clinical review  Insomnia

clinical  review

Diagnosis and treatment of insomnia

Stacy Passarella and Minh-Tri Duong

O
ver 50 million Americans report
having a sleep-related problem.1
According to the 2005 Sleep in
America Poll, 75% of people surveyed
reported having a sleep problem,
including difficulty falling asleep,
frequent awakenings, early morning
awakenings, daytime drowsiness,
snoring, or sleep apnea.2 Over 50%
of respondents reported having at
least one symptom of insomnia dur-
ing the previous year, with one third
experiencing insomnia symptoms
nearly every night. The most com-
mon symptoms reported included
daytime drowsiness (38%) and fre-
quent awakenings (32%).2 Insomnia
tends to occur more frequently in
women, especially postmenopausal
women, and the elderly. Additional
predisposing factors for insomnia in-
clude snoring and comorbid psychi-
atric or medical illnesses.3,4 Although
insomnia is a widely recognized
problem across all ages, less than half
of the respondents in the Sleep in
America Poll were likely to discuss
the problem with a physician.2
As insomnia has gained increasing
recognition as a major health issue,
the number of available treatment
options has also increased. There are
a growing number of pharmacologic
treatments available for insomnia,
most of which are heavily advertised
Purpose. The diagnostic criteria and treat-
ment of insomnia are reviewed.
Summary. Insomnia is most often de-
scribed as a subjective complaint of poor
sleep quality or quantity despite adequate
time for sleep, resulting in daytime fatigue,
irritability, and decreased concentration.
Insomnia is classified as idiopathic or
comorbid. Comorbid insomnias are associ-
ated with psychiatric disorders, medical
disorders, substance abuse, and specific
sleep disorders. Idiopathic insomnia is es-
sentially a diagnosis of exclusion. A wide
array of terminology exists for defining
the duration of insomnia symptoms,
which may add to the confusion regarding
insomnia classification. Acute insomnia
refers to sleep problems lasting from one
night to a few weeks, whereas chronic
insomnia refers to sleep problems last-
ing at least three nights weekly for at
least one month. Diagnostic tools for
identifying insomnia are multifacto-
rial. Nonpharmacologic interventions
for insomnia include sleep-hygiene
education, stimulus-control therapy,
relaxation therapy, and sleep-restriction
in magazines or on television. This
direct-to-consumer advertising has
improved the overall awareness of
some of the drug treatments avail-
able; unfortunately, this may dimin-
ish the awareness of the benefits of
behavioral therapies. Despite the
therapy. The most effective pharmaco-
logic therapies for insomnia are benzo-
diazepines, benzodiazepine-receptor
agonists, melatonin-receptor agonists,
and antidepressants. Choice of a specific
agent should be based on patient-specific
factors, including age, proposed length
of treatment, primary sleep complaint,
history of drug or alcohol abuse, and cost.
Conclusion. Many treatment options are
available for patients with insomnia. Be-
havioral therapies should be initiated as
first-line treatment in most patients. For
patients who require the addition of
pharmacologic therapy, the drugs with
the most evidence for benefit include ben-
zodiazepines, benzodiazepine-receptor
agonists, melatonin-receptor agonists,
and antidepressants. Selection of a specific
agent must take into account numerous
patient-specific factors.
Index terms: Antidepressants; Anxiolytics,
sedatives and hypnotics; Benzodiazepines;
Diagnosis; Drugs; Insomnia; Mechanism of
action; Nomenclature
Am J Health-Syst Pharm. 2008; 65:927-34
high rate of insomnia and expand-
ing appreciation of insomnia as a
major health issue, it is still under-
recognized and often inadequately
treated. In this article, normal sleep
architecture, the epidemiology and
causes of insomnia, risk factors for

Stacy Passarella, Pharm.D., BCPS, is Clinical Pharmacist; and
Minh-Tri Duong, Pharm.D., is Residency Director, Pharmacy
Practice Residency Program, and Pharmacy Services Education
Coordinator, Pharmacy Department, Tampa General Hospital,
Tampa, FL.
Address correspondence to Dr. Passarella at the Pharmacy Depart-
ment, Tampa General Hospital, P.O. Box 1289, Tampa, FL 33601
(spassarella@tgh.org).
Copyright © 2008, American Society of Health-System Pharma-
cists, Inc. All rights reserved. 1079-2082/08/0502-0927$06.00.
DOI 10.2146/ajhp060640

Am J Health-Syst Pharm—Vol 65 May 15, 2008 927

 clinical review  Insomnia
insomnia, pharmacologic and non-
pharmacologic treatment options,
and barriers to insomnia diagnosis
and treatment are reviewed. In addi-
tion, suggestions for future research
and new sleep agents on the horizon
are discussed.
Sleep basics
Sleep plays a vital role in every
healthy individual, although there
is no overall agreement on the spe-
cific functions of sleep. Potential
physiological functions on sleep may
include restorative functions and en-
ergy conservation.5 Current evidence
suggests that there are likely multiple
functions of sleep and that an indi-
vidual’s sleep needs may depend on a
person’s age or activity.5
Sleep stages. Sleep can be divided
into two general states: nonrapid
eye movement (NREM) and rapid
eye movement (REM) sleep. NREM
comprises four stages of sleep, each
progressing toward REM sleep. Stage
1 sleep represents a transition period
between wakefulness and the early
stages of sleep.5 Stage 2 sleep, some-
times known as intermediate sleep,
represents the largest percentage of
total sleep time. Stages 3 and 4 sleep
are referred to as deep sleep and are
postulated to be the restorative sleep
stages. REM sleep follows NREM
sleep. During REM sleep, physi-
ological changes (e.g., variations
in blood pressure, heart rate, and
respiratory rate) and quick, irregular
eye movements occur. REM sleep is
also the stage in which patients recall
dreaming if awakened. The specific
functions of REM sleep are not fully
understood, though evidence sug-
gests that it may be vital for memory
consolidation and, potentially, sus-
taining life.5
Normal sleep cycle. A complete
sleep cycle lasts for approximately
1.5–2 hours and is repeated four to
five times during the night.5 The
amount of time spent in each sleep
stage changes throughout the night
based on the amount of time a
928 Am J Health-Syst Pharm—Vol 65 May 15, 2008
person has been asleep. With each
sequential sleep cycle, the amount
of time in stage  2 and REM sleep
typically increases. Several factors
contribute to alterations in normal
sleep architecture, including medi-
cations and sleep disorders, such as
narcolepsy. Sleep architecture also
changes with age. As individuals age,
the amount of time spent in stages 3
and 4 sleep typically decreases while
stage 1 sleep increases.5
Sleep assessment. Objective tools
for measuring sleep and sleepiness
include tests such as the multiple
sleep latency test (MSLT), polysom-
nography, and wrist actigraphy.5 The
MSLT objectively assesses daytime
sleepiness by measuring the time it
takes for patients to fall asleep. These
tests are not indicated for routine di-
agnosis of insomnia and are required
only when the patient’s history and
presentation support their use.6 In
polysomnography, typically used
during an overnight sleep study, elec-
trodes continuously record measure-
ments, including the electroencepha-
logram, REMs, and muscle tone.5
Wrist actigraphy is used adjunctively
with other objective data and records
movement of the wrist to determine
the amount of time spent sleeping.5
Insomnia classifications
Insomnia is most often described
as a subjective complaint of poor
sleep quality or quantity despite
adequate time for sleep, resulting in
daytime fatigue, irritability, and de-
creased concentration. Specific sleep
complaints of patients with insomnia
include delayed sleep onset, frequent
awakenings, early morning awaken-
ings, and waking up feeling unre-
freshed. Classifications of insomnia
vary by organization or specific diag-
nostic criteria.
Primary and comorbid insom-
nias. Insomnia is classified as id-
iopathic (primary) or comorbid
(secondary). Comorbid insomnias
are associated with psychiatric dis-
orders (e.g., dementia, depression,
anxiety disorders),7,8 medical disor-
ders (e.g., gastroesophageal reflux
disease, chronic pain, asthma),7 sub-
stance abuse (e.g., alcoholism, abuse
of prescription or nonprescription
medications, illicit drug use),7 and
specific sleep disorders (e.g., periodic
limb movement disorder, restless legs
syndrome, circadian rhythm sleep
disorders, sleep apnea).5,7 Primary
insomnia is essentially a diagnosis of
exclusion. When all other potential
causes have been excluded, insom-
nia is classified as primary.7 Factors
associated with primary insomnia
include chronic stress, poor sleep hy-
giene, and learned insomnia. Primary
insomnia may also be associated with
a sleep-state misperception, in which
patients complain of insomnia but
have no objective evidence of a sleep
disorder.9
Acute and chronic insomnias. A
wide array of terminology exists for
defining the duration of insomnia
symptoms, which may add to the
confusion regarding insomnia clas-
sification. Generally, insomnia is
classified as either acute or chronic
depending on the duration of symp-
toms. Acute insomnia refers to sleep
problems lasting from one night to
a few weeks, whereas chronic insom-
nia refers to sleep problems lasting
at least three nights weekly for at
least one month.7 Acute insomnias
often result from emotional or physi-
cal stressors such as illness, jet lag,
and environmental disturbances.
Chronic insomnias are most often
associated with comorbid medical or
psychological disorders.7
Additional classification schemes
and diagnosis. The Diagnostic and
Statistical Manual of Mental Disor-
ders, Fourth Edition, Text Revision,
categorizes sleep disorders into pri-
mary sleep disorders, sleep disorders
related to another mental disorder,
sleep disorders due to a medical
disorder, and substance-induced
sleep disorders.10 The International
Classification of Sleep Disorders, Re-
vised, classifies sleep disorders into

four major categories: dyssomnias,
parasomnias, sleep disorders associ-
ated with comorbid diseases, and
proposed sleep disorders.11 In this
scheme, insomnia is classified as a
dyssomnia. As a dyssomnia, insom-
nia is further characterized as an
intrinsic, an extrinsic, or a circadian
rhythm sleep disorder.11
Diagnosis
Diagnostic tools for identifying
insomnia are multifactorial. As with
any medical problem, appropriate di-
agnosis must begin with a thorough
medical history and physical exami-
nation that addresses the patient’s
sleep history. A comprehensive sleep
history should include sleep habits,
drug (including prescription and
nonprescription medications) and
alcohol consumption, nicotine and
caffeine intake, comorbid illnesses,
and sleep environment. A complete
physical examination may help to
identify potential medical conditions
that may be contributing to insom-
nia symptoms. Interviewing the bed
partner or caregiver may also provide
useful information. A one- to two-
week sleep diary in which patients
record bedtime, total sleep time, time
to sleep onset, number of awakenings,
use of medications, time of awaken-
ing in the morning, and subjective
feeling in the morning may provide
additional insight into the patient’s
sleep-related problem.7 Direct ques-
tioning about insomnia symptoms
may be required, since many patients
with sleep-related problems never
discuss the issue with their primary
care providers.7 Some patients may
require a sleep study requiring assess-
ment tools such as polysomnography
and the MSLT.5,12 Effective treatments
for insomnia symptoms can be iden-
tified only after careful review of the
patient’s sleep history and sleep stud-
ies, if applicable.
Consequences of insomnia
The most common outcomes of
acute insomnia are sleepiness, mood
clinical review  Insomnia
changes, and impairment of daytime
functioning.7 Insomnia may interfere
with interpersonal relationships and
job performance and may increase
health care utilization.13-15 Further-
more, chronic insomnia has been
linked to increased absenteeism from
work, an increased risk of psychi-
atric disorders, impaired cognition,
and a negative impact on quality of
life.7,16,17 Together, these effects of
insomnia provide overwhelming evi-
dence of the need to provide appro-
priate treatment options to affected
individuals.
The management strategy is most
likely to be affected by the length
and severity of symptoms, finan-
cial impact, and comorbid medical
conditions. Treatment is inevitably
influenced by both the clinician’s
and the patient’s perceptions of each
of the treatment options. Nonethe-
less, the clinician and patient must
discuss the treatment options avail-
able and agree on the overall treat-
ment plan.
Nonpharmacologic therapies
Nonpharmacologic interventions
include sleep-hygiene education,
stimulus-control therapy, relax-
ation therapy, and sleep-restriction
therapy, collectively referred to as
cognitive behavioral therapy (CBT).
Other treatment modalities that have
been evaluated for the treatment of
insomnia include yoga, light therapy,
and acupuncture, though these treat-
ments have not been adequately
studied.18
Education on sleep hygiene fo-
cuses on environmental factors and
attitudes that negatively affect sleep.19
Sleep-hygiene recommendations
include maintaining a regular sleep
schedule, exercising regularly but
avoiding exercise too close to bed-
time, and avoiding stimulants like
caffeine or nicotine right before bed-
time. 12,19 Other recommendations
may include ensuring a comfortable
sleep environment (i.e., eliminate
noises, decrease light, and maintain a
Am J Health-Syst Pharm—Vol 65 May 15, 2008
comfortable room temperature) and
avoiding negative thinking or focus-
ing on a bedside clock.12,19
Stimulus-control therapy focuses
on eliminating maladaptive behav-
iors, with the overall goal of associat-
ing the bedroom with sleep. Patients
are instructed to go to bed only
when tired, use the bedroom only for
sleeping, establish a normal sleep–
wake schedule, and avoid napping.12
Patients are also trained to leave
the bedroom if unable to fall asleep
within 15 minutes and to return to
bed only when tired.19 Relaxation
therapy includes progressive muscle
relaxation, biofeedback, and medita-
tion.12 Relaxation techniques may
be especially helpful to patients for
whom hyperarousal is suspected as
the cause of insomnia symptoms. Re-
laxation therapy may improve both
sleep latency time and sleep main-
tenance. Sleep-restriction therapy
allows patients to improve sleep effi-
ciency by temporarily inducing sleep
deprivation.20 CBT incorporates sev-
eral of these behavioral techniques to
improve sleep.
Many studies and meta-analyses
have demonstrated the effective-
ness of various nonpharmacologic
interventions.20-23 The percentage of
patients responding to such therapy
ranges from 50% to 80%.20,23 One
large meta-analysis found that
nonpharmacologic treatments im-
proved both sleep patterns and sub-
jective reports of sleep.21 According
to the findings of another large meta-
analysis, the most effective non-
pharmacologic interventions for
insomnia were stimulus control and
sleep restriction.22 However, sleep-
hygiene education was not effective
when used alone. Improvements in
sleep-related problems secondary
to nonpharmacologic therapies
were maintained for six months or
more after therapy completion.23
Specific improvements in sleep-
related problems included decreased
sleep latency and improved sleep
maintenance. 22
929
 clinical review  Insomnia

Pharmacologic therapies develop a physical dependence to the diazepines, zolpidem has not been
Benzodiazepines. Benzodiaz- drug.29 Consequently, abrupt discon- shown to have deleterious effects on
epines improve insomnia symptoms tinuation of the drug may elicit with- the normal sleep cycle.30 There have
by binding to g-aminobutyric acid-A drawal symptoms, including anxiety, been reports that zolpidem causes
(GABA-A) receptors on postsynap- rebound insomnia, tachycardia, and parasomnias, including sleepwalking
tic neurons in the central nervous diarrhea. Dosage reductions may be and sleep-related eating disorders.35,36
system, thus inhibiting neuronal ex- especially important in the elderly Interestingly, studies have found that
citation through increased neuronal to decrease the risk of falls. Since intermittent administration of zolpi-
chloride permeability.24 Although triazolam and temazepam have short dem is as effective as nightly use.37,38
benzodiazepines are commonly pre- half-lives, tolerance to these agents Benzodiazepine-receptor agonists
scribed for insomnia, the only benzo- may occur more rapidly than with are more costly than benzodiazepines
diazepines with labeling for insomnia other benzodiazepines, thus increas- labeled for insomnia, most of which
are estazolam, flurazepam, quaze- ing the risk of rebound insomnia.8,24 are available as generics.
pam, temazepam, and triazolam. Estazolam and triazolam should be Zolpidem and eszopiclone have a
These agents vary in their onset and avoided in patients receiving cyto- relatively quick onset of action and
duration of activity (Table 1). The re- chrome P-450 (CYP) isoenzyme 3A4 have been shown to improve sleep-
sults of a meta-analysis published in inhibitors because of the resulting onset latency problems. 30,33 Since
2000 revealed that benzodiazepines decreased clearance of those ben- these agents have a longer half-life
increased total sleep time but had no zodiazepines. 25 Additional drugs than other benzodiazepine-receptor
significant effect on sleep latency.26 that interact with benzodiazepines agonists, both zolpidem and eszopic­
Potential adverse effects include day- include alcohol and other central lone improve sleep maintenance as
time sleepiness or hangover effect, nervous system depressants. well. Unlike other agents in this class,
dizziness, and impaired memory.27 Benzodiazepine-receptor agonists. the dosage of eszopiclone can be
Benzodiazepines, especially agents Benzodiazepine-receptor agonists ex- adjusted based on the desired effect.
with short half-lives, have also been ert their effects on the w-receptor of The 1- and 2-mg tablets of eszopic-
associated with anterograde amnesia. the GABA-A receptor complex and lone are most often used to improve
Agents with longer half-lives (e.g., inhibit neuronal excitation through sleep latency, and the 3-mg tablets
quazepam, flurazepam) increase the increased chloride permeability. 24 are typically reserved to address sleep
risk of hangover effect, thereby in- Agents in this class include zolpidem, maintenance problems. One of the
creasing risk of confusion, dizziness, zaleplon, and eszopiclone (Table 2), most common adverse effects of
and falls.27 Benzodiazepines cause all of which are schedule IV drugs. eszopiclone is unpleasant taste.33 Of
changes in the normal sleep archi- Benzodiazepine-receptor agonists are importance, the labeling of eszopic-
tecture, including increased stage 2 purported to cause less rebound in- lone and extended-release zolpidem
sleep and increased REM latency.28 somnia, have less potential for abuse, is not restricted to short-term use.39
Moreover, no controlled studies have be associated with fewer dependency In patients already responsive to
demonstrated the efficacy of ben- problems, and cause less of a hang- immediate-release zolpidem, the
zodiazepines for relief of insomnia over effect compared with benzo- extended-release formulation may not
symptoms after 12 weeks.27 All ben- diazepines. 27 However, published provide additional clinical benefits.
zodiazepines are schedule IV medi- reports have highlighted the abuse Zaleplon has a rapid onset of ac-
cations and have the potential for and dependency potential associated tion and short half-life, which make
abuse. Patients taking one of these with the use of these benzodiazepine- it an attractive option for patients
medications for just a few days can receptor agonists.34 Unlike benzo- who exhibit sleep latency problems
without causing hangover effects.40
Since the duration of zaleplon’s ef-
Table 1. fects are so short, patients can take
Benzodiazepines Labeled for Treatment of Insomnia24,25 zaleplon in the middle of the night if
Usual Oral at least four hours before planning to
Drug Dose (mg) Onset (min) Half-life (hr) awaken.41 Administration of any of
Estazolam      1–2   60 10–24 these agents with food should gener-
Flurazepam hydrochloride    15–30 15–30 47–100a ally be avoided as food may delay the
Quazepam    7.5–15 20–45 25–84a onset of activity and thereby dimin-
Temazepam    7.5–30 30–60   4–18 ish the drugs’ effectiveness.31-33
Triazolam 0.125–0.25 15–30   2–4 Melatonin-receptor agonists.
Includes active metabolites
a
Ramelteon is the first and only agent

930 Am J Health-Syst Pharm—Vol 65 May 15, 2008

 clinical review  Insomnia

in a new class of drugs known as

Table 2.
melatonin-receptor agonists. Ramelt-
Characteristics of Benzodiazepine-Receptor Agonists30-33,a
eon selectively targets the melatonin
receptors MT1 and MT2 located in Usual Oral
the hypothalamus, which are thought Drug Dose (mg) Onset (min) Half-life (hr)
to be involved in the sleep–wake Zolpidem tartrate    5–10 30 1.4–4.5
cycle.42 As this agent has no affin- Zolpidem tartrate, extended release 6.25–12.5 30 1.6–5.5
ity for GABA receptors, ramelteon’s Zaleplonb    10–20 20 0.5–1
Eszopiclone    2–3 30    6
adverse-effect profile differs from
Unless otherwise noted, all agents are useful for sleep-onset and sleep-maintenance insomnia.
a
that of benzodiazepines and benzo- Not useful for sleep-maintenance insomnia.
b

diazepine-receptor agonists. Ramelt-

eon is the only sedative hypnotic not
classified as a controlled substance.
The recommended dosage is 8 mg
within 30 minutes of bedtime; no
dosage reduction is necessary in the
elderly. Ramelteon is metabolized by
CYP1A2, so the potential for drug
interactions exists.42 Although ra-
melteon is labeled only for the treat-
ment of insomnias characterized by
delayed sleep onset, recent studies
have found that ramelteon not only
significantly shortens the delay to
sleep onset but also increases total
sleep time.43,44 The most common ad-
verse effects reported with ramelteon
include somnolence, fatigue, and diz-
ziness, with no evidence of rebound
insomnia.42,45 As with eszopiclone
and extended-release zolpidem, ra-
melteon is not limited to short-term
use.42 Patients should be instructed
not to take ramelteon with or imme-
diately after a high-fat meal, which
will delay absorption and beneficial
effects. Although not an absolute
contraindication, ramelteon should
generally be avoided in patients with
severe hepatic impairment.42
Antidepressants, antipsychotics,
and barbiturates. The prescribing of
antidepressants for the treatment of
primary insomnia is not uncommon,
even though not much evidence sup-
ports their efficacy or safety for this
indication. Potential explanations for
the increasing use of antidepressants
may include physicians’ perception
that antidepressants are safer than
hypnotics and the prescribing re-
strictions associated with other sleep
agents.27 Some antidepressants that
have been used to treat insomnia in-
clude trazodone, tricyclic antidepres-
sants (e.g., doxepin, amitriptyline),
and mirtazapine.12,19 Of these, traz­
odone hydrochloride is used most
frequently at doses of 50–100 mg.46,47
In one study of trazodone for pri-
mary insomnia, trazodone was more
effective in improving sleep latency
and sleep maintenance compared
with placebo, but zolpidem was
superior to trazodone.48 Some note-
worthy adverse effects of trazodone
include dizziness, sedation, hypoten-
sion, headache, and priapism.8 Some
adverse effects of tricyclic antide-
pressants include anticholinergic
effects (e.g., sedation, constipation,
dry mouth), weight gain, cardiac ar-
rhythmias, lowered seizure threshold,
and extrapyramidal symptoms. 12
Antidepressants are typically more
beneficial in patients with comorbid
depression or are reserved as alterna-
tive agents for chronic treatment.
Nonprescription agents. Anti-
histamines. First-generation antihis-
tamines, such as diphenhydramine
and doxylamine, are frequent ingre-
dients in nonprescription sleeping
aids. The use of these drugs is not
supported by much of the existing
data. Common adverse effects of
these agents include hangover effect,
dizziness, dry mouth, and consti-
pation. 18,24 Furthermore, patients
quickly develop a tolerance to the
sedative effects, and these agents
have not been shown to improve
sleep.18 Overall, recommendations
for the use of first-generation an-
tihistamines should be limited to
patients who experience infrequent
symptoms of insomnia. Use should
be cautioned in patients with comor-
bid medical conditions such as glau-
coma or those with an increased risk
of falling, especially the elderly.18
Melatonin. Melatonin, a hormone
normally produced by the pineal
gland, is a nonprescription supple-
ment sold as a sleep agent. Compared
with other natural remedies for sleep,
melatonin has few reported adverse
effects. Currently, data supporting
the use of melatonin for insomnia are
minimal.18 Since the minimum effec-
tive dosage of melatonin is unknown
and because there is no standardiza-
tion of nutraceutical ingredients in
the United States, melatonin should
not be recommended for routine
treatment of insomnia.18
Valerian. The mechanism of action
of valerian is not fully understood
but has been purported to interact
with GABA receptors.49 Currently,
there is little evidence to support its
use for the treatment of insomnia.18
However, valerian currently appears
on the Food and Drug Administra-
tion’s (FDA’s) Generally Recognized
as Safe list. Potential adverse effects
include dizziness, nausea, headache,
and upset stomach.50 FDA does not
strictly regulate nutritional supple-
ments and herbal products sold in
the United States. As a result, product
ingredients are not standardized,
which increases the risk of patient
harm and often precludes pharma-
cists from recommending nutritional
supplements.

Am J Health-Syst Pharm—Vol 65 May 15, 2008 931

 clinical review  Insomnia
Choice of agent. Choice of a spe-
cific sleep agent should be based on
patient-specific factors, including
age, proposed length of treatment,
primary sleep complaint, history
of drug or alcohol abuse, and cost.
Similar to the benzodiazepines, dos-
age reduction of the benzodiazepine-
receptor agonists in the elderly may
be prudent to minimize fall risk.
Agents with a quick onset of ac-
tion and shorter half-lives such as
temazepam and zaleplon are ideal for
patients with sleep latency problems.
On the other hand, agents with lon-
ger half-lives such as quazepam, zolp-
idem, and eszopiclone are better for
patients with sleep-maintenance is-
sues. Clinicians may choose to avoid
benzodiazepines in patients with a
history of substance abuse. In such
cases, ramelteon may be an option,
since it is the only agent approved for
the long-term treatment of insomnia
that is not a controlled substance.
Antidepressants are a reasonable
option for patients with comorbid
depression and may be offered as
an alternative choice for long-term
treatment. Benzodiazepines and an-
tidepressants may be less costly than
benzodiazepine-receptor agonists
and ramelteon. Typically, nonpre-
scription sleep agents containing
sedating antihistamines, although
relatively inexpensive, should be re-
served for patients with infrequent
symptoms who do not have any lim-
iting comorbid medical conditions.
Combining nonpharmacologic
and pharmacologic therapies
Studies directly comparing non-
pharmacologic and pharmacologic
therapies for insomnia are limited.
One small, randomized, controlled
trial of 63 patients found that CBT
alone or in combination with drug
therapy is more effective at improv-
ing delays in sleep onset than drug
therapy alone or placebo.51 In this
study, CBT included sleep-restriction
therapy, stimulus-control therapy,
and relaxation techniques. CBT was
932 Am J Health-Syst Pharm—Vol 65 May 15, 2008
also more efficacious at sustaining
benefits after discontinuation of the
intervention compared with phar-
macologic therapy. Interestingly,
the combination therapy provided
no advantage over CBT alone for
sustaining improvements in sleep
onset.51 Although these data provide
additional support for nonpharma-
cologic interventions as first-line
therapy, the sample was small, and
results may not be generalizable to
patients with sleep-maintenance
problems or patients with comorbid
conditions. Since studies have found
that nonpharmacologic therapies
offer benefits with minimal adverse
effects, nonpharmacologic therapies
should remain a first-line option for
the treatment of insomnia. Further
research is needed to identify the spe-
cific behavioral techniques, recom-
mended length of therapy, and meth-
od for delivering these techniques
that provide the best outcomes.
Barriers to diagnosis and
treatment
Several barriers contribute to
the lack of appropriate diagnosis
and treatment of insomnia, includ-
ing limited physician awareness or
training, lack of discussion during
patient consultations, patients’ be-
lief that sleep problems are irrele-
vant, and clinicians’ perception that
current treatments are ineffective or
risky.8
Many clinicians do not receive
adequate training to diagnose and
treat sleep disorders.52,53 As a result,
underdiagnosis, misdiagnosis, and
delayed diagnosis of sleep disorders
may occur, all of which contribute to
increased morbidity and increased
health care utilization.1
Two potential explanations for the
lack of discussion on sleep problems
during office visits include (1) the
patient or physician does not view
insomnia as an important medical
problem and (2) the consultation
time is perceived to be too short to
discuss sleep habits.8 In addition,
patients with sleep-related symp-
toms may fail to recognize them as
problems and therefore do not report
their symptoms to their clinician.
These explanations are supported
by the results published in the 2005
Sleep in America Poll.2 While 75% of
respondents reported having at least
one sleep-related symptom at least a
few nights weekly within the previous
year, only 21% of those believed they
had a sleep problem. Furthermore,
only 29% of respondents reported
that a physician had ever questioned
them about their sleep. 2
Insomnia has significant associat-
ed personal and social consequences.
However, many studies evaluating the
treatment of insomnia fail to assess
such outcomes. As a result, clinicians
may avoid treating insomnia because
they believe that current treatments
are ineffective in improving out-
comes or quality of life. Explanations
for limited outcomes data include
a lack of a standardized method for
documentation and a lack of effec-
tive instruments for assessment. 54
Current evaluation of outcomes of
insomnia treatment often relies on
nonvalidated assessment tools, which
may lack sensitivity and precision.55
Clinicians may also believe that
the risk of physical dependence and
abuse potential outweigh any ben-
efits of therapy. Treatment of insom-
nia with pharmacologic agents has
traditionally been recommended for
only 7–10 days, despite overwhelm-
ing evidence that patients often have
symptoms beyond this time period.8
Only within the past five years have
studies evaluated longer-term use of
sleep agents.39 In addition, clinicians
may fail to recognize the effectiveness
of behavioral therapies on improving
sleep-related symptoms.
Investigational agents and future
research
Indiplon is a nonbenzodiazepine
hypnotic that binds directly to the
GABA-A receptor.56 The drug dem-
onstrates preferential binding to the

a-subunit of GABA-A receptors.57
Indiplon is purportedly the most
potent GABA-A agonist and is 10 and
50 times more potent than zolpidem
and zaleplon, respectively.56 Cur-
rently, all dosage forms of this drug
remain unavailable. of insomnia in a general adult population.
Eplivanserin is currently in Phase
III trials for the treatment of insom-
nia in adults and is a serotonin type
2A-receptor antagonist. It is current-
ly being evaluated for the treatment
of sleep-maintenance insomnia.58
Further research is needed to di-
rectly compare benzodiazepines to
the newer hypnotic agents, including
the benzodiazepine-receptor agonists
and ramelteon, to determine the
most cost-effective treatment. These
studies should also compare hyp-
notic agents with nonpharmacolgic
therapies and combination therapy.
Although many studies evaluate the
effectiveness of a treatment on de-
creasing sleep latency or improving
sleep maintenance, few have focused
on the long-term outcomes of thera-
py, including increased quality of life,
improved job performance, and im-
proved interpersonal relationships.
Conclusion
Many treatment options are avail-
able for patients with insomnia.
Behavioral therapies should be initi-
ated as first-line treatment in most
patients. For patients who require the
addition of pharmacologic therapy,
the drugs with the most evidence
for benefit include benzodiazepines,
benzodiazepine-receptor agonists,
melatonin-receptor agonists, and
antidepressants, and selection of a
specific agent must take into account
numerous patient-specific factors.
References
1. National Center on Sleep Disorders
Research. 2003 National sleep disorders
research plan. www.nhlbi.nih.gov/health/
prof/sleep/res_plan/sleep-rplan.pdf
(accessed 2008 Feb 7).
2. National Sleep Foundation. 2005 Sleep
in America Poll. www.sleepfoundation.
org/site/c.huIXKjM0IxF/b.2419039/
k.14E4/2005_Sleep_in_America_Poll.
htm (accessed 2008 Feb 7).
clinical review  Insomnia
3. Buscemi N, Vanermeer B, Friesen C
et al. Manifestations and manage-
ment of chronic insomnia in adults.
www.ncbi.nih.gov/books/bv.fcgi?rid=
hstat1b.chapter.3477 (accessed 2008 Feb
8).
4. Klink ME, Quan SF, Kaltenborn WT et
al. Risk factors associated with complaints
Influence of previous complaints of insom-
nia. Arch Intern Med. 1992; 152:1634-7.
5. Stevens S, Comella CL, Walters AS et al.
Sleep and wakefulness. In: Goetz CG, ed.
Textbook of clinical neurology. 2nd ed.
Philadelphia: Elsevier Health Sciences;
2003:19-30.
6. Chesson A Jr, Hartse K, Anderson WM
et al. Practice parameters for the evalua-
tion of chronic insomnia. An American
Academy of Sleep Medicine Report. Sleep.
2000; 23:237-41.
7. National Heart, Lung, and Blood In-
stitute Working Group on Insomnia.
Insomnia: assessment and management
in primary care. Am Fam Physician. 1999;
59:3029-38.
8. Benca RM. Diagnosis and treatment of
chronic insomnia: a review. Psychiatr
Serv. 2005; 56:332-43.
9. Hauri PJ, Esther MS. Insomnia. Mayo
Clin Proc. 1990; 65:869-82.
10. American Psychiatric Association. Sleep
disorders. In: Diagnostic and statisti-
cal manual of mental disorders, fourth
edition, text revision. Washington, DC:
American Psychiatric Publishing; 2000.
11. International classification of sleep dis-
orders, revised: diagnostic and coding
manual. Chicago: American Academy of
Sleep Medicine; 2001.
12. Silber MH. Chronic insomnia. N Engl J
Med. 2005; 353:803-10. [Erratum, N Engl
J Med. 2005; 353:2827.]
13. Leger D, Guilleminault C, Bader G et al.
Medical and socio-professional impact of
insomnia. Sleep. 2002; 25:625-9.
14. Simon GE, VonKorff M. Prevalence,
burden, and treatment of insomnia in
primary care. Am J Psychiatry. 1997; 154:
1417-23.
15. Walsh JK. Clinical and socioeconomic
correlates of insomnia. J Clin Psychiatry.
2004; 65(suppl 8):13-9.
16. Kuppermann M, Lubeck DP, Mazonson
PD et al. Sleep problems and their cor-
relation in a working population. J Gen
Intern Med. 1995; 10:25-32.
17. Riemann D, Voderholzer U. Primary
insomnia: a risk factor to develop depres-
sion? J Affect Disord. 2003; 76:255-9.
18. NIH State of the Science Conference
Statement on Manifestations and Man-
agement of Chronic Insomnia in Adults.
J Clin Sleep Med. 2005; 1:412-21.
19. Consens FB, Chervin RD. Sleep disorders.
In: Goetz CG, ed. Textbook of clinical
neurology. 2nd ed. Philadelphia: Elsevier
Health Sciences; 2003:1207-23.
20. Lacks P, Morin CM. Recent advances
in the assessment and treatment of in-
somnia. J Consult Clin Psychol. 1992; 60:
586-94.
Am J Health-Syst Pharm—Vol 65 May 15, 2008
21. Murtagh DR, Greenwood KM. Identify-
ing effective psychological treatments for
insomnia: a meta-analysis. J Consult Clin
Psychol. 1995; 63:79-89.
22. Morin CM, Culbert JP, Schwartz SM.
Nonpharmacological interventions for
insomnia: a meta-analysis of treatment
efficacy. Am J Psychiatry. 1994; 151:
1172-80.
23. Morin CM, Hauri PJ, Espie CA et al.
Nonpharmacologic treatment of chronic
insomnia. Sleep. 1999; 22:1134-56.
24. Charney DS, Mihic SJ, Harris RA. Hyp-
notics and sedatives. In: Brunton LL, Lazo
JS, Parker KL, eds. Goodman & Gilman’s
the pharmacologic basis of therapeu-
tics. 11th ed. New York: McGraw-Hill;
2006:401-27.
25. Lacy CF, Armstrong LL, Goldman MP et
al. Lexi-Comp’s drug information hand-
book. 13th ed. Hudson, OH: Lexi-Comp
Inc.; 2005.
26. Holbrook AM, Crowther R, Lotter A et al.
Meta-analysis of benzodiazepine use in
the treatment of insomnia. CMAJ. 2000;
162:225-33.
27. Winkelman J, Pies R. Current patterns
and future directions in the treatment
of insomnia. Ann Clin Psychiatry. 2005;
17:31-40.
28. Poyares D, Guilleminault C, Ohayon MM
et al. Chronic benzodiazepine usage and
withdrawal in insomnia patients. J Psy-
chiatr Res. 2004; 38:327-34.
29. Poyares D, Pinto LR, Tavares S et al.
[Sleep promoters and insomnia.] Rev
Bras Psiquiatr. 2005; 27(suppl 1):2-7. In
Portuguese.
30. Ambien (zolpidem tartrate) package
insert. Bridgewater, NJ: Sanofi-Aventis;
2006 Jun.
31. Ambien CR (zolpidem tartrate extended
release) package insert. Bridgewater, NJ:
Sanofi-Aventis; 2006 Feb.
32. Sonata (zaleplon) package insert. Bristol,
TN: King Pharmaceuticals; 2006 Mar.
33. Lunesta (eszopiclone) package insert.
Marlborough, MA: Sepracor; 2006 Apr.
34. Liappas IA, Malitas PN, Dimopoulos NP
et al. Zolpidem dependence case series:
possible neurobiological mechanisms
and clinical management. J Psychophar-
macol. 2003; 17:131-5.
35. Morgenthaler TI, Silber MH. Amnestic
sleep-related eating disorder associated
with zolpidem. Sleep Med. 2002; 3:323-7.
36. Mendelson WB. Sleepwalking associated
with zolpidem. J Clin Psychopharmacol.
1994; 14:150. Letter.
37. Cluydts R, Peeters K, de Bouyalsky I et
al. Comparison of continuous versus
intermittent administration of zolpidem
in chronic insomniacs: a double-blind,
randomized pilot study. J Int Med Res.
1998; 26:13-24.
38. Walsh JK, Roth T, Randazzo A et al.
Eight weeks of non-nightly use of zolpi-
dem for primary insomnia. Sleep. 2000;
23:1087-96.
39. Krystal AD, Walsh JK, Laska E et al.
Sustained efficacy of eszopiclone over 6
months of nightly treatment: results of
933
 clinical review  Insomnia
a randomized, double-blind, placebo-
controlled study in adults with chronic
insomnia. Sleep. 2003; 26:793-7.
40. Elie R, Ruther E, Farr I et al. Sleep latency
is shortened during 4 weeks of treat-
ment with zaleplon, a novel benzodiaz-
epine hypnotic. J Clin Psychiatry. 1999;
60:536-44.
41. Walsh JK, Pollak CP, Scharf MB et al. Lack
of residual sedation following middle-
of the-night zaleplon administration in
sleep maintenance insomnia. Clin Neu-
ropharmacol. 2000; 23:17-21.
42. Rozerem (ramelteon) package insert.
Osaka, Japan: Takeda Pharmaceutical
Co.; 2005 Nov.
43. Yukuhiro N, Kimura H, Nishikawa H et
al. Effects of ramelteon (TAK-375) on
nocturnal sleep in freely moving mon-
keys. Brain Res. 2004; 19:59-66.
44. Erman M, Seiden D, Zammit G et al. An
efficacy, safety, and dose-response study
of ramelteon in patients with chronic
primary insomnia. Sleep Med. 2006; 7:
17-24.
45. McGechan A, Wellington K. Ramelteon.
CNS Drugs. 2005; 19:1057-65.
934 Am J Health-Syst Pharm—Vol 65 May 15, 2008
46. Walsh JK, Schweitzer PK. Ten-year trends
in the pharmacologic treatment of in-
somnia. Sleep. 1999; 22:371-5.
47. Mendelson WB. A review of the evidence
for the efficacy and safety of trazodone
in insomnia. J Clin Psychiatry. 2005; 66:
469-76.
48. Walsh JK, Erman M, Erwin CW et al. Sub-
jective hypnotic efficacy of trazodone and
zolpidem in DSMIII-R primary insom-
nia. Hum Psychopharm. 1998; 13:191-8.
49. Santos MS, Ferreira F, Cunha AP et al.
Synaptosomal GABA release as influenced
by valerian root extract—involvement of
the GABA carrier. Arch Int Pharmacodyn
Ther. 1994; 327:220-31.
50. Valeriana officinalis. Altern Med Rev.
2004; 9:438-41.
51. Jacobs GD, Pace-Schott EF, Stickgold R et
al. Cognitive behavior therapy and phar-
macotherapy for insomnia: a randomized
controlled trial and direct comparison.
Arch Intern Med. 2004; 164:1888-96.
52. Rosen RC, Rosekind M, Rosevear C et al.
Physician education in sleep and sleep
disorders: a national survey of US medi-
cal schools. Sleep. 1993; 16:249-54.
53. Papp KK, Penrod CE, Strohl KP. Knowl-
edge and attitudes of primary care physi-
cians toward sleep and sleep disorders.
Sleep Breath. 2002; 6:103-9.
54. Morin CM. Measuring outcomes in ran-
domized clinical trials of insomnia treat-
ments. Sleep Med Rev. 2003; 7:263-79.
55. Reimer MA, Flemons WW. Quality of life
in sleep disorders. Sleep Med Rev. 2003;
7:335-49.
56. Sullivan SK, Petroski RE, Verge G et al.
Characterization of the interaction of
indiplon, a novel pyrazolopyrimidine
sedative-hypnotic, with the GABAA
receptor. J Pharmacol Exp Ther. 2004;
311:537-46.
57. Petroski RE, Pomeroy JE, Das R et al. In-
diplon is a high-affinity positive allosteric
modulator with selectivity for alpha1
subunit-containing GABAA receptors. J
Pharmacol Exp Ther. 2006; 317:369-77.
58. Clinical Trials.gov. Efficacy and safety
of eplivanserin treatment for sleep
m a i n ten a n ce i n s om n i a ( G E M S ) .
w w w. c l i n i c a l t r i a l s . g o v / c t 2 / s h ow /
NCT00253968?term=Eplivanserin&
rank=2 (accessed 2006 Apr 3).