Research Analysis

Management_of_Insomnia.pdf

Home >Nursing homework help >Research Analysis

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

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.).

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, 2024248

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 time.

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 activity 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

Ta bl

e 4.

M ed

ic at

io ns

fo r

th e

Tr ea

tm en

t o f I

ns om

ni a.

M ed

ic at

io n

C la

ss a

Ty pe

s Ex

am pl

es a

nd A

pp ro

xi m

at e

H al

f-L ife

Po te

nt ia

l A dv

an ta

ge s

Po te

nt ia

l D is

ad va

nt ag

es Ef

fe ct

S iz

e (

95 %

C I)

B en

zo di

az ep

in e

re ce

pt or

on is

ts †

C on

si st

en t e

vi de

nc e

of e

ffi ca

cy fo

r sl

ee p

on se

t a nd

s le

ep m

ai nt

en an

ce fo

r ag

en ts

a pp

ro ve

d by

th e

FD A

. R an

ge o

f ha

lf- liv

es c

an a

cc om

m od

at e

di ffe

re nt

m pt

om p

ro fil

es .

Sh or

t- te

rm r

is ks

: s ed

at io

n, a

nt er

og ra

am ne

si a,

c og

ni tiv

e an

d ps

yc ho

m ot

im pa

ir m

en t,

na us

ea , h

ea da

ch es

, c om

- pl

ex s

le ep

-r el

at ed

b eh

av io

r (F

D A

w ar

n- in

g) , r

eb ou

nd in

so m

ni a

Lo ng

-t er

m r

is ks

: f al

ls , h

ip fr

ac tu

re s,

p hy

si -

ol og

ic al

d ep

en de

nc e,

d ep

re ss

io n,

d e-

m en

tia

Sh or

t- ac

tin g,

0 .8

3 (0

.6 2

1. 04

); in

te rm

ed ia

te -a

ct -

in g,

0 .6

7 (0

.5 2

to 0

.8 2)

; lo

ng -a

ct in

g, 0

.5 8

(0 .4

2 to

73 );

e sz

op ic

lo ne

, 0 .5

1 (0

.3 5

to 0

.6 8)

; z ol

pi de

m ,

0. 45

( 0.

36 to

0 .5

6) ; z

al -

ep lo

n, 0

.1 9

(0 .0

0 to

0 .3

B en

zo di

az ep

in es

Tr ia

zo la

m (

4 hr

)† , t

em az

ep am

0 hr

)† , c

lo na

ze pa

m (

hr )†

‡

N on

be nz

od ia

ze pi

ne s

(Z -d

ru gs

) Z

ol pi

de m

( 2.

5 hr

)† , z

al ep

lo n

hr )†

, e sz

op ic

lo ne

( 6

hr )†

D ua

l o re

xi n

re ce

pt or

ta go

ni st

s Su

vo re

xa nt

( 12

h r)

, l em

bo re

x- an

t ( 18

h r)

, d ar

id or

ex an

t (8

h r)

C on

si st

en t e

vi de

nc e

of e

ffi ca

cy fo

r sl

ee p

on se

t a nd

s le

ep m

ai nt

en an

ce . T

ar ge

te d

m ec

ha ni

sm o

f a ct

io n

on w

ak e-

pr om

ot -

in g

or ex

in s

ys te

m . L

ow er

r is

k of

c og

ni -

tiv e

an d

ps yc

ho m

ot or

im pa

ir m

en t t

ha n

be nz

od ia

ze pi

ne r

ec ep

to r

ag on

is ts

; l ow

te nt

ia l f

or a

bu se

a nd

p hy

si ol

og ic

de pe

nd en

ce .

Sh or

t- te

rm r

is ks

: s ed

at io

n, c

og ni

tiv e

an d

ps yc

ho m

ot or

im pa

ir m

en t,

di zz

in es

he ad

ac he

s, a

bn or

m al

d re

am s,

n ig

ht -

m ar

es , s

le ep

p ar

al ys

is , c

om pl

ex s

le ep

- re

la te

d be

ha vi

or , i

nc re

as ed

d ep

re ss

io n

C on

tr ai

nd ic

at ed

in p

at ie

nt s

w ith

n ar

co -

le ps

D ar

id or

ex an

t, 0.

23 (

−0 .0

1 to

48 );

le m

bo re

xa nt

, 0 .3

6 (0

.0 8

to 0

.6 3)

; s uv

or ex

- an

t, 0.

31 (

0. 01

to 0

.6 2)

Se da

tin g

an tid

ep re

ss an

ts D

ox ep

in (

15 h

r) , t

ra zo

do ne

h r)

,‡ , m

ir ta

za pi

ne (

hr )†

‡ , a

m itr

ip ty

lin e

(3 0

hr )†

‡

M ec

ha ni

sm s

of a

ct io

n in

vo lv

e hi

st am

in e,

ro to

ni n,

a nd

a dr

en er

gi c

re ce

pt or

Ef fic

ac y

da ta

fo r

m ai

nt en

an ce

, v ar

ia bl

e ev

id en

ce fo

r sl

ee p

on se

t. Lo

w p

ot en

tia l

fo r

ab us

In co

ns is

te nt

e ffi

ca cy

e vi

de nc

e fo

r in

so m

ni a

(o th

er th

an d

ox ep

in 3

–6 m

g) Sh

or t-

te rm

r is

ks : s

ed at

io n,

c og

ni tiv

e an

d ps

yc ho

m ot

or im

pa ir

m en

t, ca

rd ia

c co

n- du

ct io

n de

la y,

a nt

ic ho

lin er

gi c

ef fe

ct s,

us ea

, s er

ot on

in s

yn dr

om e,

in cr

ea se

d su

ic id

al ity

Lo ng

-t er

m r

is ks

: f al

ls , h

ip fr

ac tu

re s,

d e-

m en

tia , p

hy si

ol og

ic al

d ep

en de

nc e

(i .e

., re

bo un

d in

so m

ni a)

; w ei

gh t g

ai n,

et ab

ol ic

e ffe

ct s

(i .e

., ab

no rm

al g

lu -

co se

m et

ab ol

is m

, l ip

id le

ve ls

) w

ith

m ir

ta za

pi ne

D ox

ep in

, 0 .3

0 (−

0. 05

to 0

.6 4)

; tr

az od

on e,

0 .5

2 (0

.1 6

0. 89

)

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

Clinical Pr actice

M ed

ic at

io n

C la

ss a

Ty pe

s Ex

am pl

es a

nd A

pp ro

xi m

at e

H al

f-L ife

Po te

nt ia

l A dv

an ta

ge s

Po te

nt ia

l D is

ad va

nt ag

es Ef

fe ct

S iz

e (

95 %

C I)

M el

at on

in , m

el at

on in

ce pt

or a

go ni

st s

M el

at on

in (

1 hr

)‡ , r

am el

te on

( 2

hr )

ta si

m el

te on

( 1–

4 hr

)‡ M

ec ha

ni sm

o f a

ct io

n in

vo lv

es m

el at

on in

ce pt

or s.

E ffi

ca cy

d at

a fo

r sl

ee p

on -

se t.

Ef fic

ac y

ev id

en ce

fo r

in so

m ni

a in

ild re

n w

ith n

eu ro

de ve

lo pm

en ta

l d is

- or

de rs

. G en

er al

ly a

ss oc

ia te

d w

ith fe

si de

e ffe

ct s

an d

lo w

p ot

en tia

l f or

a bu

se .

N ot

e ffi

ca ci

ou s

fo r

sl ee

p m

ai nt

en an

ce Sh

or t-

te rm

r is

ks : s

ed at

io n,

fa tig

ue , d

iz zi

- ne

ss , n

au se

a, a

bn or

m al

d re

am s

M el

at on

in , 0

.1 3

(− 0.

11 to

38 );

r am

el te

on , 0

.1 2

(− 0.

14 to

0 .3

7) ; t

as im

el -

te on

Se da

tin g

an tih

is ta

m in

es D

ip he

nh yd

ra m

in e

(6 h

r) †

, d ox

- yl

am in

e (1

0 hr

)† , h

yd ro

xy -

zi ne

( 20

h r)

† ‡

W id

el y

av ai

la bl

e ov

er th

e co

un te

r an

d by

es cr

ip tio

n. M

ec ha

ni sm

o f a

ct io

n in

- vo

lv es

a nt

ag on

is m

o f c

en tr

al h

is ta

m in

e re

ce pt

or s.

Li m

ite d

ef fic

ac y

da ta

fo r

in so

m ni

a Sh

or t-

te rm

r is

ks : s

ed at

io n,

c og

ni tiv

e an

d ps

yc ho

m ot

or im

pa ir

m en

t, an

tic ho

lin er

- gi

c ef

fe ct

s (e

.g .,

dr y

m ou

th )

Lo ng

-t er

m r

is k:

d em

en tia

( an

tic ho

lin er

gi c

ef fe

ct )

In su

ffi ci

en t d

at a

Se da

tin g

an tip

sy ch

ot ic

s Q

ue tia

pi ne

( 6

hr )†

‡ , o

la nz

a- pi

ne (

30 h

r) †

‡ Se

da tin

g in

c lin

ic al

tr ia

ls o

f p at

ie nt

s w

ith

sc hi

zo ph

re ni

a or

b ip

ol ar

d is

or de

Sm al

l s tu

di es

s ug

ge st

e ffi

ca cy

o n

pa tie

nt -r

ep or

te d

an d

po ly

so m

no -

gr ap

hi c

sl ee

p m

ea su

re s

in in

so m

ni a.

ec ha

ni sm

o f a

ct io

n in

vo lv

es m

ul tip

re ce

pt or

ty pe

s (e

.g .,

se ro

to ni

n, d

op a-

m in

e, a

nd h

is ta

m in

e) .

Li m

ite d

ef fic

ac y

da ta

fo r

in so

m ni

a Sh

or t-

te rm

r is

ks : s

ed at

io n,

d iz

zi ne

ss , c

og -

ni tiv

e an

d ps

yc ho

m ot

or im

pa ir

m en

t, hy

po te

ns io

n, h

ea da

ch e,

d ry

m ou

th Lo

ng -t

er m

r is

ks : m

et ab

ol ic

e ffe

ct s

(e .g

., gl

uc os

e m

et ab

ol is

m a

nd li

pi d

le ve

ls )

an d

w ei

gh t g

ai n

In su

ffi ci

en t d

at a

M is

ce lla

ne ou

s G

ab ap

en tin

( 7

hr )†

‡ , p

re ga

ba -

lin (

6 hr

)† ‡

Ef fic

ac y

da ta

fo r

ch ro

ni c

pa in

( of

te n

oc -

cu rr

in g

w ith

in so

m ni

a) . S

ub je

ct iv

el y

se da

tin g

in c

lin ic

al tr

ia ls

fo r

ot he

r co

n- di

tio ns

. M ec

ha ni

sm o

f a ct

io n

in vo

lv es

ph a

2– de

lta r

ec ep

to rs

. E lim

in at

ed b

y re

na l e

xc re

tio n.

Ef fic

ac y

da ta

fo r

in so

m ni

a sp

ar se

a nd

in -

co ns

is te

nt Sh

or t-

te rm

r is

ks : s

ed at

io n,

d iz

zi ne

ss , c

og -

ni tiv

e an

d ps

yc ho

m ot

or im

pa ir

m en

t, ed

em a,

r es

pi ra

to ry

d ep

re ss

io n

Lo ng

-t er

m r

is ks

: d ep

re ss

io n

an d

su ic

id al

- ity

, p hy

si ol

og ic

al d

ep en

de nc

In su

ffi ci

en t d

at a

* Ef

fe ct

s iz

es fo

r ne

w (

us e,

< 4

w ee

ks )

m ed

ic at

io n

tr ea

tm en

ts o

n pr

im ar

y ou

tc om

es a

re a

s de

fin ed

b y

an y

pa tie

nt -e

va lu

at ed

s ca

le s,

in cl

ud in

g th

e In

so m

ni a

Se ve

ri ty

I nd

ex , P

itt sb

ur gh

S le

Q ua

lit y

In de

x, L

ee ds

S le

ep Q

ue st

io nn

ai re

, a nd

s le

ep d

ia ri

es .30

A n

ef fe

ct s

iz e

of 0

.2 is

c on

si de

re d

to b

e sm

al l,

0. 5

is c

on si

de re

d to

b e

m od

er at

e, a

nd 0

.8 is

c on

si de

re d

to b

e la

rg e.

† T

he B

ee rs

C ri

te ri

a (a

li st

o f m

ed ic

at io

ns d

ee m

ed t

o be

r el

at iv

el y

in ap

pr op

ri at

e fo

r pa

tie nt

s 65

y ea

rs o

f a ge

o r

ol de

r) r

ec om

m en

ds a

vo id

an ce

o f t

hi s

dr ug

. ‡

T hi

s dr

ug is

n ot

F D

A -a

pp ro

ve d

fo r

th e

tr ea

tm en

t of

in so

m ni

a. A

ll dr

ug s

in cl

ud ed

in t

he t

ab le

a re

c la

ss ifi

ed b

y th

e FD

A a

s Pr

eg na

nc y

ca te

go ry

C w

ith t

he fo

llo w

in g

ex ce

pt io

ns : t

ri az

ol am

, te

m az

ep am

( ca

te go

ry X

); c

lo na

ze pa

m (

ca te

go ry

D );

d ip

he nh

yd ra

m in

e an

d do

xy la

m in

e (c

at eg

or y

B ).

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.

References 1. American Psychiatric Association. Di- agnostic and statistical manual of mental disorders. 5th ed. Washington, DC: Ameri- can Psychiatric Publishing, 2013. 2. Ogeil RP, Chakraborty SP, Young AC, Lubman DI. Clinician and patient barriers to the recognition of insomnia in family practice: a narrative summary of reported literature analysed using the theoretical domains framework. BMC Fam Pract 2020; 21: 1. 3. Morin CM, Jarrin DC. Epidemiology of insomnia: prevalence, course, risk fac-

tors, and public health burden. Sleep Med Clin 2022; 17: 173-91. 4. Baker FC, Willoughby AR, Sassoon SA, Colrain IM, de Zambotti M. Insomnia in women approaching menopause: be- yond perception. Psychoneuroendocrinol- ogy 2015; 60: 96-104. 5. Hertenstein E, Feige B, Gmeiner T, et al. Insomnia as a predictor of mental dis- orders: a systematic review and meta- analysis. Sleep Med Rev 2019; 43: 96-105. 6. Bertisch SM, Pollock BD, Mittleman MA, et al. Insomnia with objective short

sleep duration and risk of incident cardio- vascular disease and all-cause mortality: Sleep Heart Health Study. Sleep 2018; 41(6): zsy047. 7. Shi L, Chen SJ, Ma MY, et al. Sleep disturbances increase the risk of demen- tia: a systematic review and meta-analy- sis. Sleep Med Rev 2018; 40: 4-16. 8. Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical guideline for the evaluation and management of chron- ic insomnia in adults. J Clin Sleep Med 2008; 4: 487-504.

n engl j med 391;3 nejm.org July 18, 2024 257

Clinical Pr actice

9. Carney CE, Buysse DJ, Ancoli-Israel S, et al. The consensus sleep diary: stan- dardizing prospective sleep self-monitor- ing. Sleep 2012; 35: 287-302. 10. Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: psy- chometric indicators to detect insomnia cases and evaluate treatment response. Sleep 2011; 34: 601-8. 11. Buysse DJ, Reynolds CF III, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychi- atry Res 1989; 28: 193-213. 12. Chung F, Abdullah HR, Liao P. STOP- Bang questionnaire: a practical approach to screen for obstructive sleep apnea. Chest 2016; 149: 631-8. 13. Sharon D, Allen RP, Martinez-Martin P, et al. Validation of the self-adminis- tered version of the international Restless Legs Syndrome study group severity rat- ing scale — the sIRLS. Sleep Med 2019; 54: 94-100. 14. Buysse DJ, Germain A, Moul DE, et al. Efficacy of brief behavioral treatment for chronic insomnia in older adults. Arch Intern Med 2011; 171: 887-95. 15. Kyle SD, Siriwardena AN, Espie CA, et al. Clinical and cost-effectiveness of nurse-delivered sleep restriction therapy for insomnia in primary care (HABIT): a pragmatic, superiority, open-label, ran- domised controlled trial. Lancet 2023; 402: 975-87. 16. Zachariae R, Lyby MS, Ritterband LM, O’Toole MS. Efficacy of internet-delivered cognitive-behavioral therapy for insomnia — a systematic review and meta-analysis of randomized controlled trials. Sleep Med Rev 2016; 30: 1-10. 17. Edinger JD, Arnedt JT, Bertisch SM, et al. Behavioral and psychological treat- ments for chronic insomnia disorder in adults: an American Academy of Sleep Medicine systematic review, meta-analy- sis, and GRADE assessment. J Clin Sleep Med 2021; 17: 263-98. 18. Riemann D, Baglioni C, Bassetti C, et al. European guideline for the diagnosis and treatment of insomnia. J Sleep Res 2017; 26: 675-700. 19. Qaseem A, Kansagara D, Forciea MA, Cooke M, Denberg TD. Management of chronic insomnia disorder in adults: a clinical practice guideline from the Amer- ican College of Physicians. Ann Intern Med 2016; 165: 125-33. 20. van Straten A, van der Zweerde T, Kleiboer A, Cuijpers P, Morin CM, Lancee J. Cognitive and behavioral therapies in the treatment of insomnia: a meta-analy- sis. Sleep Med Rev 2018; 38: 3-16. 21. Brasure M, Fuchs E, MacDonald R, et al. Psychological and behavioral interven- tions for managing insomnia disorder: an evidence report for a clinical practice guideline by the American College of Phy- sicians. Ann Intern Med 2016; 165: 113-24.

22. Benz F, Knoop T, Ballesio A, et al. The efficacy of cognitive and behavior thera- pies for insomnia on daytime symptoms: a systematic review and network meta- analysis. Clin Psychol Rev 2020; 80: 101873. 23. Alimoradi Z, Jafari E, Broström A, et al. Effects of cognitive behavioral therapy for insomnia (CBT-I) on quality of life: a systematic review and meta-analysis. Sleep Med Rev 2022; 64: 101646. 24. Maurer LF, Ftouni S, Espie CA, Bis- dounis L, Kyle SD. The acute effects of sleep restriction therapy for insomnia on circadian timing and vigilance. J Sleep Res 2021; 30(4): e13260. 25. Irwin MR, Carrillo C, Sadeghi N, Bjurstrom MF, Breen EC, Olmstead R. Prevention of incident and recurrent ma- jor depression in older adults with insom- nia: a randomized clinical trial. JAMA Psychiatry 2022; 79: 33-41. 26. Selvanathan J, Pham C, Nagappa M, et al. Cognitive behavioral therapy for in- somnia in patients with chronic pain — a systematic review and meta-analysis of randomized controlled trials. Sleep Med Rev 2021; 60: 101460. 27. Baglioni C, Espie CA, Altena E, et al. Cognitive behavioural therapy for insom- nia disorder: extending the stepped care model. J Sleep Res 2023; 32(6): e14016. 28. Bertisch SM, Herzig SJ, Winkelman JW, Buettner C. National use of prescrip- tion medications for insomnia: NHANES 1999-2010. Sleep 2014; 37: 343-9. 29. Milani SA, Raji MA, Chen L, Kuo YF. Trends in the use of benzodiazepines, z-hypnotics, and serotonergic drugs among US women and men before and during the COVID-19 pandemic. JAMA Netw Open 2021; 4(10): e2131012. 30. De Crescenzo F, D’Alò GL, Ostinelli EG, et al. Comparative effects of pharma- cological interventions for the acute and long-term management of insomnia dis- order in adults: a systematic review and network meta-analysis. Lancet 2022; 400: 170-84. 31. Chiu HY, Lee HC, Liu JW, et al. Com- parative efficacy and safety of hypnotics for insomnia in older adults: a systematic review and network meta-analysis. Sleep 2021; 44(5): zsaa260. 32. Soyka M, Wild I, Caulet B, Leontiou C, Lugoboni F, Hajak G. Long-term use of benzodiazepines in chronic insomnia: a European perspective. Front Psychiatry 2023; 14: 1212028. 33. Votaw VR, Geyer R, Rieselbach MM, McHugh RK. The epidemiology of benzo- diazepine misuse: a systematic review. Drug Alcohol Depend 2019; 200: 95-114. 34. Donnelly K, Bracchi R, Hewitt J, Rout- ledge PA, Carter B. Benzodiazepines, Z-drugs and the risk of hip fracture: a sys- tematic review and meta-analysis. PLoS One 2017; 12(4): e0174730. 35. Everitt H, Baldwin DS, Stuart B, et al. Antidepressants for insomnia in adults.

Cochrane Database Syst Rev 2018; 5: CD010753. 36. Yi XY, Ni SF, Ghadami MR, et al. Tra- zodone for the treatment of insomnia: a meta-analysis of randomized placebo-con- trolled trials. Sleep Med 2018; 45: 25-32. 37. Holst SC, Landolt HP. Sleep-Wake Neurochemistry. Sleep Med Clin 2022; 17: 151-60. 38. Khazaie H, Sadeghi M, Khazaie S, Hirshkowitz M, Sharafkhaneh A. Dual orexin receptor antagonists for treatment of insomnia: a systematic review and me- ta-analysis on randomized, double-blind, placebo-controlled trials of suvorexant and lemborexant. Front Psychiatry 2022; 13: 1070522. 39. Xue T, Wu X, Chen S, et al. The effi- cacy and safety of dual orexin receptor antagonists in primary insomnia: a sys- tematic review and network meta-analy- sis. Sleep Med Rev 2022; 61: 101573. 40. Muehlan C, Roch C, Vaillant C, Ding- emanse J. The orexin story and orexin re- ceptor antagonists for the treatment of insomnia. J Sleep Res 2023; 32(6): e13902. 41. Culpepper L, Wingertzahn MA. Over- the-counter agents for the treatment of occasional disturbed sleep or transient insomnia: a systematic review of efficacy and safety. Prim Care Companion CNS Disord 2015; 17(6): 10.4088/PCC.15r01798. 42. Low TL, Choo FN, Tan SM. The effi- cacy of melatonin and melatonin agonists in insomnia — an umbrella review. J Psy- chiatr Res 2020; 121: 10-23. 43. Abdelgadir IS, Gordon MA, Akobeng AK. Melatonin for the management of sleep problems in children with neurode- velopmental disorders: a systematic re- view and meta-analysis. Arch Dis Child 2018; 103: 1155-62. 44. Winkelman JW, Armstrong MJ, Allen RP, et al. Practice guideline summary: treatment of restless legs syndrome in adults: report of the Guideline Develop- ment, Dissemination, and Implementa- tion Subcommittee of the American Acad- emy of Neurology. Neurology 2016; 87: 2585-93. 45. Bertisch SM, Wells RE, Smith MT, McCarthy EP. Use of relaxation techniques and complementary and alternative medi- cine by American adults with insomnia symptoms: results from a national survey. J Clin Sleep Med 2012; 8: 681-91. 46. Edinger JD, Wamboldt F, Johnson RL, et al. Use of a blinded hypnotic tapering strategy to promote hypnotic discontinu- ation. Sleep (in press) (https://academic . oup . com/ sleep/ advance - article/ doi/ 10 . 1093/ sleep/ zsab270/ 6432064). 47. Morin CM, Bastien C, Guay B, Radou- co-Thomas M, Leblanc J, Vallières A. Ran- domized clinical trial of supervised taper- ing and cognitive behavior therapy to facilitate benzodiazepine discontinuation in older adults with chronic insomnia. Am J Psychiatry 2004; 161: 332-42.

https://academic.oup.com/sleep/advance-article/doi/10.1093/sleep/zsab270/6432064

n engl j med 391;3 nejm.org July 18, 2024258

Clinical Pr actice

48. Morin CM, Vallières A, Guay B, et al. Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial. JAMA 2009; 301: 2005-15. 49. Morin CM, Colecchi C, Stone J, Sood R, Brink D. Behavioral and pharmacologi- cal therapies for late-life insomnia: a ran- domized controlled trial. JAMA 1999; 281: 991-9. 50. Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insom- nia in older adults: a randomized con- trolled trial. JAMA 2006; 295: 2851-8. 51. Jacobs GD, Pace-Schott EF, Stickgold

R, Otto MW. Cognitive behavior therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct comparison. Arch Intern Med 2004; 164: 1888-96. 52. Morin CM, Beaulieu-Bonneau S, Ivers H, et al. Speed and trajectory of changes of insomnia symptoms during acute treatment with cognitive-behavioral ther- apy, singly and combined with medica- tion. Sleep Med 2014; 15: 701-7. 53. Sateia MJ, Buysse DJ, Krystal AD, Neubauer DN, Heald JL. Clinical practice guideline for the pharmacologic treat- ment of chronic insomnia in adults: an American Academy of Sleep Medicine

clinical practice guideline. J Clin Sleep Med 2017; 13: 307-49. 54. Mysliwiec V, Martin JL, Ulmer CS, et al. The management of chronic insomnia disorder and obstructive sleep apnea: syn- opsis of the 2019 U.S. Department of Vet- erans Affairs and U.S. Department of De- fense clinical practice guidelines. Ann Intern Med 2020; 172: 325-36. 55. Vgontzas AN, Fernandez-Mendoza J. Insomnia with short sleep duration: no- sological, diagnostic, and treatment im- plications. Sleep Med Clin 2013; 8: 309-22. Copyright © 2024 Massachusetts Medical Society.

Reproduced with permission of copyright owner. Further reproduction prohibited without permission.