CLINICAL UPDATE

The assessment and management of insomnia: an update

Andrew D. Krystal1,2,  Aric A. Prather1, Liza H.  Ashbrook2
1
Department of Psychiatry and 2Department of Neurology, University of California San  Fran­cisco School of Medicine, San Francisco, CA, USA

Insomnia poses significant challenges to public health. It is a common condition associated with marked impairment in function and quality of
life, psychiatric and physical morbidity, and accidents. As such, it is important that effective treatment is provided in clinical practice. To this
end, this paper reviews critical aspects of the assessment of insomnia and the available treatment options. These options include both non-med-
ication treatments, most notably cognitive behavioral therapy for insomnia, and a variety of pharmacologic therapies such as benzodiazepines,
“z-drugs”, melatonin receptor agonists, selective histamine H1 antagonists, orexin antagonists, antidepressants, antipsychotics, anticonvulsants,
and non-selective antihistamines. A review of the available research indicates that rigorous double-blind, randomized, controlled trials are lack­
ing  for some of the most commonly administered insomnia therapies. However, there are an array of interventions which have been demon-
strated to have therapeutic effects in insomnia in trials with the above features, and whose risk/benefit profiles have been well characterized.
These interventions can form the basis for systematic, evidence-based treatment of insomnia in clinical practice. We review this evidence base and
highlight areas where more studies are needed, with the aim of providing a resource for improving the clinical management of the many patients
with insomnia.

Key words: Insomnia, cognitive behavioral therapy, pharmacotherapy, benzodiazepines, z-drugs, orexin antagonists, antihistamines, mel­
atonin receptor agonists, antidepressants, antipsychotics, anticonvulsants

(World Psychiatry 2019;18:337–352)

Insomnia is defined as a complaint of difficulty falling or This daytime dysfunction can manifest in a wide range of
staying asleep which is associated with significant distress or ways, including fatigue, malaise; impairment in attention, con-
impairment in daytime function and occurs despite an ade- centration or memory; impaired social, family, occupational or
quate opportunity for sleep1,2. It is a common condition, with academic performance; mood disturbance, irritability, sleepi-
an approximate general population point prevalence of 10%3-6. ness, hyperactivity, impulsivity, aggression, reduced motivation,
In the vast majority of cases, insomnia co-occurs with psy- proneness for errors, and concerns about or dissatisfaction with
chiatric or physical conditions. Although it had long been be- sleep2.
lieved that, when this was the case, insomnia was a symptom The sleep disturbance must occur despite adequate oppor-
of those conditions, the available evidence suggests that the tunity for sleep in a safe, dark environment. Duration is also
relationship between such conditions and insomnia is com- key to the diagnosis: to meet criteria for chronic insomnia ac-
plex and sometimes bidirectional7-10. In fact, insomnia is a risk cording to the third edition of the International Classification of
factor for major depression, anxiety disorders, substance use Sleep Disorders (ICSD-3) or for persistent insomnia according
disorders, suicidality, hypertension and diabetes11-23. On this to the DSM-5, symptoms must be present at least three days per
basis, as well as due to the fact that insomnia is associated with week for at least three months. Short term insomnia (ICSD-3)
impairments in quality of life and an increased risk for acci- or episodic insomnia (DSM-5) has the same criteria as chronic
dents and falls, it is recommended that treatment be targeted insomnia, but lasts for fewer than three months.
specifically to addressing insomnia whenever it is present, in- If the sleep complaints are completely explained by another
cluding when it occurs along with physical or psychiatric con- physical, psychiatric or sleep disorder, the patient does not meet
ditions24,25. diagnostic criteria for insomnia. However, insomnia is not sole-
For those who meet the diagnostic criteria for insomnia, a ly a symptom of other mental disorders as was once thought29.
number of empirically supported treatments are available. Even if another disorder was the trigger or is present some of the
These include non-medication therapies as well as medication time, if insomnia is sufficiently severe to warrant independent
options25-28. The public health impact of this condition in terms clinical attention, it should be recognized as a separate, comor-
of prevalence, morbidity and consequences on health and qual- bid disorder.
ity of life highlights the need to effectively diagnose and treat it Previously, both the ICSD and the DSM described various
in clinical practice. This paper reviews the state of the art for op- subtypes of insomnia. These included psychophysiologic in-
timally diagnosing and treating insomnia based on the available somnia, paradoxical insomnia, idiopathic insomnia, behavior­
research evidence. al insomnia of childhood, insomnia due to a mental disorder,
insomnia due to a medical disorder, and insomnia due to a
drug or substance. However, the mechanism of insomnia is
DIAGNOSTIC CRITERIA FOR INSOMNIA poorly understood, and the various subtypes are difficult to
differentiate in clinical practice30. Therefore, the subtypes were
The clinical diagnosis of insomnia is based on the complaint consolidated into chronic insomnia (ICSD-3) and persistent
of trouble falling asleep, trouble staying asleep, or early morning insomnia disorder (DSM-5) in the most recent editions of the
awakening, and resultant daytime dysfunction1,2. manuals.

World Psychiatry 18:3 - October 2019 337

 A subtype of insomnia with objectively short sleep has been The specific complaint may vary over time and often includes
described and stands out for its probable association with in- more than one sleep concern. The duration, frequency and se-
creased morbidity. These individuals meet criteria for chronic verity of this concern should be elucidated as well as exacerbat-
insomnia and, by objective measure, sleep on average less than ing and relieving factors. Complaints of insomnia often arise
six hours per night. This combination of insomnia with short only when probed during evaluation of another disorder, de-
sleep duration has been linked to hypertension, type 2 diabetes, spite the impact of insomnia on multiple health issues.
and worse neurocognitive function17,31,32. Therefore, this may
ultimately become a separate category in future versions of in-
somnia classifications. Current sleep history

A good current sleep history is essential to confirm the di-

DEMOGRAPHICS OF INSOMNIA agnosis and determine the best treatment for a patient with in-
somnia. This includes sleep/wake schedule, bedtime routine,
Symptoms of insomnia are common, with about one in three nocturnal behavior, and daytime dysfunction.
people reporting some symptoms in the previous year33,34. The
point prevalence of a formal diagnosis of insomnia is 6-15%,
though occurrence rates vary by definition used35. Sleep/wake schedule
When looking at only nighttime complaints, rates are far
higher. In a large population sample in France, 57% complained A detailed account of time to bed, time to sleep, frequency
of trouble falling asleep, 53% of trouble staying asleep, and 41% of night awakenings, time to return to sleep, time waking in the
of non-restorative sleep, though only 19% met DSM-IV criteria morning, and time out of bed should be obtained.
of at least one complaint three times per week for one month36. What the patient does when not falling asleep is also impor-
For many, insomnia is a persistent condition, with 74% re- tant. For example, a patient who gets out of bed and eats ice cream
porting symptoms for at least one year37. Persistence is more or watches a favorite show when not sleeping is providing positive
common in women, the elderly, and those with more severe in- reinforcement for being awake, which is counterproductive. This
somnia. In a 3-year study, over half of participants did remit, but can be a behavior to target and eliminate during treatment.
there was a 27% relapse rate37. Family history of insomnia is also The sleep/wake schedule should be obtained for both work/
common, occurring in 35% of individuals38. school days and weekends or vacations. A large variation may
Women more commonly report symptoms of insomnia and signal a circadian rhythm disorder and serve as a target for in-
daytime consequences, and are more likely to be diagnosed with tervention.
insomnia than men. The male-to-female ratio is 1:1.4 for insom- Does the patient nap during the day? If taking a nap later in
nia symptoms and 1:2 for insomnia diagnosis5. In both men and the day, this may be decreasing sleep drive in the evening and
women, the prevalence of insomnia increases with age5,39,40. can also be a target for intervention. If the patient reports a
Insomnia is associated with lower income, lower education, strong propensity to fall asleep during the daytime, this raises
and being divorced or widowed5,36,41. It is also strongly associat- concern for another sleep disorder.
ed with physical disorders, with half of those with insomnia also
reporting multiple physical problems34,41. People with insomnia
are more likely to rate their health poorly42,43. Bedtime routine
Insomnia is very strongly associated with mental disorders,
most commonly depression, anxiety and post-traumatic stress It is important to have the right conditions to ensure proper
disorder. Across cultures, most people with major depression sleep. While someone with true insomnia will not be effectively
report insomnia44, and those with insomnia are more likely to treated by simply providing a dark, quiet environment, the clini-
have depressed mood42,43,45-47. Insomnia is also a predictor for cian – in order to confirm the diagnosis – must ensure that poor
developing mental health problems, including depression, anx- sleep is not due to poor sleep conditions.
iety, bipolar disorder and suicide45. Detailing the bedtime routine may also highlight areas for
intervention during the treatment phase. For example, mobile
phone use is associated with shorter sleep duration22.
CLINICAL ASSESSMENT OF INSOMNIA

Chief complaint Nocturnal behavior

The chief complaint for those with insomnia is typically dif- What does the patient do when not sleeping at night? Are
ficulty initiating or maintaining sleep, early morning awakening there other behaviors overnight, such as snoring or leg kicking,
or simply unrefreshing sleep. Early morning awakening is wak- that may signal alternative or concomitant diagnoses?
ing at least 30 minutes prior to the desired time, accounting for Input from a bed partner can also be helpful. In a patient
habitual bedtime, total sleep time, and premorbid pattern. who reports being awake the entire night, a bed partner often

338 World Psychiatry 18:3 - October 2019

observes long periods of sleep, suggesting there may be some a patient may consider moving a daily dose from morning to
sleep state misperception. evening or vice versa to determine how this impacts sleep.
Over-the-counter allergy medications often contain stimu-
lants such as pseudoephedrine or phenylephrine, and patients
Daytime dysfunction may not realize that this can contribute to insomnia. Withdrawal
can also contribute, such as from alcohol, benzodiazepines or
Daytime dysfunction is part of the formal criteria for insom- opioids. Pulmonary medications, including albuterol and theo-
nia and must be assessed. This includes worsened quality of life, phylline, can cause insomnia as well.
concerns about memory, fatigue, mood, and success at work or While insomnia is reported as a side effect of antihyperten-
school. sive medications, and beta-blockers are known to reduce mela-
tonin levels, there is mixed evidence about the direct impact of
these medications on sleep5,52,53.
The 3P model

The 3P model, a behavioral model of insomnia developed by Social history

Spielman48, can help the clinician focus a sleep history49. The
model highlights why insomnia occurs in certain individuals Occupation is key to the sleep history, to ensure driving safety
and what allows acute insomnia to become chronic insomnia. in patients reporting daytime sleepiness. Work or school hours
The three Ps occur in temporal order: factors predisposing an are also important, as variation in these hours, shift work, and
individual to insomnia, factors precipitating an acute episode frequent travel across time zones can all disturb sleep.
of insomnia, and factors perpetuating the insomnia from acute Use of nicotine, caffeine, alcohol and other substances should
to chronic. Predisposing factors include genetic and personal- also be noted.
ity traits leading to physiologic and cognitive hyperarousal50,51.
Precipitating factors are the triggers after which the insomnia
cycle begins and are typically stressful events, though they can Physical examination
be positive, ranging from the loss of a loved one to retirement or
marriage. Perpetuating factors allow the insomnia to continue, Insomnia is not associated with any specific features on
even when the trigger is removed. These factors include behav- physical or mental status examination. The examination can,
iors and thought structures that may appear to offer short-term however, provide information about alternative diagnoses and
relief yet cause long-term harm, such as increasing time in bed comorbid conditions. Assessments to consider include body
and reducing daytime activity. mass index, neck circumference and airway exam for obstruc-
tive sleep apnea54.

Past medical history

Differential diagnosis
There is a large interplay between many physical or psychi-
atric conditions and insomnia, and typically it is thought that Three criteria must be met for a diagnosis of insomnia: com-
a bidirectional relationship exists in which the physical or psy- plaint of trouble falling or staying asleep, adequate opportunity
chiatric condition exacerbates insomnia and vice versa. A huge for sleep, and daytime dysfunction. If a patient reports trouble
range of physical comorbidities – including pulmonary, cardiac, sleeping for the expected 7-8 hours but does not have daytime
gastrointestinal, endocrine, neurological, musculoskeletal and consequences, he/she may be a short sleeper. On the other hand,
genitourinary – can contribute. if there are insufficient hours of sleep and daytime dysfunction,
It is important to ensure that the management of these co- but the patient is able to sleep when provided opportunity, this is
morbid conditions is optimized when treating insomnia. likely to be behaviorally induced insufficient sleep. Function dur-
ing vacations and weekends can be helpful to differentiate these.
Other sleep disorders that can present with the complaint
Medications of insomnia include circadian rhythm sleep-wake disorders,
restless leg syndrome, periodic leg movement disorder, and ob-
Numerous medications can impact sleep, and a thorough structive sleep apnea.
medication list, including over-the-counter medications and Helpful questions to distinguish circadian disorders include
substances of abuse, should be elicited. the time to bed and awake on weekends, holidays and vacations
Antidepressants such as selective serotonin reuptake in- in contrast to work or school days and whether there is a normal
hibitors (SSRIs), serotonin norepinephrine reuptake inhibitors duration of refreshing sleep once the patient does fall asleep. If
(SNRIs) and monoamine oxidase inhibitors (MAOIs) can cause sleeping from 3 am to 10 am provides refreshing sleep and yet
sedation or stimulation, with individual variability. Therefore, the patient gets in bed at midnight and hopes to rise at 7 am, but

World Psychiatry 18:3 - October 2019 339

cannot fall asleep for several hours, a delayed sleep-wake phase thus the accuracy of the information regarding sleep and wake
disorder may be involved and the misaligned internal rhythm periods is unknown.
should be the target for treatment. Limited data suggest that some of these monitors do not ac­
Symptoms of restless leg syndrome include an urge to move curately reflect sleep architecture, sleep efficiency or sleep laten-
the legs at least partially relieved by moving them, typically pre- cy, and tend to overestimate sleep duration in normal sleepers
ceded by an abnormal leg sensation, and typically occurring dur- with far worse accuracy in insomnia patients61,62. Therefore,
ing times of rest at the end of the day. As the syndrome can cause these devices are not recommended to make clinical decisions
trouble falling asleep, it should be ruled out or treated directly. until there are rigorous studies establishing validity and reliabil-
Obstructive sleep apnea can present with symptoms of insom- ity. The ease of use and consumer enthusiasm, however, does
nia, more commonly in women than men. Presence of snoring, suggest that these devices may play an increasing role in evalua-
frequent awakenings, witnessed apneas should be discussed tion and treatment moving forward.
and, if concern is present, polysomnography should be perform­
ed55,56.
Polysomnography

Insomnia assessment tools Polysomnography is the gold standard to distinguish sleep

from wake. It is not needed for the diagnosis of insomnia, which
Sleep diary is based on patient self-report. This is because indices tradition-
ally derived from polysomnographic data do not reflect the sleep
Sleep diary is a form compiled by the patient, usually for at problems reported by approximately 40% of insomnia patients63.
least two consecutive weeks, in which he/she notes down the Polysomnography can be helpful to rule out other possible
time that he/she went to bed, the time of lights out, time to explanations for poor sleep, such as sleep apnea or periodic leg
sleep, time and duration of awakenings overnight, time awake in movement disorder. Therefore, it may be indicated when there
the morning, time out of bed, naps, perceived duration of sleep, is concern for sleep apnea or when a patient is not responding
and sometimes quality and depth of sleep. The use of sleep aids to treatment as expected.
and alcohol is sometimes included.
This can be very useful for the diagnosis of insomnia and is
core to the treatment, because it helps to characterize the specif- Questionnaires
ic nature of the sleep problem, delineate maladaptive behaviors
and provide an indicator of treatment outcome. If a circadian There are multiple questionnaires that can aid in the evalua-
rhythm disorder is being considered, a sleep diary can be very tion of insomnia.
useful for making the correct diagnosis. In many sleep clinics, every patient completes the Epworth
Sleepiness Scale64, given the safety concern of daytime sleepi-
Actigraphy ness when driving or operating heavy machinery. The Insomnia
Severity Index65 is commonly used in research as an outcome
Actigraphy is a device, typically worn on the wrist, that re- measure. The Dysfunctional Beliefs and Attitudes about Sleep66
cords movement and employs an algorithm to estimate sleep can help provide additional information to guide treatment. The
and wake periods. Pittsburgh Sleep Quality Index67 is also commonly used to col-
It has satisfactory reliability with the “gold standard” poly- lect information about self-perceived sleep quality.
somnography in good sleepers who spend little time awake and
still, but not in those with sleep difficulties where significant pe-
riods of waking stillness occur57-60. It is often combined with a MANAGEMENT OF INSOMNIA
light sensor to provide an estimate of the latency from lights out
to sleep onset. When a patient is diagnosed with insomnia, treatment may be
Actigraphy is not required in the evaluation of insomnia, but initiated with one of a number of available interventions. These
it can be useful for a patient whose sleep log or history is not reli- can be broadly categorized as non-medication treatments and
able or when circadian disorders are suspected. pharmacological therapies. In the sections below we review these
interventions, focusing on the available evidence from blinded
controlled trials indicating their efficacy and adverse effects.
Personal monitoring devices

Commercially available devices that purport to measure Non-medication treatments

sleep, often differentiating between light and deep sleep, are
increasingly available. There are little published data indicat- There are several different non-pharmacological treatment
ing the performance of nearly all of these consumer devices and regimens that have been tested and implemented to treat in-

340 World Psychiatry 18:3 - October 2019

somnia. Here, we review the components and evidence sup- bedroom is restricted to sleep and sex, which means that patients
porting the non-medication treatment with the best empirical are recommended not to do other activities in bed, including
background and most widespread use, i.e. cognitive behavior­ read or watch television. Additionally, patients are recommend-
al therapy for insomnia (CBT-I). ed to wake up the same time each morning, seven days per week,
Employed in a variety of formats, CBT-I has been found to and get out of bed within 10 to 15 minutes upon awakening.
be effective in reducing insomnia and improving sleep across a
wide array of clinical populations68-77. Consequently, the Ameri-
can College of Physicians has recommended this intervention Sleep restriction
as the first line treatment for adults with insomnia74.
CBT-I has been found to be as effective in the short term as Another common contributor to the development and pres-
pharmacological treatments, with better long-term persistence ervation of insomnia is the tendency for patients to spend ex-
of benefit after the end of treatment72. Further, unlike nearly all cess time in bed. On the surface, this makes reasonable sense
medications, this therapy has relatively minimal side effects. given that the patients yearn to “catch” sleep whenever they can.
Here, we provide a clinical review of the components of CBT-I Unfortunately, excess time in bed results in conditioned arousal
followed by evidence of its efficacy, including its effectiveness and fragmented sleep.
among patients with comorbidities, and its use across different In order to effectively carry out this technique, patients
treatment modalities. should provide at least one week of sleep diaries (though two
CBT-I is typically delivered over roughly four to seven ses- weeks are preferred). The goal is to reduce a patient’s time in
sions. It is unclear how many sessions confer optimal benefit, bed to the reported total sleep time. For instance, if a patient’s
though evidence suggests that fewer than four sessions are not diary report indicated an average total sleep time of six hours
generally sufficient69,78. but a time in bed of nine hours (bedtime 9 pm and wake time 6
am), the new sleep schedule would provide a time in bed of six
hours (bedtime midnight and wake time 6 am).
Educational components of CBT-I Importantly, patients are recommended to not go to sleep
until the new prescribed bedtime and only when sleepy. In
While most patients with insomnia are likely aware of some choosing the sleep opportunity window, it is important to take
of the behaviors that fall into the sleep hygiene category, it is into account the patient’s chronotype.
important to provide them with the relevant education. This in- Due to safety concerns related to sleep restriction (e.g., cog-
cludes the importance of establishing a conducive sleep envi- nitive deficits, drowsy driving), a minimum time in bed of five
ronment by keeping the bedroom dark, quiet and cool. hours has been used in the literature79. In addition, sleep restric-
Patients should also be reminded not to consume sleep dis- tion may exacerbate comorbidities. For instance, sleep restric-
turbing substances, such as caffeine, nicotine and alcohol, par- tion has been shown to lower seizure thresholds, increase pain
ticularly close to bedtime. Similarly, vigorous exercise three to sensitivity, and precipitate mania in patients with bipolar disor-
four hours prior to bedtime should be avoided. der80-82.
Additionally, a wind down routine can be helpful in readying Patients are recommended to complete sleep diaries through-
a patient for bed. This should include discontinuation of arous- out treatment. Their time in bed schedule should be reviewed in
ing activities, including exposure to bright light (e.g., computer each subsequent CBT-I session, with sessions occurring every
screen), which can negatively affect one’s circadian rhythms. one to two weeks. The sleep diaries allow the clinician to calculate
their average sleep efficiency, which is the percentage of time a
patient is asleep given his/her time in bed. We recommend 85%
Behavioral components of CBT-I or higher in average sleep efficiency as a metric for “good” sleep
quality and a threshold to be met prior to adjusting the time in
Stimulus control bed recommendation.
Once it is established that a patient’s sleep efficiency is suffi-
Conditioned arousal is one of the key factors implicated in ciently high, the clinician can begin to increase the time in bed,
the pathogenesis of insomnia. Repeated pairing of the bed/ typically by altering the prescribed bedtime by 15 min each time
bedroom and experiences of physiologic arousal, fear, anxiety and tracking the patient’s improvement in subjective sleep qual-
and frustration leads to the bed serving as a learned cue or con- ity and daytime sleepiness.
ditioned stimulus for arousal, which is incompatible with sleep Sleep restriction is typically the aspect of CBT-I that suffers the
onset and maintenance. most from non-adherence. In the event that a patient is unable or
In order to eliminate this conditioned response, patients are unwilling to carry out the prescribed time in bed, sleep compres-
recommended to remove themselves from the bed and bedroom sion can also be used. This technique consists of slowly decreas-
if not sleepy and sit somewhere quiet until the feeling of sleepi- ing time in bed over time in order to meet the original prescribed
ness returns. Similarly, at bedtime, the patients are recommend- time, and may be more palatable to patients, particularly those
ed not to go to bed unless they feel sleepy. Use of the bed and with significant anxiety about losing further sleep opportunity.

World Psychiatry 18:3 - October 2019 341

Relaxation and paradoxical intention outcomes82,83. CBT-I benefits are stronger for psychiatric than
physical comorbidities70.
These behavioral techniques complement stimulus control CBT-I has been delivered using a number of different formats,
and sleep restriction by providing the patient with tools for de- including face-to-face individual, group and digitally delivered
creasing arousal prior to bedtime and in the event of nighttime therapy. In addition, self-help manuals, books and videos have
awakenings. been developed, which allow patients to carry out treatment on
Relaxation techniques vary, but typically include diaphrag- their own. In general, all modalities are effective, though there is
matic breathing, the tensing and relaxing of muscle groups, and some evidence to suggest that face-to-face therapy outperforms
possibly visual imagery. Paradoxical intention is premised on the self-help. Digitally delivered CBT-I appears to produce effects
idea that anxiety about falling asleep is inhibiting sleep onset. comparable to in-person therapy84,85; however, it is likely that
Using this technique, patients are asked to stay awake as long as in-person supervision may be required for more complicated
possible, which leads to reduced anxiety and easier sleep onset. cases86.

Cognitive components of CBT-I Pharmacological therapies

Maladaptive beliefs and thoughts about sleep are typically A number of medications from several different classes have
addressed throughout treatment. It is important for a clinician undergone randomized, double-blind, placebo-controlled tri-
to attend to sleep-related worries, as they tend to drive the in- als in patients with insomnia. Those for which a statistically
appropriate behaviors that perpetuate insomnia. Unrealistic significant therapeutic effect compared with placebo was re-
expectations about sleep and catastrophic thinking about the ported appear in Tables 1 and 2. In addition, there are a number
consequences of sleep loss are among these worries. of medications commonly used to treat insomnia that have not
One technique for countering catastrophic thoughts is by ex- been demonstrated to have efficacy in at least one double-blind,
amining evidence from the patient’s experience. For instance, if randomized, placebo-controlled trial. These appear in Table 3.
a patient has the belief that a poor night of sleep will leave him/ In this section we review the characteristics of all of these
her unable to be effective in his/her job, a clinician could help medications (benzodiazepines, “z-drugs”, melatonin receptor
the patient identify instances when he/she was able to perform agonists, selective histamine H1 antagonists, orexin antagonists,
sufficiently despite a poor night of sleep. Additionally, providing antidepressants, antipsychotics, anticonvulsants, and non-selec-
patients with tools to reduce worry at bedtime can be helpful. tive antihistamines) and present the available evidence regarding
Another technique, known as a constructive worry exercise, their efficacy and safety as a basis for clinical decision making.
requires patients to list in the early evening three or more prob-
lems that they believe will likely keep them up at night. For each
problem, patients list the next step towards a solution. The ex- Benzodiazepines
ercise is folded and put away and, if patients awake during the
night, they are to remind themselves that they have already Benzodiazepines are a group of compounds with a similar
taken the necessary step towards resolving that problem at their chemical structure. Their sleep enhancing effect is a result of
“problem-solving best” (i.e., not in the middle of the night). positive allosteric modulation of the gamma-aminobutyric acid
(GABA) type A receptor138,139. These agents exert this modula-
tion by binding to a specific site on the GABA-A receptor com-
Evidence of efficacy of CBT-I plex (referred to as the benzodiazepine binding site), thereby
changing the conformation of the receptor constituent proteins,
Several meta-analytic reviews support the efficacy of CBT-I which leads to an enhancement of the inhibition occurring
compared to active control conditions and usual care68-70,72,78-81. when GABA binds to these receptors140,141. This enhancement
In a recent meta-analysis, van Straten et al69 pooled data from of inhibition is associated with a broad set of dose-dependent
87 randomized controlled studies that used at least one com- clinical effects, including sedation, anxiety reduction, seizure
ponent of CBT-I, which included 3,724 patients and 2,579 non- inhibition and myorelaxation139,140,142.
treated controls. The strongest effects were improvements in Of the benzodiazepine medications, triazolam, flurazepam,
insomnia symptoms, as measured using the Insomnia Sever- temazepam, quazepam and estazolam have been demonstrat-
ity Index (Hedges’ g=0.98), sleep efficiency (g=0.71), wake after ed to have therapeutic effects on both sleep onset and main-
sleep onset (g=0.63), sleep onset latency (g=0.57), and subjec- tenance in double-blind, placebo-controlled trials in younger
tive sleep quality (g=0.40). A small effect was observed for adults (Table 1). In older adults, triazolam and flurazepam have
changes in total sleep time (g=0.16). been found to have therapeutic effects on sleep onset and main-
Further, data suggest that CBT-I is effective among individu- tenance in double-blind, placebo-controlled trials, whereas
als with psychiatric and physical comorbidities70, with some ac- temazepam has been demonstrated to have therapeutic effects
cruing evidence that it may have positive effects on comorbid on sleep maintenance only (Table 2).

342 World Psychiatry 18:3 - October 2019

Table 1  Double-blind placebo-controlled trials demonstrating efficacy in the treatment of younger adults with insomnia
Efficacy for sleep Efficacy for sleep
Primary adverse effects
Medication Class onset maintenance
Dose (mg) N Dose (mg) N

Triazolam BDZ 0.2587 1,507 0.589 277 Dose-dependent sedation, psychomotor impairment, abuse potential
0.2588 83
0.589 277
90
Flurazepam BDZ 30 60 3091 157 Dose-dependent sedation, psychomotor impairment, abuse potential
91
30 157
Estazolam BDZ 291 148 291 148 Dose-dependent sedation, psychomotor impairment, abuse potential
1-292 379 1-292 379
0.25-293 15
94 94
Quazepam BDZ 30 57 30 57 Dose-dependent sedation, psychomotor impairment, abuse potential
Temazepam BDZ 3095 75 3095 75 Dose-dependent sedation, psychomotor impairment, abuse potential
96 100
Zolpidem z-drug 10 75 10 199 Dose-dependent sedation, psychomotor impairment, abuse potential
1097 203
1098 615
1099 163
100
10 199
101
Zolpidem (extended z-drug 12.5 212 12.5101 212 Dose-dependent sedation, psychomotor impairment, abuse potential
release)
12.5102 1,025 12.5102 1,025
Zolpidem (sublingual) z-drug 3.5103 295 Dose-dependent sedation, psychomotor impairment, abuse potential
104
Zaleplon z-drug 10 113 Dose-dependent sedation, psychomotor impairment, abuse potential
10-2088 83
10-2098 615
105
Zopiclone z-drug 7.5 25 7.5105 25 Bitter taste, dose-dependent sedation, psychomotor impairment,
abuse potential
7.588 1,507 7.588 1,507
106 106
Eszopiclone z-drug 3 788 3 788 Bitter taste, dose-dependent sedation, psychomotor impairment,
abuse potential
3107 830 3107 830
108 108
2-3 308 2-3 308
Ramelteon MT1/MT2 agonist 4-32109 107
8-32110 65
8111 451
4-16112 190
113
8-16 405
Doxepin H1 antagonist 6114 67 1,3,6114 67 Sedation
115
25-50 47
6116 254
3-6117 221
Suvorexant Orexin antagonist 20-40118 1,211 20-40118 1,211 Sedation, probable abuse potential
119 119
10-80 591 10-80 591
120 120
40 380 40 380

BDZ – benzodiazepine

World Psychiatry 18:3 - October 2019 343

Table 2  Double-blind placebo-controlled trials demonstrating efficacy in the treatment of older adults with insomnia
Efficacy for sleep Efficacy for sleep
Medication Class onset maintenance Adverse effects
Dose (mg) N Dose (mg) N

Triazolam BDZ 0.25121 32 0.125125 22 Dose-dependent sedation, psychomotor impairment,

abuse potential
0.25122 41 0.25122 41
0.25-0.5123 27 0.4-0.8124 25
124
0.4-0.8 25
125
0.125 22
Flurazepam BDZ 15122 41 30124 25 Dose-dependent sedation, psychomotor impairment,
abuse potential
30124 25
Temazepam BDZ 7.5-30126 40 Dose-dependent sedation, psychomotor impairment,
abuse potential
Zolpidem z-drug 5127 549 Sedation, psychomotor impairment, abuse potential
Zolpidem (extended release) z-drug 6.5128 205 6.5128 205 Sedation, psychomotor impairment, abuse potential
129
Zaleplon z-drug 5-10 422 Dose-dependent sedation, psychomotor impairment,
abuse potential
10127 549
Zopiclone z-drug 5-7.5121 48 5-7.5121 48 Bitter taste, dose-dependent sedation, psychomotor
impairment, abuse potential
Eszopiclone z-drug 2130 231 2130 231 Bitter taste, dose-dependent sedation, psychomotor
impairment, abuse potential
2131 264 2131 264
132 132
2 388 2 388
Ramelteon MT1/MT2 agonist 8133 829
8134 100
Doxepin Selective H1 3-6135 76
­antagonist
1-3136 240
137
Suvorexant Orexin antagonist 15 520 15137 520 Sedation, probable abuse potential
120 120
30 319 30 319
15-30137 819 15-30137 819

BDZ – benzodiazepine

For many years the prevailing view of these medications, and the longest nightly treatment study of a benzodiazepine was
medications used for the treatment of insomnia in general, was an 8-week trial of temazepam, where dependence was not ob-
that they were inevitably associated with tolerance (i.e., loss of served126. Studies of 2-4 weeks duration were carried out with
therapeutic benefit over time) and dependence (i.e., withdrawal triazolam (three trials) and flurazepam (one trial), without evi-
symptoms upon discontinuation) when used nightly on a long- dence of dependence occurring87,121,122.
term basis143. Until relatively recently, little data were available The adverse effects of benzodiazepines are dose-dependent
to actually assess whether this was the case25. As data have be- and reflect their broad central nervous system inhibitory ac-
come available, it has been clear that tolerance and dependence tivity. They include sedation, psychomotor impairment, and
do not inevitably occur and are not characteristic of long-term potential for abuse by a small subset of the population143. The
nightly insomnia pharmacotherapy. anxiolytic and myorelaxant effects can be useful in those with
However, data on long-term treatment are only available for comorbid anxiety or pain.
some medications, and the available information leaves open Among the available options, these agents are relatively ef-
the possibility that dependence does occur in some individu- fective at treating sleep onset problems and, as a result, may be
als25. This limitation is particularly notable for benzodiazepines: needed in some individuals with this type of sleep problem. The

344 World Psychiatry 18:3 - October 2019

Table 3  Medications used to treat insomnia not demonstrated to have efficacy in at least one double-blind placebo-controlled trial in insomnia
patients
Medication FDA approved indication Primary known side effects

Trazodone Major depressive disorder Sedation, dizziness, headache, dry mouth, blurred vision, orthostatic hypotension, priapism
Mirtazapine Major depressive disorder Sedation, dry mouth, increased appetite/weight gain, constipation
Amitriptyline Major depressive disorder Sedation, dizziness, weight gain, dry mouth, blurred vision, constipation, urinary retention
Gabapentin Partial seizures, pain Sedation, dizziness, ataxia, diplopia
Pregabalin Fibromyalgia, pain, partial seizures Sedation, dizziness, dry mouth, cognitive impairment, increased appetite, discontinuation effects
Quetiapine Schizophrenia, mania, major Sedation, orthostatic hypotension, dry mouth, tachycardia, increased appetite/weight gain
depressive disorder
Olanzapine Schizophrenia, mania Sedation, agitation, dizziness, constipation, orthostatic hypotension, akathisia, weight gain,
increased incidence of cerebrovascular events in dementia patients
Diphenhydramine Over-the-counter antihistamine Sedation, dizziness, dry mouth, blurred vision, constipation, urinary retention
Doxylamine Over-the-counter antihistamine Sedation, dizziness, dry mouth, blurred vision, constipation, urinary retention
Melatonin Over-the-counter hormone Headache, sedation

FDA – US Food and Drug Administration

only relative contraindication to their use is a history of poly- Like benzodiazepines, these agents are relatively more effec-
substance abuse or a specific predisposition to benzodiazepine tive than other options in treating problems with sleep mainte-
abuse. nance, and may be problematic in those predisposed towards
substance abuse.

“Z-drugs”
Melatonin receptor agonists
These agents are an unrelated group of compounds which
act by the same mechanism as benzodiazepines, but do not There are two melatonin receptor agonists used in the treat-
share the benzodiazepine chemical structure138-142. There is ment of insomnia: melatonin and ramelteon.
some evidence that they may differ somewhat from benzodi- Melatonin is a hormone that is taken by many individuals
azepines in that their action is relatively restricted to subsets of with insomnia. Normally, it is released by the pineal gland dur-
GABA-A receptors. As a result, they may have less broad clinical ing the dark period of the day. It binds predominantly to the
effects25,138-142. MT1 and MT2 receptors, though the mechanism by which this
Double-blind, placebo-controlled trials demonstrate the ef- might enhance sleep is not well understood152.
ficacy of zaleplon for sleep onset, and of zolpidem extended-re- No clear dose-response relationship has been established for
lease, zopiclone and eszopiclone (the S isomer of zopiclone) for the use of melatonin for treating insomnia, and there is some ev-
sleep onset and maintenance in both younger and older adults. idence that sleep enhancement may depend on the time of day
Zolpidem has a documented efficacy for sleep onset and main- and may not occur until 3-4 hours after administration153-155.
tenance problems in younger adults, but for sleep onset prob- A substantial number of studies have evaluated the effects of
lems only in older adults (Tables 1 and 2). a variety of dosages, administration times, and both immediate
More data on long-term treatment are available for “z-drugs” and prolonged release formulations of melatonin in individuals
than for benzodiazepines. The sustained efficacy of eszopiclone with sleep problems156,157. The available evidence suggests that
and zolpidem has been demonstrated in studies of nightly dos- this agent has a clear therapeutic effect in individuals with de-
ing up to one year in duration without any evidence of depend- layed sleep-phase syndrome, that it has an excellent safety pro-
ence occurring, nor was dependence found in a 6-month study of file, and that there may be a modest therapeutic effect on sleep
non-nightly treatment with extended-release zolpidem101,106,107. onset latency in individuals with insomnia (although it remains
The potential adverse effects of the “z-drugs” are the same as unclear whether this effect is of clinical significance). Some pre-
the benzodiazepines. Because of the relatively narrower effects liminary evidence supports the use of melatonin to treat sleep
of some of these agents, they may not be as helpful as benzo- problems in children with neurodevelopmental disorders, in
diazepines in addressing concomitant anxiety or pain. This ap- whom this agent has been established to have an excellent safe-
pears to be the case for zolpidem. However, eszopiclone and ty profile158-163.
zolpidem extended-release have been found to have therapeu- The most common adverse effect of melatonin is headache,
tic effects on pain, anxiety and depression concomitant with and slowing of reaction time and sedation can occur during the
insomnia144-151. day. Melatonin is without abuse potential, so it could be admin-

World Psychiatry 18:3 - October 2019 345

istered to abuse-prone individuals with insomnia. Because it is Orexin receptor antagonists
a hormone that regulates reproductive function, when taken in
higher dosages it can in theory impair fertility. Therefore, it has The name “orexins” was given to two peptides that were rela-
been recommended that it not be taken in those attempting to tively recently discovered to arise from the neurons of the lat-
conceive164-167. eral hypothalamus and to promote wakefulness/arousal118-120.
Like melatonin, ramelteon is an agonist at MT1 and MT2 re­ Agents which are orexin receptor antagonists are sleep promot-
ceptors. However, it is a substantially more potent agonist at these ing, owing to their ability to block the arousal mediated by the
receptors than melatonin. Double-blind, placebo-controlled tri- orexins.
als demonstrate the efficacy of ramelteon for sleep onset insom- Suvorexant is an agent which blocks both types of orexin re-
nia in both younger and older adults (Tables 1 and 2). Efficacy ceptors (orexin A and B) and has been demonstrated in double-
has been more consistently found with polysomnographic meas- blind placebo-controlled trials to have therapeutic effects on
ures than self-report measures of sleep onset. Nightly treatment sleep onset and maintenance (including in the last third of the
for six months was evaluated and no evidence of dependence night) in both younger and older insomnia patients, at dosages
phenomena was reported111. from 10 to 40 mg (Tables 1 and 2). This includes a placebo-con-
Ramelteon has a relatively benign profile of adverse effects, trolled trial of nightly treatment for a year, which demonstrated
among which the most commonly reported are headache, seda- sustained therapeutic effects and no significant rebound insom-
tion, fatigue and nausea. It does not have significant abuse po- nia on discontinuation120.
tential and could be used for abuse-prone individuals with sleep The adverse effect of suvorexant that is of most importance is
onset problems, though no studies have evaluated its therapeu- daytime sedation. Available studies suggest that this agent is as-
tic effects in this population. Due to its good safety profile, it may sociated with some abuse potential that is roughly comparable
be considered for use in individuals with difficulty in sleep onset to that of zolpidem, so that it is probably best avoided in people
only. predisposed to abuse.
Suvorexant is the only agent with therapeutic effects in the
last third of the night without substantially increasing morning
Selective H1 antagonists sedation that also has a robust therapeutic effect on sleep on-
set. As such, it could be considered for use in those patients with
The only highly selective histamine H1 receptor antagonist both sleep onset difficulties and early morning awakening.
that has been systematically studied is doxepin in the 3-6 mg
dosage range25.
Doxepin, originally developed as an antidepressant in dosag- Antidepressants
es of 75-150 mg/day, has H1 antagonism as its most potent phar-
macological effect168. As a result, as the dosage is decreased, this There are several medications originally developed for the
agent becomes an increasingly specific H1 antagonist168. treatment of major depressive disorder that are commonly used
Double-blind, placebo-controlled trials carried out in both for treating insomnia. These agents may produce sleep enhanc-
younger and older adults, using both self-report and polysom- ing effects by blocking the receptors for neurotransmitters that
nographic endpoints, demonstrate the sleep maintenance effi- are wake enhancing, such as norepinephrine, histamine, acetyl-
cacy of this medication in the 3-6 mg range (Tables 1 and 2). It is choline and serotonin25.
notable that the therapeutic effects appear to be largest towards The antidepressants most commonly used to treat insomnia
the end of the night, without increasing morning impairment. are trazodone 50-150 mg, doxepin 10-75 mg, mirtazapine 15 mg,
As such, this agent appears to be uniquely well suited for use in and amitriptyline 10-100 mg25. Of these agents, only doxepin 25-
individuals waking up towards the end of the night and having 50 mg has been demonstrated to have therapeutic effects in in-
difficulty returning to sleep. Studies of up to 3-month duration somnia patients in at least one placebo-controlled, double-blind,
of nightly treatment have been carried out without dependence randomized trial, and this study was small (N=47) (Table 1).
occurring136. Although trazodone is widely prescribed in the treatment of
The most common adverse effect reported in younger adults insomnia, it has not been found to have therapeutic effects in
is daytime sedation. However, in older adults there were no insomnia patients in any randomized, double-blind, placebo-
adverse effects reported more frequently with doxepin 3 mg controlled trial. It was evaluated in one such trial in younger
compared to placebo. As such, older adults with early morning adults, but significant effects compared with placebo were not
awakening would be a particularly appropriate group to treat found97. This should not be interpreted as definitive evidence
with this medication. Also, given its potent H1 antagonism, dox- that it lacks therapeutic effects in insomnia. In fact, that study
epin could also be considered for use in people with insomnia evaluated only one dose of trazodone (50 mg), whereas clini-
occurring with allergy symptoms. As this agent is without abuse cally a range of doses from 50 to 150 mg is prescribed25.
potential, it could also be used in patients with sleep mainte- There are data available on the efficacy and side effects of
nance problems who are prone to abuse, although no data exist the S isomer of mirtazapine, which is not currently available
on its use in this population. for prescription. S-mirtazapine, like doxepin, is a selective H1

346 World Psychiatry 18:3 - October 2019

antagonist and has been evaluated in a dosing range far below More concerning, though far less common, is the risk of tardive
the antidepressant dosage, at which it is expected to have only dyskinesia. The increased risk of cerebrovascular events in pa-
H1 antagonist effects of clinical significance169-171. Placebo-con- tients with dementia should also be taken into account.
trolled, randomized, double-blind trials carried out with this As these agents are without abuse potential, they can be con-
agent suggest that, like doxepin, it has robust effects on sleep sidered for use in people who are abuse-prone. They are best
maintenance, with less pronounced therapeutic effects on sleep suited, however, for insomnia occurring in patients with psy-
onset169-171. chosis or bipolar disorder.
The adverse effects of the antidepressants used to treat in- These agents should be used with caution in those with de-
somnia vary. All of them can cause daytime sedation, and mentia, hypotension or at risk for myocardial infarction, closed-
most may cause orthostatic hypotension. The tricyclic antide- angle glaucoma, constipation or urinary retention.
pressants doxepin (25-50 mg) and amitriptyline can cause dry
mouth, constipation, blurred vision, urinary retention, cogni-
tive impairment, arrhythmias, and increased appetite/weight Non-selective antihistamines
gain25. Mirtazapine’s most important adverse effects tend to be
sedation and increased appetite/weight gain. Trazodone’s most Non-selective antihistamines that are often used to treat in-
important adverse effects include sedation and orthostatic hy- somnia include diphenhydramine and doxylamine, which are
potension; it may also induce priapism25. ingredients in many over-the-counter insomnia therapies. Both
As none of these agents has significant abuse potential, they of these agents have, in addition to H1 antagonism, clinically
can be considered in people with a predisposition to substance relevant M1 muscarinic cholinergic antagonism.
abuse. They can also be considered for use in patients who fail There are highly limited data establishing the insomnia ef-
usual therapy or have concomitant conditions such as mood, ficacy of these drugs. A therapeutic effect of diphenhydramine
anxiety or pain difficulties, owing to their broad pharmacologi- 50 mg on self-reported number of awakenings, but not sleep
cal effects25. Doxepin and amitriptyline should be used with quality, total sleep time or sleep onset latency, was reported in a
caution in individuals prone to cognitive impairment, urinary placebo-controlled cross-over study in 20 older primary insom-
obstruction or glaucoma. The use of all these agents is problem- nia patients175. Diphenhydramine 25 mg was also evaluated in a
atic in patients with bipolar depression, because of the risk of parallel-group study along with a combination of valerian and
precipitating mania172. hops in 184 insomnia patients, and found to have a significant
effect vs. placebo on self-reported sleep efficiency, but not self-
reported or polysomnographic sleep onset latency, total sleep
Antipsychotics time, or polysomnographic sleep efficiency176.
The most important adverse effects of these medications are
Antipsychotics are a group of medications developed for sedation, dizziness, psychomotor impairment, cognitive impair-
treatment of psychotic conditions that are sometimes used in ment, dry mouth, blurred vision, constipation, urinary retention
clinical practice to treat insomnia, generally at a dosage lower and weight gain. Less common side effects of diphenhydramine
than that typically used to treat individuals with psychosis25. include agitation and insomnia, whereas doxylamine has been
These agents may have therapeutic effects in insomnia due to linked in case reports to coma and rhabdomyolysis177.
their broad antagonism of wake promoting neurotransmitter As these agents do not have significant abuse potential, they
receptors, such as dopamine, histamine, serotonin, cholinergic can, in theory, be considered for use in substance abuse-prone
and adrenergic receptors. insomnia patients. They are best suited for use in those with in-
The antipsychotic medications that are most commonly used somnia occurring in the setting of allergy symptoms or upper
to treat insomnia in clinical practice are quetiapine 25-250 mg respiratory infections. They are best avoided in those with closed-
and olanzapine 2.5-20 mg. There are no rigorous double-blind, angle glaucoma, decreased gastrointestinal motility, urinary re-
randomized, placebo-controlled trials demonstrating the effica- tention, asthma and chronic obstructive pulmonary disease.
cy of any antipsychotic medication for the treatment of insomnia.
A few small studies of quetiapine have been carried out. This
agent was reported to improve wake time after sleep onset as Anticonvulsants
compared to placebo in a trial of 20 patients with alcohol use
disorder in recovery and sleep disturbance173. A double-blind, Some agents originally developed for treatment of seizures
randomized, placebo-controlled trial of quetiapine 25 mg was are at times used in the management of insomnia. They include
also carried out in 13 patients with primary insomnia and dem- gabapentin and pregabalin, whose potential therapeutic effects
onstrated an advantage for quetiapine on sleep latency and total in insomnia are ascribed to a decreased release of glutamate
sleep time, although neither reached statistical significance174. and norepinephrine through binding to the alpha-2-delta subu-
The primary side effects of these agents include sedation, or- nit of N-type voltage-gated calcium channels178,179.
thostatic hypotension, dry mouth, tachycardia, increased appe- There are no double-blind, randomized, placebo-controlled
tite/weight gain, agitation, dizziness, constipation and akathisia. trials evaluating the efficacy of these agents in insomnia pa-

World Psychiatry 18:3 - October 2019 347

tients. Two double-blind, randomized, placebo-controlled clinical practice. This includes agents such as trazodone, que-
trials were carried out evaluating the effects of gabapentin 250- tiapine and gabapentin. It would be of great value to those clini-
500 mg on sleep disturbance created by putting people to bed cians who tend to prescribe these medications if they had data
five hours earlier than usual (five-hour phase advance model). delineating their risks and benefits to help guide their clinical
They reported that this agent significantly improved both self- decision making.
reported and polysomnographic wake time after sleep onset We also lack studies of the pharmacological treatment of in-
and total sleep time compared with placebo, but not sleep onset somnia in the setting of several key conditions where this treat-
latency180,181. ment is very often needed, such as dementia, mild cognitive
Therapeutic effects of gabapentin and pregabalin on sleep impairment and substance use disorders.
disturbance have also been reported in studies of patients with A final critical gap in our knowledge base reflected in our
pain, restless legs syndrome, generalized anxiety disorder, and review is that we lack research to help guide personalization of
epilepsy182-185. therapy. The vast majority of studies carried out evaluate a sin-
The most important side effects of gabapentin are sedation, gle therapy vs. a placebo or another control intervention. More
dizziness, ataxia and diplopia, whereas the most important trials are needed comparing effective treatments and aimed at
adverse effects of pregabalin include sedation, dizziness, dry optimally matching treatments to specific patient types, so that
mouth, cognitive impairment and appetite increase. Pregabalin we can move to greater personalization in clinical practice.
appears to have some abuse potential, whereas this is not the
case for gabapentin186.
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