Sleep Medicine Pharmacotherapeutics Overview Today, Tomorrow, and the Future (Part 1: Insomnia and Circadian Rhythm Disorders)

Abstract

Over the past 10 years, significant strides have been made in the understanding, development, and availability of sleep disorder therapeutics. In this review series, we discuss the current evidence surrounding the mechanisms of actions, indications, efficacy, and adverse side effects associated with the available armamentarium of sleep over-the-counter and pharmacotherapeutics. This article is the first of a two-part series that covers the therapeutics for insomnia and circadian rhythm disorders.

Full text

Postgraduate Education Corner
CONTEMPORARY REVIEWS IN SLEEP MEDICINE
CHEST
CHEST / 142 / 6 / DECEMBER 2012 1659
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I
nsomnia is the most common sleep disorder,
affecting millions worldwide. The International
Classifi cation of Sleep Disorders–Second Edition
(ICSD-2) defi nes insomnia as a functionally debili-
tating condition characterized by repeated diffi culty
with sleep initiation, maintenance, or quality despite
adequate sleep opportunity.
1
Currently, the ICSD-2
subclassifi es insomnia as either primary insomnia or
insomnia due to a secondary medical, psychiatric, or
medication-induced etiology. Primary insomnia symp-
toms can be acute and self-limiting or chronic and
persistent. In the case of adjustment insomnia, sleep
complaints develop abruptly as the result of a tangible
event, such as the loss of a loved one. Individuals clas-
sifi ed with this acute form of insomnia, however, will
typically report resolution of their sleep complaints
Sleep Medicine Pharmacotherapeutics
Overview
Today, Tomorrow, and the Future (Part 1: Insomnia and
Circadian Rhythm Disorders)
Seema Gulyani , PhD, NP ; Rachel E. Salas , MD ; and Charlene E. Gamaldo , MD
Manuscript received February 20 , 2012 ; revision accepted July 24 ,
2012 .
Affi liations: From the Division of Pulmonary and Critical Care
Medicine (Dr Gulyani ) and Department of Neurology (Drs Salas
and Gamaldo), Johns Hopkins University , Baltimore, MD.
Correspondence to: Seema Gulyani, PhD, NP, Johns Hopkins
University, 601 N Caroline St, Ste 1261, Baltimore, MD 21287;
e-mail: sgulyan1@jhmi.edu
© 2012 American College of Chest Physicians. Reproduction
of this article is prohibited without written permission from the
American College of Chest Physicians. See online for more details.
DOI: 10.1378/chest.12-0465
Over the past 10 years, signifi cant strides have been made in the understanding, development, and
availability of sleep disorder therapeutics. In this review series, we discuss the current evidence
surrounding the mechanisms of actions, indications, effi cacy, and adverse side effects associated
with the available armamentarium of sleep over-the-counter and pharmacotherapeutics. This
article is the fi rst of a two-part series that covers the therapeutics for insomnia and circadian rhythm
disorders. CHEST 2012; 142 ( 6 ): 1659 – 1668
Abbreviations : APAP 5 autotitrating positive airway pressure ; ASPD 5 advanced sleep phase disorder ; BZD 5 ben-
zodiazepine ; BZRA 5 benzodiazepine receptor agonist ; CRSD 5 circadian rhythm sleep disorder ; DSPD 5 delayed
sleep phase disorder ; FDA 5 Food and Drug Administration ; GABA 5 g -aminobutyric acid ; ICSD-2 5 International
Classifi cation of Sleep Disorders–Second Edition ; ISWR 5 irregular sleep-wake rhythm ; JLD 5 jet lag disorder
within 1 month. When the symptoms of primary insom-
nia persist beyond 3 months, the insomnia is reclas-
sifi ed as one of the following three chronic primary
insomnia subtypes: psychophysiologic insomnia, par-
adoxical insomnia, or idiopathic insomnia.
Epidemiology
The lifetime prevalence of insomnia is approxi-
mately 4% to 24%, depending on the study design
and diagnostic crite ria used.
2 - 5
Studies have shown
that the prev alence of insomnia varies with age and by
sex, with women having a lifetime risk 1.5- to 2-times
higher than men. Additional demographic factors
associated with increased risk of insomnia include
employment status, obesity, and an employment his-
tory associ ated with a rotating shift. When insomnia
evolves into a chronic and debilitating condition, the
estimated prevalence ranges from 6% to 10%.
4
Neurobiology of Insomnia
The sleep-wake state represents a dynamic interac-
tion between arousing and sleep-inducing physiologic
systems ( Table 1 ). These interconnected neurotrans-
mitter systems, which include noradrenaline, serotonin,
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acetylcholine, dopamine, histamine, and orexin, pro-
mote wakefulness, whereas g -aminobutyric acid
(GABA), glycine, melatonin, and adenosine promote
sleepiness.
6 , 7
Over-the-counter Insomnia Treatments
Most of the over-the-counter sleep-promoting agents
contain antihistamines that block histamine 1 recep-
tors, thus decreasing arousal. These drugs have low
effi cacy, which can generally be explained by the fact
that they target only one of the parallel arousing sys-
tems ( Table 2 ). Although antihistamine-based medi-
cations may improve mild insomnia for a short period
of time, they are not likely to signifi cantly improve
symp toms over an extended period and, thus, are
Table 1 —Neurotransmitters Involved in Sleep
and Arousal
Neurotransmitter Facilitates Sleepiness Facilitates Arousal
Adenosine X …
GABA X …
Galanin X …
Glycine X …
Melatonin X …
Acetylcholine … X
Dopamine … X
Glutamate … X
Histamine … X
Norepinephrine … X
Orexin 1 and 2 … X
Serotonin … X
GABA 5 g -aminobutyric acid.
not ideal. Side effects are mainly due to the diffuse
and systemic anticholinergic properties. Com mon
side effects of antihistamines typically include dry
mouth, dizziness, daytime sedation, and memory prob-
lems. These med ications are not recommended for
pregnant women or breast-feeding mothers. People
aged . 65 years are particularly sensitive to the anti-
cholinergic side effects, making these medications a
less desirable option for this age group.
Melatonin is another commonly used over-the-
counter sleep aid for insomnia. It is a sleep-promoting
hormone made by the pineal gland that regulates the
circadian rhythm by its action on melatonin receptors
in the suprachiasmatic nucleus.
8 , 9
Although melatonin
often is used and viewed as a natural supplement,
patients should be alerted to the potentially serious
side effects that can be encountered, including alter-
ations in cardiac rhythmicity, BP, GI motility, and glu-
cose metabolism.
10
Food and Drug Administration-Approved
Medications for Insomnia
The current US Food and Drug Administration
(FDA)-approved medications for insomnia use either
the GABAergic pathway or the central melatonergic
path way ( Table 3 ). These medications often are pre-
scribed to individuals with chronic insomnia. Although
acute and adjustment insomnia often are self-limited,
these medications can also be used during the symptom-
atic period in severe cases. A major issue regarding
the use of hypnotic agents for chronic insomnia is the
Table 2 —Common Over-the-counter Sleep Aids
Name Mechanism of Action FDA Indication (Insomnia) Common Side Effects Half-life
Nytol (GlaxoSmithKline plc) H1 receptor antagonist Yes Daytime drowsiness/grogginess,
daytime impairment, dizziness,
dyskinesia, xerostomia,
urinary retention
4-8 h
Sominex (GlaxoSmithKline plc) H1 receptor antagonist Yes Same as Nytol 4-8 h
Sleepinal (Blairex Laboratories, Inc) H1 receptor antagonist Yes Same as Nytol 4-8 h
Unisom (Chattem, Inc) H1 and H2 receptor
antagonist
Yes Daytime grogginess effect,
daytime impairment
6-8 h
Melatonin MT
1
and MT
2
receptor
agonist
No Daytime grogginess effect, daytime
impairment, confusion
30-50 min
Tryptophan Modulation of serotonin No Drowsiness, headaches, dizziness 1-3 h
Combination drugs
Diphenhydramine hydrochloride
a
H1 and H2 receptor
antagonist
No Daytime drowsiness, daytime
impairment
N/A
b
Tylenol PM (McNEIL-PPC, Inc) H1 receptor antagonist No Same as Nytol N/A
b
Anacin PM (INSIGHT
Pharmaceuticals, LLC)
H1 receptor antagonist No Same as Nytol N/A
b
Nyquil (Procter & Gamble) H1 and H2 receptor
antagonist
No Daytime grogginess N/A
b
Herbal aids
Valerian, kava, chamomile Unknown No Hepatotoxicity N/A
b
FDA 5 Food and Drug Administration; H 5 histamine; MT 5 melatonin; N/A 5 not applicable.
a
Made by various companies as a combination product as a sleep aid.
b
N/A because different ingredients in combination drugs have different half-lives.
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duration of treatment. Nearly all published placebo-
controlled studies have reported effi cacy and toler-
ability based on 2- to 6-week trials.
11
Although insomnia could last for years or decades,
longitudinal treatment studies evaluating the effi cacy
and outcomes of these medications beyond 1 year are
limited. Two studies done with eszopiclone 3 mg pro-
vided placebo-controlled data for 6 months of treat-
ment and found that tolerance and withdrawal did
not occur in up to 1 year of continuous therapy. The
paucity of information regarding the safety and effi -
cacy of these medications as a long-term therapeutic
suggests further investigation.
Most of the current insomnia pharmacotherapeu-
tics target the GABAergic system. These agents are
GABA
A
receptor agonists that activate the receptor by
binding to the benzodiazepine (BZD) receptor site.
Activation of the GABA
A
receptors reduces the neu-
ronal excitability of the wake/arousal centers, resulting
in sleep. The GABA
A
receptor comprises fi ve subunits
that form a central chloride channel. Most receptor
subtypes consist of two a and two b subunits and one
g subunit. The a subunits have six variants, and a 1
is of interest in insomnia because agents binding to
this subunit mediate sedation ( Fig 1 ). The BZD recep-
tor agonist (BZRA) insomnia agents (eg, zolpidem,
eszopi clone) demonstrate improvements over the ear-
lier generation of BZDs primarily because of their
faster elimination rates and more-selective binding
affi nity to specifi c a subunits. The BZRA drugs have
half-lives , 6 h, optimally allowing for the pres-
ence of peak therapeutic levels during the sleep
period while minimizing the risk of residual daytime
sedation ( Table 4 ).
On the other hand, the classic BZDs have roughly
equivalent affi nities for all of the a subunits that can
be represented in the BZD receptor. Clinical use of
BZDs, such as temazepam, continues but is limited
by side effects likely because of its indiscriminate
binding to GABA
A
receptors and unfavorable phar-
macokinetics.
12
BZDs are known to be involved in
mediating amnesic and ataxic effects in addition to
sedation (triazolam, fl urazepam) ( Table 3 ) and, there-
fore, must be prescribed with caution in vulnerable
populations, such as elderly people.
Ramelteon was the first approved melatonergic
drug for the treatment of insomnia. It acts on mela-
tonin receptors MT
1
and MT
2
, showing higher affi nities
Table 3 —FDA-Approved Drugs for Insomnia
Trade Name Generic Name Mechanism of Action Dose, mg Common Side Effects Half-life, h
Nonspecifi c sleep modulating agents
ProSom (Abbott Laboratories) Estazolam GABA
A
modulator 1-2 Daytime grogginess effect,
dry mouth, weakness,
coordination issues, dizziness
10-24
Dalmane (Valeant Pharmaceuticals
International, Inc)
Flurazepam GABA
A
modulator 15-30 GI upset, irritability drug
dependence, ataxia,
dizziness, headache
2
a
Halcion (Pfi zer, Inc) Triazolam GABA
A
modulator 0.25-0.5 Amnestic events,
euphoria, GI upset, headache,
dizziness, tingling of skin,
coordination issues
1.5-5
Restoril (Covidien plc) Temazepam GABA
A
modulator 7.5-30 Daytime grogginess effect,
GI upset, dizziness,
hypotension, blurred vision
8
Doral (Questcor Pharmaceuticals, Inc) Quazepam GABA
A
modulator 7.5-30 GI upset, hallucinations, slurred
speech, dizziness, headache
39
Specifi c sleep modulating agents
Sonata (Pfi zer, Inc) Zaleplon
GABA
A
a 1 b g 2
modulator
5-20 Dizziness, loss of appetite,
eye pain, coordination issues,
numbness, headache
1
Lunesta (Sunovion Pharmaceuticals Inc) Eszopiclone
GABA
A
a 1-3 b g 2
modulator
2-3 Disorders of taste, respiratory
effects, dizziness, headache,
GI upset, coordination issues
6
Ambien (sanofi -aventis US LLC) Zolpidem
GABA
A
a 1 b g 2
modulator
1.75-12.5
b
Headache, dizziness,
amnestic events, confusion,
slurred speech
2-3
Rozerem (Takeda Pharmaceuticals
North America, Inc)
Ramelteon Melatonin (MT
1
and
MT
2
receptor agonist)
8 Fatigue, dizziness, nausea,
GI upset, fertility issues
1-3
Silenor (Somaxon Pharmaceuticals, Inc) Doxepin H1 receptor antagonist 3-6 Urinary retention, respiratory
effects, dizziness
15
See Table 1 and 2 legends for expansion of abbreviations.
a
Produces a metabolite with a longer half-life (40-250 h).
b
Specifi c ranges: intermezzo sublingual, 1.75-3.5 mg; oral spray, 10 mg; immediate release, 10 mg; extended release, 12.5 mg.
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1662
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for these receptors than the natural ligand mela-
tonin. In chronic insomnia, ramelteon decreases sleep
onset latency and increases total sleep time and
sleep effi ciency without causing residual sleepiness,
psychomotor complaints, addiction, or withdrawal
symptoms.
13
Currently, there are no FDA-approved pharmaco-
therapies for insomnia in the pediatric population.
Doxepin, however, was approved in the adult popula-
tion for sleep maintenance insomnia and has long
been used safely in the pediatric population for anx-
iety and depression.
As discussed in a previous section, insomnia often
presents as a chronic condition requiring treatment
that far exceeds the duration approved by the FDA
for any of the currently available agents. This often
sparks questions and concerns by both patients and
Figure 1. The fi ve subunits of a GABA
A
receptor. In addition
to a Cl
2
channel pore and two GABA active binding sites, a BZD
allosteric binding site exists at the interface of the g 2 subunit and
one of four isoforms of the a subunit ( a 1, a 2, a 3, and a 5). BZDs
have nonselective binding affi nity for the BZD site regardless of
the a -subunit isoform, whereas newer BZD receptor agonist insom-
nia medications have more selective affi nity to the BZD binding
sites that contain specifi c a -subunit isoforms as depicted in the key.
This selectivity allows for not only greater control of clinical effects
but also association with specifi c side effect profi les ( Table 4 ).
BZD 5 benzodiazepine; Cl
2
5 chloride ion; GABA 5 g -aminobutyric
acid.
providers regarding the long-term consequences of
these medications. Dependence risk depends on both
the agent and the dose and may vary among individ-
uals on the basis of comorbid psychiatric illness or
polypharmacy. Studies have found that nightly treat-
ment in adults with eszopiclone 3 mg or zaleplon 5 to
10 mg for up to 1 year did not result in tolerance
or withdrawal symptoms.
14
Another study of nightly
zaleplon use in older adults demonstrated safety with
minimal risk of withdrawal upon discontinuation.
15
Non-FDA-Approved (Off-label) Medications for
Insomnia
The recognition of the prevalence and negative con-
sequences of insomnia predates the introduction of
FDA-approved therapeutics. For this reason, clini-
cians have long prescribed and continue to prescribe
several off-label medications for insomnia in lieu of
the FDA-approved options. Tricyclic antidepressants,
BZDs, and, more recently, atypical antipsychotics are
three of the most common classes prescribed strictly
for sleep promotion. Unlike most FDA-approved ther-
apeutics with half-lives in the 2- to 6-h range, most
off-label options have half-lives of . 6 h (eg, nortrip-
tyline) ( Table 5 ), increasing the likelihood of residual
grogginess or hangover sensations in the morning.
This was particularly the case with the older BZDs,
such as nitrazepam, which was associated with daytime
sedation and falls in elderly people.
16 , 17
As shown in
Table 5 , the utility of these medications for sleep pro-
motion is limited by their side effects profi le, which
is considered to outweigh their sleep-promoting bene-
fi ts based on current sleep expert consensus.
12 , 18 , 19
New Insomnia Drugs in Clinical Trials or Newly
Approved
Clinical trials targeting insomnia remain robust,
despite the overall drop in economic resources and
investments targeting pharmacotherapeutics ( Table 6 ).
Increased understanding of complex neuronal net-
works involved in sleep and wake has led to the devel-
opment of new hypnotics that target a diverse range
of receptors with increasing selectivity. Potential agents
Table 4 —Effects Mediated by GABA
A
Receptor a Subunits
Clinically Relevant Effects Side Effects
Subunit Sedation Anxiolytic Muscle Relaxant Anticonvulsive Antidepressant Amnesia Dependence
a 1
X… … X … X X
a 2
…X X … X … …
a 3
…… X … … … …
a 5
… … X … … … …
See Table 1 legend for expansion of abbreviation.
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under investigation are targeting mechanisms and
pathways, including histamine 1 receptors and orexin
receptors.
Special Consideration: Insomnia Pharmacotherapy
and Obstructive Sleep Apnea
Insomnia and sleep-disordered breathing represent
the two most common sleep disorders. Although they
may occur separately in a patient, they can also occur
concurrently. As such, the prevalence of these con-
ditions often results in the sleep practitioner raising
clinical questions regarding the impact of insomnia
on (1) altering the respiratory arousal thresholds and
apnea-hypopnea index, (2) CPAP adherence, and
(3) treatment of insomnia in the setting of obstruc-
tive sleep apnea. Current clinical trials are evaluating
the answers to these questions. A recent double-blind,
placebo-controlled study found that eszopiclone 3 mg
signifi cantly improved sleep quality and duration while
Table 5 —Non-FDA-Approved Antidepressant Medications Used as Sleep Aids
Class Generic Trade Name Dose, mg Side Effects Half-life, h
Tricyclic antidepressants Trazodone Desyrel (Bristol-Myers
Squibb Co)
100-150 Nervousness, fatigue, diarrhea 7
Amitriptyline Elavil (AstraZeneca) 75 Weight gain, xerostomia 15
Nortriptyline Pamelor (Allscrips/Allegiance),
Aventyl (Eli Lilly and Company)
25 Dysrhythmia, cardiotoxicity 15-39
H1 receptor antagonist Mirtazapine Remeron (Merck & Co, Inc) 15 Weight gain, increase of
appetite, liver toxicity
26-37
SNRI, 5-HT2 antagonist Nefazodone Serzone (Bristol-Myers
Squibb Co)
100 Headaches, dizziness,
confusion
2-4
D2 and 5-HT2 receptor antagonist Quetiapine Seroquel (AstraZeneca) 100-300 Agitation, dizziness,
extrapyramidal effects
6
5-HT 5 5-hydroxytryptamine (serotonin); D2 5 dopamine; SNRI 5 serotonin-norepinephrine reuptake inhibitor. See Table 2 legend for expansion
of other abbreviation.
lowering the stage N2 sleep respiratory arousal thresh-
old and apnea-hypopnea index without prolonging
respiratory events or worsening hypoxemia.
20
Tra-
zodone at doses as high as 100 mg has been found
to increase the arousal threshold in response to hyper-
capnia in patients with obstructive sleep apnea and
allows these patients to tolerate higher CO
2
levels.
21
One randomized, double-blind, placebo-controlled
pilot trial examined the effectiveness of ramelteon
on improving sleep parameters in older people start-
ing on autotitrating positive airway pressure (APAP)
therapy.
22
This study found that ramelteon resulted
in statistically reduced sleep onset latency relative
to placebo without any change in subjective sleep
onset latency, sleep quality, APAP adherence, or day-
time functioning parameters. These results suggest
that ramelteon may improve sleep onset latency in
this population, particularly during the critical initial
phase of starting APAP therapy. Another randomized
Table 6 —New Drugs Under Clinical Trials
Drug Name Company Indication Trial Phase Action
KI1001 Kuhnil Pharmaceutical Co, Ltd
Insomnia . 55-year-olds
III Prolonged-release
melatonin
VEC 162 (tasimelteon) Vanda Pharmaceuticals Transient insomnia III Melatonin receptor
antagonist
SKP1041 Somnus Therapeutics Inc Sleep maintenance insomnia II GABA receptor modulator
EVT 201 Evotec AG Primary insomnia II GABA receptor modulator
Brotizolam Boehringer Ingelheim GmbH Insomnia III GABA modulation
LY2624803 Eli Lilly and Company Chronic insomnia II H1 receptor antagonist
Casopitant GlaxoSmithKline plc Insomnia II NK-1 receptor inhibitor
Org 50081 Merck & Co, Inc Primary insomnia III 5-HT2C antagonist
Eplivanserin sanofi -aventis US LLC Sleep maintenance insomnia III 5-HT2A antagonist
Suvorexant Merck & Co, Inc Primary insomnia III OX1 and OX2 receptor
antagonist
Suvorexant Merck & Co, Inc Obstructive sleep apnea I OX1 and OX2 receptor
antagonist
Circadian Neurim Pharmaceuticals, Inc Primary
insomnia . 55-year-olds
Approved in Europe Prolonged-release
melatonin
Agomelatine Novartis AG Depression, improves sleep Approved in Europe MT
1
and MT
2
receptor
agonist and 5-HT2C
antagonist
NK-1 5 neurokinin 1; OX 5 orexin . See Table 1 , 2, and 5 legends for expansion of other abbreviations.
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1664
Postgraduate Education Corner
trial showed that subjects assigned to the eszopiclone
group had greater CPAP adherence, demonstrating
1.3 h more of CPAP use per night for all nights.
23 , 24
Another study by the same authors reported that pre-
medication with eszopiclone during a CPAP titration
study signifi cantly improved short-term CPAP compli-
ance. Premedication also improved sleep effi ciency,
decreased sleep onset latency, and decreased the
number of residual obstructive events observed at the
fi nal CPAP pressure.
25
Special Consideration: Insomnia and Comorbid
Depression
Insomnia is one of the diagnostic features for mood
instability in depression and anxiety. For this reason,
clinicians have long struggled with whether to treat
insomnia as a distinct condition or as a secondary phe-
nomenon related to mood stability. Data suggest that
insomnia may in fact predate complaints related to
mood. In a review of epidemiologic studies, it was
reported that insomnia predicted future risks of
depression, anxiety, substance abuse, and suicide.
26
A
community-based study in adolescents reported that
69% of insomnia cases preceded comorbid depression,
whereas anxiety disorder preceded insomnia 73% of
the time.
27 , 28
Findings suggest that long-term outcomes
signifi cantly improve when the sleep disruption is con-
currently and aggressively managed along with the
primary mood complaints in individuals with signifi -
cant sleep disruption. Enhanced rate of mood stabili-
zation and a decline in relapse rates have been found
with this dual approach.
29
Studies have shown that
more-sedating antidepressants, such as nefazodone
and amitriptyline, improve sleep symptoms and poly-
somnographic fi ndings compared with selective sero-
tonin reuptake inhibitors alone.
30
Thus, among patients
who present with signifi cant insomnia at the time of
depression, selection of more-sedating antidepres-
sants, such as mirtazapine and trazodone, may be rea-
sonable.
31
Among patients with comorbid insomnia,
BZRA hypnotics could also be an effective adjunc-
tive treatment. The combination of eszopiclone with
fl uoxetine has been associated with greater sleep
improvements and depression responses compared
with fl uoxetine alone.
32
Adding a small dose of tra-
zodone (50-100 mg) to a selective serotonin reuptake
inhibitor has been shown to improve insomnia com-
orbid with depression.
33
Circadian Rhythm Sleep Disorders
Circadian rhythm sleep disorders (CRSDs) are char-
acterized by a misalignment between one’s sleep
period and physical or social 24-h environmental
cycle.
34 , 35
Both exogenous and endogenous factors can
contribute to the misalignment.
36
Circadian and homeo-
static processes interact to regulate sleep and wake-
fulness. Light is the strongest cue that synchronizes
the circadian clock to the external environment. The
master clock regulating the endogenous circadian
rhythm is located in the suprachiasmatic nucleus,
which receives information about light through the
retinohypothalamic tract. Melatonin, which is regu-
lated by the suprachiasmatic nucleus, begins to rise
1 to 3 h before the habitual sleep time and peaks
prior to core body temperature nadir. In contrast to
light, melatonin given in the evening shifts the circa-
dian rhythm to an earlier time.
Six distinct CRSDs are currently recognized in the
ICSD-2
1
: (1) delayed sleep phase disorder (DSPD),
(2) advanced sleep phase disorder (ASPD), (3) shift
work disorder, (4) jet lag disorder (JLD), (5) free-
running disorder, and (6) irregular sleep-wake rhythm
(ISWR). The core of the biologic clock is believed
to consist of interactions among about 10 clock genes,
including Per1 , Per2 , and Per3 (circadian clock pro-
tein period 1, 2, and 3); Cry1 and Cry2 (cryptochrome 1
and 2 [photolyase-like]); Bmal1 (aryl hydrocarbon
receptor nuclear translocator-like); CLOCK (mamma-
lian clock gene); and CK1
d
/
´
(casein kinase 1 d / ε ) .
7
Per1, 2, and 3 , Cry 1 and 2 , Bmal1 , and CLOCK code
for transcriptional factors, whereas CK1
d
/
´
code for
kinases that phosphorylate these transcriptional fac-
tors. Functional abnormalities of these clock genes
affect the circadian phenotype in various species,
including insects, mice, hamsters, and humans.
37
In most cases, CRSD treatment involves a com-
bination of behavioral, over-the-counter, and phar-
macologic therapies. General statements regarding
behavioral strategies are discussed as they apply to
the specifi c CRSD conditions. In-depth discussion
of the behavioral strategies, however, are beyond the
scope of this review.
Delayed Sleep Phase Disorder
DSPD is one of the most common CRSDs, affecting
an estimated 1.7% of the general population and up
to 16% of adolescents and young adults. Nearly 10%
of those with DSPD also develop chronic insomnia
38 , 39
because of their unsuccessful attempts to conform
to conventional work or other social demands. Treat-
ment of DSPD involves a multimodal approach that
uses both behavioral and pharmacologic treatments.
Behavioral approaches usually involve the introduc-
tion of zeitgebers (environmental variables capable of
entraining the circadian rhythm) at appropriate times
in the sleep-wake cycle to assist in anchoring and
shifting forward the individual’s inherent circadian
clock. In general, techniques such as sleep restriction
with stringent wake time and timed light exposure
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have proven effective.
34 , 40
Melatonin remains effective
in advancing the sleep-wake rhythm and endogenous
melatonin rhythm in DSPD.
8 , 36
Advanced Sleep Phase Disorder
ASPD is characterized by a stable sleep schedule
that is several hours earlier than the conventional
or desired time. Conventionally viewed as morning
larks, individuals with this circadian rhythm usually
do not encounter the same diffi culties related to work
performance, attendance, or punctuality experienced
by those with DSPD. In severe cases, however, they
present with concerns of inability to fully partici-
pate in evening social events with friends and family.
Several pedigrees have exhibited a familial prepon-
derance for ASPD. So far, causative mutations of clock
genes have been found in two of the familial ASPD
pedigrees. The mutation of Per2 cosegregated with
affected patients in one of the familial ASPD pedi-
grees. Although there is rationale indicated in Ameri-
can Academy of Sleep Medicine guidelines for timed
melatonin administration, there is no clear support-
ing evidence of its effectiveness.
34
Shift Work Disorder
An estimated 20% of the US workforce does some
form of shift work, with women doing more than men.
Shift work disorder has been linked to increased
morbidity (sleep-wake disturbances, GI disturbances,
infertility, glucose metabolism dysregulation) and
mortality (malignancy and vehicular or occupational
accidents).
41
Many therapeutic modalities ranging
from behavioral to pharmacologic have been found
to be effective.
42
Behavioral modifi cations include
planned napping and timed light exposure in the work
environment. Restricting light in the morning has also
been shown to improve alertness, vigilance, mood,
and work time tasks.
35
A meta-analysis concluded that
caffeine may be an effective intervention for improv-
ing performance in shift workers.
43
Administration of
melatonin 5 to 6 mg prior to daytime sleep is indi-
cated to promote daytime sleep among night shift
workers, although the evidence is mixed.
35
Melatonin
3 mg or 0.5 mg given before naps and sleep periods
results in a signifi cant phase advancement compared
with placebo in a randomized controlled trial of sim-
ulated night workers.
44
BZDs ( Table 7 ) have been evaluated as a potential
sleep aid for shift work disorder. Studies have shown
zopiclone 7.5 mg,
45
triazolam 0.25 to 0.5 mg,
46
and
temazepam 20 mg
47
to be effective in increasing day-
time sleep duration with both subjective and objec-
tive measures. One study with zolpidem 5 to 10 mg
reported improvement in night shift-related sleep
quality over placebo; however, mood was worsened
during the following work period compared with pla-
cebo.
48
A double-blinded randomized controlled trial
of modafi nil 200 mg given 30 to 60 min before the
start of a night shift resulted in objective improve-
ment in sleepiness and improved performance on
psychomotor vigilance testing.
49
Armodafi nil 150 mg
given 30 to 60 min prior to beginning the night shift
resulted in reduced self-reported sleepiness during
work and the morning commute.
50
Signifi cant improve-
ment in performance on standardized memory and
attention testing was also demonstrated. No wors-
ening in daytime sleep parameters occurred with
armodafi nil. Both modafi nil and armodafi nil are FDA
approved for the treatment of shift work disorder.
Jet Lag Disorder
The symptoms of JLD are due to circadian mis-
alignment when crossing time zones too rapidly for
the circadian system to keep pace. Depending on the
number and direction of time zones crossed, it may
take days for the circadian system to resynchronize.
The intensity and duration of the disorder are related
Table 7 —Commonly Used Medication to Treat Circadian Rhythm Disorders
Generic Name Trade Name Dose, mg FDA Approved Side Effects Half-life, h
Melatonin N/A 0.5-3 No (OTC) Increased BP, increased blood sugar,
worsening of depression, fertility issues
1
Modafi nil Provigil (Cephalon, Inc) 200 Yes Headache, nausea, dizziness, reduced
contraceptive effectiveness
15
Armodafi nil Nuvigil (Cephalon, Inc) 150 Yes Headache, nausea, dizziness, reduced
contraceptive effectiveness
12-15
Zolpidem Ambien (sanofi -aventis US LLC) 5-10 No Headache, dizziness 2-3
Zaleplon Sonata (Pfi zer, Inc) 5-20 No Dizziness, headache 1
Triazolam Halcion (Pfi zer, Inc) 0.25-0.5 No Amnesia, ataxia, euphoria, nausea/vomiting 1.5-5
Temazepam Restoril (Covidien plc) 20 No Hypotension, blurred vision 8
Ramelteon Rozerem (Takeda Pharmaceuticals
North America, Inc)
1 No Fatigue, dizziness, nausea 1-3
OTC 5 over-the-counter. See Table 2 for expansion of other abbreviations.
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1666
Postgraduate Education Corner
to (1) the number of time zones crossed, (2) the direc-
tion of travel, (3) the ability to sleep while travel-
ing, (4) the availability and intensity of local circadian
time cues, and (5) individual differences in phase
tolerance.
35
In addition to sleep complaints, JLD can
be associated with the following somatic complaints:
GI disturbance, light-headedness, weakness, and phys-
ical clumsiness.
51
The administration of melatonin
5 to 8 mg is the most extensively studied treatment of
JLD, with demonstrated effi cacy in reducing symp-
toms of jet lag and improving sleep when traveling
across multiple time zones.
52 , 53
Effi cacy of this treat-
ment has been studied primarily under the context
of eastward travel,
54 - 56
but a few studies have also pro-
vided evidence that melatonin is useful in westward
travel.
57
One study showed that ramelteon 1 mg taken
before bedtime reduced sleep onset latency after a
5-h phase advance due to eastward jet travel.
55
A short course of a hypnotic medication has been
shown in randomized trials to reduce insomnia related
to jet lag. Eastward travelers from the United States
taking zolpidem 10 mg reported better sleep post-
travel than those taking placebo, particularly on the
fi rst 2 posttravel nights. After trans-Atlantic travel
crossing fi ve to nine time zones, zolpidem was associ-
ated with improved sleep quality and increased total
sleep time.
34 , 52
Free-Running Disorder
The earliest studies of human subjects in time-free
environments concluded that most people have an
intrinsic circadian period . 24 h, averaging about
24.2 h. Patients with free-running rhythms have cir-
cadian cycles that mimic those of individuals in time-
free environments and, thus, are believed to refl ect a
failure of entrainment. The condition is rare in people
with normal sight, but quite common in people with
retinal blindness who have no access to the entrain-
ing effects of the light/dark cycle.
58
Data from limited
studies show that both appropriately timed bright
light exposure and melatonin administration entrain
sighted patients with free-running disorder. Mela-
tonin 0.5 to 10 mg has also been shown to entrain peo-
ple with total or retinal blindness with free-running
disorder.
58 , 59
Irregular Sleep-Wake Rhythm
ISWR is characterized by the relative absence of a
circadian pattern to the sleep-wake cycle. Total sleep
time could be normal, but instead of being consoli-
dated into a distinct sleep and wake bout, sleep times
are shortened, and in extreme cases, sleep cycles are
almost randomly distributed throughout the day and
night. ISWR is commonly associated with neurologic
and psychiatric illness, such as mental retardation and
dementia in older adults, especially in people with
Alzheimer disease. There is no proven pharmaco-
therapy to treat ISWR.
Conclusions
Sleep medicine remains an area of active research.
There has been an increase in the number of sleep
over-the-counter and pharmacotherapeutics, particu-
larly for insomnia. Although the GABAergic system
remains the primary target for the current insomnia
pharmacotherapeutics, agents targeting more-diverse
mechanisms (melatonin, orexin, and histamine) are
either in the clinical trial pipeline or have recently
entered the market. Longitudinal outcome studies
evaluating the long-term use of sleep pharmacother-
apeutics remain sparse; thus, further studies are war-
ranted. Insomnia and circadian rhythm disorders
are two common conditions associated with several
medical, psychiatric, and other primary sleep condi-
tions. Therefore, treatment strategies should involve
a strong emphasis on individualized therapies based
on comorbid conditions and the available effi cacy and
outcomes data.
Acknowledgments
Financial/nonfi nancial disclosures: The authors have reported
to CHEST that no potential confl icts of interest exist with any
companies/organizations whose products or services may be dis-
cussed in this article .
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