Behavioral and Pharmacologic Therapies For Chronic Insomnia in Adults - UpToDate

10/04/2020 Behavioral and pharmacologic therapies for chronic insomnia in adults - UpToDate
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Behavioral and pharmacologic therapies for chronic

insomnia in adults
Authors: Michael H Bonnet, PhD, Donna L Arand, PhD
Section Editor: Ruth Benca, MD, PhD
Deputy Editor: April F Eichler, MD, MPH
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Mar 2020. | This topic last updated: Jan 07, 2020.
INTRODUCTION
Insomnia was previously viewed as a sleep disturbance that was secondary to a medical condition,
psychiatric illness, sleep disorder, or medication, and would improve with treatment of the underlying
disorder [1]. However, evidence over the past 20 years indicates that this view is incorrect.
It is now recognized that insomnia is often an independent disorder [2,3]. Insomnia may occur in the
absence of coexisting conditions and, when coexisting conditions exist, may persist despite successful
treatment of the coexisting condition. Treatment directed at the insomnia and the comorbidity may be
necessary. Since insomnia can precipitate, exacerbate, or prolong comorbid conditions, treatment of
insomnia may improve comorbidities [4-6].
Behavioral and pharmacologic treatment of chronic insomnia is described in this topic review. The
definition, types, epidemiology, clinical features, consequences, and diagnostic evaluation of insomnia
are reviewed elsewhere. (See "Risk factors, comorbidities, and consequences of insomnia in adults"
and "Evaluation and diagnosis of insomnia in adults" and "Overview of the treatment of insomnia in
adults".)
GENERAL APPROACH
All patients with insomnia should receive therapy for any medical condition, psychiatric illness,
substance abuse, or sleep disorder that may be precipitating or exacerbating the insomnia (table 1).
They should also receive basic behavioral counseling about sleep hygiene (table 2) and stimulus
control (table 3). (See "Overview of the treatment of insomnia in adults", section on 'Initial assessment
and counseling'.)
For patients who continue to have insomnia that is sufficiently burdensome to warrant other
interventions, treatment options include behavioral therapy, medication, or both:
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● Behavioral therapies beyond sleep hygiene and stimulus control include relaxation, sleep
restriction therapy, cognitive therapy, and cognitive behavioral therapy for insomnia (CBT-I) [7].
These therapies are not available in all medical centers, but online variants have shown some
benefit. (See 'Behavioral therapy' below.)
● Approved medications used to treat insomnia include benzodiazepines, nonbenzodiazepine

sedatives, melatonin agonists, doxepin, and suvorexant, an orexin antagonist. (See 'Medications'
below.)
● Combination therapy involves initially prescribing both CBT-I and a medication (usually for six to
eight weeks), then tapering the medication off or to an as-needed schedule while continuing CBT-I
(see 'Combination therapy' below). The use of medication prior to the initiation of behavioral
therapy appears to be less effective [8].
The choice of treatment should be individualized according to the patient's values and preferences, the
availability of advanced behavioral therapies, the severity and impact of the insomnia, and the potential
benefits versus the risks, costs, and inconveniences. For most patients, we suggest CBT-I rather than
medication as initial therapy, recognizing that both approaches are effective in short-term studies, but
that medications have a higher risk of side effects and have been inadequately evaluated for use for
longer than a year. However, access to behavioral therapy may be limited in some regions and for
some patients groups. A preference for CBT-I or other behavioral therapies over medication as initial
therapy has been endorsed in clinical practice guidelines of the American Academy of Sleep Medicine
[9], the British Association for Psychopharmacology [10], the American College of Physicians [7,11],
and the European Sleep Research Society [12]. (See 'Society guideline links' below.)
Treatment decisions must also factor in the potential health risks of untreated chronic insomnia, which
include decreased quality of life, increased risk for psychiatric comorbidities and substance abuse,
decreased performance, and the association between chronic insomnia and risk of cardiovascular
morbidity and all-cause mortality. (See "Risk factors, comorbidities, and consequences of insomnia in
adults", section on 'Adverse outcomes'.)
In clinical practice, initial treatment typically involves sleep hygiene instruction and stimulus control
procedures. If follow-up indicates that further treatment is needed, then more formal CBT-I alone or in
combination with a medication may be used for six weeks. For patients who respond to therapy (ie,
report both improved sleep at night and improvement of daytime deficits), the medication can be
tapered or used as needed while continuing the CBT-I. Patients whose symptoms recur after
discontinuation of therapy may require re-evaluation for referral for polysomnography or additional CBT-
I, with or without pharmacologic therapy.
An exception to this approach is patients who have short-term insomnia due to a self-limited stressor;
such patients may benefit from short-term medication alone. (See "Overview of the treatment of
insomnia in adults", section on 'Approach to acute insomnia'.)
BEHAVIORAL THERAPY
Behavioral therapies for insomnia include sleep hygiene education, stimulus control, relaxation, sleep
restriction therapy, cognitive therapy, and cognitive behavioral therapy [7]. Patients whose insomnia has
been successfully treated by behavioral therapy are likely to report decreased daytime symptoms and
improvement of daytime function, quality of life, and comorbidities. Behavioral therapy is well tolerated
and has a low risk of adverse effects.
Behavioral therapy beyond an introduction to sleep hygiene and stimulus control is typically
implemented over a series of six to eight sessions. The evidence suggests that the success of the
therapy is related to the experience of the individual implementing it [13].
Sleep hygiene — Sleep hygiene refers to actions that tend to improve and maintain good sleep (table
2) [14]:
● Sleep as long as necessary to feel rested (usually seven to eight hours for adults) and then get out
of bed
● Maintain a regular sleep schedule, particularly a regular wake-up time in the morning
● Try not to force sleep
● Avoid caffeinated beverages after lunch
● Avoid alcohol near bedtime (eg, late afternoon and evening) [15,16]
● Avoid smoking or other nicotine intake, particularly during the evening [16]
● Adjust the bedroom environment as needed to decrease stimuli (eg, reduce ambient light, turn off
the television or radio)
● Avoid prolonged use of light-emitting screens (laptops, tablets, smartphones, ebooks) before
bedtime [17,18]
● Resolve concerns or worries before bedtime
● Exercise regularly for at least 20 minutes, preferably more than four to five hours prior to bedtime
[19,20]
● Avoid daytime naps, especially if they are longer than 20 to 30 minutes or occur late in the day
Sleep hygiene counseling alone has not been directly compared with no intervention or a sham
intervention. However, numerous clinical trials have used sleep hygiene counseling alone as the control
intervention and showed some improvement in sleep but less than that seen with pharmacotherapy or
cognitive behavioral therapy [21-23].
Stimulus control — Patients with insomnia may associate their bed and bedroom with the fear of not
sleeping or other arousing events, rather than the more pleasurable anticipation of sleep. The longer
one stays in bed trying to sleep, the stronger the association becomes. This perpetuates the difficulty
falling asleep.
Stimulus control therapy is a strategy whose purpose is to disrupt this association by enhancing the
likelihood of sleep (table 3) [24]. Patients should not go to bed until they are sleepy and should use the
bed primarily for sleep (and not for reading, watching television, eating, or worrying). They should not
spend more than 20 minutes in bed awake. If they are awake after 20 minutes, they should leave the
bedroom and engage in a relaxing activity, such as reading or listening to soothing music. Patients
should not engage in activities that stimulate them or reward them for being awake in the middle of the
night, such as eating or watching television. In addition, they should not return to bed until they are tired
and feel ready to sleep. If they return to bed and still cannot sleep within 20 minutes, the process
should be repeated. An alarm should be set to wake the patient at the same time every morning,
including weekends. Daytime naps are not allowed.
Patients may not improve immediately. However, accumulating sleepiness will facilitate sleep during
successive nights.
Stimulus control therapy has improved sleep in randomized trials and its effects may be long lasting
[25-27]. One study suggested that stimulus control therapy is more effective among patients who are
not already taking medications for insomnia [28].
Relaxation — Relaxation therapy may be implemented before each sleep period. There are two
common techniques for relaxation therapy: progressive muscle relaxation and the relaxation response.
● Progressive relaxation is based upon the theory that an individual can learn to relax one muscle at
a time until the entire body is relaxed. Beginning with the muscles in the face, the muscles are
contracted gently for one to two seconds and then relaxed. This is repeated several times. The
same technique is used for other muscle groups, usually in the following sequence: jaw and neck,
upper arms, lower arms, fingers, chest, abdomen, buttocks, thighs, calves, and feet. This cycle is
repeated for approximately 45 minutes, if necessary.
● The relaxation response begins by lying or sitting comfortably. The eyes are closed and relaxation
is allowed to spread throughout the body. A relaxed, abdominal breathing pattern is established.
Thoughts are redirected away from everyday thoughts and toward a neutral mental focusing
device, such as a peaceful word or image.
One trial randomly assigned 57 patients with insomnia to receive progressive relaxation therapy or no
therapy [29]. Progressive relaxation therapy improved measures of sleep, but not daytime function.
Another randomized trial similarly found improvement in sleep measures among patients who received
relaxation therapy compared with a sham therapy, but the improvement was modest and smaller than
that achieved with cognitive behavioral therapy [30]. Slow-paced breathing prior to sleep onset as a
means of reducing vagal activity has been shown to improve sleep parameters [31].
Sleep restriction therapy — Some patients with insomnia stay in bed longer to try to make up for lost
sleep. This causes a circadian shift and a reduction in the homeostatic drive that makes sleep onset the
following night more difficult and results in the need to stay in bed even longer. Sleep restriction therapy
counteracts this tendency by limiting the total time allowed in bed, including naps and other sleep
periods outside of bed, in order to increase the drive to sleep [32]. This consolidates sleep and
improves sleep efficiency (the percentage of time in bed that the patient is asleep).
Sleep restriction therapy begins by decreasing the time spent in bed to the same amount of time that
the patient reports sleeping (usually determined from sleep diaries or logs completed by the patient),
but not less than five hours per night (table 4). On a daily basis, the patient reports the amount of sleep
obtained the previous night and the amount of time spent in bed. The clinician then computes the sleep
efficiency, which is the reported time asleep divided by the reported time in bed. The time in bed is
increased by 15 to 30 minutes once the sleep efficiency exceeds 85 percent. This process is repeated
until the patient reports improved sleep without residual daytime sleepiness. However, total time in bed
for some patients can remain at six hours or less for long periods of time. Naps are not permitted.
To improve compliance, the rationale for the therapy needs to be carefully explained to patients and
some close attention needs to be used to determine and schedule the time in bed in a manner that
maximizes the ability to sleep and is acceptable to the patient. Older patients tend to have more
difficulty maintaining sleep even when restricted; therefore, they are given more lenient criteria.
A 2014 systematic review identified four randomized trials of sleep restriction therapy as a stand-alone
therapy versus another intervention or control for chronic insomnia [33]. The weighted effect sizes for
improvement in subjective sleep variables were medium to large and comparable to those achieved
with cognitive behavioral interventions in other meta-analyses [34,35]. In the largest individual study,
179 older adults with primary insomnia were randomly assigned to six weeks of sleep restriction
therapy, stimulus control therapy, a multicomponent behavioral intervention, or wait-list control [36]. All
treatments resulted in significant improvements in diary-reported sleep outcomes compared with
control, and there was no advantage to a multicomponent intervention over a single component
intervention. Effect sizes were generally moderate to large and maintained at 3 and 12 months post-
treatment.
Potential adverse effects of sleep restriction therapy include increased daytime sleepiness and
decreased reaction times, as well as possible exacerbation of bipolar disorder. (See 'Adverse effects'
below.)
Cognitive therapy — Patients who are awake at night commonly become concerned that they will
perform poorly the next day if they do not obtain adequate sleep. This worry can exacerbate their
difficulty falling asleep, creating a vicious cycle of wakefulness and concern. A person may begin to
blame all negative events in their life on poor sleep. During cognitive therapy, a person works with a
therapist to deal with anxiety and catastrophic thinking, while establishing realistic expectations related
to insomnia and the need for sleep.
Cognitive behavioral therapy — Cognitive behavioral therapy for insomnia (CBT-I) is a strategy that
combines several of the previously described approaches over several weeks [37]. A sample eight-
session CBT-I program may include an introductory sleep education session, followed by two sessions
that focus on stimulus control and sleep restriction. These may be followed by two sessions that focus
on cognitive therapy and then a session on sleep hygiene. Finally, there may be a session that reviews
and integrates the previous session and a session that addresses future problems, such as stress and
relapse [38]. Patients are encouraged to complete sleep logs as they learn and apply the various
strategies. This allows improvement to be measured.
The advantage of the educational nature of CBT-I is that it provides patients with tools to apply in the
future. Disadvantages of CBT-I include the duration of therapy and the relatively few clinicians who are
skilled at all of its components. The benefit of CBT-I may be reduced when it is administered by less
experienced clinicians [13].
CBT-I has proven efficacious in moderate- to high-quality randomized trials [1,39,40]. A 2015 meta-
analysis identified 20 randomized trials of CBT-I for chronic insomnia in over 1100 participants; CBT-I
approaches incorporated at least three of the following: cognitive therapy, stimulus control, sleep
restriction, sleep hygiene, and relaxation [40]. Compared with inactive control conditions, CBT-I
improved sleep on a variety of outcome measures, including sleep onset latency (improved by 19
minutes), wake time after sleep onset (decreased by 26 minutes), and sleep efficiency (improved by 10
percent). The benefits of CBT-I appeared to persist beyond the active treatment period. Separate meta-
analyses of trials in patients with insomnia comorbid with medical, sleep, or psychiatric disorders have
found similar results [6,41,42].
Several randomized studies have suggested that alternative delivery methods such as telephone-based
CBT-I [43,44] and internet-based CBT-I [45-53] may be effective treatment options that could overcome
some of the access and economic barriers that exist for traditional CBT-I. As an example, one trial
enrolled 1711 patients with self-reported insomnia (out of nearly 10,000 screened) and randomly
assigned them to receive a six-session digital CBT-I program or a control condition (access to sleep
hygiene education material on the study website) [53]. Approximately half of patients in the intervention
arm completed all six sessions of digital CBT-I, and 20 percent did not complete any sessions.
Compared with controls in an intent-to-treat analysis, patients assigned to CBT-I showed greater
improvement in a range of self-reported health outcomes, including small improvements in functional
health and psychological well-being and larger gains in sleep-related quality of life and insomnia
symptoms. However, specific sleep data were not reported. Digital self-help approaches may be limited
by high attrition rates that average 25 percent [50].
A study comparing face-to-face and guided online CBT-I with a wait-list control has shown that both
delivery methods performed better than the wait-list control, but face-to-face CBT-I was associated with
larger treatment effects and better depression and anxiety outcomes than online delivery [54]. However,
fully automated online programs have been shown effective at improving sleep latency, wake after
sleep onset, and sleep efficiency in addition to reducing insomnia severity and may be a cost-effective
way of delivering care for some patients, while patients with more complex problems are directed to
face-to-face care. Online CBT-I programs that have peer-reviewed published support include SHUTi
(fee); Sleepio (fee), RESTORE (fee), and CBT-I Coach (free, developed by Department of Veterans
Affairs). A review of 12 insomnia therapy applications available for smartphones rated CBT-I Coach
highest overall for CBT-I components and usability [55].
A protocol for brief behavioral treatment of insomnia involving only four sessions has been developed
using primarily stimulus control and sleep restriction [56]. Brief behavioral treatment was effective for
reducing insomnia severity and subjective complaints in adults and older individuals [57,58].
CBT-I is particularly recommended for use in patients where medications are contraindicated or may be
more likely to produce side effects, such as in older adults, pregnant women, or patients with renal,
hepatic, or pulmonary disease.
Other behavioral approaches — Other behavioral therapies that may emerge as useful in the
treatment of insomnia include mindfulness meditation [59-62] and exercise training [63]. However, a
small randomized trial comparing tai chi with CBT-I in older adults found that CBT-I was associated with
greater and more sustained improvement in sleep quality, fatigue, and depressive symptoms than tai
chi [64].
Passive body heating for 10 minutes using a warm shower or bath 90 minutes before bedtime was
shown in a meta-analysis to reduce sleep onset latency and improve sleep efficiency but had no effect
on total sleep time [65].
Intensive sleep retraining is a novel procedure that involves bringing insomnia patients into a sleep
laboratory overnight, giving them continuing 25-minute sleep opportunities, and awakening them after
sleep begins in each session. The large number of sessions, seen as analogous to many stimulus
control sessions, may allow patients to reset their sleep process, and the sleep deprivation produced by
the procedure typically results in much improved sleep on the following night. In a randomized trial, an
episode of intensive sleep retraining was shown to have equal efficacy to stimulus control therapy at
reducing sleep latency, increasing sleep efficiency, and increasing total sleep time over a six-month
follow-up period [66].
Adverse effects — Adverse effects of behavioral therapy have not been well described, but one area
of caution relates to sleep restriction. Sleep restriction decreases sleep latency and increases sleep
efficiency by causing sleep deprivation (ie, total sleep time is decreased, not increased). In one study,
subjects reported increased sleepiness and had slower reaction times during a four-week treatment
period that then returned to baseline three months later, when time in bed had increased to about
seven hours [67]. These effects are similar to those seen during chronic partial sleep deprivation and
suggest that patients using this therapy should be carefully monitored and instructed to avoid
hazardous activity and driving when time in bed has been significantly reduced. Sleep restriction should
be used with caution in patients with underlying bipolar disorder, since sleep deprivation can trigger
manic episodes [68].
COMBINATION THERAPY
Combination therapy involves prescribing both cognitive behavioral therapy for insomnia (CBT-I) and a
medication, usually for six to eight weeks. The medication is then tapered off or changed to an as-
needed schedule, while continuing the CBT-I.
Two trials from the same investigators illustrate the effects of combination therapy:
● The first trial randomly assigned 78 patients with persistent insomnia to receive CBT-I alone,
temazepam alone, CBT-I plus temazepam, or placebo for eight weeks [69]. At the end of the
treatment phase, all of the therapies had significantly decreased the wake time after sleep onset
compared with placebo, although there were no significant differences when the treatment groups
were compared with each other. Two years following the completion of treatment, only the CBT-I
alone group had maintained its reduction in the wake time after initial sleep onset.
● The second trial randomly assigned 160 patients with persistent insomnia to receive CBT-I plus
zolpidem or CBT-I alone for six weeks [70]. Both groups had decreased sleep onset latency,
decreased wake time after sleep onset, and increased sleep efficiency when compared with
baseline after six weeks. However, there was no significant difference in the remission rate when
the groups were compared with each other (44 versus 39 percent). The patients then underwent
secondary randomization. Patients in the CBT-I alone group were randomly assigned to no
treatment or maintenance CBT-I, while patients in the CBT-I plus zolpidem group were randomly
assigned to either maintenance CBT-I or maintenance CBT-I plus as-needed zolpidem. The
improvement of sleep latency, wake time after sleep onset, and sleep efficiency was maintained in
all groups at 6, 12, and 24 months, with slight advantage to maintenance CBT-I without continued
use of zolpidem as needed [71].
Taken together, the evidence indicates that CBT-I alone, drug therapy alone, and combination therapy
all improve measures of insomnia (eg, wake time after sleep onset) within weeks of initiating the
therapy. Continuing CBT-I alone after the completion of initial therapy appears to be the best option for
maintaining improvement long-term. CBT-I also increases the likelihood that the medication can
eventually be tapered [72].
If sleep restriction therapy is combined with hypnotic medication, clinicians should be aware that the
combination of chronic partial sleep deprivation and medication hangover could significantly increase
daytime sleepiness and behavioral risk. (See 'Adverse effects' above.)
The evidence is insufficient to justify combination therapy as routine initial management for insomnia
patients. Many patients will improve with CBT-I alone, without pharmacologic therapy.
MEDICATIONS
Choice of an agent — Medications or classes of medications that are approved to treat insomnia
include benzodiazepines, nonbenzodiazepine hypnotics, melatonin agonists, doxepin, and suvorexant
[73,74]. Although all of these agents or classes have been shown to be more effective than placebo at
improving short-term sleep outcomes, the magnitude of effect is variable; most trials have been industry
sponsored, raising concerns about publication bias; and confidence in the overall estimation of risk-to-
benefit ratio is low [74]. The potential benefits of pharmacologic therapy on sleep quality and daytime
function are balanced against the risk of side effects as well as physical and psychological addiction
with long-term use. These risks may be increased in certain clinical settings:
● Pregnancy – Sedative-hypnotics may increase the risk of fetal malformations if used during the first
trimester.
● Alcohol consumption – Sedative-hypnotics should not be combined with alcohol because there is a
risk of excessive sedation and respiratory suppression whenever central nervous system
suppressants are combined.
● Renal or hepatic disease – Most sedative-hypnotic medications undergo hepatic and renal
clearance. Metabolic clearance may be delayed in patients who have renal or hepatic disease,
leading to accumulation and excessive sedation.
● Pulmonary disease or sleep apnea – Many sedative-hypnotics are respiratory suppressants that
can worsen obstructive sleep apnea or hypoventilation.
● Nighttime decision makers – Sedative-hypnotics should not be taken by individuals who may be
called upon to make important decisions during the night (eg, clinicians on-call or single parents
responsible for the care of young children) because they can cause excess sedation and impair
decision-making.
● Older adults – The risk of adverse effects is increased in older adults, especially those who are
older than 75 years. This is a consequence of multiple comorbidities and central nervous system
changes associated with aging. (See 'Older adults' below.)
Randomized trials directly comparing the effect of different medications on insomnia are rare. Indirect
comparisons of benzodiazepines and nonbenzodiazepines suggest that these classes of medication
have a similar impact on sleep onset latency (ie, they decrease objective sleep onset latency by
approximately 10 minutes and subjective sleep onset latency by 15 to 20 minutes) [75]. However, the
benzodiazepines are more likely to prolong total sleep time, perhaps because they tend to have longer
half-lives [75,76].
In one of the few trials that directly compared different medications, 382 patients with primary insomnia
received each of six interventions in random order for two nights each, with a three- to seven-day wash-
out period in between [77]. The agents included placebo, eszopiclone (1, 2, 2.5, and 3 mg), and
zolpidem (10 mg). Compared with placebo, eszopiclone at doses of 2.5 and 3 mg decreased the
median wake time after sleep onset, but zolpidem and eszopiclone at doses of 1 and 2 mg did not. The
wake time after sleep onset refers to the amount of time that the patient is awake between sleep onset
and the final morning arising time. There were no differences in any of the objective sleep outcomes
when eszopiclone (2 and 3 mg) and zolpidem were compared directly.
When selecting among various sedative-hypnotic medications, we suggest choosing on the basis of the
type of insomnia (ie, sleep onset or sleep maintenance) and the duration of effect:
● For patients with sleep onset insomnia, a relatively short-acting medication is a reasonable choice
for an initial trial of pharmacologic therapy. This may improve the insomnia with less residual
somnolence the following morning. Examples of short-acting medications (duration of effect ≤8
hours) include zaleplon, zolpidem, triazolam, and ramelteon.
● For patients with sleep maintenance insomnia, a longer-acting medication is preferable for an initial
trial of pharmacologic therapy. Examples of longer-acting medications include zolpidem extended
release, eszopiclone, temazepam, lorazepam, estazolam, low dose doxepin, and suvorexant.
However, longer-acting medications may increase the risk for hangover sedation.
● For patients with awakening in the middle of the night, both zaleplon and a specific sublingual
tablet form of zolpidem have been developed for use during the night, with the constraint that there
will be at least four hours of time in bed remaining after administration.
Other issues to be considered when prescribing a medication for insomnia include cost and adverse
effects. The benzodiazepines and older nonbenzodiazepines (specifically, zaleplon and zolpidem) tend
to be less expensive than the other nonbenzodiazepines and ramelteon. The adverse effects are
discussed below. (See 'Risks and side effects' below.)
Benzodiazepines — Benzodiazepines are a class of sleep promoting medications that bind to several
gamma-aminobutyric acid (GABA) type A receptor subtypes [78]. They reduce the time to the onset of
sleep, prolong stage 2 sleep, prolong total sleep time, and may slightly reduce the relative amount of
rapid eye movement (REM) sleep [79]. In addition, they decrease anxiety, impair memory, and have
anticonvulsive properties.
Benzodiazepines commonly used for the treatment of insomnia include triazolam, estazolam,
lorazepam, temazepam, flurazepam, and quazepam. A primary difference among these medications is
their duration of action. Triazolam is short acting; estazolam, lorazepam, and temazepam are
intermediate acting; flurazepam and quazepam are long acting (table 5A) [79]. Diazepam is also long
acting, but is generally not used to treat insomnia because it has a long duration of effect and can lead
to the accumulation of active metabolites. The long-acting benzodiazepines should be avoided in older
adults because there is increased risk for adverse effects in this patient population [80].
Meta-analyses of randomized, placebo-controlled trials indicate that benzodiazepines decrease sleep

latency and the number of awakenings, while improving sleep duration and sleep quality [75,76,81,82].
Typical changes associated with these medications include decreases in the duration to sleep onset by
approximately 10 minutes and increases in the total sleep time of 30 to 60 minutes [75,76].
The side effects of benzodiazepines are described below. (See 'Risks and side effects' below.)
Nonbenzodiazepines — Nonbenzodiazepine benzodiazepine receptor agonists have a structure that

is different from the benzodiazepines and includes more targeted action at one kind of GABA type A
receptor. A consequence of their greater specificity is less anxiolytic and anticonvulsant activity.
Nonbenzodiazepines appear to improve both subjective and objective sleep outcomes. Specifically,
meta-analyses of randomized, placebo-controlled trials indicate that nonbenzodiazepines decrease
sleep latency and the number of awakenings, while improving sleep duration and sleep quality
[73,75,76,81-83]. Nonbenzodiazepines have increased adverse events compared with placebo.
Nonbenzodiazepines commonly used to treat insomnia include zaleplon, zolpidem, eszopiclone, and
zolpidem extended release (table 5B):
● Zaleplon – Zaleplon has a very short half-life of about one hour. As a result, it is effective for
patients who have difficulty falling asleep (ie, sleep onset insomnia), but may not be effective for
patients who have difficulty maintaining sleep (ie, sleep maintenance insomnia) [84]. Due to the
very short half-life, the potential for hangover sleepiness is minimal after normal sleep periods.
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Occasional side effects include headache, dizziness, nausea, abdominal pain, and somnolence
[78]. Zaleplon is not indicated for long-term use.
● Zolpidem immediate release – Zolpidem has a half-life of approximately 1.4 to 4.5 hours. It is
indicated for the short-term treatment of insomnia characterized by difficulty with sleep initiation.
The most common side effects are headache, dizziness, and somnolence, which can in turn lead
to falls. Zolpidem is not approved for long-term use.
Zolpidem is also available in a dissolvable tablet and as an oral spray for patients who have
difficulty swallowing a pill. A dissolvable tablet (1.75 to 3.5 mg) can be taken in the middle of the
night for sleep maintenance insomnia, with the requirement that at least four hours be available to
sleep after administration and at least five hours be available prior to driving. In January of 2013,
the US Food and Drug Administration (FDA) issued a safety announcement recommending use of
a lower dose in women (5 mg for immediate release products, 1.75 mg for middle of the night
preparation) than had been previously recommended [85]. This should also be considered in men.
(See 'Dosing precautions' below.)
● Zolpidem extended release – Zolpidem extended release has a half-life of about 1.4 to 4 hours,
but is released over a longer duration. It was developed to improve both sleep onset insomnia and
sleep maintenance insomnia while avoiding hangover effects, although it has never been directly
compared with regular zolpidem [86]. Side effects of zolpidem extended release are relatively few,
with the most common being headache, somnolence, and dizziness, which can in turn lead to falls
[78]. In January of 2013, the FDA recommended use of a lower dose in women (6.25 mg) than had
been previously recommended [85]. This lower dose should also be considered for men. In a
follow-up safety announcement, the FDA added a warning that patients should not drive or engage
in other activities that require complete mental alertness the day after taking zolpidem extended
release because zolpidem levels can remain high enough the next day to impair these activities
[87].
Sleep may be worse during the first night following discontinuation of this medicine. Zolpidem
extended release is not limited to short-term use and there is little evidence for abuse or
dependence in most patients. In theory, however, such medications could be habit forming with
long-term use. (See 'Adverse effects of nonbenzodiazepines' below.)
● Eszopiclone – Eszopiclone has the longest half-life of the approved nonbenzodiazepines,

approximately six hours. This may extend to nine hours in older adult patients. Eszopiclone is
effective for both sleep onset insomnia and sleep maintenance insomnia [88,89]. Patients taking
eszopiclone may report an unpleasant metallic taste. Other reported side effects are shared with
nonbenzodiazepines as a class (headache, dizziness, parasomnias, next-day impairment in some
patients) [78,90]. (See 'Adverse effects of nonbenzodiazepines' below.)
Sleep may be worse on the first night after discontinuation of this medication. Eszopiclone is not
limited to short-term use and there is little evidence for abuse or dependence in most patients. In
theory, however, such medications could be habit forming with long-term use.
Most clinical trials evaluated short-term therapy (eg, seven days), although a few longer clinical trials
have been performed. In one randomized trial, patients treated with eszopiclone for six months had
improved quality of life, decreased work limitation, and improved sleep compared with placebo [91].
This persisted throughout the trial and the subsequent six month open label extension. In another
randomized trial of 1018 patients with insomnia, zolpidem extended release taken for up to six months
improved sleep onset, sleep maintenance, morning sleepiness, next-day concentration, and work
performance compared with placebo [92,93].
Adverse effects associated with the nonbenzodiazepines are similar to those associated with
benzodiazepines. This is discussed below. (See 'Risks and side effects' below.)
Melatonin agonists — Ramelteon is a melatonin agonist. In randomized trials, short-term use of

ramelteon is associated with improvement in sleep onset in patients with insomnia, but the effect size is
relatively small and may not be clinically significant [74].
A 2014 meta-analysis that included 11 trials and over 5700 patients found that ramelteon was
associated with significant improvement in subjective sleep latency (-4.6 minutes) and total sleep time
(7.3 minutes) compared with placebo but no significant difference in other parameters, including
subjective total sleep time, number of awakenings, and wakefulness after sleep onset [94]. Although
most studies examined short-term treatment and outcome in middle-aged adults [94], a small number
of individual trials have demonstrated persistence of subjective benefit for at least six months, and
improvement in older adults [95-99]. Subjective efficacy extended to one year in an open label trial
[100].
Although ramelteon is approved in the United States and Japan, the European Medicines Agency
(EMA) concluded in 2008 that there was inadequate evidence that the drug was effective for insomnia
[101]. It did not approve ramelteon for use. Tasimelteon is a second melatonin agonist that has been
approved in the United States for treatment of non-24-hour sleep-wake disorder (N24SWD), a circadian
sleep-wake rhythm disorder that occurs primarily in blind individuals [102,103]. (See "Non-24-hour
sleep-wake rhythm disorder".)
Ramelteon binds to melatonin receptors expressed in the suprachiasmatic nucleus with much higher
affinity than melatonin itself and has a half-life of 1.5 to 5 hours [104,105]. Ramelteon is metabolized by
the liver and should be used with caution in patients with hepatic insufficiency. It is contraindicated in
patients taking fluvoxamine, since fluvoxamine may decrease the metabolism of ramelteon [106].
Ramelteon is more effective in treating sleep onset insomnia compared with sleep maintenance
insomnia.
Adverse effects associated with melatonin agonists are generally milder than those associated with
benzodiazepines and nonbenzodiazepines. The most common adverse effect is somnolence. (See
'Adverse effects of melatonin agonists' below.)
Orexin receptor antagonists — Orexin receptor antagonists are a novel class of drugs in
development for the treatment of insomnia. Orexin A and orexin B are hypothalamic neuropeptides that
play a key role in promoting wakefulness and regulating the sleep-wake cycle [107]. Suvorexant, an
oral dual orexin receptor antagonist with a 12-hour half-life, was approved by the FDA in August 2014
[108], and a second drug, lemborexant, was approved in December 2019 but is not yet clinically
available [109].
The efficacy of suvorexant was demonstrated in a multicenter international trial of 781 patients with
primary insomnia who were randomly assigned to receive nightly suvorexant or placebo in a 2:1 ratio
for one year, followed by a two-month randomized discontinuation phase [110]. The dose of suvorexant
used was 40 mg for patients <65 years of age and 30 mg for patients ≥65 years. At one month, patients
treated with suvorexant had improved subjective total sleep time (39 versus 16 minutes; difference 23
minutes, 95% CI 16-29) and subjective time to sleep onset (-18 versus -8 minutes, 95% CI -15 to -5)
compared with placebo. Two-thirds of patients in each arm completed one year of treatment;
improvements in subjective sleep persisted at one year. The most common adverse effect was
somnolence, which was more common in patients treated with suvorexant than placebo (13 versus 3
percent). There was a trend toward rebound insomnia with discontinuation of suvorexant. A meta-
analysis of four trials including in 3076 patients (average age 56 years) with primary insomnia found
that suvorexant decreased subjective sleep latency by approximately 7 minutes at 1 and 3 months,
increased subjective sleep time by approximately 18 minutes at 1, 3, and 12 months, and improved
subjective sleep quality at 1, 3, and 12 months [111].
In next-day driving performance testing, some men and women treated with 20 mg of suvorexant had
impaired driving performance (5 out of 52 driving tests stopped early due to somnolence), and the FDA
has approved suvorexant at a maximum dose of 20 mg per night [108,112]. Treatment should be
initiated at the lowest dose (5 mg), so that the lowest effective dose can be determined. Suvorexant is
metabolized by cytochrome P450 3A4 (CYP3A4), and there is potential for increased toxicity when
used in combination with CYP3A4 inhibitors (table 6). The recommended dose of suvorexant is 5 mg in
patients taking moderate CYP3A4 inhibitors, and it is not recommended for use in combination with
strong CYP3A4 inhibitors. Due to the potential for dependence and abuse, it is a schedule C-IV
controlled substance. The most common side effect is daytime somnolence. Like other sedatives, it has
the potential to worsen sleep-disordered breathing in vulnerable patients. (See 'Adverse effects of
orexin antagonists' below.)
The role for this drug in the treatment of insomnia remains to be determined, as suvorexant and other
similar drugs in development have not yet been compared directly with other therapies for insomnia.
Another orexin receptor antagonist, almorexant, is also in development [113,114].
Other medications — Numerous other medications have a sedating effect, but are not recommended
for routine use in patients with insomnia. These include antidepressants, diphenhydramine,
antipsychotics, and barbiturates.
Antidepressants — One antidepressant, doxepin, has been approved by the FDA at doses of 3
and 6 mg primarily for the treatment of insomnia (table 5C). Other antidepressants (eg, amitriptyline,
trazodone) are sedating because of central anticholinergic or antihistaminergic activity. Such
antidepressants may be useful in the management of patients who have insomnia associated with
depression, although they are not approved by the FDA for treatment of insomnia.
Despite their modest sleep-promoting effects, the routine use of sedating antidepressants other than
low dose doxepin to treat insomnia in patients who are not depressed has not been recommended
because the sedating effect tends to be short-lived and other side effects are common [1,115,116]. The
American Academy of Sleep Medicine (AASM) practice guideline includes doxepin among the drugs
listed as options for management sleep maintenance in chronic insomnia but suggests against use of
trazodone based on paucity of data and the small effect sizes observed in a single randomized trial in
patients with primary insomnia [74].
A limited number of randomized trials have shown mixed results among adults with and without
comorbidities:
● Doxepin – In a trial that randomly assigned 240 older adult patients with insomnia to receive low
dose doxepin (1 or 3 mg) or placebo for 12 weeks, patients who received the 3 mg dose of doxepin
had a reduction of wake time after sleep onset, increased total sleep time, increased sleep
efficiency, and increased self-reported sleep quality when compared with placebo [117]. Patients
who received the 1 mg dose of doxepin had inconsistent improvement of some outcomes
measures at several time points.
● Trazodone – A systematic review identified seven randomized trials of trazodone in 429 patients
with insomnia using doses ranging from 50 to 150 mg nightly for one to four weeks [118].
Trazodone improved subjective sleep quality and number of awakenings but did not have an effect
on any other objective sleep measures compared with placebo. There was significant
heterogeneity in patient populations, and the overall quality of the evidence was rated as low to
moderate. In the largest trial, 306 nondepressed patients with insomnia were randomly assigned to
receive trazodone, zolpidem, or placebo for two weeks [119]. After one week of therapy, trazodone
improved subjective sleep latency, sleep duration, wake time after sleep onset, and number of
awakenings compared with placebo. However, after two weeks, the trazodone group did not differ
significantly from the placebo group.
Diphenhydramine — Many over-the-counter sleep aids contain diphenhydramine (a sedating

antihistamine) or a combination of diphenhydramine plus pain relievers. There is little evidence that
diphenhydramine improves insomnia and it may cause sedation the next day (due to its long half-life).
Additional side effects include decreased alertness, diminished cognitive function, delirium, dry mouth,
blurred vision, urinary retention, constipation, and increased intraocular pressure [1]. Routine use of
diphenhydramine to treat insomnia is not recommended [74].
Antipsychotics — Antipsychotics have been used to treat insomnia. However, there are few trials
that demonstrate effectiveness of these medications and all have potentially significant adverse effects.
The routine use of antipsychotics to treat insomnia in patients without psychosis is not recommended
[1].
Barbiturates — Barbiturates have similarly been used to treat insomnia. However, all have
potentially significant adverse effects. Routine use of barbiturates to treat insomnia is not
recommended [1].
Over-the-counter — Herbal products, hormones, and alcoholic beverages have been used as sleep
aids by patients with insomnia but there are sparse data upon which to evaluate their efficacy. These
agents are not regulated by the FDA.
● Herbal products – A variety of herbal products are purported to be useful for insomnia. There is
little evidence from randomized controlled trials about the efficacy of many herbals, however, and
for those that have been well studied (eg, valerian), there is little evidence of benefit. A meta-
analysis that included 14 randomized trials in over 1600 patients found no significant difference
between any herbal medicine and placebo on any of 13 clinical efficacy measures of insomnia
[120]. The majority of the trials (11 out of 14) studied valerian; chamomile, kava, and wuling were
studied in one trial each. Unlike the other herbals studied, valerian was associated with a greater
number of adverse events per person compared with placebo. Valerian may also produce
hepatotoxic effects [1]. Contamination with undesirable substances poses a problem for many such
natural remedies. (See "Overview of herbal medicine and dietary supplements".)
● Melatonin – Melatonin is a hormone that is normally secreted by the pineal gland. It is not
recommended as a treatment for insomnia in most patients [74], except when sleep disturbances
are due to delayed sleep-wake phase syndrome (a circadian sleep-wake rhythm disorder) or in
patients with low levels of endogenous melatonin, such as in aging [1,74,121-126]. It appears to be
safe when used short-term (three months or less) [123]. (See "Delayed sleep-wake phase
disorder", section on 'Management'.)
● Alcohol – Alcohol is commonly self-prescribed as a sleep aid because it decreases the time
required to fall asleep, at least in the short-term. However, alcohol can promote sleep disturbances
later in the night and promotes upper airway instability and sleep apnea. These negative effects,
coupled with the significant risk of dependence and interaction with other medications, preclude the
use of alcohol to treat insomnia [127]. (See "Insomnia in patients with a substance use disorder",
section on 'Alcohol'.)
Placebo effect — A meta-analysis of the use of true placebo (with participants who were unaware
that they might receive a placebo) versus no treatment for insomnia included 13 studies with 566
patients [128]. Statistically significant decreases in subjective sleep onset latency and increases in
subjective total sleep time and sleep quality indicative of small to moderate effect size were found.
There were no significant effects for objective sleep parameters.
Risks and side effects
Common to all hypnotics — The most common adverse effects associated with the
benzodiazepines and nonbenzodiazepines are residual daytime sedation, drowsiness, dizziness,
lightheadedness, cognitive impairment, motor incoordination, and dependence [1,75,76,81]. In addition,
most hypnotics are respiratory suppressants that can worsen obstructive sleep apnea or
hypoventilation.
Risks are increased if hypnotics are combined with other central nervous system depressant drugs or
alcohol. A formal boxed warning from the FDA warns about serious risks and death from the
combination of opioid pain or cough medicines with benzodiazepines and recommends limiting
combined use to patients in whom alternative treatment options are inadequate. The FDA has also
warned about the use of opioid addiction medications (methadone and buprenorphine) in combination
with benzodiazepines and recommends limiting doses or considering other treatment options for
insomnia.
Long-term use of hypnotics may be habit forming, and rebound insomnia may occur when some short-
acting medications are discontinued. Less common adverse effects include complex sleep-related
behaviors (eg, sleep walking, driving, making telephone calls, eating, or having sex while not fully
awake), anterograde amnesia (particularly with triazolam or when used with alcohol), aggressive
behavior, and severe allergic reaction [79,129]. Lethal overdose is possible [130], particularly with
concurrent use of alcohol or another central nervous system depressant. (See 'Suicide risk' below.)
The incidence of infection (eg, upper respiratory, otitis media, urinary tract, conjunctivitis, others) may
be increased among patients taking a nonbenzodiazepine, according to one meta-analysis [131]. Two
subsequent studies, one in humans and one in mice, have also reported an increased risk of
pneumonia associated with benzodiazepines and the nonbenzodiazepine zopiclone, possibly related to
modification of GABA type A activity during infection [132,133]. A study in mice suggested that this risk
could extend to all hypnotics that act at this site [133].
Adverse effects of nonbenzodiazepines — The adverse effects of nonbenzodiazepine hypnotics

are generally similar to those associated with the benzodiazepines. However, risks of complex sleep-
related behaviors and next-morning impairment have been increasingly recognized, and
nonbenzodiazepines should not be considered any safer than other hypnotics per se. One study found
that zolpidem accounted for 12 percent of all emergency department visits for adverse drug events
related to psychiatric medication in the United States over the period of 2009 to 2011, and 21 percent of
all such visits involving adults ≥65 years of age [134].
Complex sleep-related behaviors — Complex sleep-related behaviors, including sleepwalking,

sleep driving, eating, and other behaviors performed while not fully awake, can occur in patients taking
nonbenzodiazepines. These events appear to be more common with zolpidem, zaleplon, and
eszopiclone than other medications used for sleep [135]. (See "Disorders of arousal from non-rapid eye
movement sleep in adults", section on 'Clinical features' and "Approach to abnormal movements and
behaviors during sleep".)
The incidence and risk factors for complex sleep-related behaviors are not well characterized. Across
studies, estimates for sleep-related behaviors of any severity related to nonbenzodiazepine hypnotics
range widely, from 3 to 25 percent [136-139]. While most events are non-serious, rare cases of injury
and even death have been described via mechanisms such as accidental overdose, motor vehicle
crash, and drowning. Higher dose appears to be a risk factor for complex sleep-related behaviors,
although in at least one study, higher doses were associated with risk in younger adults but not older
adults [136].
In 2019, the FDA identified 66 reports of serious injury or death ascribed to nonbenzodiazepines in the
medical literature and submitted through safety monitoring over a 26-year period [135]. A boxed
warning on the risk of rare but serious complex sleep-related behaviors was added to all formulations of
zolpidem, zaleplon, and eszopiclone, along with the following information and guidance:
● These events can occur with just one dose of these medicines as well as after a longer duration of
treatment. Events have been reported both with and without prior alcohol or other central nervous
system depressant use. These events can occur without a prior history of such events.
● Eszopiclone, zaleplon, and zolpidem are contraindicated in patients who report an episode of
complex sleep behavior after taking these insomnia medicines.
● Tell patients to discontinue their insomnia medicine if they experience an episode of complex sleep
behavior even if it did not result in a serious injury.
● When starting patients on eszopiclone, zaleplon, or zolpidem, follow the dosing recommendations
in the prescribing information and start with the lowest possible dose.
Dosing precautions — There has been increasing recognition that variability in

nonbenzodiazepine metabolism may affect next-morning drug levels and side effects, especially among
older adults and women. The safety announcements reviewed below suggest that clinicians should
have increased sensitivity to next-day residual effects when prescribing any of the drugs in this class
and should educate patients accordingly.
Importantly, despite these warnings, a large database study in the United States found that in the year
2015 among 3.8 million zolpidem users, 64 percent of older adults and 68 percent of women reported
taking higher than the recommended dose of zolpidem [140]. In addition, 41 percent of patients taking
zolpidem reported concurrent sustained use of one or more other central nervous system depressants
(eg, opioids, benzodiazepines).
● In 2013, the FDA published a safety communication that the recommended dose for zolpidem be
set at the lowest dose (5 mg for all except zolpidem extended release, which is now 6.25 mg) for
women and also be considered for men [85]. In addition, a new warning was issued for zolpidem
extended release, advising that individuals refrain from driving or other activities that require
mental alertness the day after taking the drug [87]. These recommendations were based on
studies showing that blood levels of zolpidem above about 50 ng/mL appeared capable of
impairing driving sufficiently to increase the risk of an accident. This blood level was found in about
15 percent of women and 3 percent of men eight hours after administration of 10 mg of zolpidem.
Eight hours after use of the extended-release formulation of zolpidem, 33 percent of women and
25 percent of men still had this elevated blood level.
Additional recommendations were not made for older adults, who have previously been advised to
use the lowest doses of these medications, but additional care is warranted for these patients.
(See 'Older adults' below.)
● In 2014, a similar safety communication was issued for eszopiclone, based on data that the 2 and
3 mg doses may be associated with impairment of driving skills, memory, and coordination lasting
more than 11 hours without subjective awareness in some patients [141]. A starting dose of 1 mg is
now recommended in all patients.
Adverse effects of melatonin agonists — Ramelteon has fewer side effects than the
nonbenzodiazepines or benzodiazepines [142]. It is not associated with hypnotic side effects (eg, next
day residual performance deficits), withdrawal, or rebound insomnia, and it does not appear to be habit
forming [99,142]. Ramelteon has little abuse potential and is not a scheduled substance with the United
States Drug Enforcement Administration (DEA), unlike most other drugs used to treat insomnia. The
most common side effects are somnolence, dizziness, nausea, fatigue, and headache [1,79]. Elevated
prolactin levels and decreased testosterone levels may occur, but routine monitoring of either is not
indicated in the absence of other clinical indications.
Adverse effects of orexin antagonists — The most common adverse effects of suvorexant are
daytime somnolence, fatigue, abnormal dreams, and headache [111]. A dose-response relationship
was found for adverse effects using 10 to 80 mg doses nightly in a small study [143]. As with other
hypnotics, next-day driving may be impaired due to the long half-life of the drug [144].
Other potential side effects include sleepwalking, REM sleep behavior disorder (RBD), suicidal ideation,
and the emergence of sleep paralysis, hypnogogic hallucinations, and mild cataplexy (as seen in
narcolepsy). Risk of RBD is likely highest in patients with Parkinson disease and other alpha-
synucleinopathies, which are known to be associated with RBD [145]. (See "Rapid eye movement
sleep behavior disorder".)
Suvorexant is metabolized by cytochrome P450 3A4 (CYP3A4), and there is potential for increased
toxicity when used in combination with CYP3A4 inhibitors (table 6).
Limited data suggest that suvorexant has relatively minor effects on the severity of sleep-disordered
breathing in vulnerable patients [146,147], although like other sedatives, it should be used cautiously in
these patients until there is more experience with the drug. In a sleep laboratory study, 26 patients with
mild to moderate obstructive sleep apnea were given 40 mg of suvorexant or placebo for four
consecutive nights in a crossover design, and the mean apnea-hypopnea index (AHI) increased by a
mean of 2.7 (95% CI 0.2-5.1) after multiple doses of suvorexant [147]. The AHI rose by ≥5 events per
hour in eight patients (range 5 to 20) and decreased by ≥5 events in three patients.
Older adults — Older adults have a particularly high risk of adverse effects from hypnotic drugs,
including excessive sedation, cognitive impairment, delirium, night wandering, agitation, postoperative
confusion, balance problems, and impaired performance of daily activities [148-150]. An increased risk
of falls with severe consequences, including traumatic brain injury and hip fracture, has been observed
in association with both benzodiazepines and nonbenzodiazepines such as zolpidem [149,151].
In a meta-analysis of 24 randomized trials (2417 patients) that evaluated the impact of

pharmacotherapy in adults older than 60 years with insomnia, there was an improvement of sleep
quality, total sleep time, and frequency of nighttime awakening [152]. However, the magnitude of these
benefits was relatively small compared with the two- to fivefold increase in adverse cognitive or
psychomotor events. This suggests that additional caution is necessary when deciding whether
pharmacotherapy is indicated for an older patient with insomnia.
Mortality — Several observational studies have found an association between use or prescription of
hypnotic drugs and all-cause mortality and/or cancer, with adjusted hazard ratios ranging from 1.1 to
4.5 [153-158]. The association has been observed in the general adult population [153-155,157,158],
postmenopausal women [156], and in patients with schizophrenia [159]. Other studies in older adults
have failed to find a significant association between hypnotic use and mortality after adjusting for
potential confounders [160-162].
One of the larger studies suggested that hypnotic drugs (including frequently prescribed agents such as
zolpidem and temazepam) were associated with an increased risk of both cancer and death, even at
prescription levels of less than 18 doses per year over a 2.5-year duration [153]. Another large
retrospective case-control study included over 34,000 patients age 16 years and older first prescribed
an anxiolytic or hypnotic drug or both between 1998 and 2001, matched by age, gender, and primary
care practice with nearly 70,000 controls [158]. Over an average follow-up period of 7.6 years,
prescription of anxiolytic and hypnotic drugs was associated with a twofold increased hazard of death
after adjusting for a wide range of potential confounders, including medical and psychiatric
comorbidities, sleep disorders, and other drugs. After excluding deaths during the first year of follow-up,
this effect translated to four excess deaths per 100 people followed over a seven-year period.
The associations found in these observational studies do not indicate causality, however. Chronic
insomnia has been associated with a variety of medical and psychiatric comorbidities, many of which
are associated with premature mortality, and it is difficult to exclude residual confounding by indication
or other unmeasured factors. A prospective investigation of long-term hypnotic use compared with
placebo and behavioral treatment is needed.
Suicide risk — Insomnia itself is associated with increased risk for suicide, which may be primarily
mediated by underlying depression [163].
A 2017 systematic review identified several retrospective and prospective observational studies
showing a positive association between suicidality and use of hypnotics but concluded that none of the
studies adequately controlled for depression or other psychiatric disorders that may be linked with
insomnia [164]. Other studies suggest that treating insomnia in patients with depression in some cases
hastens recovery from depression [4,165], and in other cases at least improves insomnia and next-day
functioning, if not necessarily impacting depression severity [166,167].
In the United States, most hypnotics carry warnings or cautions about suicide risk in patients with
depression. While not studied or validated formally, safe prescribing practices that may help to mitigate
risk of suicide and other risks include using the lowest possible effective dose to control symptoms,
avoiding concurrent use of alcohol and other sedatives, and regular follow-up to assess drug efficacy,
side effects, and ongoing need for medication (table 7) [164]. Patients with comorbid depression should
be assessed for suicidal ideation before prescribing hypnotics and if present, monitored closely while
considering other treatment options for insomnia. (See "Unipolar depression in adults: Assessment and
diagnosis", section on 'Suicide risk' and "Suicidal ideation and behavior in adults", section on 'Patient
evaluation'.)
Drug interactions — Concurrent use of any sleeping medication and alcohol (or another central
nervous system depressant) increases the risk of central nervous system depression and, therefore, is
contraindicated.
Most benzodiazepines (except lorazepam, oxazepam, and temazepam) and nonbenzodiazepines are
metabolized by the CYP3A4 system [79]. Inhibitors of the CYP3A4 system (eg, clarithromycin) increase
the risk of toxicity related to benzodiazepines and nonbenzodiazepines, while inducers of the CYP3A4
system (eg, rifampin) may decrease the effectiveness of benzodiazepines and nonbenzodiazepines.
Ramelteon is metabolized by the CYP1A2 system and, to a lesser extent, the CYP2C9 and CYP3A4
systems [79]. Fluvoxamine is a potent inhibitor of the CYP1A2 system and should not be used with
ramelteon because it markedly increases serum concentrations of ramelteon. Other inhibitors of the
CYP1A2 (eg, ciprofloxacin), CYP2C9, or CYP3A4 systems may also increase the risk of ramelteon
toxicity, while inducers of the CYP systems (eg, rifampin) may decrease the effectiveness of ramelteon.
Suvorexant is metabolized by the CYP3A system and should not be administered in combination with
strong inhibitors of CYP3A (eg, ketoconazole, many antiretroviral drugs) (table 6). Conversely,
suvorexant effects can be decreased when co-administered with strong CYP3A inducers (eg, rifampin,
carbamazepine, phenytoin).
OTHER STRATEGIES
Devices — Several devices are marketed direct to consumers for insomnia, but the available evidence
is insufficient to support their clinical utility. Clinicians and patients should be aware that medical
devices undergo a different regulatory approval process than medications, and clearance of a device by
the US Food and Drug Administration (FDA) should not be taken as proof of efficacy. Examples include
the following:
● A forehead device that applies a specified temperature to the skin was cleared by the FDA in 2016
for use in patients with primary insomnia [168]. The device clearance was based on a randomized
sham-controlled trial of the device in 116 adults with insomnia who were treated and monitored by
polysomnography for two nights [169]. There were no statistically significant differences in either of
the prespecified primary endpoints (latency to persistent sleep, sleep efficiency). A post-hoc
analysis showed a 12-minute reduction in the latency to stage 1 and stage 2 sleep, measures that
did not require sustained sleep. The clinical significance of this finding is unknown, and further data
are needed.
● A number of cranial electrical stimulation devices have been cleared by the FDA. Most versions
use a battery-operated device to deliver low-voltage alternating current to the brain via scalp
electrodes. Despite being available for many years and marketed for various conditions including
insomnia and chronic pain, there is insufficient evidence to determine efficacy. A 2018 systematic
review identified three trials of cranial electrical stimulation in patients with insomnia with conflicting
or inconclusive results [170].
Acupuncture — Acupuncture as a treatment for insomnia was assessed in a meta-analysis of 33

studies (n = 2293) that found insufficient evidence to support or refute acupuncture as an efficacious
treatment for insomnia [171]. A subsequent trial compared acupuncture with CBT-I in 160 cancer
survivors with insomnia, and both therapies resulted in significant improvement in insomnia severity
and similar improvements in fatigue, anxiety, depression, and quality of life [172]. However, CBT-I was
more effective in improving sleep latency, wake after sleep onset, and sleep quality. All improvements
were maintained at 12 weeks, but CBT-I was more effective across all measures.
FOLLOW-UP
If the treatment is successful, patients will report both improved sleep at night and improvement of
daytime deficits. Discontinuation of the medication should be considered in any patient who is receiving
pharmacologic therapy alone or combination therapy.
Patients who have little improvement during the initial trial of cognitive behavioral therapy,
pharmacologic therapy, or combination therapy may have other causes of poor sleep. Adherence with
the prescribed therapy should be confirmed and then additional diagnostic evaluation performed. Such
patients often require referral to a sleep disorders center to be evaluated for sleep apnea or other
underlying causes. Such an evaluation is indicated earlier (ie, prior to the failure of routine therapy) if
there is clinical suspicion that sleep apnea or another etiology exists. (See "Overview of the treatment
of insomnia in adults", section on 'Follow-up and monitoring'.)
SOCIETY GUIDELINE LINKS
Links to society and government-sponsored guidelines from selected countries and regions around the
world are provided separately. (See "Society guideline links: Insomnia in adults".)
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These articles
are best for patients who want a general overview and who prefer short, easy-to-read materials.
Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These
articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth
information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also locate patient education articles on a variety of
subjects by searching on "patient info" and the keyword(s) of interest.)
● Basics topic (see "Patient education: Insomnia (The Basics)")
● Beyond the Basics topics (see "Patient education: Insomnia (Beyond the Basics)" and "Patient
education: Insomnia treatments (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
● All patients with insomnia should receive therapy for any medical condition, psychiatric illness,
substance abuse, or sleep disorder that may be precipitating or exacerbating the insomnia. They
should also receive general behavioral suggestions, particularly advice regarding sleep hygiene
(table 2) and stimulus control (table 3). (See 'General approach' above.)
● Short-term insomnia (less than one month) usually results from psychologic or physiologic stress.
For patients with an identifiable trigger for acute insomnia, education and reassurance may be all
that is needed. When acute insomnia is severe or associated with substantial distress, we suggest
short-term use of a short- or intermediate-acting benzodiazepine receptor agonist (Grade 2C).
(See "Overview of the treatment of insomnia in adults", section on 'Approach to acute insomnia'
and 'Benzodiazepines' above and 'Nonbenzodiazepines' above.)
● In most patients with chronic insomnia, we suggest cognitive behavioral therapy for insomnia
(CBT-I) as first-line therapy, rather than medication (Grade 2B). An alternative type of behavioral
therapy is reasonable if CBT-I is not available. (See 'Behavioral therapy' above.)
● Short-term use of a medication in combination with CBT-I is a reasonable alternative to CBT-I

alone in patients with severe distress (eg, deterioration in daytime function or excessive anxiety
regarding sleeplessness, which may interfere with the ability to follow sleep restriction and stimulus
control aspects of CBT-I). (See 'Combination therapy' above.)
● Patients given behavioral plus pharmacologic therapy should continue behavioral therapy for six to
eight weeks. In patients who respond to therapy, the medication can be tapered while continuing
the behavioral therapy. Patients whose symptoms recur may require evaluation in a sleep
disorders center, prior to the institution of long-term therapy. (See 'General approach' above and
'Follow-up' above.)
● When pharmacotherapy is used for chronic insomnia, selection of medication should be

individualized based on patient age and comorbidities, side effect profiles, cost, and clinician and
patient preference (table 5A-C). (See 'Choice of an agent' above.)
• For patients who require medication for sleep onset insomnia, we suggest a short-acting
medication rather than a longer-acting agent (Grade 2C). (See 'Choice of an agent' above.)
• For patients who require medication for sleep maintenance insomnia, we suggest a longer-
acting medication rather than a short-acting agent (Grade 2C). Alternatively, a formulation of
zolpidem has been approved for use in the middle of the night. Patients should be warned
about the risk for daytime drowsiness, impaired driving, dizziness, and lightheadedness. (See
'Choice of an agent' above.)
● Long-term treatment with medication alone is not the optimal treatment strategy for patients with
insomnia. (See 'Risks and side effects' above.)
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Fall-Related Injury. Sleep 2016; 39:1009.
152. Glass J, Lanctôt KL, Herrmann N, et al. Sedative hypnotics in older people with insomnia: meta-
analysis of risks and benefits. BMJ 2005; 331:1169.
153. Kripke DF, Langer RD, Kline LE. Hypnotics' association with mortality or cancer: a matched cohort
study. BMJ Open 2012; 2:e000850.
154. Hausken AM, Skurtveit S, Tverdal A. Use of anxiolytic or hypnotic drugs and total mortality in a
general middle-aged population. Pharmacoepidemiol Drug Saf 2007; 16:913.
155. Belleville G. Mortality hazard associated with anxiolytic and hypnotic drug use in the National
Population Health Survey. Can J Psychiatry 2010; 55:558.
156. Hartz A, Ross JJ. Cohort study of the association of hypnotic use with mortality in
postmenopausal women. BMJ Open 2012; 2.
157. Kripke DF, Klauber MR, Wingard DL, et al. Mortality hazard associated with prescription
hypnotics. Biol Psychiatry 1998; 43:687.
158. Weich S, Pearce HL, Croft P, et al. Effect of anxiolytic and hypnotic drug prescriptions on mortality
hazards: retrospective cohort study. BMJ 2014; 348:g1996.
159. Tiihonen J, Suokas JT, Suvisaari JM, et al. Polypharmacy with antipsychotics, antidepressants, or
benzodiazepines and mortality in schizophrenia. Arch Gen Psychiatry 2012; 69:476.
160. Gisev N, Hartikainen S, Chen TF, et al. Mortality associated with benzodiazepines and
benzodiazepine-related drugs among community-dwelling older people in Finland: a population-
based retrospective cohort study. Can J Psychiatry 2011; 56:377.
161. Vinkers DJ, Gussekloo J, van der Mast RC, et al. Benzodiazepine use and risk of mortality in
individuals aged 85 years or older. JAMA 2003; 290:2942.
162. Lovato N, Lack L. Insomnia and mortality: A meta-analysis. Sleep Med Rev 2019; 43:71.
163. Bryan CJ, Gonzales J, Rudd MD, et al. DEPRESSION MEDIATES THE RELATION OF
INSOMNIA SEVERITY WITH SUICIDE RISK IN THREE CLINICAL SAMPLES OF U.S.
MILITARY PERSONNEL. Depress Anxiety 2015; 32:647.
164. McCall WV, Benca RM, Rosenquist PB, et al. Hypnotic Medications and Suicide: Risk,
Mechanisms, Mitigation, and the FDA. Am J Psychiatry 2017; 174:18.
165. McCall WV, Blocker JN, D'Agostino R Jr, et al. Treatment of insomnia in depressed insomniacs:
effects on health-related quality of life, objective and self-reported sleep, and depression. J Clin
Sleep Med 2010; 6:322.
166. Fava M, Asnis GM, Shrivastava RK, et al. Improved insomnia symptoms and sleep-related next-
day functioning in patients with comorbid major depressive disorder and insomnia following
concomitant zolpidem extended-release 12.5 mg and escitalopram treatment: a randomized

controlled trial. J Clin Psychiatry 2011; 72:914.
167. Fava M, Schaefer K, Huang H, et al. A post hoc analysis of the effect of nightly administration of
eszopiclone and a selective serotonin reuptake inhibitor in patients with insomnia and anxious
depression. J Clin Psychiatry 2011; 72:473.
168. https://www.accessdata.fda.gov/cdrh_docs/reviews/DEN140032.pdf.
169. Roth T, Mayleben D, Feldman N, et al. A novel forehead temperature-regulating device for
insomnia: a randomized clinical trial. Sleep 2018; 41.
170. Shekelle PG, Cook IA, Miake-Lye IM, et al. Benefits and Harms of Cranial Electrical Stimulation
for Chronic Painful Conditions, Depression, Anxiety, and Insomnia: A Systematic Review. Ann
Intern Med 2018; 168:414.
171. Cheuk DK, Yeung WF, Chung KF, Wong V. Acupuncture for insomnia. Cochrane Database Syst
Rev 2012; :CD005472.
172. Garland SN, Xie SX, DuHamel K, et al. Acupuncture Versus Cognitive Behavioral Therapy for
Insomnia in Cancer Survivors: A Randomized Clinical Trial. J Natl Cancer Inst 2019; 111:1323.
Topic 7691 Version 73.0
GRAPHICS
Risk factors and comorbidities of chronic insomnia in adults
Psychiatric conditions Neurological conditions

Depression Neurodegenerative diseases (eg, Alzheimer dementia,
Parkinson disease)
Anxiety
Neuromuscular disorders including painful peripheral
Substance use disorders
neuropathies
Posttraumatic stress disorder
Cerebral hemispheric and brainstem strokes
Medical conditions Brain tumors
Pulmonary Traumatic brain injury
Chronic obstructive pulmonary disease
Headache syndromes (eg, migraine, cluster, hypnic
Asthma headache, and exploding head syndromes)
Rheumatologic Fatal familial insomnia
Arthritis
Medications and substances
Fibromyalgia
Chronic pain Central nervous system stimulants
Cardiovascular Central nervous system depressants
Heart failure Bronchodilators

Ischemic heart disease
Antidepressants
Nocturnal angina
Beta antagonists
Hypertension
Diuretics
Endocrinologic
Glucocorticoids
Hyperthyroidism
Urinary Caffeine
Nocturia Alcohol
Gastrointestinal Other sleep disorders

Gastroesophageal reflux
Restless legs syndrome
Diabetes
Periodic limb movement disorder
Cancer
Sleep apnea
Pregnancy
Circadian sleep-wake rhythm disorders
Menopause
Delayed sleep-wake phase disorder
Lyme disease Advanced sleep-wake phase disorder
Human immunodeficiency virus (HIV) infection Irregular sleep-wake rhythm disorder

Non-24-hour sleep-wake rhythm disorder
Chronic fatigue syndrome
Shift work disorder
Dermatologic (eg, pruritus)
Jet lag
Graphic 50646 Version 10.0
Sleep hygiene: Basic rules for a good night's sleep
Sleep only as much as you need to feel rested and then get out of bed
Keep a regular sleep schedule
Do not try to sleep unless you feel sleepy
Exercise regularly, preferably at least 4 to 5 hours before bedtime
Avoid caffeinated beverages after lunch
Avoid alcohol near bedtime: no "night cap"
Avoid smoking, especially in the evening
Do not go to bed hungry
Make the bedroom environment conducive to sleep
Avoid prolonged use of light-emitting screens before bedtime
Deal with your worries before bedtime
Stimulus control therapy rules
1. Go to bed only when sleepy.
2. Do not watch television, read, eat, or worry while in bed. Use bed only for sleep and sex.
3. Get out of bed if unable to fall asleep within 20 minutes and go to another room. Return to bed only when sleepy.
Repeat this step as many times as necessary throughout the night.
4. Set an alarm clock to wake up at a fixed time each morning, including weekends.
5. Do not take a nap during the day.
Data from: Bootzin RR, Perlis ML. Nonpharmacologic treatments of insomnia. J Clin Psychiatry 1992; 53:37.
Sleep restriction rules
1. Determine the patient's average sleep time from a sleep diary.
2. Use this average sleep time as the new time allowed in bed each night.
3. Set a consistent wake time based upon the type of insomnia and patient need.
4. Have patient avoid daytime naps.
5. If sleep efficiency increases above 90 percent (85 percent for patients over 65 years of age), then increase time in bed
by 15 to 30 minutes.
6. If sleep efficiency decreases below 85 percent (80 percent for patients over 65 years of age), then decrease time in bed
by 15 to 30 minutes.
Adapted from: Spielman AJ, Yang CM, Glovinsky PB. Insomnia: Sleep restriction therapy. In: Insomnia Diagnosis and Treatment,
Sateia MJ, Buysse DJ (Eds), Informa UK Ltd, London 2010.
Benzodiazepines in the management of insomnia in adults
Dose in Potential for

Adult dose Half-life
Benzodiazepine older adults Indication drug
(usual)* (hours)
(≥65 years) interactions ¶
Estazolam 1 to 2 mg 0.5 mg Sleep onset or Intermediate (10 CYP3A4 to

sleep to 24) minimally active
maintenance metabolite.
insomnia
Flurazepam 15 to 30 mg 15 mg Sleep onset or Long (40 to 114; Non-CYP

sleep 120 to 160 older glucuronidation in
maintenance adults) liver. No active
insomnia metabolite.
Lorazepam 0.5 to 2 mg 0.5 to 1 mg Sleep onset or Intermediate (10 Non-CYP

sleep to 14) glucuronidation in
maintenance liver. No active
insomnia metabolite.
Temazepam 7.5 to 30 mg 7.5 to 15 mg Sleep onset or Intermediate (8 Primarily non-CYP

sleep to 15) glucuronidation in
maintenance liver to minimally
insomnia active metabolite.
Triazolam 0.125 to 0.25 0.125 to 0.25 mg Sleep onset Short (2 to 5) CYP3A4. No active
mg insomnia metabolite.
* Initiate treatment using lowest dose shown for those with low body weight, debilitated patients, and those receiving treatment
with opioid analgesics or other central nervous system or cardiorespiratory depressants.
¶ For specific drug interactions, including management recommendations and combinations that should be avoided, use Lexi-
Interact drug interactions program included with UpToDate.
Nonbenzodiazepine benzodiazepine receptor agonists (BZRAs) in the management of

insomnia in adults
Dose
in
Adult Potential for
older Half-life
Nonbenzodiazepine Preparation(s) dose Indication drug
adults (hours)
(usual)* interactions ¶
(≥65
years)
Eszopiclone Tablet 1 to 3 mg 1 to 2 Sleep onset Intermediate Moderate

mg or sleep (6) Eszopiclone is
maintenance metabolized in
insomnia part by CYP3A4
Zaleplon Capsule 5 to 20 mg 5 mg Sleep onset Short (1) Low

insomnia
Zolpidem Tablet, sublingual Men 5 to 10 5 mg Sleep onset Short (1.4 to Low to moderate
tablet, oral liquid (5 mg or sleep 4.5) Zolpidem is
mg per spray) Women 5 maintenance metabolized in
mg insomnia part by CYP3A4
Zolpidem extended Coated tablet Men 6.25 to 6.25 mg Sleep onset Intermediate Metabolized more
release 12.5 mg or sleep (1.6 to 4 Δ) slowly by women,
maintenance particularly with
Women
insomnia age
6.25 mg
Zolpidem middle of the Dissolvable tablet Men 3.5 mg 1.75 mg Sleep Short (1.4 to
night (sublingual) Women maintenance 4.5)
1.75 mg insomnia
(middle of the
night)
Zopiclone (not available in Tablet 3.75 to 7.5 Sleep onset Intermediate Moderate
the United States) mg insomnia (5 to 7) Zopiclone is
metabolized by
CYP2C8 and 3A4
* Initiate treatment using lowest dose shown for those with low body weight, debilitated patients, and those receiving treatment
with opioid analgesics or other central nervous system or cardiorespiratory depressants.
¶ For specific drug interactions, including management recommendations and combinations that should be avoided, use Lexi-
Δ Duration of effect longer than predicted by half-life due to sustained release.
Cytochrome P450 3A (including 3A4) inhibitors and inducers
Strong inhibitors Moderate inhibitors Strong inducers Moderate inducers

Atazanavir Amiodarone* Apalutamide Bexarotene
Ceritinib Aprepitant Carbamazepine Bosentan
Clarithromycin Cimetidine* Enzalutamide Cenobamate
Cobicistat and Conivaptan Fosphenytoin Dabrafenib

cobicistat-containing
Crizotinib Lumacaftor Dexamethasone ¶
coformulations
Cyclosporine* Lumacaftor-ivacaftor Efavirenz
Darunavir
Diltiazem Mitotane Eslicarbazepine
Idelalisib
Duvelisib Phenobarbital Etravirine
Indinavir
Dronedarone Phenytoin Lorlatinib
Itraconazole
Erythromycin Primidone Modafinil
Ketoconazole
Fedratinib Rifampin (rifampicin) Nafcillin
Lopinavir
Fluconazole Rifabutin
Mifepristone
Fosamprenavir Rifapentine
Nefazodone
Fosaprepitant* St. John's wort
Nelfinavir
Grapefruit juice
Ombitasvir-paritaprevir-
ritonavir Imatinib
Ombitasvir-paritaprevir- Isavuconazole
ritonavir plus dasabuvir (isavuconazonium
sulfate)
Posaconazole
Lefamulin
Ritonavir and ritonavir-
containing Letermovir
coformulations Netupitant
Saquinavir Nilotinib
Telithromycin Ribociclib
Voriconazole Schisandra
Verapamil
For drug interaction purposes, the inhibitors and inducers of CYP3A metabolism listed above can alter serum
concentrations of drugs that are dependent upon the CYP3A subfamily of liver enzymes, including CYP3A4, for
elimination or activation.
These classifications are based upon US Food and Drug Administration (FDA) guidance. [1,2] Other sources may use a
different classification system resulting in some agents being classified differently.
Data are for systemic drug forms. Degree of inhibition or induction may be altered by dose, method, and timing of
administration.
Weak inhibitors and inducers are not listed in this table with exception of a few examples. Clinically significant
interactions can occasionally occur due to weak inhibitors and inducers (eg, target drug is highly dependent on
CYP3A4 metabolism and has a narrow therapeutic index). Accordingly, specific interactions should be checked using a
drug interaction program such as Lexicomp interactions included within UpToDate.
Refer to UpToDate topics on specific agents and indications for further details.
* Classified as a weak inhibitor of CYP3A4 according to FDA system. [1]

¶ Classified as a weak inducer of CYP3A4 according to FDA system. [1]
Data from: Lexicomp Online (Lexi-Interact). Copyright © 1978-2020 Lexicomp, Inc. All Rights Reserved.
References:
1. US Food & Drug Administration. Clinical drug interaction studies - Study design, data analysis and clinical implications;
Guidance for industry (October 24, 2017) available at: https://www.fda.gov/media/82734/download.
2. US Food & Drug Administration. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and Inducers.
Available at: FDA.gov website.
Other drugs for the management of insomnia in adults
Dose in
older Potential for
Other Mechanism Adult dose Half-life
adults Indication drug
drugs of action (usual) (hours)
(≥65 interactions*
years)
Doxepin Histamine H1 3 to 6 mg 3 to 6 mg Sleep Long (15 Moderate

receptor maintenance drug; 31 Doxepin is
antagonism ¶ insomnia active metabolized in
metabolite) part by CYP2D6
Ramelteon Melatonin 8 mg 8 mg Sleep onset Short (1 to Moderate

receptor insomnia 2.6 drug; 2 to Ramelteon is
agonist 5 active metabolized in
metabolite) part by CYP1A2
Suvorexant Orexin 10 to 20 mg 10 to 15 mg Sleep onset or Intermediate Significant drug

receptor sleep (12) interactions
antagonist maintenance anticipated
insomnia Suvorexant is
metabolized by
CYP3A
If used in
combination with
moderate
inhibitors of
CYP3A,
recommended
dose is 5 mg;
may increase to
10 mg
Avoid use of
suvorexant with
strong inhibitors
or inducers of
CYP3A
Trazodone Δ 5HT2, alpha-1 25 to 100 mg 25 to 100 mg Sleep onset or Intermediate Moderate

adrenergic, sleep (5 to 9) Trazodone is
and histamine maintenance metabolized by
H1 receptor insomnia CYP3A4 to an
antagonism ¶ active metabolite;
use with caution
in combination
with other
serotonergic
drugs
* For specific drug interactions, including management recommendations and combinations that should be avoided, use Lexi-
¶ Although classified as antidepressants, these drugs are not therapeutic for treating depression at the doses used for insomnia.
Δ Not approved by the US Food and Drug Administration for insomnia indication.
Safe prescribing practices for hypnotic medications in patients with insomnia*
Prescribe the lowest possible effective dose
Avoid prescribing a dose greater than the maximum recommended dose
Avoid combining with alcohol or other sedatives, including opioids
Use increased caution in older adults and patients with renal and liver dysfunction
In patients with comorbid depression, assess for suicidal ideation before prescribing and if present, monitor closely
while considering other treatment options
Instruct patients on proper timing of the drug in relation to desired sleep onset
Instruct patients on drug half-life and expected duration of effect
Advise against use if there is insufficient time for drug elimination between planned bedtime and rise time
Discuss risk of next-day impairment in alertness, memory, coordination, and driving
Discuss risk of complex sleep-related behaviors such as sleep walking, eating, and driving
Schedule regular follow-up to review efficacy, side effects, non-pharmacologic options, and assess ongoing need for
medication
* For detailed prescribing information, clinicians should refer to the individual drug information topics within UpToDate.
Comprehensive information on drug-drug interactions can be determined using the drug interactions tool (Lexi-Interact online).
This tool can be accessed from the UpToDate online search page or through the individual drug information topics in the section
on Drug interactions.
Adapted from: McCall WV, Benca RM, Rosenquist PB, et al. Hypnotic medications and suicide: Risk, mechanisms, mitigation, and
the FDA. Am J Psychiatry 2017; 174:18.
Contributor Disclosures
Michael H Bonnet, PhD Nothing to disclose Donna L Arand, PhD Nothing to disclose Ruth Benca, MD,
PhD Grant/Research/Clinical Trial Support: Merck [Insomnia (Suvorexant)]. Consultant/Advisory Boards: Merck
[Insomnia (Suvorexant)]; Jazz Pharmaceuticals [Hypersomnia (Sodium oxybate, solriamfetol)]; Eisai [Insomnia
(Lemborexant)]; Genomind [Genetic testing for personalized medicine)]. April F Eichler, MD, MPH Nothing to
disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be provided
to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate
standards of evidence.
Conflict of interest policy

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Behavioral and pharmacologic therapies for chronic

● Approved medications used to treat insomnia include benzodiazepines, nonbenzodiazepine

Meta-analyses of randomized, placebo-controlled trials indicate that benzodiazepines decrease sleep

Nonbenzodiazepines — Nonbenzodiazepine benzodiazepine receptor agonists have a structure that

● Eszopiclone – Eszopiclone has the longest half-life of the approved nonbenzodiazepines,

Melatonin agonists — Ramelteon is a melatonin agonist. In randomized trials, short-term use of

Diphenhydramine — Many over-the-counter sleep aids contain diphenhydramine (a sedating

Risks and side effects

Adverse effects of nonbenzodiazepines — The adverse effects of nonbenzodiazepine hypnotics

Complex sleep-related behaviors — Complex sleep-related behaviors, including sleepwalking,

Dosing precautions — There has been increasing recognition that variability in

In a meta-analysis of 24 randomized trials (2417 patients) that evaluated the impact of

Acupuncture — Acupuncture as a treatment for insomnia was assessed in a meta-analysis of 33

SOCIETY GUIDELINE LINKS

INFORMATION FOR PATIENTS

● Basics topic (see "Patient education: Insomnia (The Basics)")

SUMMARY AND RECOMMENDATIONS

● Short-term use of a medication in combination with CBT-I is a reasonable alternative to CBT-I

● When pharmacotherapy is used for chronic insomnia, selection of medication should be

Use of UpToDate is subject to the Subscription and License Agreement.

7. Brasure M, Fuchs E, MacDonald R, et al. Psychological and Behavioral Interventions for

disorders. J Psychopharmacol 2010; 24:1577.

54. Drerup ML, Ahmed-Jauregui S. Online Delivery of Cognitive Behavioral Therapy-Insomnia:

72. Baillargeon L, Landreville P, Verreault R, et al. Discontinuation of benzodiazepines among older

82. Krystal AD. A compendium of placebo-controlled trials of the risks/benefits of pharmacological

83. Huedo-Medina TB, Kirsch I, Middlemass J, et al. Effectiveness of non-benzodiazepine hypnotics

86. Hindmarch I, Legangneux E, Stanley N, et al. A double-blind, placebo-controlled investigation of

101. http://www.emea.europa.eu/htms/human/opinion/opinion.htm (Accessed on January 28, 2009).

108. http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm409950.htm (Accessed on A

141. www.fda.gov/Drugs/DrugSafety/ucm397260.htm (Accessed on May 27, 2014).

145. Tabata H, Kuriyama A, Yamao F, et al. Suvorexant-Induced Dream Enactment Behavior in

concomitant zolpidem extended-release 12.5 mg and escitalopram treatment: a randomized

Topic 7691 Version 73.0

Risk factors and comorbidities of chronic insomnia in adults

Psychiatric conditions Neurological conditions

Cardiovascular Central nervous system depressants

Heart failure Bronchodilators

Gastrointestinal Other sleep disorders

Human immunodeficiency virus (HIV) infection Irregular sleep-wake rhythm disorder

Graphic 50646 Version 10.0

Sleep hygiene: Basic rules for a good night's sleep

Keep a regular sleep schedule

Do not try to sleep unless you feel sleepy

Exercise regularly, preferably at least 4 to 5 hours before bedtime

Avoid caffeinated beverages after lunch

Avoid alcohol near bedtime: no "night cap"

Avoid smoking, especially in the evening

Do not go to bed hungry

Make the bedroom environment conducive to sleep

Avoid prolonged use of light-emitting screens before bedtime

Deal with your worries before bedtime

Graphic 71116 Version 4.0

Stimulus control therapy rules

1. Go to bed only when sleepy.

5. Do not take a nap during the day.

Graphic 77189 Version 3.0

Sleep restriction rules

1. Determine the patient's average sleep time from a sleep diary.

4. Have patient avoid daytime naps.

Graphic 69303 Version 7.0

Benzodiazepines in the management of insomnia in adults