Research Analysis

Conduct an analysis of the elements of the research article you identified. Be sure to include the following:

Your topic of interest.
A correctly formatted APA citation of the article you selected, along with link or search details.
Identify a professional practice use of the theories/concepts presented in the article.
Analysis of the article using the “Research Analysis Matrix” section of the template
Write a 1-paragraph justification stating whether you would recommend this article to inform professional practice.
Write a 2- to 3-paragraph summary that you will add to your Academic Success and Professional Development Plan that includes the following:
Describe your approach to identifying and analyzing peer-reviewed research.
Identify at least two strategies that you would use that you found to be effective in finding peer-reviewed research.
Identify at least one resource you intend to use in the future to find peer-reviewed research

Module 3 | Part 3: Research Analysis

I have identified one topic of interest for further study. I have researched and identified one peer-reviewed research article focused on this topic and have analyzed this article. The results of these efforts are shared below.

Directions: Complete Step 1 by using the table and subsequent space below identify and analyze the research article you have selected. Complete Step 2 by summarizing in 2-3 paragraphs the results of your analysis using the space identified.

Step 1: Research Analysis

Complete the table below

Topic of Interest:

Research Article:
Include full citation in APA format, as well as link or search details (such as DOI)

Professional Practice Use:

One or more professional practice uses of the theories/concepts presented in the article

Research Analysis Matrix

Add more rows if necessary

Strengths of the Research

Limitations of the Research

Relevancy to Topic of Interest

Notes

Step 2: Summary of Analysis

Craft a summary (2-3 paragraph) below that includes the following:

·
Describe your approach to identifying and analyzing peer-reviewed research

·
Identify at least two strategies that you would use that you found to be effective in finding peer-reviewed research

·
Identify at least one resource you intend to use in the future to find peer-reviewed research

T h e n e w e ngl a nd j o u r na l o f m e dic i n

n engl j med 391;3 nejm.org July 18, 2024 247

Clinical Practice

From the School of Psychology and Cen-
tre de Recherche CERVO–BRAIN Re-
search Center, Université Laval, Quebec,
QC, Canada (C.M.M.

)

; and the Depart-
ment of Psychiatry, University of Pitts-
burgh Medical Center, Pittsburgh (D.J.B.).

N Engl J Med 2024;391:247-58.
DOI: 10.1056/NEJMcp2305655
Copyright © 2024 Massachusetts Medical Society.

A 50-year-old woman presents with a 6-month history of difficulty falling asleep and
staying asleep several nights per week, which affects her work performance. She re-
ports having had mild-to-moderate symptoms of anxiety and depression for the past
year. She has hypothyroidism, for which she has received levothyroxine therapy; TSH
and thyroid hormone levels were normal when measured the previous month. She
has tried over-the-counter sleep aids (valerian and melatonin), which have had lim-
ited effect, and occasionally has tried hypnotic sleep aids (lorazepam and eszopi-
clone). She is worried about drug dependence, but also believes that her sleep prob-
lem is getting worse. How would you manage this patient’s insomnia?

The Clinic a l Problem

Insomnia disorder is characterized by dissatisfaction with sleep
quality or duration associated with difficulty falling or staying asleep and sub-
stantial distress or daytime impairments. The disorder is a sleep disturbance

that occurs 3 nights or more per week, persists for more than 3 months, and is
not the result of inadequate opportunities for sleep.1 It frequently co-occurs with
other medical conditions (e.g., pain) and psychiatric disorders (e.g., depression),
as well as other sleep disorders (e.g., restless legs syndrome and sleep apnea).

Insomnia is the most prevalent sleep disorder in the general population and
among the most frequent issues raised by patients during primary care visits, al-
though it often goes untreated.2 Approximately 10% of adults meet the criteria for
insomnia disorder and another 15 to 20% report occasional insomnia symptoms.3
Insomnia is more prevalent among women and persons with mental or medical
problems, and its incidence increases in middle age and later, as well as during
perimenopause and menopause.3,4 Although the pathophysiological mechanisms
of insomnia disorder are still poorly understood, psychological and physiological
hyperarousal are recognized as core features.

Insomnia can be situational or episodic, but it follows a persistent course in
more than 50% of patients. The first episode typically arises from stressful life
situations, health problems, atypical work schedules, or travel across several time
zones (jet lag). Although most persons resume normal sleep after adjusting to the
precipitating event, chronic insomnia may develop in persons who are vulnerable
to the disorder. Psychological, behavioral, or medical factors often perpetuate
chronic sleep difficulties. For instance, sleeping late in the morning or napping
during the day can initially help persons cope with sleep disturbances; however,
those same practices can exacerbate sleep difficulties over time and become treat-

Patrick G. O’Malley, M.D., M.P.H., Editor

Management of Insomnia
Charles M. Morin, Ph.D., and Daniel J. Buysse, M.D.

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence
supporting various strategies is then presented, followed by a review of formal guidelines, when they exist.

The article ends with the authors’ clinical recommendations.

CME

n engl j med 391;3 nejm.org July 18, 2024

248

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

248

ment targets. In perimenopausal women, vaso-
motor symptoms may serve as both a precipitating
and perpetuating factor. Chronic insomnia is
associated with increased risks of major depres-
sion,5 hypertension,6 Alzheimer’s disease,7 and
work disability.

The assessment and diagnosis of insomnia
rests on a careful history to document symptoms,
course, co-occurring conditions, and other con-
tributing factors (Table 1).8 A 24-hour history of

sleep–wake behaviors may identify additional be-
havioral and environmental targets for interven-
tion (Fig. 1). Patient-reported assessment tools and
sleep diaries can provide valuable information
about the nature and severity of insomnia symp-
toms, help screen for other sleep disorders, and
monitor treatment progress (Table 2).

S tr ategies a nd E v idence

Current treatment options for insomnia include
prescribed and over-the-counter medications, psy-
chological and behavioral therapies (also referred
to as cognitive behavioral therapy for insomnia
[CBT-I]), and complementary and alternative ther-
apies. The usual treatment trajectory involves the
use of over-the-counter medications and, when
the disorder is brought to the attention of a prac-
titioner, prescription medication. Few patients
receive CBT-I, owing in part to the lack of ade-
quately trained therapists.

CBTI-I

CBT-I involves a combination of strategies aimed
at changing the behavioral practices and psycho-
logical factors (e.g., excessive worries and un-
helpful beliefs about sleep) that contribute to
insomnia. The core components of CBT-I include
behavioral and sleep-scheduling strategies (sleep
restriction and stimulus control instructions),
relaxation methods, psychological and cognitive
interventions (or both) aimed at changing un-
helpful beliefs and excessive worrying about in-
somnia, and sleep hygiene education (Table 3).

Key Points

Treatment Approaches to Insomnia

• Insomnia is common, and it frequently occurs when other medical, psychiatric, and other sleep
disorders are present.

• Persistent insomnia is associated with substantial distress, functional impairment, and adverse health
outcomes, including increased risks of major depression, hypertension, and work disability.

• Current guidelines recommend cognitive behavioral therapy for insomnia (CBT-I) as a first-line
treatment for persistent insomnia. CBT-I includes practical strategies for modifying sleep habits,
regulating sleep–wake schedules, reducing arousal from sleep, and reframing unhelpful beliefs about
sleep and insomnia.

• Medications with an indication for insomnia (e.g., benzodiazepine receptor agonists, dual orexin
receptor antagonists, and doxepin) that are approved by the Food and Drug Administration are
recommended as alternative or adjunctive treatments. There is inadequate evidence to support over-
the-counter medications, antipsychotics, or alternative agents for insomnia.

• Recommended therapies for insomnia produce clinically meaningful reductions in insomnia
symptoms, sleep-onset latency, and time awake after sleep onset. CBT-I alone or with medication can
promote rapid and sustained alleviation of insomnia symptoms over tim

Table 1. Key Elements of Assessment.

Typical sleep schedule: bedtime, rise time, and daytime napping

Nature of sleep concern: frequency, duration, course, triggers, and exacerbat-
ing factors

Daytime symptoms and effects: activities that are cancelled or avoided as a
result of sleep problems

Symptoms of other sleep disorders that may produce insomnia

Loud snoring, restless sleep, and excessive daytime sleepiness (sleep
apnea)

Urge to move the legs or unpleasant leg sensations in the evening (rest-
less legs syndrome)

Unusual or aggressive behaviors during sleep: sleepwalking, rapid-eye
movement (REM)–sleep behavior disorder

Medical and psychiatric history: identify contributing medical problems and
psychiatric conditions

Environmental factors

Bedroom environment, noise, light level, and temperature

Sleep hygiene: alcohol use; use of tea, coffee, or nicotine; exercise patterns

Previous treatments and outcomes

Prescribed and over-the-counter medications and supplements

Behavioral measures to improve sleep

n engl j med 391;3 nejm.org July 18, 2024 249

Clinical Pr actice

Additional psychological interventions, such as
Acceptance and Commitment Therapy and Mind-
fulness-Based Therapy, have been adapted for
insomnia, but fewer data support their efficacy,
and they take more time to yield benefits (Ta-
ble 3). CBT-I is prescriptive, focused on sleep, and
oriented toward problem solving. It is typically
guided by a mental health therapist (e.g., a psy-
chologist) in the context of four to eight consulta-
tion visits. There are several variants in the
methods for implementing CBT-I, including ab-
breviated and group formats,14 the involvement
of other providers (e.g., a nurse practitioner),15
and the use of telehealth or digital platforms.16

CBT-I is currently the first-line treatment rec-
ommended in the practice guidelines of several
professional organizations (labeled as a “strong
recommendation” on the basis of the Grading of
Recommendations Assessment, Development, and

Evaluation [GRADE] method).17-19 Evidence from
clinical trials and meta-analyses indicates that
CBT-I produces substantial improvements in pa-
tient-reported outcomes, typically measured with
the use of a standardized effect-size method (ei-
ther Cohen’s d or Hedges’ g). The effect size is a
measure of the magnitude of difference between
groups, with conventional thresholds for the size
of effect as follows: 0.2, small; 0.5. moderate; and
0.8, large. In meta-analyses of these trials, CBT-I
showed improvement in insomnia-symptom se-
verity (effect size, 0.98; 95% confidence interval
[CI], 0.82 to 1.15), sleep-onset latency (effect size,
0.57; 95% CI, 0.50 to 0.65), and time awake after
sleep onset (effect size, 0.63; 95% CI, 0.53 to
0.73). Improved sleep continuity was also associ-
ated with a corresponding increase in sleep ef-
ficiency (the ratio of time asleep to time spent in
bed; effect size, 0.71; 95% CI, 0.61 to 82). Total

Figure 1. Use of 24-Hour History for Insomnia Assessment.

Insomnia manifests as a sleep problem but affects — and is affected by — daytime behaviors. A thorough insomnia history helps evalu-
ate symptoms and behaviors both at night and during the day. Shown are key parts of an insomnia assessment across a 24-hour day.

Evening
activities, light level,

and arousal

Naps and dozing
(number, duration,

timing, and
situations)

Meal
and exercise

timing

Work, school,
and family
activities

Morning
light level

and activit

Ease of

awakening

Awakenings
(number, duration,

and timing)

Response to
awakenings

Final
awakening

time

Sleep
duration

Out-of-bed
time

Insomnia Assessment
over 24 Hr

Bedtime, level
of sleepiness

Activities and mental
state before sleep

Time to fall asleep
(sleep latency)

n engl j med 391;3 nejm.org July 18, 2024250

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

sleep time had increased modestly at the end of
treatment (effect size, 0.16; 95% CI, 0.08 to 0.24),
although additional benefits were often seen
several weeks or months after the end of thera-
py.17,20,21 Effect sizes are strongest for global in-
somnia symptom severity. Efficacy does not ap-
pear to be moderated by age, insomnia severity,
the presence of coexisting conditions, or hypnotic
medication use. Smaller improvements have been
noted for daytime symptoms (e.g., fatigue and
mood) and quality of life,22,23 which have been
attributed in part to the use of generic measure-
ments not specifically developed for insomnia.
Overall, approximately 60 to 70% of patients
have a clinical response, which is defined as a
reduction of 7 points on the Insomnia Severity
Index (ISI; scores range from 0 to 28, with
higher scores indicating more severe insomnia).
A sample ISI form is shown in the Supplemen-
tary Appendix, available with the full text of this
article at NEJM.org. Approximately 50% of per-
sons with insomnia had remission (total ISI
score, <8) after 6 to 8 weeks of treatment, and 40 to 45% had sustained remission for 12 months. Daytime sleepiness is a potential adverse event in the early phase of restricting time in bed, but that effect tends to resolve as the sleep time is increased.24

Digital CBT-I (eCBT-I) has gained in popularity
over the past decade and could eventually narrow

the important gap between demand and access
to CBT-I. The SHUTi and Sleepio applications
have substantial published evidence supporting
their efficacy. A meta-analysis of 11 randomized
clinical trials involving 1460 participants that
tested Web-based CBT-I found that eCBT-I had a
positive effect on several sleep outcomes (i.e.,
insomnia severity, sleep efficiency, subjective
sleep quality, wake after sleep onset, sleep-onset
latency, total sleep time, and number of noctur-
nal awakenings), with effect sizes ranging from
0.21 to 1.09. These effects were similar to those
observed in trials of face-to-face CBT-I and were
maintained for 4 to 48 weeks after follow-up.16
Additional digital CBT-I products (e.g., CBT-i
Coach, Go! To Sleep, and Sleep Reset) use simi-
lar therapeutic principles but have no or limited
published efficacy data.

Treating co-occurring conditions such as de-
pression and chronic pain may alleviate insom-
nia symptoms but generally does not completely
resolve them. Conversely, the treatment of insom-
nia improves sleep in the context of co-occurring
conditions but has less consistent effects on the
co-occurring conditions themselves. For instance,
the treatment of insomnia alleviates depression
symptoms and reduces the incidence and recur-
rence of depression25 but has only small effects
on chronic pain.26

Stepped-care approaches may help to address

Table 2. Tools for the Clinical Assessment of Insomnia.

Domain and Measure Description

Sleep–wake characteristics: sleep
diary

Completed daily by the patient to collect information about sleep schedule (bed-
time, arising time, napping) and estimates of sleep–wake characteristics
(sleep latency, number and duration of awakenings, and sleep time). Useful
for determining the nature, frequency, and severity of sleep problems and
monitoring progress during treatment.9

Insomnia symptom severity:
Insomnia Severity Index

A 7-item, patient-reported scale for assessing perceived severity of insomnia
symptoms and daytime distress and impairments. Scores range from 0 to
28; 0 to 7 indicates no significant insomnia, 8 to 14 indicates subthreshold
insomnia, 15 to 21 indicates moderate insomnia, and 22 to 28 indicates severe
insomnia. The scale includes guidelines for defining clinical insomnia and re-
sponse or remission after treatment.10

Sleep quality: Pittsburgh Sleep
Quality Index

A 19-item patient-reported scale measuring overall sleep quality and a screening
tool for other sleep disorders.11

Screening for sleep apnea and rest-
less legs syndrome

STOP–Bang An 8-item patient-reported questionnaire for evaluating risk of sleep-related
breathing disorders.12

International Restless Legs
Syndrome Rating Scale

A 10-item patient-reported questionnaire assessing frequency, severity, and effect
of restless legs syndrome (scores range from 0 to 40, with higher scores indi-
cating more severe symptoms).13

n engl j med 391;3 nejm.org July 18, 2024 251

Clinical Pr actice

resource limitations with traditional psychologi-
cal and behavioral therapies. One such model
recommends education, monitoring, and self-help
approaches at the first level, digital or group-
based psychological and behavioral treatment at
the second level, individual psychological and
behavioral treatment at the third level, and phar-
macotherapy as a short-term adjunct at each level.27

Medications

Prescribing patterns for hypnotic medications in
the United States have changed substantially over
the past 20 years.28 Prescriptions for benzodiaz-

epine receptor agonists have steadily decreased
and prescriptions for trazodone have steadily
increased, notwithstanding the absence of a
Food and Drug Administration (FDA) indication
for the use of trazodone to treat insomnia. In
addition, orexin receptor antagonist drugs were
introduced in 2014 and are widely used. Hyp-
notic medications are prescribed at higher rates
for women, older adults, and non-Hispanic White
patients, which reflects the epidemiologic char-
acteristics of insomnia.29 The main classes of
sleep-promoting medications are summarized in
Table 4. Controlled data are sparse regarding the

Table 3. Psychological and Behavioral Therapies for Patients with Insomnia.

Therapy Description

Sleep restriction This intervention limits the amount of time spent in bed (the sleep window) to match as
closely as possible the actual sleep time and strengthens the homeostatic sleep drive
(the increase in sleep propensity that accumulates with an increased duration of wake-
fulness). After the initial restriction, the sleep window is gradually adjusted upward or
downward on a weekly basis and as a function of sleep efficiency (time asleep ÷ time
spent in bed × 100) until an appropriate sleep duration is established.

Stimulus control Go to bed only when sleepy.
Get out of bed when unable to sleep.
Use the bed and bedroom for sleep and sex only (no reading, watching television, etc.).
Arise at the same time every morning.
Avoid napping.

Relaxation training This method involves the use of clinical procedures (e.g., progressive muscle relaxation
and imagery training) aimed at reducing autonomic arousal, muscle tension, and in-
trusive thoughts that interfere with sleep. Most relaxation procedures begin with some
professional guidance and are practiced daily over a period of a few weeks. Relaxation
training is not always included in cognitive behavioral therapy for insomnia (CBT-I).

Cognitive therapy This psychological approach uses Socratic questioning and behavioral experiments to
revise common misconceptions about sleep and to reframe unhelpful beliefs about
insomnia and its daytime consequences. This method is also intended to reduce ex-
cessive worrying about sleep difficulties and their daytime consequences. Additional
cognitive strategies may also involve paradoxical intention (willingly trying to stay
awake rather than trying to fall asleep) in order to alleviate the performance anxiety
triggered by attempting to force sleep.

Sleep hygiene education The patient receives education regarding general guidelines about health practices (e.g.,
diet, exercise, and substance use) and environmental factors (e.g., light level, noise,
and excessive temperature) that may promote or interfere with sleep. This may also
include some basic information about normal sleep and changes in sleep patterns
with aging.

Acceptance and commit-
ment therapy (ACT)

ACT is a type of psychotherapy aimed at educating the patient to stay focused on the
present moment and accept life experiences, thoughts, and feelings (even negative
ones) without trying to change them. ACT involves the use of different methods (e.g.,
acceptance, defusion, mindfulness, and committed action) and processes in order to
increase psychological flexibility.

Mindfulness This approach is a meditation method that involves observing one’s thoughts and feel-
ings and letting go of the need to change or ruminate about things. Originally de-
signed as a method of reducing stress and anxiety, mindfulness has been adapted for
the management of insomnia and can be included as one component of ACT.

Brief behavioral treatments
for insomnia

This abbreviated version of CBT-I emphasizes behavioral components and is typically
implemented in fewer (one to four) sessions. It involves education about sleep regula-
tion and factors that promote or interfere with sleep, along with a tailored behavioral
prescription based on stimulus control and sleep-restriction therapy.

n engl j med 391;3 nejm.org July 18, 2024252

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

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n engl j med 391;3 nejm.org July 18, 2024 253

Clinical Pr actice

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n engl j med 391;3 nejm.org July 18, 2024254

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

long-term efficacy and side-effect profiles of hyp-
notic medications, despite their frequent long-
term use.

Benzodiazepine Receptor Agonist Hypnotics
Benzodiazepine receptor agonist hypnotics in-
clude benzodiazepines and nonbenzodiazepines
(also known as Z-drugs). These subclasses have
different chemical structures, but both are allo-
steric modulators of a common binding site on
γ-aminobutyric acid type A (GABA A) receptors,
which accounts for their similar actions and side
effects. Some benzodiazepine receptor agonists
(e.g., zolpidem) have relative specificity for sub-
populations of GABA A receptors that are re-
sponsible for sleep promotion relative to anxio-
lytic, myorelaxant, and anticonvulsant effects. In
practice, however, pharmacodynamic differenc-
es among benzodiazepine receptor agonists are
less salient than differences in pharmacokinetic
properties, particularly elimination half-life.
Clinical trials and meta-analyses have shown the
efficacy of benzodiazepine receptor agonists for
reducing sleep-onset latency and wakefulness
after sleep onset, with small increases in total
sleep time (Table 4).30,31 Patient-reported side ef-
fects of benzodiazepine receptor agonists include
anterograde amnesia (in <5%), next-day sedation (in 5 to 10%), and complex behaviors during sleep, such as sleepwalking, eating, or driving (in 3 to 5%), a side effect that is responsible for black-box warnings for zolpidem, zaleplon, and eszopiclone. These side effects are more likely to occur with higher doses, coprescription with other sedating medications, and (in the case of amnesia and sedation) longer-duration agents. The devel- opment of drug tolerance and physiological de- pendence marked by rebound insomnia and with- drawal syndromes occurs with repeated nightly use in 20 to 50% of patients.32 Although misuse of benzodiazepine receptor agonists (i.e., use without a prescription or at larger doses or longer duration than prescribed) is relatively common, substance use disorder involving benzodiazepine receptor agonists is uncommon.33 Epidemiologic data show dose-dependent and duration-depen- dent increases in the risks of hip fractures34 and dementia with long-term use of benzodiazepine receptor agonists, but confounding by indication may contribute to these observed risks.

Sedating Heterocyclic Drugs
Sedating antidepressant drugs, including tricyclic
drugs (e.g., amitriptyline, nortriptyline, and
doxepin) and heterocyclic drugs (e.g., mirtaza-
pine and trazodone), are commonly prescribed to
treat insomnia. Of these, only doxepin (at a dose
of 3 to 6 mg daily, taken at night) is FDA-approved
for insomnia. The lower doses used in insomnia
than in depression and the more rapid onset of
action in insomnia than in depression suggest
distinct mechanisms of action for these indica-
tions. Despite their widespread use, the efficacy
of the sedating antidepressants in the treatment
of insomnia is not well supported by controlled
trials, except in the case of doxepin. Meta-anal-
yses of trazodone trials have shown inconsistent
effects on sleep-onset latency, wake after sleep
onset, and total sleep time.35,36 Given these limi-
tations, current evidence suggests that sedating
antidepressants in aggregate increase sleep qual-
ity, sleep efficiency, and total sleep time, with
little effect on sleep latency.35 Clinicians and pa-
tients often prefer these medications, despite their
lack of specific FDA indication for insomnia, be-
cause of their mild side effects at low doses and
clinical experience of efficacy. Side effects can
include sedation, dry mouth, cardiac conduction
delay, hypotension, and hypertension. Sedating
heterocyclic drugs approved for the treatment of
schizophrenia and bipolar disorder, such as que-
tiapine and olanzapine, are sometimes used to
treat insomnia. However, the cardiovascular,
metabolic, and neurologic risks of these drugs
weigh against their use except in persons with
co-occurring psychiatric disorders.

Orexin Receptor Antagonists
Orexin (hypocretin)–containing neurons in the
lateral hypothalamus stimulate wake-promoting
nuclei in the brainstem and hypothalamus and
inhibit sleep-promoting nuclei in the ventrolat-
eral and median preoptic areas.37 Conversely,
inhibiting orexinergic neurotransmission inhib-
its wakefulness and promotes sleep. Three dual
orexin receptor antagonists — suvorexant, lem-
borexant, and daridorexant — are FDA-approved
for insomnia. Clinical trials support their efficacy
for sleep-onset and sleep-maintenance symp-
toms.30,38,39 Side effects include sedation, fatigue,
and abnormal dreaming, but they produce less

n engl j med 391;3 nejm.org July 18, 2024 255

Clinical Pr actice

cognitive impairment than benzodiazepine re-
ceptor agonists.40 Because a deficiency in endog-
enous orexin causes narcolepsy with cataplexy,
orexin antagonists are contraindicated in patients
with this condition.

Melatonin and Melatonin Receptor Agonists
Melatonin is a pineal hormone that is endoge-
nously secreted during darkness at night. Exog-
enous melatonin produces supraphysiologic blood
levels for varying durations depending on the
specific dose and formulation. The appropriate
dose of melatonin for treating insomnia is not
defined. Controlled trials involving adults have
shown a small effect on sleep onset, with little
effect on wakefulness during sleep or on total
sleep time.41,42 Melatonin is increasingly used to
treat sleep problems in children, although its
efficacy and safety are not well established ex-
cept in children with neurodevelopmental dis-
orders.43

Drugs that bind to melatonin MT1 and MT2
receptors are approved for the treatment of
sleep-onset insomnia (ramelteon) and circadian-
rhythm sleep–wake disorder (tasimelteon). Like
melatonin, these drugs have little effect on
wakefulness after sleep onset or on total sleep
time.42 Somnolence and fatigue are the most
common side effects.

Other Medications
Antihistamine medications obtained over the
counter (diphenhydramine and doxylamine) and
by prescription (hydroxyzine) are among the most
commonly used medications for the treatment of
insomnia. Data supporting their efficacy are
weak,41 but their availability and perceived safety
as compared with benzodiazepine receptor ago-
nists probably contribute to their popularity.
Sedating antihistamines can cause excessive se-
dation, anticholinergic side effects, and an in-
creased risk of dementia. Gabapentinoids, such as
gabapentin and pregabalin, are commonly used
for the treatment of chronic pain and are also
first-line agents for the treatment of restless legs
syndrome.44 These drugs produce sedation and
increase slow-wave sleep, and are prescribed off-
label for insomnia, particularly when accompa-
nied by pain. Fatigue, somnolence, dizziness, and
ataxia are the most common side effects.

Complementary and Alternative Therapies

Alternative treatments are widely used among
persons with insomnia.45 Cannabis, cannabidiol
(CBD), and delta-9-tetrahydrocannabinol (THC)
preparations are also widely used to treat sleep
problems, but are associated with mixed find-
ings. The overall quality of evidence supporting
the efficacy of cannabinoids for insomnia is
low, owing to the absence of large, well-con-
trolled clinical trials and the apparent develop-
ment of tolerance to hypnotic effects that can
result from chronic administration. Variation
in cannabis-derived preparations is also rele-
vant. For instance, CBD is stimulating at low
doses and sedating at high doses, and THC has
the opposite effects.

Selection of Hypnotic Medication

When medication is the selected treatment, a
short-acting benzodiazepine receptor agonist,
orexin antagonist, or low-dose heterocyclic drug
is a reasonable first choice in most clinical sce-
narios. Benzodiazepine receptor agonists may
be preferred in the treatment of patients with
insomnia with predominantly sleep-onset symp-
toms, in younger adults, and when short-term
use is likely (e.g., in response to acute or periodic
stressors). Low-dose heterocyclic drugs or orexin
antagonists may be preferred in treating patients
with symptoms that are predominantly related
to sleep maintenance or early awakening, older
adults, and patients with substance use disorders
or sleep apnea. The Beers Criteria list of medica-
tions deemed to be relatively inappropriate for
patients 65 years of age or older includes benzo-
diazepine receptor agonists and heterocyclic
drugs, but does not include doxepin, trazodone,
or orexin antagonists. Initial medication treat-
ment often includes nightly use for 2 to 4 weeks
followed by reevaluation of effects and side ef-
fects. Intermittent administration (2 to 4 times
per week) is encouraged if long-term use is ap-
propriate. Patients should be instructed to take
medications 15 to 30 minutes before bedtime.
With prolonged medication use, drug dependence
develops in some patients, particularly with the
use of benzodiazepine receptor agonists. A sys-
tematic tapering schedule (e.g., by 25% per week)
can help to reduce or discontinue the use of
hypnotics after long-term use.46,47

n engl j med 391;3 nejm.org July 18, 2024256

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

Combination Therapy or Single Therapy

Evidence from the few head-to-head comparative
studies available indicates that both CBT-I and
hypnotic medications (mostly Z-drugs) produce
equivalent improvements in sleep continuity in
the short term (4 to 8 weeks),48-51 although medi-
cation has been shown to increase total sleep
time more than CBT-I. Combined therapy pro-
duces improvement in sleep more quickly than
CBT-I alone, but this advantage decreases by
the fourth or fifth week of treatment,52 and
CBT-I used alone produces more sustained ben-
efits over time than medication or combined
therapy. Some patients may have less adherence
to behavioral recommendations when the easier
alternative of taking a sleep medication is also
available.

Guidelines

Current guidelines that have been endorsed by
health care and professional organizations rec-
ommend CBT-I as the first-line treatment for
insomnia and medications as alternative or ad-
junctive treatment, within the context of shared
decision making.17-19,53,54 Guidelines recommend
CBT-I with a strong level of support, and sub-
components such as brief behavioral treatment,
sleep restriction, and stimulus control are rec-
ommended with lower levels of support. Among
medications, guidelines make weak recommen-
dations with moderate-quality evidence for the
use of FDA-approved hypnotic medications (e.g.,
benzodiazepine receptor agonists, doxepin, and
orexin antagonists) and weak evidence against
the use of other agents, including heterocyclic
drugs such as trazodone and antipsychotic agents.
Recommendations in this article are generally con-
sistent with these guidelines.

A r e a s of Uncerta in t y

Evidence is lacking regarding the long-term ef-
ficacy of medications and the development of
tolerance to medications for insomnia. The role
of intermittent medication and the appropriate
schedule for administration are still unclear. Al-
though network meta-analyses address the rela-
tive efficacy and side effects of different medica-
tion classes, few large trials have directly compared
different active medications. Telehealth and digi-
tal CBT platforms offer potential solutions for
some patients, although more information is
needed to identify the patients who benefit most.
Additional work is needed to identify reliable in-
somnia phenotypes55 and test whether persons
with those phenotypes have different responses
to more personalized therapeutic approaches.

Conclusions a nd
R ecommendations

The patient in the vignette spends long periods
of time in bed with considerable variability in
the time taken to fall asleep and the time sleep-
ing. She described anxiously worrying about
falling asleep and staying asleep. We would initi-
ate CBT-I with a focus on reducing overall time
in bed to improve sleep consolidation, maintain-
ing regular sleep–wake times to strengthen cir-
cadian sleep regulation, and performing cogni-
tive exercises to reduce sleep-focused rumination.
If insomnia recurred in the setting of stressful
life events, we would prescribe doxepin for inter-
mittent use on those occasions.

The content of this article is solely the responsibility of the
authors and does not necessarily represent the views of the
Patient-Centered Outcomes Research Institute or its Board of
Governors or Methodology Committee.

Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

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