There was a significant difference in percent change in improved sleep onset latency
(CBT 52%, combination therapies 52%, zolpidem 14%, placebo 17%). No
significant differences were found among the groups in total sleep time. The authors
concluded that CBT, alone or in combination with pharmacotherapy, was more
effective than pharmacotherapy alone or placebo for the treatment of sleep onset
insomnia. Avoidance of medications with their associated costs, adverse effects, and
drug interactions is the primary advantage of CBT. Disadvantages of CBT include
possible longer time to effective treatment, higher initial cost, and relative paucity of
trained providers in many areas.
CASE 84-4, QUESTION 4: What are the concerns about the use of lorazepam or another benzodiazepine in
Specific concerns need to be addressed about the risks most associated with
benzodiazepines in the elderly regarding dependence, risk of falls, cognitive dulling,
and memory loss. Concern about dependence and the nontherapeutic use of
benzodiazepines has been an important factor in limiting the long-term treatment of
In insomnia patients specifically, the risks of
dependence and recreational use of benzodiazepines are relatively low. Dose
escalation appears to occur only when treatment is ineffective, or when the patient
has a history of substance abuse or anxiety. Although still controversial, the risk of
dependence and abuse associated with the newer nonbenzodiazepine drugs may be
lower than that associated with benzodiazepine hypnotic drugs. An even greater
concern with benzodiazepine use in the elderly is the risk of falls and subsequent hip
fractures. Using 42 months of Medicaid healthcare claims data in New Jersey for
more than 125,000 individuals older than 65 years, the association of hip fractures
and benzodiazepine use was evaluated.
90 Compared with not being exposed to a
benzodiazepine, exposure to any benzodiazepine was associated with a 54% higher
rate of hip fracture, and after adjusting for potential confounding variables,
benzodiazepine use was associated with a 24% higher rate of hip fracture. Use of
short half-life benzodiazepines was found to be no safer than use of long half-life
benzodiazepines, and the risk of hip fracture was highest during the first 2 weeks
after starting a benzodiazepine. These findings support the usual recommendation
that the elderly should be given lower doses than their younger adult counterparts, but
they challenge the suggestion that only long half-life drugs should be avoided in the
elderly owing to clearance concerns. Elderly patients should also be monitored
closely to prevent cognitive decline caused by benzodiazepines and avoid use when
CASE 84-4, QUESTION 5: What are the concerns about the use of diphenhydramine in S.D.?
Sedating antihistamines are not recommended for treating insomnia in the elderly,
as there is no evidence of sustained benefit and they pose significant risk of
anticholinergic effects, notably cognitive impairment, dry mouth, urinary retention,
36,88,92 Duration of sedative effect efficacy from antihistamines is
also problematic with tolerance to sedative effects developing quickly (3–7
S.D.’s primary sleep complaint is related to his nocturia. He is self-treating his
urinary symptoms with saw palmetto, which he did not mention at his ED visit
(perhaps because no one asked whether he used any OTC or herbal medications). His
primary treatment, therefore, must be directed at assessing and more successfully
treating his nocturia. S.D. also likely experienced lorazepam withdrawal symptoms.
The many potential risks associated with benzodiazepines in the elderly led to a
valid decision to discontinue lorazepam. The choice of diphenhydramine was poor,
however, not only because of limited short-term efficacy but also because of its
potential to worsen both urinary symptoms and memory impairment. Clinicians must
ask patients about OTC and herbal medications they may be using to self-treat their
symptoms. The best treatment of sleep complaints in elderly persons is to identify any
underlying treatable cause, review and identify any sleep hygiene issues, and avoid
using benzodiazepines or sedating antihistamines, whose risks often outweigh any
Typical sleep need in children varies from 12 to 14 hours in children 1 to 3 years of
age to between 8.5 and 9.5 hours in adolescents.
95 All major sleep disorders can
occur in youth, and therefore evaluation for insomnia, RLS, PLMS, sleep apnea, and
narcolepsy are needed whenever symptoms warrant. Trouble initiating and
maintaining sleep are more common in children with ADHD (25%–50%) and autism
spectrum disorders (44%–83%). Of infants and toddlers, 10% to 30% have bedtime
sleep resistance that can be managed behaviorally with parental education.
Inconsistent bedtime, falling asleep away from bed, fears, and psychiatric and
medical conditions can all contribute to poor sleep in children.
At least 5% to 10% of high school students have delayed sleep phase syndrome, a
physiologic condition in which they do not fall asleep until between 1 and 3 AM and
they awaken between 9 AM and noon. School schedules dictate earlier awakening,
resulting in chronic sleep deprivation. Poll data indicate that 28% of high school
students fall asleep in school at least once a week, and 14% are late or miss school
Behavioral interventions to promote good sleep habits (e.g., consistent bedtime
and wake-time, before-bedtime ritual) should be initiated during childhood and
continued throughout adolescence to promote a lifetime of healthy sleep. No
hypnotics are FDA-approved for insomnia in children and adolescents, and
significant data are lacking to guide clinicians on medications to improve sleep in
youth. Diphenhydramine, clonidine and melatonin are commonly used in children and
some adolescents; however, the use of Z-hypnotics is also increasing, although this
class has not been well studied in this population.
Pregnant women have insomnia symptoms more often than their nonpregnant
counterparts, and many ingest hypnotic or sedating medications. Despite frequent
usage of hypnotics, healthcare providers are often reluctant to prescribe medications
to pregnant woman for fear of teratogenicity. Doxylamine is FDA pregnancy category
A, though this indication derived from the treatment of hyperemesis gravidarum and
97 Diphenhydramine is in FDA pregnancy category B and is generally
considered the safest sleeping medication in pregnancy.
woman should only use it on an as-needed basis. Sedating antihistamines are not
compatible with breast-feeding as they have the potential to dry up milk supply due to
99 Melatonin, ramelteon, and suvorexant should not be used
because of unknown risks to the fetus.
Regarding the most commonly prescribed hypnotic, zolpidem, The American
Academy of Pediatrics considers zolpidem compatible with breast-feeding, but the
risk versus benefit should be considered on an individual basis.
98,99 Other Zhypnotics do not have sufficient data in pregnancy and lactation to make
Benzodiazepine hypnotics are pregnancy category D or X. They should be avoided
in pregnancy due to the risk of respiratory depression, neonatal flaccidity, and
feeding difficulties if given in the second and third trimester and the controversial
risk of cleft palate if benzodiazepines are given in the first trimester.
Benzodiazepines are not recommended in breast-feeding as the risks outweigh
pounds, body mass index 29.8 kg/m
) and has developed hypertension. E.S.’s current BP reading is 145/92 mm
Hg. Medications include lisinopril 10 mg and aspirin 81 mg both taken in the morning.
evaluated in a sleep laboratory?
E.S. reports diminished sleep quality, excessive snoring, gasping for air, and
weight gain. Although a number of causes could be responsible for E.S.’s symptoms,
one of the most serious is sleep apnea. OSA is a neurologic disorder characterized
but no cessation of breathing, it is termed hypopnea. The brain responds to episodes
of apnea and hypopnea with mini-arousals, waking the individual to stimulate
101,102 These frequent mini-arousals prevent the individual from obtaining
quality sleep by not allowing sufficient time in deep, slow-wave sleep, or REM.
Obstructive sleep apnea (OSA), the most common type, may be induced when extra
body weight (note E.S.’s weight gain) places pressure on the throat and uvula,
narrowing the space into which air must travel; this results in the difficulty or
cessation of breathing and excessive snoring. An estimated 3% to 7% of men and 2%
to 5% of women meet the criteria for OSA.
The apnea/hypopnea index (AHI), measured using polysomnography (i.e., EEG,
electrooculogram, electromyogram), represents the number of episodes per hour. The
AHI score accompanied by symptoms of excessive daytime sleepiness is used to
diagnose OSA as follows: >5 to 14 (mild), 15 to 29 (moderate), and >30 (severe).
Risk factor for OSA includes age 65 years and older, obesity (BMI >30), male
gender, craniofacial anatomy that alters mechanical and neural properties of the
upper airway, genetic predisposition, cigarette smoking, alcohol consumption before
sleep, and comorbid conditions such as hypertension, diabetes mellitus, polycystic
ovary syndrome, hypothyroidism, and pregnancy.
103 Hypertension and weight gain
may be contributing to E.S.’s sleep difficulty. Untreated OSA is associated with an
increased risk of hypertension, coronary artery disease, and cerebrovascular
104–106 Although sleep apnea occurs in approximately 5% of women and 15%
of men in the general population, it occurs in up to 40% of patients with
104 Treatment of OSA can improve BP control and lead to more restful
sleep. Of note, OSA also occurs in nonobese individuals and in all ages, including
103,105 Sleep-disordered breathing, including snoring, is a significant risk factor
for hypertension even in young individuals of normal weight.
Overnight evaluation by polysomnography in a sleep laboratory would confirm or
rule out sleep apnea and allow distinction between OSA and the less-common central
102,105 Central sleep apnea results when breathing repeatedly starts and
stops during sleep because the brain does not send proper signals to the muscles that
control breathing (i.e., the diaphragm does not move in attempts to take in air).
Treatment of central sleep apnea requires continuous positive airway pressure
(CPAP) as opposed to being alleviated through weight loss or anatomic
manipulations. Central sleep apnea can occur along with OSA.
CASE 84-6, QUESTION 2: Results from the sleep laboratory study clearly document E.S.’s sleep problem
Why should E.S.’s sleeping difficulties not be treated with a hypnotic medication?
Hypnotics, alcohol, or any CNS depressant can be lethal for patients with sleep
laboratory study may have saved E.S. from a potential life-threatening breathing
disorder that could have been exacerbated by a hypnotic with CNS depressant
OSA can be treated by tracheostomy, nasal surgery, tonsillectomy,
uvulopalatopharyngoplasty, and either nasally or orally administered continuous
positive airway pressure CPAP.
98 Weight loss and CPAP therapy are the most
effective treatments and must be maintained for continued therapeutic efficacy.
In CPAP, the patient wears a lightweight mask to bed each night, and a constant flow
of air is provided mechanically to prevent breathing cessation and to allow for more
restful sleep. Although CPAP is effective for both OSA and central sleep apnea, the
results are short-lived, and apneic episodes typically reappear when CPAP therapy
is stopped. Preliminary studies in individuals with nocturnal bradycardia and sleep
apnea show that insertion of a permanent cardiac pacemaker significantly improved
106 At this time, the best treatment for E.S.’s
hypertension and sleep apnea is weight loss and CPAP.
ineffective or impractical, what drug treatments are potentially effective for E.S.’s sleep apnea?
agents are best used as an adjunct to nightly CPAP usage and morning administration
of modafinil 200 to 400 mg or armodafinil 150 to 200 mg.
dated evidence from the 1980’s suggesting benefit by improving patients AHI, but it
is not FDA-approved and has only been used in small numbers of patients with sleep
Narcolepsy is an incurable neurologic disorder characterized by irrepressible sleep
attacks typically occurring 3 to 5 times a day. These sleep attacks can intrude at any
time during the individual’s waking state. Narcolepsy may be present with or without
cataplexy, although cataplexy is present in 60% to 90% of patients.
the loss of muscle tone in the face or limb muscles and often is induced by emotions
or laughter. Cataplexy can be subtle, with the patient limp and not moving, or
dramatic, in which the patient collapses to the floor.
and sleep paralysis are other secondary symptoms not present in all persons with
narcolepsy. Hypnagogic hallucinations are perceptual disturbances (i.e., auditory,
visual, tactile) that occur while experiencing a sleep attack. The patient may see
imaginary objects, hear sounds, or feel sensations. Sleep paralysis is a terrifying
experience that can occur when falling asleep or when awakening and can last
several minutes. Patients are unable to move their limbs, to speak, or even to breathe
deeply. Narcoleptics learn, however, that sleep paralysis episodes are benign and
brief (lasting <10 minutes). Between 10% and 20% of patients experience the tetrad
of symptoms that include EDS, cataplexy, hypnagogic hallucinations, and sleep
paralysis. Except for daytime sleepiness, these symptoms are thought to be
expressions or partial expressions of REM sleep.
Symptoms of narcolepsy often begin at puberty, but patients usually are not
diagnosed until years later, in their late teens or early 20s. Early symptoms consist of
excessive daytime sedation and poor sleep quality. The sleep cycle becomes
progressively more erratic with frequent bursts of REM and decreased regularity of
deep or slow-wave sleep. Polysomnography in a sleep laboratory is ideal to confirm
narcolepsy. Sleep architecture is notably different. Instead of the 90-minute delay
narcolepsy progress directly into REM sleep.
hypocretin 1 level of less than 110 pg/mL is also diagnostic for narcolepsy.
Postmortem brain studies of patients with narcolepsy show 85% to 95% decrease in
hypocretin-containing neurons.
An autoimmune response of unknown origin is thought to damage
hypocretin/orexin-secreting cells in the hypothalamus. Without functional
hypocretin/orexin cells, the sleep–wake cycle is disrupted. Hypocretin/orexin is also
involved in control of body weight, water balance, and temperature.
Optimal treatment of narcolepsy involves treating both sleep attacks and cataplexy.
Schedule II controlled substances, methylphenidate and dextroamphetamine, were the
first drugs used to treat narcolepsy, with 65% to 85% of patients deriving significant
improvements in wakefulness. Mixed amphetamine salts are also FDA-approved for
101 The mechanism of action of methylphenidate and amphetamines is
related to increasing neurotransmission of dopamine and norepinephrine. Modafinil,
a Schedule C-IV controlled substance, is an effective treatment with less abuse
potential. Its exact mode of action is not fully understood, but it is thought to increase
wakefulness through noradrenergic, adrenergic, histaminergic, GABA-modulating,
glutamatergic, and hypocretin/orexin-stimulating mechanisms.
dextroenantiomer of modafinil. Its therapeutic effect, side effect profile, half-life, and
abuse potential are similar to those for modafinil.
drugs decrease the number of sleep attacks, improve task performance, and increase
the time to fall asleep, but they cannot eliminate sleep attacks altogether. Research is
underway exploring the possible use of immunosuppression at the time of narcolepsy
onset. One hypothesis suggests that immunosuppression therapy during a period of
pathologic immune response could prevent or reduce damage to the hypocretin
system that otherwise would lead to the development of narcolepsy.
Cataplexy does not respond to psychostimulants or modafinil but may be lessened
with low doses of antidepressants. TCAs (imipramine and clomipramine) were the
first antidepressants used, but protriptyline, desipramine, and SSRIs (fluoxetine,
sertraline, and paroxetine) are also used.
101 SSRIs and protriptyline offer the
advantage of less daytime sedation, compared with tertiary TCAs. The effectiveness
evidence exists to recommend antidepressants as effective treatments for cataplexy,
given that most studies are small and uncontrolled.
however, that large-scale studies on such a rare disorder are difficult to conduct.
Antidepressants are not considered effective in decreasing sleep attacks.
Sodium oxybate (Xyrem), a salt form of the CNS depressant γ-hydroxybutyrate, is
FDA-approved for treatment of cataplexy and EDS in narcolepsy. Its therapeutic
effects are related to decreased REM, improved sleep consolidation, and increased
stage 3 and 4 slow-wave sleep.
101,112 Sodium oxybate must be administered twice
during the night while the patient is in bed to consolidate 6 to 8 hours of sleep. In two
randomized, double-blind, placebo-controlled trials, sodium oxybate 9 g/night (i.e.,
450 mg at bedtime, then 450 mg 2–4 hours later), but not 3 or 6 g/night, significantly
reduced the median frequency of cataplexy attacks by 69% in patients with
narcolepsy, whereas 4.5 to 9 g for 8 weeks significantly reduced the median
frequency of cataplexy attacks by 57% to 85% in a dose-related manner. Both trials
showed 6% to 30% reduction in EDS as measured on the Epworth Sleepiness Scale
and 20% to 43% reduction in daytime sleep attacks.
107 Because of a significant abuse
potential, sodium oxybate is a Schedule III controlled substance. It is only available
through restricted distribution, the Xyrem Success Program, which uses only one
central pharmacy in the United States for dispensing.
Mixed Amphetamine Salts and Fluoxetine
Anorexia, gastrointestinal complaints (abdominal pain, nausea, vomiting,
diarrhea), anxiety, irritability, insomnia, and headaches are common side effects of
101 Though rare, psychotic reactions can occur in narcoleptic patients
taking stimulants at any dose; however, psychosis generally resolves when the
stimulant is discontinued. Stimulants, even at high dosages (e.g., 80 mg
methylphenidate), usually do not bring a patient to a normal level of alertness, and
sometimes nocturnal sleep is disrupted. To prevent stimulant-induced insomnia,
doses should be taken before 3 PM. Tolerance to the therapeutic effects of stimulants
may, however, develop in some patients with narcolepsy.
allow the patient to recapture therapeutic benefit; however, many patients opt for an
increased stimulant dose instead. Exceeding maximal recommended doses of
stimulant significantly increases the risk of psychosis, substance abuse, psychiatric
hospitalization, tachyarrhythmia, and anorexia according to a case–control study in
116 patients with narcolepsy taking stimulants.
101,113 Seizures have also been
Fluoxetine may improve cataplexy, but it can worsen nocturnal insomnia and
contribute to restlessness, headache, nausea, and sexual side effects including
In addition, fluoxetine is a potent CYP2D6 inhibitor resulting in
114 G.B. should be monitored closely during the
initiation of fluoxetine therapy, and the amphetamine dose should be lowered by 30%
to 60% to minimize side effects and prevent toxicity. The optimal therapeutic dose of
fluoxetine to manage cataplexy has not been established, but low doses may be
effective and minimize the risk of side effects.
oxybate offer any advantage for G.B.?
Modafinil’s efficacy relative to other CNS stimulants has not been adequately
assessed in controlled clinical trials; however, it has less potential for insomnia and
adverse CNS reactions at recommended dosages between 200 and 400 mg/day
It also has less abuse potential compared with
stimulants and is a Schedule IV controlled substance. Headache was the only adverse
experience rated significantly higher than placebo in 283 patients taking the
recommended dose of either 200 or 400 mg/day of modafinil. Anorexia, nervousness,
restlessness, and pulse and BP increases are dose-related side effects to discuss
during counseling. The maximal tolerable single daily dose may
be 600 mg/day, because 800 mg/day produced increased BP and pulse in one
116 Gradual dosage titration improves tolerability. Armodafinil, an
active stereoisomer of modafinil, is effective at usual doses between 150 and 250
mg/day. It has a similar adverse effect profile as modafinil.
Improved daytime wakefulness is an advantage of sodium oxybate compared with
antidepressants. A controlled trial involving 278 patients showed an increase in
slow-wave sleep (stages 3 and 4) and decreased nightly sleep disruption in patients
taking sodium oxybate with modafinil compared with modafinil alone.
oxybate can be administered safely with stimulants and modafinil; however,
coadministration with other CNS depressants, including hypnotic medication, is
contraindicated because of the risk of respiratory depression.
CASE 84-7, QUESTION 3: What counseling should G.B. receive as he switches to modafinil and sodium
People taking modafinil should receive counseling regarding the potential for drug
interactions. Modafinil induces CYP3A4 metabolism primarily in the gut and inhibits
CYP2C19. Decreased levels of triazolam and ethinyl estradiol have been associated
with modafinil coadministration.
118 Enzyme inhibition may also occur. Modafinil’s
inhibition of CYP2C19 is the proposed mechanism behind modafinil-associated
119 Monitoring for drug interactions is crucial because modafinil
and armodafinil are increasingly used for other indications, including daytime
sleepiness associated with Parkinson disease, shift work, fibromyalgia, sleep apnea,
fatigue associated with multiple sclerosis, and ADHD.
Sodium oxybate should not be given to those with sleep-disordered breathing,
sleep apnea, or an alcohol or substance abuse disorder.
nausea, headache, dizziness, and enuresis. Safe coadministration of modafinil and
sodium oxybate has been described in clinical trials
side effects including panic, psychosis, depression, and new-onset suicidal ideation
123 The risk of serious side effects versus benefits in managing
cataplexy and nocturnal insomnia should be discussed with G.B. and his family.
Close monitoring, particularly during the first weeks and months of treatment and
when dosages are adjusted up or down, should be advised.
instructed how to properly administer sodium oxybate, drinking half the dose on an
empty stomach immediately before bedtime and then setting his alarm for 4 hours
later to take the midnocturnal dose.
Naps and Other Behavioral Interventions
CASE 84-7, QUESTION 4: The benefits, possible risks, and importance of regular physician assessment
Strategically timed 15- to 20-minute naps taken at lunch and then again at 5:30 PM
can be refreshing for patients with narcolepsy and increase their time between sleep
attacks. Narcolepsy support groups are available and may help G.B. better cope with
such a life-changing chronic illness. It also is important for G.B. to avoid alcohol and
to regulate his bedtime and wake-up time in the attempt to normalize his sleep
The authors acknowledge Julie A Dopheide and Glen L. Stimmel for their
contributions to this chapter in earlier editions.
A full list of references for this chapter can be found at
http://thepoint.lww.com/AT11e. Below are the key references and websites for this
chapter, with the corresponding reference number in this chapter found in parentheses
An American Academy of Sleep Medicine report. Sleep. 2006;29:1415. (32)
Morin CM et al. Chronic Insomnia. Lancet. 2012;379:1129. (37)
Moszczynski A et al. Neurobiological aspects of sleep physiology. Neuro Clin. 2012;30:963. (16)
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