TRIPASS XR تري باس

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

temperature changes.

1,15–17

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.

15–18

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

subcortical neurons.

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.

15,18–20

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

emergence of slow-wave sleep.

15,16,18 Opiate peptides (e.g., enkephalin, endorphin)

and GABA, an inhibitory neurotransmitter, also promote sleep.

15,21

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.

22,23

GABA-facilitating hypnotics, such as benzodiazepines, induce sleep and decrease

arousals between stages, providing more continuous stage 2 sleep.

18,22,24

Benzodiazepines, however, also may decrease stage 4 slow-wave sleep and

suppress REM, leading to REM sleep rebound on abrupt discontinuation.

15,22,24

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.

18,20

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

triggers REM sleep.

18

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.

Diagnosis

The International Classification of Sleep Disorders, Third Edition (ICSD-3)

25 and the

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5)

26 are

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.

INSOMNIA

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

daytime consequences.

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.

27

Chronic insomnia is also more common in individuals with high blood pressure,

breathing difficulties, gastrointestinal (GI) disorders, cancer, and chronic pain,

among other conditions.

27–29

Insomnia and excessive daytime sleepiness (EDS) in the

elderly are leading predictors of institutionalization.

30

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

sleep.

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.”

25

Patient Assessment

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.

31

p. 1764

p. 1765

Table 84-1

Classification of Sleep–Wake Disorders

26

Insomnia disorder: too little or unrestfulsleep; can have no identifiable underlying cause or be comorbid with a

medical condition or another sleep or mental disorder

Hypersomnolence disorder:sleeping too much or experiencing drowsiness at times when individualshould be

alert

Narcolepsy/hypocretin deficiency: characterized by EDS, regardless of the time of day resulting in suddenly

falling asleep; patients may also experience cataplexy, sleep paralysis, and hypnagogic hallucinations.

Breathing-related sleep disorders: most individuals with breathing problems that interfere with sleep experience

fragmented sleep and complain of daytime drowsiness

Obstructive sleep apnea hypopnea

Centralsleep apnea

Sleep-related hypoventilation

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

Sleep terror type: individuals cry out in apparent fear during the first part of the sleep cycle but do not awaken;

considered pathological only in adults

Sleep walking type: recurring sleepwalking, usually during the first part of the sleep cycle

1.

a.

b.

c.

d.

2.

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

Restless leg syndrome: individuals experience the need to move their legs during periods of inactivity, especially

at night; can lead to fragmented sleep and daytime drowsiness

Substance/medication-induced sleep disorder: can result in insomnia or hypersomnolence

Other specified, or unspecified, sleep disorder:sleep–wake disorders that do not meet criteria for any of the

above categories

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.

31

Table 84-2

Nonpharmacologic Treatments for Insomnia

32–34

Cognitive-behavioral therapy: focus is on modifying behavioral and cognitive factors that lead to and foster

sleep disturbances

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.

Sleep restriction: create “sleep debt” by limiting amount of time in bed to only the total number of hours

actually spent sleeping, then increasing time in bed as sleep efficiency improves.

Relaxation therapy: target physiologic hyperarousal resulting from stress and tension (e.g., meditation,

progressive tensing and relaxing of muscles, yoga, stretching).

Paradoxical intention: encourage patient to engage in most feared behavior, “staying awake,” to reduce

performance anxiety associated with falling asleep.

Sleep hygiene: not considered effective on its own; useful adjunctive treatment.

Avoid caffeine, stimulants, heavy meals, and alcohol at bedtime; exercise early in the day before dinner to

relieve stress and prime brain for sleep; turn the face of the clock away from view; establish a beforebedtime ritual; use the bedroom only for sleep and intimacy; make sure bedroom is dark, quiet,

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.

26

Nonpharmacologic Treatment

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.

32,33 They may be more

effective than pharmacotherapy for sleep onset latency and sleep efficiency.

34,35 The

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

and chronicity of insomnia.

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.

32

Pharmacologic Treatment

Pharmacotherapy is indicated for a variety of reasons, including when nondrug

interventions fail or cannot be implemented, sleep

p. 1765

p. 1766

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.

32 Patients often do not seek

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.

35–37

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.

35,38

Available agents vary in onset, duration, and potential for daytime impairment,

mostly because of their individual pharmacokinetic profiles (Table 84-3).

39 The

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

metabolites is desirable.

35,38,39 Age, sex, socioeconomic status, and comorbidities

also influence the hypnotic prescribed.

37–40

INSOMNIA IN A NORMALLY HEALTHY PATIENT

CASE 84-1

QUESTION 1: P.B., a 36-year-old man, is requesting a medication for treatment of his sleep disorder. He

returned to Boston, Massachusetts, from a month long business trip to California 2 days ago and is now having

difficulty falling asleep. When he initially arrived in California 4 weeks ago, he went to sleep immediately at 7

PM and awoke at 3 AM. His sleep pattern adjusted during his 4-week visit in California, but upon returning to

Boston, it now takes him 2 to 3 hours to fall asleep. He has difficulty awakening in the morning and, as a result,

sleeps past 9 AM. He needs to be able to wake-up by 6 AM and be alert during the day in his job as an

accountant.

What information provided by P.B. is important in the assessment of his sleep disorder? What additional

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

problems and takes no prescription medications. He has been taking pseudoephedrine at night for nasal

congestion since returning from California. He denies drinking alcoholic beverages and coffee but admits to

recently increasing his cola intake from infrequent consumption of 1 to 2 cans between lunch and bedtime to try

to stay awake. He denies a long history of sleep disorder, but adds, “I have not been able to sleep as well since

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.

NONPRESCRIPTION SLEEP AIDS

CASE 84-1, QUESTION 3: P.B. would like to purchase a nonprescription sleep medication. What would you

recommend?

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

antihistamine.

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

doxylamine or hydroxyzine.

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

continued use.

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

after traveling.

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

circadian rhythm.

42

If P.B.’s sleep disturbances persist despite adhering to cognitivebehavioral interventions, a prescription hypnotic may be necessary.

p. 1766

p. 1767

Table 84-3

Sedative-Hypnotic Agents FDA-Approved for Treatment of Insomnia

36–38,61

Generic

a

(Brand

Dose (mg)

Healthy Half-Life Duration of Insomnia

Elderly

Hepatic Onset

Name) Adults Impairment (minutes) (hours) Action

b Indication

Benzodiazepines

Estazolam

(generics)

1–2 0.5–1 60–120 10–24 Intermediate Sleep onset

and sleep

maintenance

f

Flurazepam

(generics)

15–30 NR 60–120 >100

c Long Sleep onset

and sleep

maintenance

f

Quazepam

(Doral,

generics)

7.5–15 NR 30–60 47–100

c Long Sleep onset

and Sleep

maintenance

f

Temazepam

(Restoril,

generics)

7.5–30 7.5 60–120 3.5–18.4 Intermediate Sleep onset

and sleep

maintenance

f

Triazolam

(Halcion,

generics)

0.125–0.25 0.125 15–30 1.5–5.5 Short Sleep onset

f

Nonbenzodiazepine Receptor Agonists

Zaleplon

(Sonata)

10–20 5–10 30 1 Short Sleep onset

f

Zolpidem

Oral tablet

(Ambien)

5–10

d 5 30 1.4–4.5 Short Sleep onset

f

ER oral tablet

(Ambien CR)

6.25–12.5

d 6.25 30 1.62–4.05 Intermediate Sleep onset

and sleep

maintenance

g

Sublingual

tablet

e

(Intermezzo)

1.75–3.5

d 1.75 20–38 1.4–3.6 Short Middle-of-thenightawakening

h

Sublingual

tablet

e

(Edluar)

5–10

d 5 30 1.57–6.73 Intermediate Sleep onset

f

Mucous

membrane

spray

(Zolpimist)

i

5–10

d 5 10 2.7–3 Short Sleep onset

f

Eszopiclone

(Lunesta)

1–3 (start with

1 in all

patients)

1–2 30 6 Intermediate Sleep onset

and sleep

maintenance

g

Melatonin Agonist

Ramelteon

(Rozerem)

8 8 30 1–5

c Short Sleep onset

g,j

Orexin Receptor Antagonists

Suvorexant

(Belsomra)

10–20 (5–10

with moderate

CYP3A4

inhibitor)

Elderly—Not

specified

Severe

hepatic

30 12 Intermediate Sleep onset

and

maintenance

g

dysfunction =

NR

Antidepressants

Doxepin

(Silenor)

6 3 30 15.3 (31

c

)

Intermediate Sleep

maintenance

g,j

aDispense with a product-specific Medication Guide.

bTime the patient feels the effects after a single dose; usually approximates half-life with multiple doses; individual

variability exists; and tolerance may develop with continued use, lessening the duration; short = 1 to 5 hours;

intermediate = 5 to 12 hours; long = >12 hours.

cHalf-life includes the parent compound and its active metabolites.

d

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

jNot a controlled substance.

FDA, U.S. Food and Drug Administration; NR, Not recommended; ER, Extended-release.

Short-acting hypnotics (Table 84-3)

35,38,41,43

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

destination.

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

p. 1767

p. 1768

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.

35,37,41 Of the

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

withdrawal problems, likely related to its high binding affinity at different gammaaminobutyric acid (GABA)A receptor subtypes.

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

-subunit of the GABAA

receptor.

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

-receptor

subunit and also lack significant anxiolytic and muscle relaxant effects compared

with triazolam.

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.

MELATONIN

CASE 84-1, QUESTION 6: P.B. would like to try melatonin for improved sleep but wonders whether it is

safe and effective. What information is available on the safety and efficacy of melatonin for circadian rhythm

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.

41,46

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.

41,46

RAMELTEON

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.

49

Its half-life ranges from 1 to 2.6 hours. The halflife of its active metabolite, M II, is 2 to 5 hours. Ramelteon undergoes hepatic

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

(3%).

49,50

In clinical trials, no evidence of cognitive impairment, rebound insomnia,

withdrawal effects, or abuse potential was demonstrated even at doses up to 20 times

the usual treatment dose.

51 These results were markedly different than the abuse

potential and side effects of triazolam at treatment doses and doses up to 3 times

higher than usual.

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

impairment.

NONBENZODIAZEPINE RECEPTOR AGONISTS (ZOLPIDEM,

ZALEPLON, AND ESZOPICLONE)

CASE 84-1, QUESTION 8: It has been a month since his return and P.B. continues to have difficulty falling

asleep. What alternative medications (aside from triazolam and ramelteon) offer rapid onset, have low risk of

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

selectivity for the α1

-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

chronic insomnia. Both zolpidem controlled-release and eszopiclone are FDAapproved for chronic insomnia and are effective for up to 3 to 6 months of therapy.

38

Zolpidem has been studied up to 12 months and was not associated with rebound

insomnia or withdrawal symptoms.

53

p. 1768

p. 1769

Additionally, eszopiclone was studied for 12 months of nightly administration and

found to be well tolerated with no tolerance observed.

54 Another potential advantage

of NBRAs α1

-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.

38,44

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

increase in the Tmax

from 1.4 to 2.2 hours.

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

latency to effect.

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.

56

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

mg zolpidem extended-release.

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

at bedtime.

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.

38,43 The most

common adverse effects with zaleplon include dizziness, headache, and

somnolence.

58