochemicals
The neurochemistry of sleep also can be understood by considering the effect of
hypnotic drugs on specific neurotransmitters. GABA is facilitated when a
benzodiazepine compound attaches to the GABA–chloride ionophore complex and
causes chloride channels to open and inhibit overexcited areas of the brain.
GABA-facilitating hypnotics, such as benzodiazepines, induce sleep and decrease
arousals between stages, providing more continuous stage 2 sleep.
Benzodiazepines, however, also may decrease stage 4 slow-wave sleep and
suppress REM, leading to REM sleep rebound on abrupt discontinuation.
Antihistamines that promote sleep do so by blocking histamine-containing neurons
involved in maintaining wakefulness. The excitatory effects of caffeine and other
methylxanthines are attributed to their antagonism of adenosine receptors. Adenosine
is a sleep-promoting neurotransmitter or neuromodulator.
Neurotransmitter alteration may or may not affect REM sleep. Drug-induced
noradrenergic and serotonergic modulation usually decreases REM sleep. An
increase in dopaminergic neurotransmission can increase wakefulness but has no
direct effect on REM sleep. In contrast, increased cholinergic neurotransmission
It is useful to think of the brain centers, neurochemicals, and
neuropeptides involved as an interactive network regulating our sleep–wake cycle.
Hence, drugs or disease states that alter neurotransmission can have significant
impact on the sleep–wake cycle.
The International Classification of Sleep Disorders, Third Edition (ICSD-3)
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)
the latest editions of guides used for classification and diagnosis of sleep disorders.
Both ICSD-3 and DSM-5 categorize sleep disorders largely based on
pathophysiology and presumed etiology rather than numbers of hours of sleep. See
Table 84-1 for DSM-5 classifications of sleep disorders.
During the course of a year, approximately one-third (30%–36%) of the population
will experience insomnia, and 10% to 15% will consider the problem severe due to
25 Sleep research also shows that chronic insomnia can predict
untreated illness or may contribute to injury and illness.
2,27–29 Children, adolescents,
and adults with persistent insomnia are twice as likely to develop anxiety and 4 times
as likely to develop depression when compared to people without insomnia.
Chronic insomnia is also more common in individuals with high blood pressure,
breathing difficulties, gastrointestinal (GI) disorders, cancer, and chronic pain,
Insomnia and excessive daytime sleepiness (EDS) in the
elderly are leading predictors of institutionalization.
To meet the criteria for insomnia disorder according to ICSD-3 and DSM 5, the
sleep disturbance must cause significant distress or impairment in important areas of
functioning (i.e., social, occupational, educational, academic, behavioral) and occur
at least three nights per week over a 3-month period despite adequate opportunity for
25,26 The insomnia disorder can be further classified based on duration as
follows: episodic (1–3 months), persistent (>3 months), and recurrent (two or more
episodes in 1 year). Insomnia with duration less than 1 month, previously referred to
as transient insomnia, would be classified as “other specified insomnia disorder.”
When first assessing a patient, it is important to determine whether the sleep problem
is related to difficulty falling asleep, maintaining sleep, early morning awakening,
nonrestorative–quality sleep, excessive daytime sleepiness, or a combination of these
problems. Answers to the questions, “How long does it take you to fall asleep, and
how many hours do you sleep?” should be compared with the patient’s normal sleep
pattern to determine how it varies. Questions such as “How do you feel during the
day: well rested, sleepy, or something else?” can help assess functional impairment.
In addition, the patient’s sleep schedule, including bed time, sleep onset latency,
number and length of nighttime awakenings, time to sleep reinitiation, and total wake
and sleep time should be reviewed.
Classification of Sleep–Wake Disorders
medical condition or another sleep or mental disorder
fragmented sleep and complain of daytime drowsiness
Obstructive sleep apnea hypopnea
Circadian rhythm sleep–wake disorders
Sleep phase syndrome: falling asleep and waking earlier or later than desired
Irregular sleep–wake type: falling asleep and waking at irregular times
Non-24-hour sleep–wake type: falling asleep and waking progressively later than desired
Shift work type:sleep changes associated with work schedule
Non-REM sleep arousal disorders
considered pathological only in adults
Sleep walking type: recurring sleepwalking, usually during the first part of the sleep cycle
Nightmare disorder: troubling dreams that awaken individuals or make them fearful of falling asleep
REM sleep behavior disorder: individuals may speak, thrash about, and/or awaken during REM sleep
at night; can lead to fragmented sleep and daytime drowsiness
Substance/medication-induced sleep disorder: can result in insomnia or hypersomnolence
EDS, Excessive daytime sleepiness; REM, Rapid eye movement.
The next step involves investigating the possible causes of the sleep disorder and
any concomitant conditions. All coexisting medical, psychiatric, drug, environmental,
and social causes must be considered and treated along with the sleep disorder.
Impact of the sleep disturbance on daytime functioning should be assessed to evaluate
the severity of the disorder. A sleep diary in which the patient records bed and wake
times, estimated time to fall asleep, number and duration or awakenings, time and
type of medication/substance ingestion, time and duration of any naps, and sleep
quality can help to elucidate the type of sleep disorder.
Nonpharmacologic Treatments for Insomnia
Cognitive: identify and stop thought patterns that interfere with sleep
Behavioral:stimulus control, sleep restriction, relaxation, paradoxical intention.
Stimulus control: train the brain to re-associate the bed and bedroom with sleep and re-establish a
consistent sleep–wake schedule.
actually spent sleeping, then increasing time in bed as sleep efficiency improves.
progressive tensing and relaxing of muscles, yoga, stretching).
performance anxiety associated with falling asleep.
Sleep hygiene: not considered effective on its own; useful adjunctive treatment.
comfortable; avoid daytime napping.
Additionally to assessing patient symptoms and determining the cause of insomnia,
it is important to discuss patient expectations. Not all patients need the same amount
of sleep, and too much sleep can be as problematic as too little sleep.
The first-line treatment for chronic insomnia should be psychological and behavioral
therapies. Cognitive-behavioral therapies (CBTs) are effective, long-lasting
interventions for insomnia and considered the standard of care.
effective than pharmacotherapy for sleep onset latency and sleep efficiency.
sleep benefits of these interventions are not immediate and can take several weeks to
successfully implement. Results vary depending on the individual and their severity
34 Table 84-2 lists established cognitive and behavioral
interventions with brief descriptions in addition to important sleep hygiene strategies
to include in patient counseling.
Pharmacotherapy is indicated for a variety of reasons, including when nondrug
interventions fail or cannot be implemented, sleep
disturbances produce significant distress or impairment and immediate symptom
relief is required, patient preference is for drug therapy, or if insomnia is comorbid
with another medical, sleep, or psychiatric disorder.
treatment for insomnia from their healthcare provider when pharmacologic treatment
is warranted. Instead, alcohol or OTC sleep aids are used with unfavorable results
that can worsen insomnia or next-day functioning.
The ideal hypnotic has a rapid onset of effect (within 20 minutes, the natural time
to fall asleep), helps the patient sleep throughout the night, does not cause daytime
impairment, and carries no abuse potential. Currently, there are no ideal hypnotics.
Hypnotics that are benzodiazepine receptor agonists come closest to the ideal.
Available agents vary in onset, duration, and potential for daytime impairment,
mostly because of their individual pharmacokinetic profiles (Table 84-3).
selection of an appropriate hypnotic should consider the type of insomnia to be
treated and the physiologic characteristics of the patient. For example, if someone
cannot fall asleep but has no trouble staying asleep and wants to prevent next-day
carryover effects, a rapid-acting hypnotic with short half-life and no active
35,38,39 Age, sex, socioeconomic status, and comorbidities
also influence the hypnotic prescribed.
INSOMNIA IN A NORMALLY HEALTHY PATIENT
information should be obtained from P.B. to assist in the assessment of his sleep disturbance?
P.B. describes a circadian rhythm sleep–wake disorder, specifically sleep phase
syndrome related to a time-zone shift (previously referred to as “jet lag”). His major
complaint is difficulty falling asleep and awakening later than desired, because he
reports no trouble staying asleep or awakening too early. It is important for P.B. not
to be sedated during the day so that he can fulfill his job obligations. Additional
information needed from P.B. includes the duration of insomnia, methods already
tried to relieve insomnia and their efficacy, concomitant medications, coexisting
medical conditions or psychiatric disorders, alcohol use, caffeine use, and current
life stressor. P.B. should be advised that assessing all of the aforementioned
information is necessary in treating his sleep problem.
CASE 84-1, QUESTION 2: In response to your additional questions, you learn that P.B. has no medical
traveling; I don’t know why.” What factors could be contributing to P.B.’s complaints?
Several factors are contributing to P.B.’s type of sleep disorder. His circadian
rhythm has been disrupted because of travel, but he also takes a stimulating
decongestant (i.e., pseudoephedrine) and drinks a caffeine-containing beverages (i.e.,
average can of cola has about 35 mg of caffeine; PB consumes 35–70 mg/day). In
addition, he sleeps in new surroundings that may require time for adjustment. All
these factors can contribute to difficulty in falling asleep. Circadian rhythm sleep
disorder results from a mismatch between the sleep–wake schedule required by a
person’s environment and the circadian sleep–wake pattern.
An individual risk-versus-benefit assessment is essential before recommending
any medication, including OTC products. Although OTC products (i.e.,
antihistamines, melatonin, valerian, and other herbals) are commonly advertised as
sleep aids, data supporting the use of these products are limited. Antihistamines can
cause drowsiness and may help patients fall asleep. The ability to cause sedation
does not necessarily lead to hypnotic efficacy. Some patients do not feel well rested
the next day after taking an antihistamine, but instead feel slow, lethargic, and not
mentally sharp. This “hangover effect” can be significant and may be related to the
lipid solubility and central histaminic (H1
) and muscarinic blocking effects of the
35,41 Antihistamines with low lipid solubility (e.g., cetirizine,
loratadine) do not cross the blood–brain barrier readily and do not cause sedation.
Although diphenhydramine is the most common antihistamine found in
nonprescription sleep medications, some preparations contain the antihistamines
CASE 84-1, QUESTION 4: What additional counseling is needed for P.B.?
Tolerance can develop to the sedative effects of antihistamines after 3 to 7 days of
35,37–38,41 Because of a high incidence of daytime sedation and risk of
cognitive psychomotor impairment,
33 antihistamines are a poor choice for P.B., an
accountant who must stay alert and functional throughout the day. Any attempt to
manage P.B.’s sleep disorder should start with nonpharmacologic interventions
before initiating any drug therapy.
TIME-ZONE SHIFT: NONPHARMACOLOGIC TREATMENT VERSUS
TRIAZOLAM OR NONBENZODIAZEPINE RECEPTOR AGONISTS
CASE 84-1, QUESTION 5: P.B. asks whether he can try triazolam for the treatment of his sleep
disturbances. What would you recommend?
P.B. should be informed about the likely causes of his sleep disturbances (i.e.,
time-zone shift, caffeine-containing beverages, pseudoephedrine, new surroundings).
He also should understand that it may take 1 to 3 weeks for his system to readjust
42 The importance of nonpharmacologic interventions, particularly
those that pertain to reestablishing a desired sleep–wake cycle and sleep hygiene
education, to improve sleep (Table 84-2) should be emphasized. In addition, an hour
of bright light in the morning can serve as an environmental stimulus, normalizing the
Sedative-Hypnotic Agents FDA-Approved for Treatment of Insomnia
Healthy Half-Life Duration of Insomnia
Name) Adults Impairment (minutes) (hours) Action
1–2 0.5–1 60–120 10–24 Intermediate Sleep onset
7.5–30 7.5 60–120 3.5–18.4 Intermediate Sleep onset
0.125–0.25 0.125 15–30 1.5–5.5 Short Sleep onset
Nonbenzodiazepine Receptor Agonists
10–20 5–10 30 1 Short Sleep onset
d 5 30 1.4–4.5 Short Sleep onset
d 6.25 30 1.62–4.05 Intermediate Sleep onset
d 1.75 20–38 1.4–3.6 Short Middle-of-thenightawakening
d 5 30 1.57–6.73 Intermediate Sleep onset
d 5 10 2.7–3 Short Sleep onset
1–2 30 6 Intermediate Sleep onset
30 12 Intermediate Sleep onset
aDispense with a product-specific Medication Guide.
intermediate = 5 to 12 hours; long = >12 hours.
cHalf-life includes the parent compound and its active metabolites.
In women start with the lower dose.
eTo be dissolved under the tongue and not swallowed whole.
fFDA approved for short-term (7–10 consecutive days) treatment of insomnia.
gNot limited to short-term use.
hTake only if 4 hours remaining before planned wake time.
iTo be sprayed over the tongue immediately before bedtime
FDA, U.S. Food and Drug Administration; NR, Not recommended; ER, Extended-release.
Short-acting hypnotics (Table 84-3)
like triazolam are effective to induce
and regulate sleep if the stay will be relatively short (<5 days) and if critical
activities must be accomplished during the first 48 hours after arrival at the
42 Triazolam, indicated for difficulties with sleep latency, has a rapid
onset of sedative-hypnotic activity (within 15–30 minutes). Triazolam also has a
short half-life of approximately 1.5 hours that does not contribute to next-day
impairment at recommended doses (0.125–0.25 mg for healthy adults, 0.125 mg for
elderly). Women may be more susceptible to the adverse effects of hypnotics than
men, possibly due to greater oral bioavailability.
35,41 P.B. could ask his physician
to prescribe triazolam 0.125 mg, as needed. Disadvantages of benzodiazepines, and
triazolam in particular, include the impairment in new learning or anterograde
amnesia and the potential for complex sleep behaviors (e.g., eating, sleeping, driving,
or other activities while being asleep). These effects can interfere with daytime
functioning and result in the inability to remember new information learned on the
trip. P.B. should be cautioned regarding tolerance to the hypnosedative effects and
physiologic dependence that can occur with long-term use of a benzodiazepine and
the potential for rebound insomnia with abrupt discontinuation.
benzodiazepine receptor–active hypnotics, triazolam is most commonly associated
with rebound insomnia (i.e., daytime nervousness, jitteriness, and insomnia worse
than before) if abruptly stopped after more than 7 to 10 days of continuous use and
43–45 The pharmacologic properties of
benzodiazepines, including sedation, anterograde amnesia, antianxiety and
anticonvulsant activity, muscle relaxation, and ethanol potentiation, occur as a result
of interaction with various GABAA receptor subunits. The sedative effects of
benzodiazepines are primarily mediated via activity at the α1
45 Nonbenzodiazepine hypnotics (NBRA; also known as Z-hypnotics) such
as zaleplon, zolpidem, and eszopiclone have fewer reports of rebound insomnia and
anterograde amnesia at recommended doses due to selectivity for the α1
subunit and also lack significant anxiolytic and muscle relaxant effects compared
43 Also, triazolam’s short half-life and rapid decrease in blood levels
create the potential for withdrawal symptoms including anxiety and insomnia.
Triazolam is highly effective in inducing sleep when used on an as-needed basis.
Long-acting hypnotics, such as flurazepam, may prevent the traveler from awakening
in the morning and should be avoided.
CASE 84-1, QUESTION 6: P.B. would like to try melatonin for improved sleep but wonders whether it is
or other types of sleep disorders?
Melatonin is a naturally occurring hormone secreted by the pineal gland, located in
the center of the brain. The pineal gland is connected to the retina via a nerve
pathway that runs through the suprachiasmatic nucleus of the hypothalamus, the
body’s circadian clock. The pineal gland produces melatonin (a by-product of
serotonin metabolism) only during the nocturnal phase of the circadian cycle and only
in the presence of relative darkness.
Studies in adults show that melatonin has at least mild sleep-promoting properties
when administered before the period of natural increase in endogenous melatonin
(~10 PM to midnight). It causes significantly more sleepiness when taken at 8 PM
compared with 11:30 PM, theoretically because the brain’s receptors are already
saturated with melatonin late at night.
41,46 Doses between 0.5 and 5 mg taken close to
the target bedtime in the new time zone can decrease sleep disturbances. A
systematic review of 10 clinical trials showed melatonin was more effective for
travel eastward crossing multiple time zones.
46 Melatonin 0.5 to 10 mg has been
found effective for entraining the circadian rhythms in blind people, alleviating
insomnia in developmentally disabled, handicapped, or autistic spectrum children
and adults, and treating short-term, initial insomnia in children with attention deficit
hyperactivity disorder (ADHD).
41,46,47 The safety and effectiveness of melatonin for
long-term use or other sleep disorders has not been established. Consumers selecting
melatonin products over the counter should be advised the purity of melatonin is not
regulated by the FDA. Although doses of 0.5 to 5 mg melatonin are well tolerated,
side effects include sleepiness, headache, and nausea.
41,46,47 Melatonin use has been
associated with reports of depression, liver disease and vasoconstrictive,
immunologic, and contraceptive effects.
CASE 84-1, QUESTION 7: P.B.’s doctor gave him a prescription for ramelteon 8 mg at bedtime. How does
ramelteon compare with melatonin?
Ramelteon is a highly selective melatonin agonist at melatonin 1 and 2 receptors
(MT1, MT2). MT1 regulates sleepiness and MT2 adjusts circadian rhythms and
regulates phase shifts from day to night.
48,49 Ramelteon is approved by the FDA for
insomnia characterized by difficulty falling asleep. Clinical studies in primary
insomnia show it decreases the time to fall asleep by 10 to 19 minutes, and it
increases total sleep time by 8 to 22 minutes.
48–50 One controlled trial showed it was
superior to placebo in decreasing time to fall asleep during a 6-month period,
although ramelteon’s onset was 15 minutes faster than placebo after week one but
only 9 minutes faster at 6 months.
metabolism by cytochrome P-450 isoenzyme CYP1A2. Increases in serum
concentration occur even with mild liver disease, so caution is recommended for
patients who have at least moderate liver disease. Fluvoxamine is a strong inhibitor
of CYP1A2 and given with ramelteon dramatically increases its serum concentration.
Coadministration with fluvoxamine or any potent CYP1A2 inhibitors should be
avoided. The most common adverse events observed with ramelteon include
headache (7%), dizziness (5%), somnolence (5%), fatigue (4%), and nausea
In clinical trials, no evidence of cognitive impairment, rebound insomnia,
withdrawal effects, or abuse potential was demonstrated even at doses up to 20 times
51 These results were markedly different than the abuse
potential and side effects of triazolam at treatment doses and doses up to 3 times
48,49,52 Of note, no study has directly compared ramelteon and
another hypnotic for insomnia management.
52 Ramelteon is a reasonable option for
patients with initial insomnia with no abuse potential and little to no risk of next-day
NONBENZODIAZEPINE RECEPTOR AGONISTS (ZOLPIDEM,
daytime sedation, and can be administered safely for weeks to months if necessary?
Considering their rapid onset of action, NBRA medications (zaleplon, zolpidem,
and eszopiclone) are all potential alternatives for P.B. They have varying degrees of
-subunit on the GABAA receptor. This selectivity imparts
hypnotic efficacy with no significant anxiolytic, muscle relaxant, or anticonvulsant
effects. Consequently, NBRAs have a lower risk of abuse, withdrawal, and tolerance
compared with older nonselective benzodiazepines such as triazolam and
temazepam. These attributes make NBRAs more desirable for the treatment of
Zolpidem has been studied up to 12 months and was not associated with rebound
insomnia or withdrawal symptoms.
Additionally, eszopiclone was studied for 12 months of nightly administration and
found to be well tolerated with no tolerance observed.
54 Another potential advantage
-subunit selectivity is little to no change in sleep architecture or sleep
stages. Temazepam and flurazepam increase the percentage of stage 2 sleep but can
suppress REM and stage 3 and 4 deep restorative sleep. In contrast, NBRAs do not
interfere with these sleep stages and have lower rates of uncomfortable REM
rebound (vivid dreams, increased autonomic instability) on discontinuation.
The NBRAs differ with respect to pharmacokinetics and adverse events.
Zolpidem, the first NBRA, was marketed in the United States in 1991. It is absorbed
rapidly, reaches peak serum levels in 1.5 hours, and is eliminated rapidly with an
average half-life of approximately 2.5 hours.
42 For faster sleep onset, zolpidem
should be taken on an empty stomach for faster absorption. A food-effect study
demonstrated that administration of a zolpidem 10 mg tablet 20 minutes after a meal
resulted in a decrease in AUC and Cmax of 15% and 25%, respectively, and an
55 Zolpidem is metabolized by the
oxidative cytochrome P-450 isoenzyme CYP3A4; therefore, drug interactions should
be considered when zolpidem is coadministered with CYP3A4 inhibitors such as
diltiazem or fluoxetine. Zolpidem has no active metabolites, and it has a low risk of
residual daytime sedation in recommended doses.
38,43 Zolpidem controlled-release
(CR) has no clear advantage over zolpidem, except that it may provide a slightly
longer duration of sleep. Zolpidem CR is a bilayered tablet that has a first layer that
dissolves quickly to induce sleep and a second layer that releases zolpidem more
gradually to improve sleep maintenance. Serum concentrations peak in 2 hours
compared with 1.5 hours for immediate-release zolpidem, with an associated longer
39 Of note, zolpidem has been approved as oral spray to help with
sleep onset. Due to buccal absorption, it has a rapid-onset of action of 10 minutes.
In 2013, the FDA approved a new label change and dosing for zolpidem products to
recommend avoiding driving the day after using zolpidem controlled-release. Also,
gender metabolism differences exist where women metabolize zolpidem slower than
men, resulting in blood levels nearly two-fold higher. As a result, in women or the
elderly, the recommended starting dose is 5 mg zolpidem immediate-release or 6.25
57 For P.B., though the usual adult dose in males for
zolpidem immediate-release is 10 mg at bedtime, women, elderly, or patients such as
P.B, who express concern that a medicine may be too strong, should begin with 5 mg
Zaleplon offers a shorter elimination half-life (approximately 1 hour) and duration
of effect than zolpidem (see Table 84-3). It is least likely of all hypnotic agents to
cause residual daytime sedation and has the least effect on memory and psychomotor
performance. An assessment of psychomotor performance, arousal, memory, and
cognitive functioning with zaleplon revealed no cognitive impairment.
common adverse effects with zaleplon include dizziness, headache, and
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