Download Using Antihistamines as a Sleep Aid

Using Antihistamines as a Sleep Aid
Fahad Alshahrani
Bachelor of Science in Pharmacy (King Saud University, Saudi Arabia)
November 2012
Thesis submitted in fulfilment of the requirements for the degree of
Master of Pharmacy at the University of Canberra, Australian
Capital Territory, Australia
Abstract
Background:
Approximately 8.9% of the Australian population aged 20 years and over experience a sleep
disorder. Many treatments are used for the treatment of sleep disorders including
antihistamines, available without a prescription. Few studies have investigated the usage of
antihistamine sleep aids and their efficacy.
Objectives:
The aims of this study were to determine the:

characteristics of patients requesting antihistamines as sleep aids; and

usage and perceived efficacy of antihistamine therapy for insomnia in a sub-sample of
the study population.
Design:
The study was based on a convenience sample of community pharmacy clients seeking an
antihistamine product as a sleep aid in a community pharmacy. It was conducted in 7
community pharmacies around the Australian Capital Territory (ACT) metropolitan area.
Participants were surveyed in two phases.
The phase I survey was completed by clients recruited by the participating pharmacies whilst
in the pharmacy.
A more detailed phase II survey was administered by the researcher during a follow-up
telephone call and assessed the effectivness of the antihistamine and other factors related to
causes of insomnia, such as caffeine, alcohol consumption and smoking status.
Both questionnaires based on DSM-IV and ICSD criteria as well as the Insomnia Severity
Index.
Results
Seventy-three participants completed the Pharmacy questionnaire with 48 agreeing to
participate in the telephone follow-up survey. The population was predominantly female
(n=47, 63.5%). The likelihood of seeking treatment significantly increased with age, female
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gender, and smoking. Difficulty initiating or maintaining sleep and frequent awakening also
increased with increasing age. Participants with a lower education level were more likely to
experience sleep problems. Herbal (52.1%) and non-prescription products (50.7%) had been
used before receiving the antihistamine, indicating a lack of effect. Using antihistamine was
associated with marked improvements in sleep parameters with 97.9% of participants rating
an antihistamine as helpful. The main antihistamine side effects reported were drowsiness and
nausea.
Conclusion
Poor sleep pattern symptoms were associated with many factors including increasing age.
Antihistamines were an effective treatment to improve sleep patterns.
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Acknowledgments
I take this opportunity to express my profound gratitude and deep regards to my guide Dr.
Greg Kyle for his exemplary guidance, monitoring and constant encouragement throughout
the course of this thesis. The blessing, help and guidance given by him time to time shall
carry me a long way in the journey of life on which I am about to embark.
I also take this opportunity to express a deep sense of gratitude to staff members of Saudi
Arabian Cultural Mission for thier cordial support and guidance, which helped me in
completing this task through various stages.
I am obliged to staff members of Australian Pharmacy Group and Capital Chemist
Pharmacies for their cooperation during the period of my project.
Lastly, I thank almighty, my wife, my parents, and friends for their constant encouragement
without which this project would not be possible.
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Table of Contents
Abstract .................................................................................................................................................. iii
Acknowledgments ................................................................................................................................... v
List of Tables .......................................................................................................................................... ix
List of Figures ........................................................................................................................................ xi
Abbreviations ....................................................................................................................................... xiii
Form B................................................................................................................................................... xv
Chapter 1: Introduction and Literature Review ....................................................................................... 1
Sleep and sleep physiology ................................................................................................................. 1
Sleep stages ..................................................................................................................................... 2
Physiological changes during sleep ................................................................................................. 4
Cardiovascular ........................................................................................................................ 4
Sympathetic-nerve activity ...................................................................................................... 4
Respiratory .............................................................................................................................. 4
Cerebral blood flow................................................................................................................. 5
Renal........................................................................................................................................ 5
Endocrine ................................................................................................................................ 5
Function of sleep ............................................................................................................................. 5
What controls sleep? ....................................................................................................................... 6
Role of Serotonin (5-HT) in the Sleep – wake cycle....................................................................... 7
Insomnia .............................................................................................................................................. 9
Definition of insomnia..................................................................................................................... 9
Why is insomnia a problem? ........................................................................................................... 9
Classification of insomnia: ............................................................................................................ 10
Assessment of insomnia ................................................................................................................ 12
Role of the pharmacist ................................................................................................................... 14
Epidemiology of Insomnia ............................................................................................................ 15
Causes of Insomnia ........................................................................................................................... 18
Consequences of insomnia ................................................................................................................ 20
Economic consequences ................................................................................................................ 20
Cognitive, social and vocational consequences............................................................................. 20
Health consequences ..................................................................................................................... 21
Treatment of Insomnia ...................................................................................................................... 24
1-Non-pharmacological treatment of Insomnia ............................................................................. 24
2-Complementary and Alternative Medicines (CAM) .................................................................. 29
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3-Social Treatment ........................................................................................................................ 44
4-Pharmacologic treatment of primary insomnia .......................................................................... 47
Chapter 2: Methodology........................................................................................................................ 65
Project Site ........................................................................................................................................ 65
Participants ........................................................................................................................................ 65
Ethics ................................................................................................................................................. 67
Chapter 3: Results ................................................................................................................................. 69
Part 1: Pharmacy Questionnaire ........................................................................................................ 69
Part 2: Telephone interview survey ................................................................................................... 76
Chapter 4: Discussion and Conclusion .................................................................................................. 87
Conclusion......................................................................................................................................... 93
References ............................................................................................................................................. 95
Appendix A ......................................................................................................................................... 132
Appendix B ......................................................................................................................................... 134
Appendix C ......................................................................................................................................... 135
viii
List of Tables
Tables
Table 1
Physiological changes during the NREM and REM sleep
Table 2
General Effects of Alcohol Use and Cessation on Sleep Architecture
45
Table 3
Medications with TGA indication for insomnia
47
Table 4
Age and Gender Cross tabulation
70
Table 5
Condensed Age and Gender Cross tabulation
70
Table 6
Difficulty falling asleep and age cross tabulation
72
Table 7
Frequency of staying asleep
72
Table 8
Difficulty staying asleep and age cross tabulation
73
Table 9
Frequency of awakening from sleep
73
Table 10
Awakening from sleep and age cross tabulation
73
Table 11
Frequency of self-reported refreshing sleep
74
Table 12
Refreshing sleep and Age Cross tabulation
74
Table 13
Product (s) previously used for insomnia
75
Table 14
Other treatments used by participants by age group
75
Table 15
Frequency of caffeine consumption
78
Table 16
Caffeine consumption and difficulty falling asleep Cross tabulation
78
Table 17
Caffeine consumption with age group Cross tabulation
79
Table 18
Frequency of alcohol drinking per week
79
Table 19
Difficulties Falling Asleep and Alcohol Consumption Cross tabulation
80
Table 20
Smoking and Difficult falling asleep Cross tabulation
80
Table 21
Sleep latency time before and after using antihistamine
81
Table 22
Quality of sleep before and after using antihistamine
81
Table 23
Nap length time before and after using antihistamine
82
Table 24
Wake time after sleep onset before and after using antihistamine Cross
tabulation
82
Table 25
Effect of antihistamine on daytime sleepiness
83
Table 26
Effect of Antihistamine on ability to stay awake during the day
84
Table 27
Effect of antihistamine on work performance
84
Table 28
Side effects of antihistamine
84
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Page
2
List of Figures
Figures
Page
Figure 1
Age group of participants
69
Figure 2
Education levels of participants
71
Figure 3
Distribution of highest education level by gender
71
Figure 4
Frequency of using Antihistamine
76
Figure 5
Age group for Part 2 telephone survey
77
Figure 6
Education level of respondents for Part 2 telephone survey
77
Figure 7
Frequency of taking antihistamine
83
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Abbreviations
5-HT
5-hydroxytryptamine
5-HTP
5-hydroxytryptophan
AASM
American Academy of Sleep Medicine
ACC
Anterior Cingulate Cortex
ACT
Australian Capital Territory
AIHW
Australian Institute of Health and Welfare
AMH
Australian Medicines Handbook
BBB
Blood Brain Barrier
BEACH
Bettering the Evaluation and Care of Health
BzRAs
Benzodiazepine Receptor Agonists
CAM
Complementary and Alternative Medicines
CBT
Cognitive Behavioural Treatment
CBT-I
Cognitive Behavioural Therapy treatments for Insomnia
CDC
Centers for Disease Control and Prevention
CT-I
Cognitive Therapy for chronic Insomnia
CYP
Cytochrome P
DRN
Dorsal Raphe Nuclei
DSM- IV
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition
DSST
Digit Symbol Substitution Test
ECG
Electrocardiography
EEG
Electroencephalogram
EMG
Electromyography
EOG
Electro-oculography
ESS
Epworth Sleepiness Scale
FDA
Food and Drug Administration
GAD
Generalized Anxiety Disorder
GABA
Gamma Amino Butyric Acid
GP
General Practitioner
HT 7
Heart-7 Points
ICSD
International Classification of Sleep Disorders
IL-6
Interleukin-6
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ISI
Insomnia Severity Index
MAOIs
Monoamine oxidase inhibitors
MDD
Major Depressive Disorder
NREM
Non Rapid Eye Movement
NRS
Numerical Rating Scale
OTC
Over-the-counter
PCG
Posterior Cingulate Gyrus
PCPA
P-chlorophenylalanine
PSG
Polysomnographic
PSQI
Pittsburgs's sleep-quality index
RAS
Reticular Activating System
REM
Rapid Eye Movement
SCN
Suprachiasmatic Nuclei
SCT
Stimulus Control Therapy
SCT
Symbol Copying Task
SHE
Sleep Hygiene Education
SRT
Sleep Restriction Therapy
SSRIs
Selective Serotonin Reuptake Inhibitors
SWS
Slow Wave Sleep
TGA
Therapeutic Goods Administration
TNF-α
Tumour Necrosis Factor α
TST
Total Sleep Time
VAS
Visual Analogue Scale
WASO
Wakening After Sleep Onset
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Chapter 1: Introduction and Literature Review
Sleep and sleep physiology
Sleep is a reversible state of unconsciousness and unresponsiveness to the surrounding
environment (Carskadon & Dement, 2005). It is typically accompanied by horizontal posture
(lying down), behavioral stillness, closed eyes, and differential breathing (Carskadon &
Dement, 2005).The current understanding of the physiology of sleep suggests that it is a
multifaceted biobehavioral process (Hallet al.,2008; Hall, 2010). Alterations in sleep occur
throughout the lifespan of an individual, from infancy through old age, and may also be
affected by several factors such as gender, socioeconomic status, marital status and mental or
physical health conditions (Carrieret al., 2001; Carskadon &Dement, 2005; Hall et al., 2009;
Ohayonet al.,2004).
It was widely believed that sleep is a passive and inactive state,however sleep is now
considered to be an active state in which several different metabolic processes, tissue
restoration, memory consolidation, and homeostatic balance are sustained (Adam, 1980;
Alvarez &Ayas, 2004; Ancoli-Israel, 2006; Benca&Quintas, 1997). Brain and body activity
have both been demonstrated during sleep (Adam, 1980; Alvarez & Ayas, 2004; AncoliIsrael, 2006; Benca & Quintas, 1997), hence its dismissal as an inactive process. Memory
consolidation also occurs during sleep (Stickgold, 2005) and sleep quantitatively and
qualitatively changes new memory representations (Diekelmann & Born, 2010). Although it
is well-recognized that sleep is an important homeostatic process, several aspects remain
elusive such as why sleep is required for a healthy lifestyle, the duration of sleep required and
the degree of adverse effects which occur when insufficient sleep is achieved (Okun, 2011).
Studies investigating sleep deprivation or restriction in healthy individuals found significant
alterations in central and peripheral physiology associated with functional changes in
cognition, performance and behavior (Irwinet al., 2006; Lim & Dinges, 2008; Redwine et al.,
2000; Sariet al., 2008; Spiegelet al., 1999; Spiegelet al., 2002; Spiegelet al., 2004; Strickeret
al., 2006; Vgontzaset al., 2004).
Sleep is identified based on behavioral and physiological changes which occur in the brain’s
electrical rhythms during sleep (Chokroverty, 2009). Behavioral changes involve “a lack of
mobility or slight mobility, slow eye movements, characteristic sleeping posture, reduced
1
response to external stimulation, increased reaction time, elevated arousal threshold, a
weakened cognitive function and a reversible unconscious state” (Chokroverty, 2010).
Physiological changes have been observed in studies investigating findings of
electroencephalogram (EEG), electro-oculography (EOG) and electromyography (EMG)
(Karlen et al., 2009; Shinar et al, 2006). These changes are listed in Table 1. Sleep onset is
characterized by steady alterations in these behavioral and physiological aspects(Madsen et
al., 1991a; NHLBI, 2003 ; Somers et al., 1993).
Table 1: Physiological changes during the NREM and REM sleep
Physiological Process
Brain activity
NREM sleep*
Decreases from wakefulness
Heart rate
Blood pressure
Slows from wakefulness
Decreases from wakefulness
Sympathetic nerve
activity
Muscle tone
Respiration
Decreases from wakefulness
Similar to wakefulness
Decreases from wakefulness
Airway resistance
Body temperature
REM sleep*
Increases in motor and sensory areas, while
other areas are similar to NREM
Increases and varies compared to NREM
Increases (up to 30 percent) and varies from
NREM
Increases significantly from wakefulness
Absent
Increases and varies from NREM, but may
show brief stoppages; coughing suppressed
Increases and varies from wakefulness
Is not regulated; no shivering or sweating;
temperature drifts toward that of the local
environment
Increases from wakefulness
Is regulated at lower set point
than wakefulness; shivering
initiated at lower temperature
than during wakefulness
Sexual arousal
Occurs infrequently
Greater than NREM
*NREM – Non-rapid eye movement
REM – Rapid eye movement
Sources: Madsen et al., (1991a), NHLBI (2003), Somers et al., (1993).
Sleep stages
Based on experimental findings from physiological measurements (EEG, EOG and EMG),
sleep can be divided broadly into two phases, each with independent functions and controls:
non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. In an adult human,
the first one third of sleep is principallyNREM or slow-wave sleep and the most REM sleep
occurs in the last third of the sleep cycle (Carskadon & Dement 2005). NREM sleep
comprises 75 to 80% of the total sleep period in adult humans and is categorized into four
stages (NREM stages 1 to 4) as per the traditional Rechtschaffen and Kales scoring
manual(Rechtschaffen & Kales,1968). However, the American Academy of Sleep Medicine
(AASM) published a sleep scoring manual in 2007, which only divides sleep into three stages
(N1, N2, N3) based on EEG findings (Iber et al.,2007).
2
REM sleep comprises the remaining 20 to 25% of the total sleep period (Chokroverty, 2010).
A well-defined characteristic of REM sleep is rapid eye movements in all directions and
abolition of skeletal muscle activities throughout the body (except the diaphragm and
extraocularmuscles) (Wills & Garcia, 2002). Blood pressure and heart rate fluctuate and
irregular respiration and tongue movements also occur (Chokroverty, 2010). NREM sleep is
characterized by a general reduction in responsiveness to external stimuli associated with
slow eye movements (Czisch et al.,2004). As a result, the healthy adult experiences a
sequence of stages from wakefulness to sleep onset to NREM and then to REM sleep.Each
phase is associated with specific physiological characteristics involving brain activity which
can be monitored by an electroencephalogram (EEG), muscle tone measured by an
electromyogram (EMG), and eye movements detected by an electroculogram (EOG)
(Carskadon & Dement, 2005; Fuller et al., 2006).
For more than 40 years, the only standard for describing the sleep process was the Manual of
Sleep Classification devised by Rechtschaffen and Kales (Rechtschaffen & Kales, 1968). This
manual divides sleep into seven distinct stages: wake, stage 1, stage 2, stage 3, stage 4, stage
REM, and movement time. Although widely accepted, the rules of Rechtschaffen and Kales
have been criticised for allowing subjective analysis (Danker-Hopfe et al., 2004).
Consequently, there is enormous variation in the visual evaluation of sleep stages (DankerHopfe et al., 2004). Furthermore, the rules set down by Rechtschaffen and Kales were
formulated for young healthy adults (Himanen & Hasan, 2000) and may not be relevant or
directly applicable to elderly individuals.
The Manual of Sleep Classification by Rechtschaffen and Kales was revised in 2007 by the
American Academy of Sleep Medicine (AASM) (Iber et al.,2007) and produced a new
guideline for terminology, recording method, and scoring rules concerning sleep processes.
The manual developed by the AASM (Iber et al., 2007) is an amalgamation of a review of the
literature, analysis and consensus. It addresses seven topics: digital analysis and reporting
parameters, visual scoring, arousal, cardiac and respiratory events, movements and paediatric
scoring (Iber et al., 2007). A significant alteration is a change in terminology: in the AASM
classification, sleep stages S1 to S4 (as per Rechtschaffen and Kales’ manual) are referred to
as N1, N2, and N3; with N3 reflecting slow wave sleep and is a combination of Rechtschaffen
and Kales stages S3 and S4 (Anderer et al., 2010). Stage REM is now called stage R,
wakefulness is called W stage and the stage “movement time” has been eliminated from the
AASM manual (Anderer et al., 2010). The AASM manual also states that 3 EEG derivations
3
must be recorded (Silber et al., 2007). The AASM manual has also other definitions such as
the sleep-wake transition, slow wave sleep, REM sleep, arousals and major body movements
(Moser et al., 2009). The ASSM manual also simplifies several context rules and the
recommendation of sampling rates and filter settings for polysomnographic (PSG) reporting
and user interfaces to aid computer-assisted sleep analysis (Iber et al.,2007).
Physiological changes during sleep
Changes occur is several body systems during sleep (Choudhary & Choudhary, 2009). These
alterations do not cause major discomfort in healthy individuals, but may have a detrimental
impact on fragile individuals, for example patients suffering from cardiovascular diseases
(Parker and Dunbar, 2005). The physiological changes that occur during sleep are:

Cardiovascular:Alterations in blood pressure and heart rate occur. For example,
transient rises in blood pressure and heart rate occur with K-complexes1, arousals, and
large body movements (Blasi et al., 2003; Catcheside et al., 2002; Tank et al., 2003).
These are predominantly regulated by the autonomic nervous system (Trinder et al.,
2001). In addition, the risk of myocardial infarction in the morning is increased due to a
sharp increase in heart rate and blood pressure that accompany awakening (Mulcahy et
al., 1993);

Sympathetic-nerve activity: A reduction in sympatheticvascular tone occurs during
NREM sleep; but, due to the momentary increase in blood pressure and heart rate that
follows K-complexes, a burst of sympathetic-nerve activity arises during NREM sleep
(Wolk et al., 2005). There is an increase in sympathetic activity during REM sleep
when compared to wakefulness (Somers et al., 1993). This may provide protection to
the brain against potentially damaging intravascular pressure changes or hyperperfusion
during REM sleep (Cassaglia et al.,2009).

Respiratory: During REM sleep, ventilation and respiratory flow become accelerated
and irregular (Krieger, 2000; Simon et al., 2002). Additionally, rib cage movement is
decreased and upper airway resistance is increased due to the absence of tone in the
intercostal muscles and upper airway muscles during REM sleep (Parker and Dunbar,
2005). Several factors are involved in hypoventilation during NREM sleep including
1
Negative sharp wave which is immediately followed by a positive component from background activity on the EEG
(Colrain et al., 2010).
4
diminished pharyngeal muscle tone (Krieger, 2000; Simon et al., 2002). Ventilation and
respiratory flow usually show ineffective adaptive responses during sleep. Furthermore,
the cough reflex is suppressed during both REM and NREM sleep (Lee & Birring,
2010). More generally, there is also a reduction in ventilatory responses tohypoxia and
hypercapnoeaduring NREM sleep compared to wakefulness and further decreases occur
during REM sleep (Choudhary & Choudhary, 2009). Similarly, the arousal response to
respiratory resistance (resistance to breathing in or out) is lowest in stage 3 and stage 4
sleep (Douglas, 2005).

Cerebral blood flow: During NREM sleep, cerebral blood flow and metabolism are
drastically reduced (Zoccoliet al.,2002). However, total blood flow and metabolism in
REM sleep are similar to wakefulness (Madsen et al., 1991a), but increase in the limbic
system (involved with emotions), and visual association areas (Madsen et al.,
1991b).Limbic lobe regions such as the anterior cingulate cortex (ACC) and posterior
cingulate gyrus (PCG) are less activated during NREM sleep compared to wakefulness
(Kaufmann et al.,2006).

Renal: During sleep (REM and NREM) urine flow and excretion of sodium and
potassium are reduced (Agarwal,2007). These alterations in renal function during sleep
are multifaceted and include changes in renal blood flow, glomerular filtration,
hormone secretion, and sympathetic neural stimulation (Van Cauter, 2000; Buxton et
al., 2002).

Endocrine: Sleep regulates the secretion of growth hormones, thyroid hormone, and
melatonin (Brandenberger et al.,2000; Shibui et al.,2003). Growth hormone secretion
reaches a maximum during early sleep and usually occurs throughout slow wave
sleep(Born& Wagner, 2009). Melatonin induces sleepiness by decreasing the alerting
effect from the suprachiasmatic nucleus, and is influenced by the light-dark cycle, with its
secretion being suppressed by light (Parker and Dunbar, 2005).
Function of sleep
Sleep has a restorative function and its requirement is a fundamental physiological need
having similar homeostatic properties to hunger or thirst (Rohers et al., 2005). Mounting
evidence emphasizes the importance of sufficient sleep showing it is highly correlated to the
health of an individual. Several studies have demonstrated that disturbed sleep adversely
5
affects health contributing to ailments ranging from the common cold (Cohen et al., 2009) ,
depression (Cole & Dendukuri, 2003)
postpartum depression (Okun et al., 2009) and
cardiovascular disease (Gangwisch et al., 2006; Meisinger et al., 2007). Therefore, disturbed
sleep or sleep deprivation can affect the entire body, as a consequence of the multifaceted
regulation of sleep by multiple brain regions, immune and endocrine factors, and various
neurotransmitters (Benca & Quintas, 1997). In addition to health, several studies have shown
that sleep is important for facilitating consolidation of memory and improved ability for
learning (Lauderdale et al., 2006).
What controls sleep?
Sleep is controlled by a complex mechanism. Sleep and wakefulness are predominantly
regulated by the reticular formation in the brainstem and the reticular activating system (RAS)
in association with the thalamus (Cook,2008). These reticular systems network with NREM
sleep mechanisms in the basal forebrain, generating slow wave electrical activity in the
cerebral cortex (Cook, 2008). The REM sleep generator, located in the pons, periodically
disrupts this process to reactivate the brain (Cook,2008). Wakefulness is caused by activating
the brainstem and basal forebrain structures by a direct excitatory effect of orexins on
cholinergic neurons in the basal forebrain and monoaminergic and cholinergic neurons in
brainstem (Eggermann et al., 2001; Sakurai, 2007). This activation disrupts sleep cycles and
causes stimulation and arousal of the nervous system (Amzica, 2002; Zisapel, 2007).
Sleep is also regulated by three important hormones synthesized in the pons: noradrenaline,
acetlylcholine and serotonin (also known as 5-hydroxytryptamine or 5-HT)(Cook,2008).
Other regulatory hormones include orexin and hypocretin2which are deficient in narcolepsy
(Nishino et al., 2010). Regulation of circadian rhythms is achieved by the hypothalamus,
specifically,the suprachiasmatic nucleus which is reset daily by light, and by melatonin
released from the pineal gland during darkness (Datta and MacLean, 2007).
2
Orexin and hypocretin are neuropeptide, produced in hypothalamic neurons, are fundamental regulators of sleep and
wakefulness. These peptides activate wake-active monoaminergic and cholinergic neurons in the brain and hypothalamus
stem to maintain a long, consolidated awake period. (Sakurai, 2007).
6
Role of Serotonin (5-HT) in the Sleep – wake cycle
There is much controversy surrounding the debate as to the role 5-HT plays in sleep
regulation (Jouvet, 1999; Ursin, 2002). The literature of the 1960s and early 1970s indicated
that NREM sleep requires the 5-HT system. If this system is not functional, possibly as a
result of damage to the raphe nuclei (housing neuronal cell bodies producing 5-HT) or the
exhaustion of 5-HT by p-chlorophenylalanine (PCPA- a 5-HT synthesis inhibitor), insomnia
occurs which can be reversed by administering 5-hydroxytryptophan (5-HTP) (a precursor of
5-HT) (Jouvet, 1999; Ursin, 2002). However, from the late1970s, the literature showed that 5HTwas responsible for the initiation and maintenance of slow wave sleep (SWS) (Monti,
2011). For example, by inducing a rise in the release and synaptic availability of 5-HT (by
electrically stimulating the dorsal raphe nuclei (DRN)), wakefulness was stimulated
(Cespuglio et al., 1979). Conversely, inactivation of DRN stimulates sleep (Cespuglio et al.,
1979). The claim that 5-HT promoted wakefulness was supported by the rates of serotonergic
raphe neuronal firing (Cespuglio et al., 1981; Lydic et al., 1987; McGinty & Harper, 1976;
Trulson & Jacobs, 1979) and release of 5-HT (Cespuglio et al., 1990; Gemma et al., 1979;
Portas et al., 1994; Portas et al., 1998). Furthermore, DRN activity issleep state-dependent;
peaking throughout wakefulness, decreasing during NREM sleep, and ceasing to fire during
REM sleep (Ursin, 2002). Indeed NREM sleep can be increased when 5-HT2 receptors are
blocked (Dugovic, 1992). Serotonergic neurons in the DRN reduce the activity of neurons
located in the preoptic area, the anterior hypothalamus and the adjacent basal forebrain which
enhance sleep(Saper et al., 2001; Ursin, 2002). In addition, noradrenergic (brainstem) and
hypocretinergic/orexinergic (hypothalamus) neurons promote wakefulness and also stimulate
the activity of each other (Jones, 2005).
An endeavour to incorporate and unite these seemingly conflicting data led to the hypothesis
that 5-HT directly stimulates wakefulness and also promotes the synthesis and/or release of
factors which induce sleep (Jouvet, 1999).Serotonin subtype receptors (5-HT1A and 5-HT2)
are involved in sleeping and waking (Bjorvatn & Ursin, 1998; Ursin, 2002) Sleep occurs as a
result of the 5-HT inducing the release of sleep-promoting factors which inhibit neurons
involved in stimulating wakefulness (Jouvet, 1999). . Studies conducted on rats and mice
indicate that regulation of arousal states by 5-HT relies on the degree and timing of activation
of the 5-HT system and the time that has elapsed following activation (Imeri et al., 2005;
Imeri et al., 2000;Morrow et al., 2008). Enhancement of 5-HT release, by administration of
5-hydroxytryptophan, results in the initial response being an increase in wakefulness and a
7
decrease in NREM sleep (Imeri et al., 2005; Imeri et al., 2000;Morrow et al., 2008). This
rapid increase strongly indicates a direct effect of 5-HT. However, if the dose of 5hydroxytryptophan is too low, activation of the 5-HT system may be insufficient to stimulate
sleep-inducing factors, as the 5-HT activation needs to be maintained for sufficient time. A
higher physiological dose of 5- hydroxytryptophan results in an increase in NREM sleep,
following a short delay, (Imeri et al., 2005; Imeri et al., 2000;Morrow et al., 2008). This
delayed increase in NREM sleep constantly happens in the dark stage of the light-dark cycle,
independent of when 5- hydroxytryptophan was administered (Imeri et al., 2005; Imeri et al.,
2000;Morrow et al., 2008). These findings indicate that the exact consequence of serotonergic
activation on sleep-wake behaviour rely on both the degree and timing of activation.
The data generated from the studies discussed above concur with observations that
administration of selective serotonin re-uptake inhibitors over a short period of time increases
wakefulness first and then increases NREM sleep (Ursin, 2002). The earliest studies
exploring the relationship between 5-HT and sleep only reported behavioural observations
and did not contain polygraphically defined determinations of vigilance states (Ursin, 2002).
Even so, these studies showed biphasic responses to administration of 5-HT in which
behavioural ‘activation’ was followed by ‘depression’ (Ursin, 2002).
Serotonin suppresses REM sleep
Serotonergic neurons in the raphe nuclei and noradrenergic neurons in the locus coeruleus, are
regarded as part of the mechanisms that regulate REM sleep by inhibiting the neurons that
promote REM sleep (Lu et al., 2006; McCarley, 2007). Reduced serotonergic activity allows
generation of REM-sleep, consistent with findings that inhibition of the 5-HT system by
pharmacological agents stimulates REM sleep whereas stimulation of 5-HT synaptic
availability hinders REM sleep (Ursin, 2002). Thus, experimental findings show that
administration of 5-hydroxytryptophan activates the 5-HT system which inhibits REM sleep,
irrespective of the dose and timing of administration (Imeri et al., 2000; Imeri et al., 2005;
Morrow et al., 2008). The finding that mice deficient in 5-HT1A or 5-HT1B receptor subtypes
experience longer REM sleep than control mice indicates that 5-HT1A or 5-HT1B receptor
subtypes mediate REM sleep inhibition by 5-HT (Adrien et al., 2004) . A similar response is
found by blocking the same receptor subtypes with pharmacological agents (Adrien et
al.,2004). Naturally, this does not preclude 5-HT inhibiting REM sleep by interacting with
8
other 5-HT receptor subtypes. In conflict with the ‘REM-off’ role of 5-HT, findings which
show that a 5-HT7 receptor antagonist inhibits REM sleep (Hagan et al., 2000) and people
deficient in 5-HT7 receptors spend a shorter time in this phase of sleep (Hedlund et al., 2005)
suggest that 5-HT may play a facilitator (or permissive) role in regulation of REM-sleep via
this specific receptor subtype.
Insomnia
Definition of insomnia
Insomnia is defined according to the International Classification of Sleep Disorders (ICSD) as
an almost nightly complaint of insufficient sleep or the feeling of being unrested after the
habitual sleep period (International Classification of Sleep Disorders: Diagnostic and Coding
Manual,1990). Insomnia criteria have also been specified in the Diagnostic and Statistical
Manual of Mental Disorders (DSM IV) (Diagnostic and Statistical Manual of Mental
Disorders,1994) as difficulty initiating sleep (sleep onset), maintaining sleep (sleep
maintenance), and/or poor quality of sleep (non-restorative sleep) for at least one month.
Thus, the presence of long sleep latency (onset), frequent nocturnal awakenings, or prolonged
periods of wakefulness during the sleep period or even frequent transient arousals are
evidence of insomnia. As a result, insomnia can be thought of both as a symptom and as a
sign.
Why is insomnia a problem?
Hajak (2000) estimated that one third of the adult population in the industrialized world
experience sleep disorders. It impacts on all aspects of life – work productivity, family life
and mental health (Léger & Bayon, 2010).
Insomnia is a common sleep disorder that is a significant health problem in Australia
(Dollman et al., 2003). According to ‘Wake up Australia: The Value of Healthy Sleep’
(Access Economics, 2004), over 1.2 million (6%) Australians suffer from sleep disorders and
insomnias are high prevalent. Insomnia is a very common complaint for presentation to
medical practitioners (Attarian, 2000). Consequently, management of insomnia has become a
major health challenge in Australia. The Bettering the Evaluation and Care of
Health(BEACH) program (April 2006 and March 2008) found sleep disorders were managed
9
across Australia 2,987 times at a rate of 1.6 contacts per 100 general practitioners (GP)
encounters which extrapolates to approximately 1.7 million GP visits annually across
Australia (Charles et al., 2009). The research found that insomnia was more likely to be
treated in female patients than males (Charles et al., 2009).
Age is a significant factor with sleep problems and, according to Ancoli-Israel (2005), occurs
in over 50% of adults aged 65 and older (Ancoli-Israel, 2005). Age alters normal sleep
patterns but it is not necessarily a factor for sleep disorders as total sleep time linearly
decreases with age at a rate of approximately10 minutes per decade (Ohayon et al., 2004).
Foley et al (1995) found greater than 50% of people aged over 65 reported difficulty in
initiating sleep and, after falling asleep, problems in maintaining their sleep. This issue can
lead to daytime sleepiness, feelings of being un-rested, chronic fatigue and an increased risk
of falls and accidents (Foley et al.,1995). Insomniacan also result in memory impairment and
decreased productivity which has an impact on quality of life (Roth and Ancoli-Israel,1999;
Simon and VonKorff,1997). Moreover, insomnia is a significant issue for older adults who
suffer from ill health and depend on medications (Cook, J. & Ancoli-Israel, S. (2006)because
many commonly prescribed medications have insomnia as a side effect (Kim et al.,2009).
These medications are central nervous system stimulants (e.g. modafinil, methylphenidate),
antihypertensives (e.g. β-blockers, α-blockers), respiratory medications (e.g. theophylline,
salbutamol),
chemotherapy,
decongestants
(e.g.
pseudoephedrine),
hormones
(e.g.
corticosteroids, thyroid hormones), psychotropics (e.g. SSRIs, atypical antidepressants, MAO
inhibitors) and diuretics (Kamel & Gammack, 2006; Neikrug & Ancoli-Israel, 2010).
Therefore, stimulating medications and diuretics should, wherever possible, be administered
in the morning and sedating medications should be taken before bedtime. Insomnia has a
higher prevalence in older women who are either separated, divorced or widowed (Legeret
al., 2000), however, Doghramji (2006) found that the prevalence of insomnia also increased
also in men over the age of 85.
Classification of insomnia:
The ICSD and DSM-IV list different classes of insomnia based on the cause (DSM-IV,1994;
ICSD, 1990). The DSM-IV differentiates between primary sleep disorders, sleep disorders
related to other mental disorders, sleep disorders due to general medical conditions, and
10
substance stimulated sleep disorders (DSM-IV,1994). Likewise, the ICSD classifies insomnia
as follows (ICSD, 1990):

Intrinsic insomnia: e.g. psychophysiological insomnia, sleep state misperception;

Extrinsic insomnia: e.g. inadequate sleep hygiene, environmental sleep disorder, hypnotic
dependent sleep disorder;

Insomnia associated with a mental disorder: psychoses, mood disorders, alcoholism;

Insomnia associated with neurological disorders: dementia, parkinsonism, fatal familial
insomnia; and

Insomnia associated with other medical disorders: cardiac ischemia, nocturnal asthma,
fibromyalgia, gastroesophageal reflux.
It is important to distinguish between primary and secondary insomnia to identify any
associated conditions and ensure these conditions are treatedappropriately rather than
focusing solely on the insomnia alone.
The ICSD-2 codes insomnia under the broad heading of dyssomnias, either intrinsic or
extrinsic sleep disorders (ICSD-2 2nd, 2005). Based on the severity, it classifies insomnia into
three types as follows (ICSD-2 2nd,2005):
1. Mild insomnia: almost nightly feeling of an insufficient amount of sleep or not feeling
adequately rested. There is little or no evidence of impairment of social or occupational
functioning, but there may be restlessness, irritability, mild anxiety, daytime fatigue, and
tiredness.
2. Moderate insomnia: nightly feeling of an insufficient amount of sleep or not feeling
adequately rested after the habitual sleep episode. There is mild or moderate impairment of
social or occupational functioningand restlessness, irritability, anxiety, daytime fatigue, and
tiredness are always present.
3. Severe insomnia: nightly feeling of an insufficient amount of sleep or not feeling
adequately rested.There is severe impairment of social or occupational functioning with
restlessness, irritability, anxiety, daytime fatigue, and tiredness.
It is important to differentiate between the different types of insomnia and investigate factors
that couldaffect the onset, duration, remissions and relapses of insomnia. An accurate
diagnosis is particularly important to determine appropriate therapies and indicate therapeutic
success in relieving symptoms or preventing relapses.
11
Assessment of insomnia
The diagnosis of insomnia takes into consideration three main aspects:

History of the sleep patterns of the patient;

Medical history; and

Psychiatric history (Sateia and Pigeon, 2004).
The sleep history requires a chronological review of sleep patterns from childhood (Pigeon,
2010). Assessing the sleep history can allow for the identification of the time of onset of
insomnia and any factors which may have contributed to its initiation (Buysse et al.,2005). A
sleep history should also include details of situations which have occurred during the patient’s
life,a 24 hour sleep behavior diary, how an unsatisfactory night varies from a night in which
the individual has experienced satisfactory sleep, identifying any sleep patterns that exist, any
treatment the individual may have received and the extent of their success (Pigeon,2010).
A component of the sleep history includes any investigations to identify any secondary causes
of insomnia (Ward & Ward, 2006). Differential diagnosis involves differentiation of primary
insomnias from a co-morbid insomnia (Pigeon,2010). There are many reasons to delay
commencing insomnia treatment including untreated or unstable medical or psychiatric
conditions, substance abuse, stablemedical conditions (e.g.gastroesophageal reflux disease,
cardiopulmonary disorders, seizure disorders, some neuroendocrine disorders, sleep apnea,
bipolar disorder), severe mental illness or active substance dependence, arthritis and urinary
retention(Kim et al., 2009; Pigeon, 2010). Other authors recommend treating co-morbid
conditionsand insomniaconcurrently as individual conditions could result in greater
improvements in each than treating either separately (Roth, 2009).
Several self-report instruments are widely used for the assessment of sleep quality and
daytime sleepiness (Buysse et al., 2008). Among the most popular are the “Pittsburgh Sleep
Quality Index" (Buysse et al., 1989), which gives a global assessment of sleep and the
Insomnia Severity Index(Bastien et al.,2001) designed for insomnia. The most constructive
and helpful self-report measure is to keep a daily sleep diary for 1 -2 weeks (Winkelman,
2009). A sleep diary records the time the patient goes to bed, an estimate of the time it takes
for the patient to fall asleep, number of awakenings and the length of time a patient spends
awake during the night, final awakening and time the patient gets out of bed (Pigeon, 2010).
These data, averaged over the 1-2 week period, allows a patient’s sleep continuity, including
latency to sleep, wake time, average time spent in bed, total sleep time and sleep efficiency
12
(sleep time divided by time spent in bed) to be determined(Pigeon, 2010). A wrist-worn
actigraph can determine objective measures of sleep (Sadeh, 2011). This device measures
physical activity during sleep with an inbuilt 3-dimensional accelerometer and a light sensor
(Paquet et al., 2007). The periods of time which are spent asleep and awake are determined by
analyzing the movement data (Saddichha, 2010).
Although not as useful as a full-night polysomnograhic recording, actigraphyis more reliable
thansleep logs which depend on the patients’ recall of how many times they woke up or how
long they slept during the night (Ancoli-Israel et al.,2003). Unless paradoxical insomnia or
another sleep disorder (forexample, sleep apnoea) is suspected, polysomnography is not used
in the routinediagnosis of insomnia (Kushida et al., 2005) because it can be invasive, high
cost, and disruptive to sleep (Blackwellet al., 2008). Polysomnography is considered the gold
standard as it combines measurements taken by an electroencephalogram (EEG),
electrooculography (EOG), electromyography (EMG), electrocardiography (ECG), pulse
oximetry, and air flow rate (Blackwell, 2008). Together, these measurements can reveal
several findings such as periodic limb movement disorder, sleep apnoea, and
narcolepsy(Krystal et al.,2002).
The Epworth Sleepiness Scale (ESS) rates the likelihood of becoming drowsy and dozing off
during situations when one is normally awake such as: sitting and reading; watching
television; sitting inactively in a public place; being a passenger in a car for an hour; lying
down to rest in the afternoon; sitting and talking to someone; sitting quietly after lunch
without alcohol or waiting at a traffic signal in a car (Johns, 1991). The ESS is rated on the
following 4-point scale:

0 – no chance of dozing;

1 – slight chance of dozing;

2 – moderate chance of dozing; and

3 – high chance of dozing.
A total score higher than 16 across the eight questions (maximum possible score: 24) is
suggestive of daytime drowsiness, while a score of 11 is indicative of a possible disorder
characterized by excessive sleepiness.
A vital consideration for family members or primary care practitioners is that any assessment
of sleep is not the norm in standard practice. Therefore, simple questions such as "how are
you sleeping?" can reveal the presence of a chronic insomnia and could be used as a
13
screeningtool in the community pharmacies. As the prevalence of insomnia is relatively high
in the population, valuable information can be obtained from asking these simple questions,
leading to a more comprehensive assessment of sleep or possibly a referral for dealing with
insomnia.
Role of the pharmacist
Patients suffering from insomnia are likely to attemptself-treatment (Wickwire & Collop,
2010). Of these approximately one-third decide to self-medicate (Daley et al., 2009 &Bartlett
et al., 2008). A sleep health survey conducted in 2008 demonstrated that in Australia, 89% of
patients with insomnia stated that they did not seek professional medical advice regarding
their insomnia (Bartlettet al., 2008). Studies revealed that alcohol and over-the-counter (OTC)
sleep aids were typically used by insomniacs to self medicate (Sivertsen et al., 2009; Drake et
al., 2003). Sedating antihistamines and herbal sleep promoting products are the only products
available without prescription that are approved for insomnia treatment (Kippist et al.,
2011).In Australia, sedating antihistamines (in single ingredient products) are classified as
Pharmacist Only Medicines, that is, a patient must discuss the appropriateness of the medicine
with a pharmacist before purchase (Therapeutic Goods Administration, 2011). The prospect
for pharmacists to act as a primary intervention delivery point is apparent.
In a study concerning pharmacies in the Greater Sydney Area (New South Wales, Australia),
pharmacists providing medicines to treat obstructive sleep apnea, stated that they believed
they should have an increased role in the treatment of sleep disturbances such as insomnia
(Black et al., 2007).
Kippist et al (2011) found that pharmacists should educate patients complaining of acute
insomnia with regard to positive sleep health. However, pharmacists may require training,
about approaches for the management/treatment of insomnia. Acute insomnia should be
managed before it progresses to chronic insomnia (Pigeon, 2010). Therefore, pharmacists
have an important role to provide advice about positive sleep health practices to those
presenting to a community pharmacy with acute insomnia (Kippist et al., 2011). Pharmacists
have an important role in screening sleep disorders such as insomnia and providing sleep
health education. Implementing individual counseling and treatment recommendations for
insomnia, will help to reduce the burden of disease and the risks of potential consequences.
14
Many medications can affect sleep and sleep patterns. These include:

Stimulants (e.g. modafinil, methylphenidate);

Antihypertensives (e.g. β-blockers, α-blockers);

Respiratory medications (e.g. theophylline, salbutamol);

Chemotherapy;

Decongestants (e.g. pseudoephedrine);

Hormones (e.g. corticosteroids, thyroid hormones);

Psychotropics (e.g. SSRIs, atypical antidepressants, MAO inhibitors); and

Diuretics (Kamel & Gammack, 2006; Neikrug & Ancoli-Israel, 2010).
Therefore, pharmacists have an important role to investigate other potential causes of
insomnia when an antihistamine is requested as a sleep aid to improve quality use of
medicines.
In an Australian study assessed practice, when over the counter pharmacist-only sleep
medication (Restavit) was requested in the Australian community pharmacy setting, and
found that only 30% of requests were handled entirely by the pharmacist (Kashyap et al.,
2012). A history of symptoms and underlying causes of insomnia was only taken in 28% of
the interactions (Kashyap et al., 2012). As the pharmacist is the primary point of contact for
people who request assistance with insomnia, this suggests a gap in patient care in community
pharmacy. Other authors have found that if a pharmacist investigates the underlying causes
of insomnia, they can provide information on lifestyle changes that can reduce the risk of
primary insomnia (Roth et al., 2007; Wolkove et al,. 2007).
Epidemiology of Insomnia
Insomnia is frequently associated with being female and in the elderly (Ohayon,2002).Other
sociological and economical factors have been also correlated with insomnia (Ohayon,2002).
This section provides a commentary about several of these factors.
Gender
Several studies have provided strong evidence that insomnia is more prevalent in women,
showing a higher rate of reported insomnia symptoms (Léger et al., 2000; Ohayon et al.,
1997), daytime consequences (Hoffmann, 1999; Léger et al., 2000) and dissatisfaction with
sleep (Yeo et al., 1996). A meta-analysis study reported that insomnia is approximately 1.4
15
times more prevalent among women than men (95% confidence interval: 1.28–1.55) (Zhang
& Wing, 2006). This ratio has been shown to increase slightly after 45 years of age
(Voderholzeret al., 2003). It has also been reported that women are twice as likely to be
diagnosed with insomnia (Ohayon,2002). Together, these findings suggest that an intrinsic
factor in women may be a causative factor of insomnia. Owens et al (1998) and Punyahotra et
al (1997) suggested menopause could be this intrinsic factor. A random sample study of 3243
subjects (aged ≥18 years) using phone interviews,found that menopausal women exhibited
higher rates of sleep disturbances than women who were pre-menopausal (Ohayon, 2006).
Other studies disagree; most notably Young et al. (2003) assessed objective and subjective
sleep quality of 589 premenopausal, perimenopausal, and postmenopausal women using
objective
measures(full
in-laboratory
polysomnography)
and
self-reported
sleep
problems.They found that menopause was not associated with decreased sleep quality (Young
et al., 2003).
Age
Individuals of all ages complain of unsatisfactory sleep andtheprevalence of insomnia
increases with age (Ancoli-Israel and Ayalon,2006; Wolkove et al.,2007), approaching 50%
in thoseaged over 65 years (Ancoli-Israel, 2005; Hetta et al., 1999). In 2000, the National
Institute of Aging in United States conducted a survey of 9000 metropolitan adults, and found
that 28% of participants experienced disturbed sleep, reporting difficulty in initiating and
maintaining sleep (Ancoli-Israel, 2000). In the USA, the rate of insomnia in the elderly is
approximately 5% (Kamel and Gammack, 2006). Several studies indicate that elderly patients
experience less slow wave sleep (SWS) and REM sleep (Ancoli-Israel, 2000; Ancoli-Israel
and Ayalon, 2006).Consequently, the elderly spend most of the night in stage 1 and 2 light
sleep. Australian estimates also show an increasing incidence of insomnia symptoms with
age (Deloitte Access Economics, 2011).
Certain physiological changes occur with aging and have been correlated to detrimentally
affecting sleep. One such physiological change that is known to occur with age is the
circadian rhythm (Münch et al., 2005)where the timing and functioning is altered. As age
increases, an individual feels sleepy earlier and consequently wakes up earlier (Carrier et al.,
2002). In addition,decreased melatonin levels have been demonstrated in the elderly, reducing
their ability to sleep (Dijk et al., 2000).As a consequence of a disrupted sleep patterns, there is
a reduction in sleep quality and total sleep time, producing discontinuoussleep and multiple
early morning stirrings.
16
Socioeconomic status
Several studies have demonstrated a relationship between socioeconomic status and frequency
of sleep complaints (Grandner et al., 2010). These studies illustrate that individuals with a
relatively low socioeconomic status exhibit a higher frequency of sleep complaints (Adams,
2006; Friedman et al., 2007; Hale, 2005; Lauderdale et al., 2006; Patel, 2007). Arber et al
(2009) also reported that employment status is associated with sleep problems. Unemployed
women have reported an increased frequency of sleep problems (Arber et al., 2009; Grandner
et al., 2010) implying that these factors could be additive. Sleep complaints were attributed to
other issues such as race/ethnicity, marital status, income, and educational level(Grandner et
al., 2010). Men who are homemakers had a considerably higher incidence of sleep complaints
that their female homemaker (Grandner et al., 2010). These findings indicate that various
mechanisms may contribute to the susceptibility of men and women to sleep complaints.
Grandner et al. (2010) suggested that sleep complaints reported by men may be influenced by
the effects of both socioeconomic factors such as education, employment, and income in
association with socio-demographic factors such as race, marital status and age.Gellis et
al.(2005) found that the frequency of insomnia in individuals of lower education status was
high, even after accounting for ethnicity, gender and age.
Marital Status
There is a lack of research efforts exploring the correlation between sleep complaint
frequency and marital status. Hale (2005) found that single people were either short or long
sleepers in comparison to married couples. Divorced individuals experience more sleep
complaints than those who are married or single (Ohayon,2002).
Education and Income
It has been reported that individuals with a lower education status and lower income are more
prone to insomnia (Hartz et al., 2007; Rocha et al., 2002). Such studies propose that there is
an inverse relationship between degree of sleep complaints and the level of education
achieved by both men and women; men of lower educational levels aremore likely to exhibit
sleep problems than women (Grandneret al.,2010). Studies involving multivariate analyses
show that education and income status are independent of the prevalence of insomnia (Arber
et al.,2009). A better indication to assess sleep problems including insomnia would be to
analyze a combination of several factors such as age, gender, education and income status.
17
Causes of Insomnia
The most widely accepted model describing the characteristics of chronic insomnia, the 3-P
model, was initially proposed by Spielman (Spielman, 1986 & Spielman and Glovinsky,
1991) and later refined by Morin (1993). The model addresses three main points:
Predisposing conditions, Precipitating circumstances, and Perpetuating factors (Spielman,
1986 & Spielman and Glovinsky, 1991; Morin 1993).
Predisposing conditions include hyperarousal, familial historyand anxiety predisposition and
may increase an individual’s susceptibility to develop insomnia (Morin, 1993). The recent
advances achieved in the genetics of sleep disorders (Taheri and Mignot, 2002) will expand
our understanding of these predispositions and also the invulnerabilities for developing
insomnia by augmenting the current knowledge of circadian rhythm disorders, narcolepsy,
and sleep apnea.
The most commonly studied predisposition is hyperarousal, more specifically cognitive
hyperarousal (Bonnet and Arand 1995; Morin 1993, Perlis et al. 1997). Robertson et al (2007)
demonstrated that patients suffering from insomnia are cognitively aroused and are less sleepy
in the bedroom before sleep than individuals who do not suffer from insomnia. Functional
neuroimaging has revealed that individuals with insomnia exhibit elevated activation during
sleep from subcortical areas but reduced prefrontal cortical activation while the individual is
awake (Nofzinger et al. 2004). This shows the brain activity of patients with insomnia is
elevated during sleep and reduced during the wake state. These findings positively correlate
with the symptoms of insomnia during the night and fatigue during the day. Nofzinger (2005)
suggests that daytime fatigue may stem from the sleep deficit and unsatisfactory restoration of
the prefrontal cortex during the previous night. The reduced prefrontal cortical activation
during the day in insomniacs can be treated using multicomponent, nonpharmacological
treatments, acting to enhance prefrontal activation during the day using cognitive behavioral
therapy, body temperature and bright light interventions, sleep hygiene, and physical activity
counseling (Altena et al. 2008).
A study conducted by Espie (2002), suggests that hyperarousal does not comprehensively
elucidate the development of insomnia. Espie suggests that falling asleep is automatic, and
can be disturbed and hampered by several factors (Espie, 2002). Therefore, hyperarousal and
other variables which precipitate and maintain insomnia are mechanisms that hinder the
18
normal automatic process governing satisfactory and restorative sleep. Espie suggests that an
effective treatment such as Sleep stimulus control therapy can restore normal sleep and wake
mechanisms (Espie, 2002).
Precipitating factors such as illness, family, work and other aspects of life that induce stress
may detrimentally affect the sleep patterns of an individual (Bastien et al. 2004). The
preliminary reaction to sleep difficulty is usually worry and reflection about insomnia, and
this can predict whether acute symptoms will convert into a chronic condition (B´elanger et
al. 2006). As insomnia progresses, patients exhibit behavioral and cognitive responses that
gradually become maladaptive and feed into a cycle of insomnia. This may lead to the
development of increased arousal.
Maladaptive sleep habits (such as extended time in bed, irregular sleep-wake schedules,
irregular napping or sleep-incompatible activities in bed), dysfunctional cognitions (including
worry and unrealistic expectations) and arousal (physiologic, emotional, and cognitive) are
the perpetuating or maintaining factors that are targeted by insomnia treatments (Bootzin et al.
1996).
Circadian rhythm disorders arealso a causative factor for insomnia (Bjorvatn & Pallesen,
2009). In combination, interaction of circadian and sleep homeostatic processes cause sleep
and wake timing (Achermann, 2004; Borbely& Achermann, 1999). The homeostatic
mechanisms involved in balancing sleep and wake states and are dependent on wakefulness
(Vitiello, 2009). With increasing wakefulness, the drive to sleep is increased (Vitiello, 2009).
Conversely, when sleep occurs, the drive is decreased. Therefore, wakefulness can lead to the
onset and maintenance of sleep throughout the night. Although daytime wakefulness in
individuals suffering from insomnia seems normal, sleep is difficult, and can become
disturbed. Thus, sleep homeostasis can become deregulated (Pigeon&Perlis, 2006). The
circadian clock regulates sleep and wakefulness (Zee & Manthena, 2007). Cues such as light,
meal times, and social activityaid the control of circadian rhythms (Harvey et al., 2011).
Maladaptive sleep behaviors, developed as a result of insomnia, can disturb the cues the
circadian clock needs to regulate the sleep - wake cycle (Pigeon & Perlis 2006).
19
Consequences of insomnia
Economic consequences
The annual cost of work place accidents due to insomnia in Australia was estimated to be
approximately A$1.9 billion (Hillman et al., 2006).A recent report shows that indirect costs
related to sleep disorders and conditions attributable to them were estimated to be A$4.3
billion in 2010 (Deloitte Access Economics, 2011). These studies show that insomnia has
finanacial consequences and the economic impact is increasing. More detailed analyses are
available in the USA where insomnia is projected to have direct and indirect costs in excess of
US$100 billion annually (Fullerton, 2006). The direct costs consist of physician visits,
prescriptions and procedures have been estimated to cost US$13 billion per annum (Walsh &
Engelhardt, 1999). In fact, Ozminkowski and colleagues suggest that insomnia costs a young
adult patient approximately US$1,253 more in direct health care expenses than individuals
who do not suffer from insomnia (Ozminkowski et al., 2007).The indirect costs linked with
insomnia include motor vehicle and workplace accidents, reduced productivity, and
absenteeism account for the majority of the economic consequences of insomnia. Patients
with insomnia are two and a half times more likely to be involved in a motor vehicle accident
as a consequence of unsatisfactory sleep and rest as opposed to individuals who do not suffer
from insomnia (Hillman et al., 2006; Roth & Ancoli-Israel, 1999).
Cognitive, social and vocational consequences
A number of studies demonstrate that individuals with chronic insomnia experience more
difficulty with intellectual, social and/or vocational functioning, as opposed to individuals
who do not suffer from insomnia or have occasional bouts of insomnia (Drake et al, 2003;
Léger et al, 2006; Szelenberger et al, 2000). There appears to be debate concerning the
association of insomnia and cognitive activity. Many subjective studies report that there is a
positive
correlation
between
chronic
insomnia
and
compromised
cognitive
performance(Carey et al., 2005; Roth & Roehrs, 2003: Shochat et al., 1999). In contrast,
objective investigations have not discovered any reliable evidence of cognitive deficits in
patients with chronic insomnia (Orff et al.,2007). According to Espie et al (2006) and Harvey
(2002), this inconsistency may be related to an attentional bias for negative performance.
However Orff and colleagues suggest that this discrepancy may be due to the patient’s
appreciation of the fact that additional effort is needed to uphold normal performance (Orff et
al.,2007).
20
Chronic insomnia is also linked to impaired social functioning, specifically, a reduced
capability to deal with trivial annoyances and a decreased ability to appreciate time with
family and social life. This is accompanied by impaired interpersonal relationships with
spouses (Shochat et al., 1999). In regards to vocational aspects of life, patients with insomnia
report a decrease in job satisfaction and productivity, and increased absence (Léger et
al.,2006).
Health consequences
1. Mood disorders
There is mounting evidence that insomnia plays a role in new onset and recurrent major
depressive disorder (MDD) (Pigeon& Perlis, 2007). Several cross-sectional studies have been
conducted to determine the incidence of both insomnia and depression (Livingston et al,
1993; Stewart et al, 2006; Taylor et al, 2005). These studies demonstrated that the prevalence
of both disorders is relatively high and often are experienced by individuals of all ages, but
particularly, in older patients and women (Livingston et al, 1993; Taylor et al, 2005. Overall,
the prevalence of insomnia was 15% and that of depression is 8-9%(Benca, 2005; Tsuno et
al., 2005). Baseline estimates of prevalence rates for insomnia and depression in a study
based on the National Institute of Mental Health Epidemiologic Catchment Area data were
10% and 5% respectively(Ford & Kamerow, 1989). Among the patients suffering from
insomnia, 23% were depressed while among patients with depression, 42% reported insomnia
(Ford & Kamerow, 1989).A more stringent diagnostic approach was taken by Stewart et
al(2006) andthe prevalence rates obtained from this study were 5% for insomnia and 3%
depression. Of those with insomnia, 21% were depressed, whereas of those with depression,
40% had insomnia (Stewart et al, 2006).
Generally, these studies show that the probability of experiencing depression as a
consequence of insomnia background is approximately twice that of having insomnia in the
context of depression. However the overall incidence of experiencing both conditions
concurrently is the same regardless of the primary complaint.
One recent study investigating and scrutinising clinical trial data obtained from a primary
care-based depression intervention indicates that comorbid insomnia is a risk factor highly
correlated with unremitting depression (Pigeon et al., 2008). Patients with insomnia that
21
persevered across a baseline and three month assessment had a reduced depression treatment
responseat 6 and 12 months compared to patients with insomnia at one or neither of the
baseline and two month time points.
There is also a relationship between insomnia and suicide among adolescents. A study found
suicide completers showed high rates of sleep difficulties including insomnia when compared
with community controls both within the week preceding suicide and within their most recent
depressive episode (Goldstein et al., 2008).
Insomnia is a risk factor for developing depression, although it is not the only contributing
risk factor. Together these data demonstrate that incident and persistent insomnia can be
predictive for new onset depression and recurrent depression.
2.Anxiety disorders & substance abuse disorders
Experimental data concerning the relationship between sleep disorders such as insomnia and
generalized anxiety disorder (GAD) is more scarce. Mahendran et al (2007) conducted a
retrospective chart audit involving patients presenting with insomnia, where GAD was the
most common associated psychiatric disorder. However, causality was not assessed – merely
association.Mahendran et al (2007) stated that sleep disturbance is a common symptom of
several mood disorders including depression and GAD. A cross-sectional study showed that
among individuals with insomnia, 36% presented with at least one anxiety disorder compared
to only 19% of individuals who did not suffer from insomnia (Breslau et al., 1996). In
insomniac patients, 8% also had GAD, 6% a panic disorder, 5% obsessive-compulsive
disorder and 25% had various other phobias (Breslau et al., 1996).
Similar evidence shows that there is a strong correlation between substance abuse and sleep
disturbances such as insomnia (Ford & Kamerow, 1989, Weissman et al., 1997, Breslau et al.,
1996). Substance abuse was twice as prevalent in patients suffering from insomnia than those
who do not experience insomnia (Ford & Kamerow, 1989, Weissman et al., 1997, Breslau et
al., 1996). Patients with insomnia undergoing alcohol withdrawal treatment are also twice as
likely to report using alcohol as a sleep aid than individuals without insomnia (Brower et al.,
2001).
3. Medical disorders and conditions
A strong correlation exists between sleep and immunity (Krueger et al., 2001). Insomnia has
been shown to be linked to alterations in innate immunity including reduced activity of
22
natural killer cells (Cover & Irwin, 1994; Irwin et al., 1996). Higher levels of interleukin-6
(IL-6) during the evening and a change in the circadian distribution of IL-6 and tumour
necrosis factor α (TNF-α) from night to dayhave been reported by Vgontzas et al (2002). In
addition, Burgos et al (2006) suggest that IL-6 secretion is negatively correlated with reported
sleep quality duration of slow wave sleep. Although suggestive, these data do not provide
solid evidence of a direct correlation between insomnia and an increased likelihood of
developing an immune-mediated disease. Similarly, although evocative, the scarce data
collected from studies concerning the consequences of insomnia on the adaptive immune
system, do not definitively correlate insomnia to the development of infectious diseases.
Sleep disturbance (not necessarily insomnia) has been associated with Type II diabetes
mellitus and glucose homeostasis dysregulation, gastrointestinal distress, and several chronic
pain conditions (Gottlieb et al, 2005; Jarrett et al, 2000; Wilson et al, 2002). Insomnia has
also been demonstrated to be highly prevalent in HIV-infected patients (Rubinstein et al.,
1998). Longitudinal epidemiologic studies show that insomnia significantly increases the
possibility of developing hypertension and cardiovascular disease (Phillips and Mannino,
2007; Suka et al, 2003). Suka et al (2003) assessed the effect of insomnia on the development
of hypertension in Japanese telecommunication workers (n= 4,797 male) using the annual
health check database were followed up for four years or until they
developed
hypertension.The result showed increased risk of hypertension was associated with insomnia
[OR 1.96:(1.42-2.70)] (Suka et al., 2003). Phillips and Mannino (2007) followed 11,863
participants without cardiovascular disease and 8,757 participants without hypertension over
6 years, the result showed that insomnia was correlated to only a slight increase in the risk of
developing hypertension [OR 1.2:(1.03-1.30)] and a larger risk of cardiovascular disease [OR
1.5:(1.1-2.0)].
While definitive evidence is yet to be obtained linking insomnia to psychiatric disorders, the
available data make this a reasonable proposition. As consequences on society and individuals
are substantial, research efforts and development of treatment strategies should be directed
towards this disorder, although the current treatments are effective.
23
Treatment of Insomnia
1-Non-pharmacological treatment of Insomnia
A wide range of insomnia interventions involve psychological and behavioural treatments.
During the 1970s and 1980s, the common treatments for insomnia were relaxation,
paradoxical intention, and stimulus control therapy (Bootzin & Epstein, 2011). The 1999
review by the American Academy of Sleep Medicine (AASM) (Morin et al., 1999a), found
the evidence supporting sleep restriction therapy and multicomponent treatment was limited,
and these treatments were therefore rendered somewhat effective. Presently, multicomponent
treatment packages are perceived to be effective and have increased in popularity (Nau et al.,
2005). These usually include a combination of stimulus control therapy, sleep restriction
therapy, and sleep hygiene and education and relaxation training (McCurry et al., 2007).
Several cognitive behavioural therapy treatments for insomnia (CBT-I) studies dedicate
particular sessions to cognitive restructuring (Morin et al., 1999b; Jacobs et al., 2004), during
which incorrect understanding and outlooks taken by the patient are recognised, confronted,
and transformed. Other CBT-I studies employ cognitive components during education that
consider fallacies about sleep, sleep requirements, the relationship between sleep and aging,
sleep loss, sleep drive, and circadian rhythms (Edinger et al., 2001; Epstein & Dirksen, 2007).
Cognitive therapy has not been subjected to controlled testing as a single-component
intervention for insomnia (Bélanger et al., 2006), but it has been subjected to trials in an open
clinical series (Harvey et al., 2007). Therefore CBT is regularly recommended as an initial
therapy, however the evidence supporting it as part of a multi-faceted treatment approach is
strong.
Polysomnography has demonstrated the efficacy of multi-component programs (Edinger et
al., 2001; Morin et al., 1999b), and the CBT component has shown better results than
pharmacological treatment (Morin et al., 1999b). These studies were conducted on elderly
patients suffering from primary insomnia and may not be generalizable. The findings of
Lichstein et al (2000) indicated that CBT was also effective for secondary insomnia cases by
demonstrating that insomniacs who also sufferred from medical and psychiatric disorders
were successfully treated using CBT. Using the multi-component program, Espie et al (2001)
reported that two thirds of the participants exhibited sleep within the normal range following
treatment. Therefore, in 2006 the AASM recommended the use of multi-component therapy
and concludes that they are effective in the treatment of chronic insomnia (Morgenthaler et
al., 2006).
24
Stimulus Control Therapy
The first non-pharmacological treatment exclusively designed for insomnia was stimulus
control therapy (SCT), proposed by Bootzin (1972, 1977). Since its introduction, SCT has
become the gold standard against which novel non-pharmacological interventions are tested
(Bootzin & Epstein, 2011). The theory behind SCT is that the bed and bedroom no longer act
as discriminative stimuli for sleep (Ebben & Spielman, 2009; Harsora & Kessmann, 2009).
Insomniacs tend to associate the bed and bedroom with behaviours that are not conducive for
sleep (Passarella & Duong, 2008) such as watching television, eating, reviewing the day’s
events, planning, worrying, lying awake and becoming anxious and frustrated from trying to
fall asleep. There is also a Pavlovian conditioning component where the bed and bedroom
become conditioned stimuli for stress and frustration which accompany the experience of
being unable to fall asleep (Bootzin & Epstein, 2011). SCT endeavours to reinforce the bed
and bedroom as positive cues for inducing sleep, to weaken them as cues for behaviours that
are not conducive with sleep, and to initiate a regular sleep-wake pattern (Pigeon, 2010).
The stimulus control instructions are as follows (Bootzin 1972, 1977):
1. Only lie down to go to sleep when sleepy;
2. The bed should only be used for sleep and not for other activities including reading,
watching television, eating, or worrying in bed. The only exception to this rule is sexual
activity;
3. If you cannot fall asleep quickly (within10 minutes) leave the bedroom and move to
another room until you feel sleepy;
4. If you still cannot fall asleep, repeat step 3. Do this as often as is necessary throughout the
night;
5. Wake up and get out of bed at the same time every morning, regardless of how much sleep
you achieved during the night to help achieve a consistent sleep rhythm; and
6. Do not nap during the day.
Establishing new sleep habits is important to overcome symptoms of insomnia and therefore,
the bed and bedroom must be reserved for sleep and sexual activities only (Lande &
Gragnani, 2010). By leaving the bed and bedroom when an individual cannot sleep reduces
sleep anticipatory anxiety, dysfunctional sleep-related cognitions, and arousal (Morin &
25
Epsie, 2003). In addition, this will also probably increase the individual’s sleep debt and
homeostatic sleep drive. Undergoing SCT increases the likelihood that the patient will quickly
fall asleep and stay asleep throughout the night, thus reinforcing the bed and bedroom sleep
(Morin, 2004). Furthermore, abiding by a set time for waking each day will affect the
circadian clock and allow the development of a regular sleep-wake schedule (Morin, 2004).
The procedures and instructions of SCT are thoroughly rationalised and explained to patients
before they undergo treatment (Bootzin & Epstein, 2000). Meta-analyses and systematic
reviews (Morin et al., 1999a: Morin et al., 2006) indicate that SCT is extremely effective, and
is probably the most successful, single-component non-pharmacological intervention for
insomnia. Despite its lack of testing as a single intervention during the past decade (Pallesen
et al., 2003, Reidel et al., 1998), SCT is frequently included in multicomponent interventions
(Lichstein et al., 2000; Morin et al., 1999b: Morin et al., 2004; Rybarczyk et al., 2002).
Sleep Restriction Therapy
Spielman et al (1987) devised a behavioural treatment for insomnia known as sleep restriction
therapy (SRT). SRT is based on the fact that patients suffering from insomnia waste too much
time in bed trying to sleep, leading to greater wakefulness, disrupted sleep, and variability in
the timing of sleep and wake. SRT focuses on consolidating sleep and initiating and
maintaining a steady sleep-wake schedule by reducing the time the patient spends in bed, this
will maximise the homeostatic drive for sleep (Vitiello, 2009) reversing unregulated sleep
homeostasis which is the consequence of a long period to get to sleep commonly seen in
insomniacs. The update issued by AASM in 2006 suggests that SRT is effective and, as per
their guidelines, is recommended in the treatment of chronic insomnia (Morgenthaler et al.,
2006).
A personalized sleep-wake schedule involves reducing the time spent in bed to the estimated
average time the individual spends asleep (Harvey & Tang, 2003). This is usually determined
during two weeks at least of the patient maintaining sleep diaries (Petit et al, 2003). The
therapist and the patient then decide allowable time in bed for the following week (Taylor &
Roane, 2010). A bedtime is then determined that allows the patient an amount of time in bed
equivalent to the baseline average total sleep time (Taylor & Roane, 2010). For example, if
the mean total sleep time is 5.5 hours, and the wake time is 5:30 am, then a bedtime is set at
midnight for thefirst week of treatment. During treatment, the bedtime is extended 15 -30
minutes each week, depending on the sleep experienced the preceding week (Spielman et al.,
1987).
26
Wohlgemuth & Edinger (2000) suggest that the time spent in bed is possibly less than what is
required as the total sleep time. The concept of ‘total sleep time’ is frequently underestimated
by insomniacs (Smith et al, 2002). Consequently, partial sleep deprivation results, an increase
in the homeostatic sleep drive occurs and sleep consolidation occurs (Morin, 2004). Thus,
patients develop a regular sleep-wake cycle (Spielman et al, 1987). These individuals are not
prescribed less than 5.5 hours in bed (Taylor & Roane, 2010). The treatment plan usually
takes six weeks to notice an improvement (Rubenstein et al. 1990), although Spielman &
Glovinsky (1991) advise a treatment period of eight weeks. As six weeks is required to notice
an improvement in patients, the study could be enhanced by extending the period of the
experiment to at least 10-12 weeks.
SRT has commonly been used as a single treatment (Friedman et al. 2000) and has become
included in multicomponent treatments (Edinger et al., 2001; Espie et al., 2001). Studies
which conducted a follow up of patients undergoing SRT, demonstrated that these patients
continue to experience restricted sleep following 6–12 months post-treatment, increasing total
sleep time and sleep efficiency (Spielman et al., 1987; Friedman et al., 2000). An adjustment
of SRT is sleep compression. This involves steadily decreasing the time spent in bed over the
course of the treatment rather than the abrupt decline used in SRT (Spielman et al., 1987).
Studies show that older adults with insomnia experience more success with sleep compression
(Lichstein et al., 2001; Reidel et al., 1995).
Sleep Hygiene and Education
Sleep hygiene and education (SHE) involves educating the clients on sleep and providing
advice on lifestyle choices concerning sleep hygiene (Harvey & Tang, 2003). Sleep education
informs individuals about several aspects of sleep including sleep processes and function,
developmental changes which occur during sleep, sleep homeostasis, circadian rhythms, and
individual sleep requirements (Bootzin et al., 1996; Lacks, 1987). Sleep hygiene is a set of
rules designed to improve sleep experienced by individuals. Such rules are, for example, to
place the bedroom clock out of sight and to avoid consumption of caffeine (4 hours before
bedtime), nicotine (2 hours before bedtime) and alcohol (2 hours before bedtime) (Hauri,
1991; Pallesen et al., 2001; Yang et al., 2010). Experts in the field have not yet agreed upon a
standard definition for sleep hygiene (Stepanski & Wyatt, 2003), and consequently, the phrase
is often erroneously used by healthcare providers to refer to stimulus control therapy (SCT)
(Edinger & Wohlgemuth, 1999). There are no studies documented in the literature that
employ the same set of sleep hygiene instructions. Although there is a principal set of sleep
27
hygiene instructions, specific recommendations are varied (Stepanski & Wyatt, 2003). A
critical strategy used in insomnia intervention is education, (Morin et al., 1999a), which helps
patients suffering from insomnia to understand theory-based interventions such as SCT and
sleep restriction therapy (SRT). Therefore, SHE is usually provided during the early stages of
the cognitive-behavioural treatment (CBT) intervention period (Morin et al., 1999a).
Although the effectiveness of SHE is limited (Morin et al., 1999a), it is still a vital part of
multicomponent intervention studies (Edinger & Sampson 2003; Espie et al., 2007; Morin et
al., 2004; Reidel, 2000).
Cognitive Therapy
Cognitive therapy is a component of CBT and is a successful means of treating insomnia
(Morin, 2004). There are two types cognitive therapy used to treat insomnia. The first is a
cognitive therapy devised by Morin (1993) which is based on Beck’s therapy for depression
(Beck et al., 1979). This therapy uses a cognitive restructuring approach that targets the
erroneous beliefs and attitudes about sleep harboured by insomniacs. The second cognitive
therapy is Harvey’s (2005) approach which focuses on cognitive processes which sustain
insomnia. These include observing sleep related threat, misperceptions of sleep and daytime
deficit, and behaviours that support obstructive beliefs (Harvey, 2005).
Although the two therapies target beliefs and attitudes about sleep, they employ different
approaches to achieve the therapeutic goal of treating insomnia.
Cognitive Restructuring
Cognition plays a significant role in the manifestation of insomnia (Morin, 1993). The
primary targets of cognitive restructuring are the dysfunctional cognitions and sleep
disturbing thoughts concerning insomnia harboured by individuals suffering from insomnia
(Milner & Belicki, 2010). These included impractical sleep expectations, misperceptions
about the causes of insomnia and misguided perceptions of the consequences of insomnia
(Bélanger et al. 2006). Cognitive restructuring treatment is personalized and begins with the
identification of the problems specific to the patient. This is achieved by examining specific
examples of disrupted sleep and asking the patient to complete a questionnaire entitled
‘Dysfunctional Beliefs and Attitudes about Sleep’ (Morin et al., 1993). The dysfunctional
cognitions which are held by the patient are challenged and reformed using various
psychological techniques. Multicomponent treatment studies in regards to insomnia have
included cognitive restructuring as a component of the treatment (Morin et al., 1999b, Morin
et al., 2004).
28
Cognitive Therapy for Insomnia
Based on previous theoretical work concerning cognitive processes which occur during
insomnia and success of cognitive therapy in other psychological disorders, Harvey
developed a cognitive model (Harvey, 2002) and therapy (Harvey, 2005) for insomnia. This
model suggests that cognitive processes which maintain insomnia include daytime variables
(Harvey, 2002). The five actions that maintain insomnia are worry, selective attention to and
monitoring for sleep-related threats, misperception of sleep and daytime deficits, unhelpful
beliefs about sleep, and counterproductive safety behaviours (Harvey, 2005). The cognitive
therapy for chronic insomnia (CT-I) developed by Harvey occurs in three stages (Harvey,
2005). The first stage (conceptualisation) involves the therapist and patient developing a
personalised cognitive model of daytime and night-time issues that explain the errant cycles
experienced by the patient (Harvey, 2005). The intervention phase (second stage) uses the day
time and night time models for experiments designed and employed by the patient to test and
revert processes which are involved in maintaining insomnia (Harvey, 2005). The final stage
of CT-I deals with findings recorded during the behavioural experiments, identification of
treatment gains, relapse prevention, and setting goals to maintain the benefits achieved
throughout the treatment (Harvey, 2005).
A trial of Harvey’s approach (Harvey et al., 2007) involving 19 patients receiving individual
treatment from 6 to 22 sessions (average 14) demonstrated a major enhancement in sleep and
reduction in daytime impairment that was sustained through a one year follow-up period.
Although these findings are promising, there was no control group in the study, and several
sessions were provided which reduced cost-efficiency compared to other treatment options.
2-Complementary and Alternative Medicines (CAM)
Acupuncture
Acupuncture is a widely accepted alternative medicine that involves inserting thin needles
into meridian points around the body (Sok et al., 2003). A few studies have assessed the
efficacy of acupuncture in the treatment of insomnia by utilising polysomnography,
particularly those conducted by Montakab (1999) and Spence et al (2004). While both of
these studies provided evidence supporting improved sleep with acupuncture, the study
conducted by Spence et al (2004) was not placebo-controlled. The placebo acupuncture
simulates the acupuncture procedure without penetrating the skin(Streitberger & Kleinhenz,
1998). This study also showed an increase in secretion of nocturnal endogenous
29
melatonin(Spence et al, 2004). Spence et al (2004) also found decreased stress/anxiety
experienced by patients compared to pre-treatment levels. This was measured using StateTrait Anxiety Inventory form which is a questionnaire involving two, 20-item scales designed
to gauge state and trait anxiety (Spielberger, 1972). The majority of studies conducted on
acupuncture mainly report subjective measures to evaluate patient satisfaction, subjective
relief of symptoms, and duration of sleep (Spence et al, 2004). Although the results of this
study are subjective, from a patient’s perspective, acupuncture appears to be extremely
successful (Sok et al., 2003).
Yeung et al (2009) conducted a randomised, single-blind, placebo-controlled, parallel-group
to evaluate the short-term efficacy of electroacupuncture for the treatment of primary
insomnia. The study involved 60 Chinese adults who report having insomnia 3 or more nights
per week (Yeung et al., 2009). Participants were either subjected to electroacupuncture 3
times per week for 3 weeks or placebo acupuncture “non-invasive acupuncture” connected to
the same electric stimulator but with zero frequency and amplitude (Yeung et al., 2009).
Yeung et al (2009)did not demonstrate any significant difference between the placebo
acupuncture and the electroacupuncture. Although, a placebo-needle does not penetrate the
skin, the patient feels that penetration (Streitberger & Kleinhenz, 1998). The placebo needle
has been shown to be sufficiently reliable (Streitberger & Kleinhenz, 1998; White et al.,
2003) to be used in research of the effects of acupuncture (Streitberger & Kleinhenz, 1998).
Huang et al (2009) conducted a study to evaluate the therapeutic effects of needle-rolling
acupuncture therapy for chronic insomnia. A total of 180 chronic insomniacs were randomly
divided into two groups, a treatment group (90 cases) treated by the needle-rolling therapy
and a positive control group (90 cases) treated with clonazepam (Huang et al., 2009). The
treatment course for both the two groups was 5 treatments per week for 4 weeks (Huang et
al., 2009). The therapeutic effects were evaluated based on improvement of symptoms as
assessed in traditional Chinese medicine and the Pittsburgs's sleep-quality index (PSQI)
(Huang et al., 2009). The needle rolling group showed significant improvement in the
effective rate, the total score of PSQI, and in the scores of sleep-quality, sleep-efficiency,
hypnotic and daytime function (Huang et al., 2009). However, after a 3-month follow-up
period, no significant difference between the two groups was observed for the effective rate,
but there were still significant improvements in the needle rolling group in sleep-efficiency,
hypnotic, and daytime function of the PSQI (Huang et al., 2009).
30
Wang et al (2008) carried out a randomised single-blind trial to determine the efficacy of
short-term abdominal acupuncture as a treatment for insomnia in Chinese women over two
weeks. Forty-four patients between the ages of 22 and 56 were divided into two groups:
acupuncture (n = 23) or medication (n = 21) group (Wang et al., 2008). The acupuncture
group received abdominal acupuncture once a day for the first three days and once every three
days for the remaining duration of the study (Wang et al., 2008). In addition, they also
received a placebo tablet once a day (Wang et al., 2008). Subjects in the medication group
were treated with sham acupuncture and received an effective dose of 1mg of the
benzodiazepine derivative estazolam (positive control) once a day (Wang et al., 2008). The
effect of abdominal acupuncture in relieving insomnia was more effective than the estazolam
and sham acupuncture treatment in adult women (Wang et al., 2008). Although, this study
confirms abdominal acupuncture to be an effective treatment for insomnia, it had two main
drawbacks: the small sample size and the short time span of the study. Furthermore, due to
the short testing period, this study did not conduct any follow-up and thus could not comment
on the potential effectiveness and side effects of prolonged acupuncture use.
Da Silva et al (2005)studied the effects of acupuncture on pregnant women who suffered from
insomnia compared to patients undergoing conventional treatment alone (sleep hygiene). The
study examined 30 conventionally treated pregnant women who were divided into two
groups: study group (hygiene and acupuncture) and control group (sleep hygiene only (Da
Silva et al., 2005). The study group consisted of 17 patients with the remaining 13 patients in
the control group (Da Silva et al., 2005). The patients were all treated for 8 weeks (Da Silva
et al., 2005). This study demonstrated that acupuncture alleviated insomnia during pregnancy
with the study group showing a statistically significant decrease in insomnia than the control
group (Da Silva et al., 2005). Although this study showed that acupuncture was effective for
the treatment of insomnia, objective measures such as polysomnography and actigraphy were
not used for the evaluation of insomnia.Patients were asked to give a single rating on a
Numerical Rating Scale (NRS) of zero to 10, where zero represented good sleep and 10 the
worst insomnia possible. Using a scale such as the NRS used in this study cannot be taken as
an objective measure. Nonetheless, subjective self-reported measures indicate the impact on
the individual, however, more reliable data may be generated by using objective measures
such as polysomnography and actigraphy.
Nordio and Romanelli (2008), evaluated the efficacy of an acupressure device, heart 7insomnia control consisting of “a soft rubber pin, kept in place by an adhesive plaque”
31
(Nordio and Romanelli, 2008). This device was positioned on heart 7 points (HT7 points)
located on the wrists in 20 insomniacs, every night for 3 weeks compared to a placebo
treatment in which the device was placed on non-HT7 points in 20 insomniacs (Nordio and
Romanelli, 2008). The results of this study indicated that the device H7-insomnia control is
more effective in enhancing the quality of sleep in insomniacs, than the placebo treatment.
Chen et al (1999) tested the efficacy of acupressure in improving the sleep quality of
insomniacs. This study included 84 patients divided into 3 groups, each consisting 28
patients. The groups were the acupressure group, a placebo acupressure group, and a control
group (Chen et al., 1999). The same massage routine was used in the acupressure group and
the placebo acupressure group, with different acupoints and conversation whereas only
conversation was used in the control group (Chen et al., 1999). This study found that
acupressure was significantly more effective than both the placebo acupressure and control
treatments in the PSQI total score, sleep latency, sleep duration and sleep quality (Chen et al.,
1999).
In summary, acupuncture is effective at improving sleep quality and duration. However, these
apparently positive results must be integrated with clinical trials. Thus, the beneficial effect of
acupuncture may be as a result of the small sample sizes or short follow-up periods used and
need to be confirmed in large and rigorously designed randomised controlled trials.
Valerian
Valerian is a flowering plant which approximately200 species (Komori et al., 2006). The
species Valeriana officinalis is commonly employed in the treatment of insomnia and anxiety
(Benke et al., 2009; Bent et al., 2006). Valerian is extracted using a variety of extraction
methods either aqueous or ethanol extracts (Wheatley, 2005), with differing yeilds. The
aqueous extraction method yields approximately 270–900 mg of valerian extract while the
ethanolic valerian extraction produces 300–600 mg of valerian extract (Taibi et al., 2007).
Valerian results in sedation most likely by the inhibiting the breakdown of γ-aminobutyric
acid (GABA) or GABA-like metabolites (Ringdahl et al., 2004). Moreover, Muller et al
(2002) published in vitro research which revealed another mechanism of action, finding
valerian binding at A1 adenosine receptors; however, the in vivo implications of this research
remain unclear.
One study (n = 128) of valerian examined the effects of an aqueous valerian extract
administered in doses of 400 mg to participants who were “good sleepers” (comprising 52%
32
of participants) and “poor sleepers” (comprising 48% of participants) in a randomized,
double-blinded, placebo-controlled crossover study (Leathwood et al., 1982). Subjective sleep
latency and sleep quality were significantly improved (Leathwood et al., 1982). Elderly
“poor sleepers” reported the most considerable improvement in sleep quality (63%)
(Leathwood et al., 1982). However, almost half of this group (43%) was treated with placebo,
and the difference was not statistically significant (Leathwood et al., 1982). In younger
individuals who considered themselves as poor sleepers, valerian significantly improved sleep
quality (Leathwood et al., 1982). No difference between placebo and valerian concerning
subjective daytime sleepiness was reported (Leathwood et al., 1982). The major limitation of
this study was the lack of data for objective sleep measures.
In an uncontrolled study conducted by Dominguez et al (2000), patients suffering from
insomnia who were receiving mental health services were given valerian for two weeks to
complement their psychotropic program. The initial dose of valerian was 470 mg and was
administered on nights 1–3 (Dominguez et al., 2000). The dose was increased to the
maximum dose of 1,410 mg after the first week if patients found lower doses to be ineffective
(Dominguez et al., 2000). After one week of treatment, 11 of the 20 participants reported a
“moderate” improvement in their sleep quality at a mean valerian dose of 940 mg
(Dominguez et al., 2000). By the second week, all participants had raised their dose to 1,410
mg (Dominguez et al., 2000). Nine rated their insomnia “moderately to extremely” improved,
while six patients rated their insomnia “extremely” improved (Dominguez et al., 2000).
However, Dominguez et al (2000) neglected to mention which features of their sleep
disturbances were improved.
Coxeter et al (2003) conducted a study where 450 mg of valerian was administered to chronic
insomniacs for a period of one week during which the participants kept a sleep diary. Coxeter
et al (2003) could not demonstrate that valerian was more effective than a placebo in a series
of randomized n-of-1 trials (Coxeter et al., 2003). Similarly, Jacobs et al (2005) conducted a
randomized, double-blind, placebo-controlled trial using a novel Internet-based design
showed that a dose of 6.4 mg of valerenic acids which is an active ingredient of valerian
(Dietz et al., 2005) given for 28 days did not significantly reduce insomnia or anxiety in
comparison to a placebo in an Internet-based study (Jacobs et al., 2005). However, there are
doubts about the results generated by Jacobs et al (2005) as the dose administered appears to
be very low, but it is difficult to extrapolate an equivalent dose of valerian due to no
information being provided about the valeric acid concentration in the product(s) used. The
33
use of the Internet in the literature is limited and internet recruitment of participants may lead
to samples containing dubious representativeness. In particular, obtaining external validity
may pose a problem (Braithwaite et al., 2003). It remains unclear as to whether randomised
controlled trials can be conducted solely using the Internet. Thus, the results obtained by
Jacobs et al (2005) may not be valid.
In a randomised, crossover, double-blind, placebo-controlled trial carried out by Balderer &
Borbély (1985), an aqueous solution of valerian extract was administered to 18 participants
who did not experience sleep problems. Of these participants, 8 attended polysomnographic
studies and were given either placebo or valerian (900 mg) for 5 nights in a laboratory setting
(Balderer & Borbély, 1985). The remaining 10 participants were monitored for wrist-activity
and were given either placebo, valerian (450 mg) or valerian (900 mg) over a period of 3
nights at home (Balderer & Borbély, 1985). In the laboratory study, the latency to stage 2
sleep was reduced from an average of 25.4 minutes to 19.2 minutes and wakefulness after
sleep onset decreased from an average of 29.6 minutes to 19.0 minutes (Balderer & Borbély,
1985). However, these results were not statistically significant, probably due to the small
sample size. Conversely, in the home study, valerian significantly enhanced sleep latency and
wake time after sleep onset in a dose-dependent manner when comparing 450 mg and 900 mg
doses. However, there was no reported change in sleep quality and data concerning wrist
activity was inconclusive (Balderer & Borbély, 1985). The participants exhibited a
considerable increase in activity during the middle third of the night when administered
valerian (900 mg), in comparison to placebo, but this nighttime activity was reduced in the
last third of the night (Balderer & Borbély, 1985). Also, there were mixed results regarding
objective assessments of sleep latency. Although this study provides insights into the effect
of valerian on sleep, its major limitation is the fact that valerian was only administered for 1
or 2 nights in to participants who did not complain of sleep disturbances.
Leathwood & Chauffard (1985) evaluated the effect of an aqueous valerian extract (450 mg
and 900 mg doses) and placebo in 8 patients suffering from insomnia by recording objective
measures (wrist actigraphy). The results revealed a reduction in sleep latencies following a
450 mg dose of valerian for four non-consecutive nights (from 15.8 ± 5.8 minutes to 9.0 ± 3.9
minutes, P < .01) (Leathwood & Chauffard, 1985). Conversely, a dose of 900 mg did not
produce additional improvements in sleep latency and the higher dose yielded a considerably
higher rate of morning sleepiness (Leathwood & Chauffard, 1985). However, in contrast to
34
the previous study, increasing the dose of valerian to 900 mg did not show any additional
benefit. In fact, the 900-mg dose led to a significant increase in morning sleepiness.
Schulz et al (1994) conducted a placebo-controlled study, using polysomnography, to
elucidate the effect of valerian in elderly patients experiencing disturbed sleep. Eight elderly
insomniacs were given valerian and 6 were administered a placebo (Schultz et al., 1994). The
participants took valerian (450 mg) or placebo 1 hour before retiring on day 1 of the study,
and on days 2-8, they took valerian or placebo 3 times a day with food but not at bedtime
(Schultz et al., 1994). Participants given valerian exhibited no change in sleep efficiency,
however, Valerian was shown to reduce the proportion of stage 1 sleep with no change was
seen in the placebo group (Schulz et al, 1994). Slow wave sleep (SWS; sleep stages 3 and 4)
showed a significant gradual increase to night 8 but REM sleep was unchanged by valerian
(Schulz et al., 1994). However, when compared to placebo, no differences in
polysomnographic parameters were observed in the valerian group, neither was there a
change in sleep quality and day or evening alertness (Schulz et al., 1994). The limitations of
this study include its small sample size and the fact that many vital sleep parameters,
including sleep latency, were different between the participants who were given placebo or
valerian.
Using polysomnographic measurements, Donath et al (2000) compared the effects of using
valerian for 1 night against a 14-day period in a randomized, double-blind, placebo-controlled
trial of 16 insomnia patients administered 600 mg of valerian-root extract. Donath et al (2000)
reported that one 600mg dose of valerian did not considerably alter subjective or objective
sleep measures. However, following a 14-day period, significant changes were observed
including reduced subjective sleep latency and a reduced objective latency to slow-wave sleep
when compared to placebo (Donath et al 2000). However, no alterations in subjective sleep
quality or other objective measures including sleep efficiency were noted. Although slowwave sleep time was shown to be increased when given valerian, slow-wave sleep time was
also increased with placebo, with no statistically significant difference between the two
(Giedke & Breyer-Pfaff, 2000).
Stevinson & Ernst (2000) reviewed nine randomised, double-blind, placebo-controlled
clinical trials which were designed to establish the effectiveness of valerian for the treatment
of insomnia. However, some of these studies had methodological flaws in areas such as
randomisation, blinding, compliance, withdrawal, confounding variables, diagnostic criteria,
35
and statistical analysis. Thus, Stevinson & Ernst (2000) found the evidence supporting the use
of valerian to treat insomnia was inconclusive.
Valerian products are also marketed which contain additional herbal extracts such as hops,
lemon balm and passion flower, each ingredient with its own sedative effects (Taibi et al.,
2007). Such products which contain a combination of ingredients may exhibit an additive
orsynergistic effect, increasing the effectiveness of the product, thus these products are
thought to be more effective than a single ingredient. The efficacy and safety of a valerianhops combination was evaluated by Morin et al (2005) against diphenhydramine in the
treatment of mild insomnia in a multicenter, randomised, placebo-controlled, parallel-group
study. A total of 184 adults (110 women, 74 men; mean age of 44.3 years) with mild
insomnia were given two tablets of standardised extracts of a valerian and hops combination
each night for 28 days (n = 59), placebo for 28 days (n = 65), or 2 tablets of diphenhydramine
(25 mg) for 14 days followed by placebo for 14 days (n = 60) (Morin et al 2005). Slight
improvements of subjective sleep parameters were observed in participants taking the
valerian-hops combination or diphenhydramine (Morin et al 2005). Although insignificant,
valerian-hops caused a larger decrease in sleep latency compared to placebo and
diphenhydramine (Morin et al 2005). Diphenhydramine yielded significantly larger increases
in sleep efficiency and total sleep time as compared to placebo throughout the initial 14 days
of treatment (Morin et al 2005). No significant differences among the groups were reported
for any of the sleep continuity variables measured by polysomnography (Morin et al 2005).
Furthermore, no changes in sleep stages 3-4 and rapid eye movement sleep were observed
with any of the treatments tested (Morin et al 2005). Participants in the valerian and
diphenhydramine groups expressed that the severity of their insomnia was lower relative to
placebo following the 14-day treatment period (Morin et al 2005). The quality of life of the
participants who were administered a combination of valerian-hops had significantly
improved as compared to the placebo group following 28 days of treatment (Morin et al
2005). No significant residual effects or serious adverse events were reported with the use of
either valerian or diphenhydramine (Morin et al 2005). Similarly, after discontinuation of
valerian or diphenhydramine, no rebound insomnia was observed (Morin et al 2005). Thus,
Morin et al (2005) concluded that both a valerian-hops combination and diphenhydramine
alone caused a slight hypnotic effect as compared to placebo. Furthermore, improved sleep
was achieved with a valerian-hops combination and led to an enhanced quality of life (Morin
et al 2005). Both treatments seemed to be safe as they did not cause severe side effects nor did
36
they cause rebound insomnia following discontinuation.Thus, a valerian-hops combination
and diphenhydramine may be a helpful part of a treatment strategy for mild insomnia.
Lindahl and Lindwall (1989) showed that a valerian preparation containing valerian 400 mg,
hops 375 mg, and lemon balm 160 mg was more effective than a control after one night of
administration, without causing any adverse side effects. This study is limited, however, as
the duration of the treatment was short (only 1 night), the small sample size, and the deficit of
objective sleep measures. In contrast, Leathwood et al (1982) demonstrated that a valerian
product with valerian 120 mg and hops 60 mg yielded no changes in sleep latency or sleep
quality in healthy individuals following administration for three non-consecutive nights,
however, the doses were lower than those used by Lindahl and Lindwall (1989) (without the
lemon balm). This particular preparation caused several more reports of individuals feeling
“more sleepy than usual” when compared to the placebo group (Leathwood et al., 1982).
Similar results were achieved in patients suffering from mild insomnia who were given a
preparation of valerian 374 mg and hops 83.8 mg for 28 days (Morin et al., 2005). No
significant effect in sleep parameters using sleep diaries and PSG were observed (Morin et al.,
2005).
The effectiveness of valerian for other sleep-related problems, apart from insomnia, has also
been studied. Poyares et al (2002) investigated valerian as a possible method to assist in
benzodiazepine withdrawal in a doubleblind study consisting of 19 participants. Participants
decreased their benzodiazepine use and randomly received either a placebo or 100mg of a
valerian extract 3 times a day (Poyares et al 2002). The sleep patterns of all participants were
compared to those of healthy individuals (Poyares et al 2002). Using a visual analogue scale,
subjective reports of sleep quality were 7.4 ± 0.9 on valerian compared to 5.4 ± 0.8 on
placebo (Poyares et al 2002). The result of this study revealed that the placebo significantly
reduced objective sleep latency, while valerian slightly increased sleep latency following
treatment (Poyares et al 2002). However, wakefulness after sleep onset, was found to be
decreased when administered valerian and increased when given the placebo (Poyares et al
2002). Therefore, the overall sleep efficiency was similar in both groups following treatment
with either valerian or placebo (Poyares et al 2002). Poyares et al (2002) suggest that the
reduced wakefulness after sleep onset may justify the subjective observation of improved
sleep in patients given valerian, although the sleep latency was increased.
37
The main conclusion that these studies suggest is that although valerian produces minimal
adverse effects, it does not drastically improve the symptoms of disturbed sleep associated
with insomnia (Taibi et al., 2007).
Conflicting results have been obtained by the research conducted to determine the
effectiveness of valerian as a sleep aid. The contradictory results are likely to be the
consequence of differences in the individuals taking part in the study, the design and
methodology of the study, the preparation and extraction methods used, dose and sleep
assessment measures.
St. John’s wort
St. John’s wort (Hypericum perforatum) is a herb used for several medicinal purposes such as
in the treatment of depression, anxiety, and fatigue. The active ingredients in St. John’s wort
are believed to be hyperforin and hypericin (Meolie et al., 2005). Unfortunately, most clinical
studies do not address the effect of St. John’s wort on insomnia (instead, the main focus of the
research is on depression). No double-blind placebo controlled studies examining the effects
of St. John’s wort on insomnia were found in the literature. However, limited data on the
effects of St. John’s wort on sleep were located.
A placebo-controlled, PSG study of healthy individuals who did not suffer from mood or
sleep disturbances evaluated the effect of St. John’s wort on sleep (Sharpley et al., 1998). A
dose of 0.9 mg St. John’s wort considerably increased REM sleep latency versus a placebo
(84 vs 69 minutes, respectively, P = .03) (Sharpley et al., 1998). A second group of healthy
individuals were given a higher dose of St. John’s wort (1.8 mg) (Sharpley et al., 1998). The
average REM latency was not significantly increased when given this higher dose of St.
John’s wort versus a placebo(104 vs 64 minutes, respectively, P = .15) (Sharpley et al., 1998).
Another placebo-controlled, double-blind, randomized crossover study conducted on11 older
female volunteers (mean age 59.8 ± 4.8 years) study examined the effects of St. John’s wort
on sleep (Schulz, 2001). The findings revealed a pronounced increase in slow-wave activity
when given St. John’s wort and in comparison to individuals taking the placebo (Schulz,
2001). Slow-wave sleep increased during active treatment with St. John’s wort, and decreased
when being treated with the placebo (Schulz, 2001). It was unclear as to whether or not the
alterations in sleep architecture reported were correlated with an improvement in insomnia.
Furthermore, these studies were conducted on healthy individuals, and therefore, the results
obtained from these studies may not apply to patients suffering from symptoms characteristic
38
of insomnia. In addition, these studies made extracts of St. John’s wort, and therefore it the
effectiveness of commercially available St. John’s wort is unknown. Furthermore, the
components and extraction methods used by these studies were different and thus prevent the
simplification of the generated results.
Several studies have documented the adverse effects associated with St. John’s wort. These
are gastrointestinal complaints, dizziness, fatigue, anxiety and headaches (Barnes et al., 2001;
Greeson et al., 2001; Harrer et al., 1999; Müller et al., 1997; Schulz, 2001; Woelk, 2000). In
a study involving commercially available St. John’s wort preparations the side effects which
were the most common were gastrointestinal symptoms, allergic reactions, tiredness, anxiety
and confusion (Woelk et al., 1994). A few studies also report photosensitivity and
phototoxicity as side effects of use of St. John’s wort (Bove, 1998; Brockmöller et al., 1997;
Lane-Brown, 2000).
Drug interactions involving St. John’s wort have also been well documented. Several studies
conducted in vivo demonstrate the ability of St. John’s wort to stimulate the cytochrome P450
(CYP) system, particularly isoenzyme 3A4 (Breidenbach et al., 2000a; Breidenbach et al.,
2000b; Dürr et al., 2000; Markowitz et al., 2000; Roby et al., 2000; Ruschitzka et al., 2000).
Many prescribed drugs are metabolised by theCYP450 isozyme 3A4 (CYP3A4), and
therefore there is a significant risk of a pharmacokinetic drug interaction(Izzo & Ernst, 2009).
Hyperforin can induce CYP3A4 and is likely to be the most common component for St John’s
wort interactions (Moore et al., 2000). The difficulty in predicting interactions lies in the fact
that many of the St. John’s wort products available on the market are standardised for
hypericin content only (Henderson et al., 2002). Intestinal P-glycoprotein is also induced by
St. John’s wort (Dürr et al., 2000; Hennessy et al., 2002). The most significant interactions
are usually seen in patients suffering from cardiovascular disease, HIV, cancer and depression
(Mannel, 2004). Serum digoxin levels are significantly decreased (Dürr et al., 2000; Gurley et
al., 2008). Furthermore, a decrease in the bioavailability of indinavir, a nonnucleoside
reverse-transcriptase inhibitor has been reported (Piscitelli et al., 2000). Decreased serum
cyclosporin levels, and acute organ rejection following kidney, heart and liver transplants
have been documented (Barone et al., 2000; Di et al., 2008; Karliova et al., 2000; Ruschitzka,
2000). St. John’s wort also reduces the concentration of amitriptyline and its metabolite
nortriptyline (Johne et al., 2002). Menstrual bleeding has occurred in a few women who are
taking oral contraceptives, which may a consequence of an increase in CYP3A4 induction and
subsequent decrease in hormone concentrations (Yue et al., 2000).
39
Pharmacodynamic interactions can also occur with St Johns Wort. When sertraline,
nefazodone or paroxetine are taken in conjunction with St. John’s wort, serotonin syndrome
has been reported (Lantz et al., 1999). This may be associated with the serotonin-inducing
effects of St. John’s wort, and consequently, St. John’s wort should not be used concurrently
with selective serotonin reuptake inhibitors.
Kava
Kava is derived from the roots of Piper methysticum, a plant indigenous to the South Pacific
(Humberston et al, 2003). Kava has sedative and anesthetic properties and as such,
supplements containing kava are used to ease menopausal symptoms, anxiety and insomnia
(Bilia et al, 2002). These products are usually made from raw plant material or concentrated
extracts. However, an unforseen side effect of kava kava has been reported since 1999, that is,
severe hepatotoxicity (including cases of liver failure which necessitated a liver
transplantation) (From the Centers for Disease Control and Prevention [CDC], 2003). In
2002, the FDA issued a statement concerning the potential for developing hepatotoxicity
when using products containing kava kava (FDA, 2002). In Australia, Therapeutic Goods
Administration (TGA) initiated a voluntary recall of kava-containing medicines following
hepatotoxicity and deaths from liver failure associated with medicine containing kava (TGA,
2005). Also, the TGA issued safety alerts to Australian consumers and health professionals
about concerns, “the most serious of which involved death or liver transplantation.” (TGA,
2005).The CDC published the results of its investigation in the United States with regards to
the cases of liver failure caused by kava kava and reviewed the cases in Europe (Morbidity
And Mortality Weekly Report, 2002). Since then, many European countries have limited the
sale of products containing kava kava (Centers for Disease Control and Prevention, 2003).
Hepatotoxicity induced by kava arises from administration of anxyolytic ethanolic, acetonic
kava extracts and aqueous kava extracts (Teschke, 2010). Thus, due to the possibility of
developing severe liver toxicity, particularly in patients with a pre-existing liver disease or
liver injury, kava kava (either ethanolic or aqueous) should not be advocated in the treatment
of insomnia.
A meta-analysis conducted by Pittler & Ernst (2000) showed that in the treatment of anxiety,
kava caused stomach complaints, restlessness, tremor, headache and tiredness. Wheatley
(2001) showed that stress-induced insomnia was alleviated after treatment of kava for a
period of six weeks at a dose of 120 mg of kava. The insomnia was further reduced by six
40
weeks treatment with 600 mg valerian (Wheatley, 2001). The side effects of kava reported in
this study were gastric disturbances, and dry mouth (Wheatley, 2001).
A frequent symptom which occurs in association with an anxiety disorder is sleep
disturbances (Ohayon et al., 2000). Jacobs et al (2005) reported that a dose of 300 mg kava
for 28 days did not produce a significant decrease in anxiety or insomnia using the Insomnia
Severity Index and State-Trait Anxiety Inventory, respectively. Conversely, administration of
kava (200 mg) for four weeks (compared to placebo) produced major improvements in sleep
quality, restorative effects of sleep and reduced anxiety in individuals experiencing anxiety
derived sleep disturbances from a non-psychotic origin (Lehrl, 2004). Several sleep
questionnaire scores showed significant improvement in sleep and anxiety including the
Hamilton Rating Scale for Anxiety, self-rating scales of well being, and the Clinical Global
Impressions scale (Lehrl, 2004).
As is the case in many of these products, there are some non-controlled data suggesting the
effectiveness of kava toalleviate insomnia. However, there is a limited number of objective
and/or placebo controlled trials to show the efficiency of kava in treatment of insomnia.
Furthermore, the benefits of using kava must be weighed against the risks of consuming this
product; in particular the potential of developing liver toxicity.
Melatonin
Melatonin (N-acetyl-5-methoxytryptamine) is a hormone synthesised in the pineal gland
located in the posterodorsal aspect of the diencephalon, just above the cerebellum (GrozinskyGlasberg et al., 2010). Its biosynthesis and secretion occurs nocturnally and its release is
inhibited in the presence of light (Reiter et al., 2010) on the retinal ganglion cells (Brainard et
al., 2008; Jasser et al., 2006).
Melatonin secretion is synchronised by the environmental light/dark cycle via the
suprachiasmatic nucleus (Sarrazin et al., 2011). Melatonin levels begin to rise in the evening
and peak between 2:00 and 4:00am (Arendt et al., 2008). The high density of melatonin
receptors in the hypothalamic suprachiasmatic nuclei (SCN) (Dubocovich et al., 2010),
suggests that melatonin promotes sleep and regulates the sleep-wakefulness cycle by acting
on specific receptors. The mechanism by which melatonin acts during sleep, (excluding its
modulation and regulation of the circadian rhythm, known as phase shifting), remains elusive,
but it is thought that melatonin acts by stimulating specific melatonin receptors (Roth, 2001).
41
Melatonin has a half-life ranging from 0.5-2 hours, with doses up to 5 mg producing less
residual daytime drowsiness (Randall et al., 2008). The most common adverse effects
reported in published studies are headache, dizziness, and drowsiness (Buscemi et al., 2005;
Pandi-Perumal et al., 2007). Melatonin supplements have been demonstrated to be relatively
safe when taken for a short period of time (days to weeks) (Randall et al., 2008). Treatment
with prolonged release of melatonin showed efficacy for primary insomnia without
withdrawal symptoms, or suppression of endogenous melatonin production, with up to 12
months continuous therapy (Lemoine et al., 2011).
Riemann et al (2002) observed a delay in the secretion of melatonin and considerable
reductions in melatonin concentrations during the night in insomniacs. Melatonin in doses
ranging from 0.3–5 mg produced no major differences in sleep measures compared to placebo
therapy (Montes et al., 2003; James et al., 1990). These sleep measures included sleep
efficiency; total sleep time; latency to sleep; number of nocturnal awakenings; average length
of the non-REM/REM cycle; proportion of stage 1, 2, delta sleep, and REM sleep; total
minutes of each sleep stage; and in the latency to REM sleep (Montes et al., 2003; James et
al., 1990). Furthermore, a double blind randomised placebo controlled crossover study found
healthy older volunteers (aged over 65 years) had no improvement in the quality of their sleep
when administered 5 mg immediate release melatonin at bedtime (Baskett et al., 2003).
Touitou (2001) suggests that the endogenous melatonin secretion significantly decreases as
the age of an individual increases. Consequently, sleep efficiency decreases and circadian
rhythm disturbances increase. Conversely, a major improvement in subjective evaluations of
sleep and daytime alertness in patients suffering from insomnia was shown when they were
administered a much higher melatonin dose of 75mg, in a placebo-controlled study
(MacFarlane et al., 1991). An oral dose of 0.1-0.3 mg melatonin is sufficient to achieve
physiologic circulating levels of melatonin (Zhdanov, 2005). As the dose of melatonin used
by Macfarlane et al (1991)was significantly higher than the physiologic dosage range (0.5–1
mg), the safety issues regarding this dose require further intensive study.
Supplemental melatonin seems to improve sleep efficiency in people with a secondary sleep
disorders (Buscemi et al., 2004) and age-related insomnia (Luthringer et al., 2009;
Riemersma-van der Lek et al., 2009). Buscemi et al. (2004) produced an evidence based
report in which they highlighted the increased sleep efficiency following treatment with
melatonin. Improved sleep efficiency was observed in elderly patients at doses ranging from
0.1–3.0 mg (Garfinkel et al., 1995; Zhdanova et al., 2001). These doses increased nocturnal
42
plasma concentrations to within the normal physiological range (Garfinkel et al., 1995;
Zhdanova et al., 2001).
Overall, the data available regarding melatonin as a treatment for the management of primary
insomnia shows mixed results. However, melatonin has the ability to alter phase shifting and
therefore it is effective in elderly patients suffering from primary insomnia with reductions in
endogenous melatonin and insomnia associated with sleep circadian rhythm disorder.
Melatonin improves the quality of sleep (Lemoine et al., 2007) and alleviates symptoms of jet
lag (Herxheimer and Petrie, 2002).
Tryptophan
L-tryptophan is an essential amino acid that cannot be synthesised by the body and must be
obtained from the diet (Paredes et al., 2009). Once absorbed, L-tryptophan can be
endogenously converted to both serotonin and then melatonin (Martins and Gloria, 2010;
Russo et al., 2009). It is well documented that low serotonin levels are correlated with
depression, anxiety, and insomnia (Reimold et al., 2008; Vashadze, 2007) – see above (Role
of serotonin). Despite this, there is a lack of evidence supporting the use L-tryptophan
supplements to treat these disorders (Fetveit 2009; Randall et al., 2008). Nonetheless, Ltryptophan supplements have been used in the treatment of some forms of depression,
anxiety, and insomnia (Silber and Schmitt, 2010).
In chronic insomniacs, supplemental L-tryptophan appears to be a successful hypnotic agent
with sleep maintenance disturbances that were distinguished by 3-6 awakenings during the
night (Lindsley et al., 1983). Lindsley et al (1983) observed that patients suffering from
chronic insomnia self-reported a 100% improvement after taking L-tryptophan 1 g nightly for
1 week. L-tryptophan lacked any significant effects on sleep parameters measured using PSG
at doses of less than 1g (Randall et al., 2008; Hajak et al., 1994). Decreases in sleep latency
were reported at doses of 1-3g, but findings regarding to total sleep time, SWS and REM
sleep were inconsistent.
Schneider-Helmert and Spinweber (1986) conducted a review of several studies investigating
the effectiveness of tryptophan in the treatment of insomnia. Patients with chronic insomnia
(characterised by problems in both sleep onset and sleep maintenance) were demonstrated to
have improved sleep quality following continued administration of low L-tryptophan doses
(1-5g) (Schneider-Helmert and Spinweber 1986). However, the minimum effective dose (1g
from these studies) varies between individuals, and may also change depending on the degree
of the sleep disturbance. Accordingly, the administered dose of L-tryptophan should be
43
between 1-5 g and based on the severity of the insomnia (Schneider-Helmert and Spinweber,
1986). The hypnotic effects occurred late during the treatment after 3 nights of administration
(Spinweber, 1986), and sometimes after discontinuation (Hartmann et al., 1983). Treatment
with L-tryptophan can also decrease sleep onset time on the first night of taking the
supplement (Schneider-Helmert and Spinweber, 1986). The studies reviewed by SchneiderHelmert and Spinweber (1986) administered doses ranging from 1–15g in young patients with
insomnia. There was no dose-dependent response relationship (Schneider-Helmert and
Spinweber, 1986).
Insomnia may be aggravated when the selective serotonin reuptake inhibitor, fluoxetine, is
used to treat depression (Jindal, 2009). Levitan et al (2000) conducted a randomised, doubleblind, placebo-controlled study where L-tryptophan (2–4 g) and fluoxetine (20 mg) were coadministered to 30 patients with depression for 8 weeks and found a considerable reduction in
depression and an SWS protective effect. A reduction in slow wave sleep was observed in the
group given fluoxetine plus placebo tryptophan but was not apparent in the fluoxetine plus
active tryptophan group (Levitan et al., 2000).
L-tryptophan is not associated with impaired visuomotor, cognitive, or memory performance
(Schneider-Helmert and Spinweber, 1986). However, L-tryptophan was withdrawn from the
market in the United States due to an association between tryptophan use and eosinophilic
myalgia syndrome (Michelson et al., 1994). This was caused by contamination during the
manufacturing process linked to genetically engineered bacteria used (Belongia et al., 1990).
Consequently, the FDA has made tryptophan available by prescription in the USA since 1991
and it is also available in Australia by prescription with the exception of medicines which
contain a dose of less than 100 mg to be taken daily (Meolie et al., 2005). However, in
Australia in 2001, the Complementary Medicines Evaluation committee recommended the
TGA that tryptophan is unsuitable for use as an active ingredient in therapeutic goods as the
evidence supporting its safety is lacking (TGA, 2001).
3-Social Treatment
Alcohol
Several studies show that alcohol ingested at bedtime shortens sleep latency, increases slow
wave sleep (SWS), and suppresses rapid eye movement (REM) during the first half of sleep
(Feige et al., 2006). In the second half of sleep, when the level of alcohol in the blood is low,
44
REM sleep increases and sleep is shallower as arousal reactions increase (Brower, 2001;
Feige et al., 2006). Many insomniacs use alcohol as a sleep aid due to its sedative effect,
however, evidence suggests that alcohol consumed within an hour of bedtime disturbs the
second half of the sleep period (Roehrs and Roth, 2001; Roehrs et al., 1999). Alcohol alters
the proportions of the various sleep stages with a reduction of REM sleep dependent on the
dose of alcohol (Sagawa et al., 2011). An increase in the number of nocturnal awakenings
and/or disruption of lighter stage of sleep (stage 1) during the second half of the night occur
when a relatively high dose of alcohol is consumed (Sagawa et al., 2011). This disruption of
sleep during the second-half of the night is known as the rebound effect (Roehrs and Roth,
2001). The rebound effect occurs as alcohol is metabolized (Roehrs and Roth, 2001). Table 2
summarises the effects of alcohol use and cessation on Sleep Architecture.
Table 2: General Effects of Alcohol Use and Cessation on Sleep Architecture.
Drinking Behaviour
REM
Sleep
Slow Wave
Sleep
Sleep
Continuity
Sleep
Latency
Total Sleep
Time
High dose
↓↓
↑↑
↓
↓
↓
Low dose
↓↑
↓↑
↓↑
↑
↑
Chronic Use
↓
↑
↓
↑
↓
Cessation After Chronic
Use
↑↑
↓
↓
↑↑
↓
Acute Use
Taken from Stein and Friedmann, 2005
↓ / ↑ - decrease / increase
↓↓ / ↑↑ - marked decrease / increase ↓↑ - decrease OR increase
Danel and Touitou (2004) reviewed research on alcohol and circadian rhythms and concluded
that alcohol acts on the circadian timing system’s biological clock, causing it to become
“desynchronized.” This conclusion was based on studies of daytime and night time melatonin
levels in current or abstinent alcoholics (Danel and Touitou, 2004). Findings from such
studies generally show suppressed melatonin levels compared to age-matched non-alcoholic
controls (Kuhlwein et al., 2003).
Using alcohol as a sleep aid could risk development of alcohol dependence and usage may
increase due to insomnia symptoms, which the subject may not link to the alcohol consumed.
A ‘pre- and post-’ survey was conducted by Weissman et al. (1997) assessing alcohol use in
three groups:
45

Sleep disorder with no psychiatric disturbance (uncomplicated insomnia);

Sleep disorder with a psychiatric disturbance (complicated insomnia); and

No sleep disorder (no insomnia).
The two surveys were conducted one year apart found the uncomplicated insomnia group had
a higher risk for developing alcohol dependence and abuse than individuals who did not have
insomnia or the complicated insomnia groups (Weissman et al., 1997). Janson et al (2001)
conducted a longitudinal population study using mailed survey responses in 1984 (n=3201)
and 1994 (n=2975) and found the prevalence of insomnia increased from 10.3% to 12.8%.
Individuals with insomnia in 1994 exhibited significantly more signs of alcohol dependence
than those who did not suffer from insomnia (Janson et al., 2001).
Moreover, in a study of the effects of alcohol consumption on sleep-induced breathing
abnormality, Issa and Sullivan (1982) found that alcohol exacerbated breathing disturbances
during sleep in a dose-dependent manner. Other clinical studies reported that alcohol
consumption before bedtime was associated with an increase in the number and duration of
hypopnea and apnoea (Scanlan et al., 2000; Tsutsumi et al., 2000). Roth et al (1985)
suggested that alcohol may negatively affect disordered breathing during sleep by one or
more of:

reduced hypoglossal nerve activity;

altered carotid-body receptor function;

depressed arousal response; and/or

sleep fragmentation.
A study found about 30% of people suffering from chronic insomnia indicated that they use
alcohol to initiate sleep and 67% of these patients reported that alcohol was effective (AncoliIsrael and Roth, 1999). However, in PSG studies conducted by Brower et al (2001), alcohol
adversely altered measures of sleep continuity and severe alcohol dependence and depression
occurred in insomniacs. Johnson et al (1998) reported that males and people which have never
been married or those separated or divorced/widowed were 1.5 times more likely to use
alcohol to help induce sleep than females or married people.
Therefore, the consumption of alcohol, and its discontinuation have been correlated with
disturbances of the sleep cycle. Consequently, alcohol consumption is discouraged in patients
46
with a sleep disorder, and pharmacists should counsel patients against the use of alcohol as a
sleep aid.
4-Pharmacologic treatment of primary insomnia
The majority of studies conducted focus on the treatment of primary insomnia with
benzodiazepine receptor agonists (BzRAs). Consequently, the literature contains significantly
more evidence for the safety and effectiveness of particular drugs for the treatment of primary
insomnia than for comorbid insomnia. Several classes of drugs are currently approved for the
treatment of insomnia (Schutte-Rodin et al., 2008). These drugs include Therapeutic Goods
Administration (TGA) approved drugs (nine BzRAs, and the histamine-1 antagonist; Table
3). The melatonin-receptor agonist ramelteon is not available in Australia. This section aims
to illustrate the mechanism of action, effectiveness and safety of these classes of drugs, with a
particular focus on BzRAs.
Table 3: Medications with TGA indication for insomnia
Tmax
(mg)
Elimination
half-life
(hours)
Flunitrazepam
0.5-2
20-30
1-2
Nitrazepam
2.5-10
27 (16-48)
2 (05-5)
Temazepam
5-20
10 (5-15)
05-1
Triazolam
0.125, 0.25
1.5-5.5
2
Oxazepam
7.5-30
4-15
2-3
Clobazam
10-30
17-49
1-4
Lorazepam
1-2
12-16
2
Zolpidem
5-12.5
2.4 (+/- 0.2)
0.5-3
Zopiclone
3.75, 7.5
5.26 +/- 0.76
1.75
Diphenhydramine
50
2.4 - 9.3
1-4
Doxylamine
25-50
10.1
2-4
Dose
Generic Name
Source: (MIMS, 2012)
47
(hours)
Benzodiazepine receptor agonists Hypnotics
Benzodiazepine receptor agonists (BzRA) hypnotics are commonly used in the treatment of
insomnia and are usually prescribed as first-line therapy (Wilson and Nutt, 2011). All
members of this class have been demonstrated to have some degree of effectiveness for
insomnia (Schutte-Rodin et al., 2008). The major differences between these drugs are their
pharmacokinetic profiles (Roehrs and Roth, 2003). The margin of safety or therapeutic index
(the effective dose relative to lethal dose) is broad for BzRA hypnotics and toxicity is rare
(O'Malley, 2007). Furthermore, abuse or dependence on BzRAs in the therapeutic context is
uncommon (Neubauer, 2003); however, Kan et al (2004) identified a series of factors which
increase the risk of developing dependence on benzodiazepines: administration of higher
doses; taking the drug for an extended period of time;younger age; and a history of drug or
alcohol abuse (Kan et al., 2004). Consequently, the prescriber and pharmacist should make
opportunities to counsel patients with these characteristics about dependence in community
and hospital practice.
The mechanism of action employed by BzRAs is common among hypnotics as they act as
allosteric modulators of gamma-aminobutyric acid (GABA) activity (Lankford et al., 2008).
The drug binds to benzodiazepine sites on the GABA-A receptor complex which activates
chloride ion channels, and causes the inhibitory effects of GABA activity (Nutt, 2006). Some
BzRAs such as clobazam, flunitrtrazepam, lorazepam, nitrazepam, oxazepam, temazepam and
triazolam have a benzodiazepine chemical structure, while other BzRAs lack this structure,
including zopiclone, zaleplon and zolpidem (Terzano et al., 2003). Those which exhibit the
chemical structure of benzodiazepines seem to be non-selective, having almost equal affinity
for GABA-A receptor complexes containing any of the four alpha subunits (alpha-1, alpha-2,
alpha-3 and alpha-5) (Stahl, 2008). In contrast, BzRAs which do not exhibit the characteristic
benzodiazepine structure usually exhibit more selectivity (Ebert and Wafford, 2006). For
example, zolpidem and zaleplon are highly selective for the GABA-A receptor complex
containing the alpha-1 subunit which may be associated with sedation effects (Nutt and Stahl,
2010). Eszopiclone appears more selective than other non-benzodiazepines, exhibiting
comparable affinity for alpha-1, alpha-2, alpha-3 and alpha-5 subunits (Nutt & Stahl, 2010).
However, Doble et al (1995) provide evidence in support of the theory that eszopiclone binds
in a different manner than benzodiazepines. Although the functional significance of the range
of binding affinities among BzRAs and their effect on sleep remains unclear, it is thought that
the non-selective binding of benzodiazepines results in increased side effects (Stahl, 2008).
48
There are several differences among BzRAs which are clinically relevant. These are mainly
related to the pharmacokinetic properties of these drugs, specifically, the duration of drug
activity. The most important factors used in determining the duration of action of a drug are
elimination half-life, drug dose and formulation (for example, extended release, sublingual
absorption) (Ebert et al., 2006; Neubauer, 2009; Zammit, 2009a).Variation in the ability to
metabolise and eliminate BzRAs in individuals leads to differences in the effectiveness and
safety of these drugs among different patients. It should be noted that it is common for
benzodiazepines without an indication for insomnia (not approved by FDA), such as
lorazepam, clonazepam and alprazolam, to be used as hypnotics (NIH, 2005). Also, these
drugs are not approved by the TGA in Australia for insomnia (AMH, 2012). The
pharmacologic properties of these drugs are comparable to that of benzodiazepine hypnotics
(AMH, 2012); therefore, although the efficacy of these drugs in insomnia has not been as
thoroughly investigated, their effects on sleep are similar. However, they exhibit longer halflives from 11-40 hours (Stahl, 2008).
Efficacy and effectiveness in primary insomnia
The majority of clinical trials on insomnia report hypnotic efficacy as measured by patient
reports or polysomnography (PSG), or both (NIH, 2005). A meta-analysis of clinical trials
with benzodiazepines and zolpidem conducted by Nowell et al (1997) demonstrated that,
collectively, these drugs result in significant improvements in the quality and quantity of
sleep in patients with chronic insomnia. However, it is noteworthy that the median duration
of the studies evaluated in this meta-analysis was merely one week (Nowellet al., 1997).
Nonetheless, other meta-analyses largely support the findings by Nowell et al (1997)
concerning the short-term efficacy of BzRAs (Dündar et al., 2004; Holbrook et al., 2000;
Smith et al., 2002). However, there may be significant limitations because meta-analyses
often combine data from several drugs which may differ greatly in their pharmacokinetic
properties or multiple doses of the same drug, affecting the outcome variables studied in the
meta-analysis. Therefore, meta-analyses can only allow broad conclusions regarding a
specifics group of drugs. More specific conclusions can be found in the individual studies
which should be considered when determining which drug has the highest chance of success
for treatment of a particular patient. A significant limitation of Holbrook et al (2000) is that
they used benzodiazepines as a single medicine. This assumption cannot be made as
benzodiazepines are in fact a class of several drugs with different pharmacokinetics properties
and side effects. In addition, Holbrook et al (2000) indicate that a potential limitation to their
49
study is that they only assessed studies spanning over a short period (14 days or less) and
therefore, no comments concerning the efficacy and safety of long-term trials can be made.
Dundar et al (2004) reported that limitations of the data analysed hampered their ability to
draw conclusions from their review. They found only small differences between the drugs
analysed in their study, but these differences were difficult to quantify (Dundar et al, 2004).
Smith et al (2002) indicate that absence of random assignment is a significant limitation of
this meta-analysis. Similarities and differences among BzRAs are discussed in the following
section.
BzRA hypnotics result in insignificant decrease sleep latency and a significant increase in
total sleep time, when compared with placebo (Holbrook et al., 2000; Holbrook et al., 2001).
An exception is zaleplon, which did not increase total sleep time, in most trials (Walsh et al.,
2000). Zalelplon has a short half-life (approximately one hour) compared with other
hypnotics, and is therefore less effective for treating sleep maintenance (Ebbens and Verster,
2010) . Benzodiazepines act to reduce sleep latency, increase total sleep time and reduce the
amount of time spent in stage 2 sleep, although they have little effect on the sleep
maintenance which isthe most common problem in the elderly (McCall, 2005).
Tolerance is the reduced effectiveness of a drug that occurs with continued administration of a
constant dose, or alternatively, increasing the dose in order to maintain a particular level of
effect (Bélanger et al., 2009). Tolerance to the hypnotic effects of BzRAs has not been
reported in the majority of short-term studies for therapeutic doses for a period of 4 weeks
(Terzano et al., 2003). Oswald et al (1982) found that two benzodiazepines, lormetazepam
and nitrazepam, preserved their hypnotic effect over 24 weeks of continuous therapy as
measured by patient self-reports. Other PSG studies demonstrated that zolpidem 10 mg and
zaleplon 10 mg retained efficacy for 5 weeks of continuous nightly use (Scharf et al., 1994;
Walsh et al., 2000). A study of primary insomniacs reported continued hypnotic efficacy of
eszopiclone for 6 months measured by patient self-reports of reduced sleep latency, wakening
after sleep onset (WASO), total sleep time, number of awakenings, and sleep quality when
given eszopiclone 3 mg or placebo (Krystal et al., 2003). These 6-month findings have been
replicated in other studies (Walsh et al., 2007) and assessment of open-label extension data
has indicated continued efficacy of eszopiclone for 12 months (Roth et al., 2005). Additional
evidence supporting the sustained efficacy following nightly BzRA use includes a 3-month
study with indiplon, a non-marketed hypnotic (Scharf et al., 2007). Walsh et al (2000) and
Perlis et al (2004) assessed a “when necessary” treatment schedule for zolpidem 10 mg for up
50
to 12 weeks. Sleep latency, total sleep time, number of awakenings, and sleep quality were all
improved on nights when zolpidem was taken when compared with a placebo (Walsh et al.,
2000; Perlis et al., 2004). Investigator global ratings, which considered both medication and
non-medication nights, indicated a reduced severity of insomnia with zolpidem (Walsh et al.,
2000). More recently, Krystal et al (2008) found an extended-release formulation of
zolpidem, given to individuals for 3 to 7 nights per week for 6 months, generated similar
results.
In addition to clinical trials, some population studies have reported on the use and efficacy of
hypnotics. Ohayon et al (1999) reported that 67% of chronic insomniacs with long-term use
of hypnotic medications exhibited a significant improvement in sleep quality while 14.4% of
patients reported no significant improvement. Balter and Uhlenhuth (1991) interviewed
individuals suffering from insomnia or those who had taken a sleep aid. The greatest
treatment satisfaction was reported by individuals who took hypnotics with 84% of triazolam
users, 82% of flurazepam users, and 74% of temazepam users reporting they would take the
medication again to help them sleep (Balter and Uhlenhuth, 1991).
Several long-term, open-label studies examining both middle aged and older adults also
contribute to the evidence base about BzRAs effectiveness (Ancoli-Israel et al., 2005;
Kummer et al., 1993; Maarek et al., 1993; Roth et al., 2005; Schlich et al., 1991). Patients
and physicians expressed a continued benefit regarding BzRAs over a 6-12 month period,
without detrimental side effects related to long-term use (Walsh, 2005).
Improvement in the daytime symptoms of insomnia is the primary goal of insomnia treatment
(Schutte-Rodin et al., 2008). The few studies that have examined patient-reported daytime
measures in patients suffering from primary insomnia usually exhibit improvement (Krystal et
al., 2003; Walsh et al., 2007). Two 6-month investigations of primary insomniacs each found
a significant improvement in patient reported daytime alertness and ability to function and a
stronger sense of wellbeing in the treatment (eszopiclone) group compared to the placebo
group (Krystal et al., 2003; Walsh et al., 2007).
Safety in primary insomnia
Detrimental side effects to BzRAs in clinical trials are rare and usually mild (Curry et al.,
2006; Hall-Porter et al., 2010). Side effects appear more severe with use of benzodiazepines
than with the newer BzRAs (NIH, 2005). The median rate of these side effects in hospital
51
inpatients treated with any hypnotic was found to be about 1 in every 10,000 doses
(Mendelson et al., 1997). Many of the BzRA adverse effects occur as a result of the BzRA
sedation mechanism (Ebert and Wafford, 2006a; Roth and Roehrs, 1992). Persistence of the
hypnotic effect of the drug after the individual is awake, causes undesirable responses
including drowsiness, sleepiness and impairment of psychomotor performance (Vermeeren et
al., 2004). The probability of residual sedation occurring is determined by the duration of
drug action (Buysse, 2008) and influenced by pharmacokinetic factors such as elimination
half-life, administered dose and tissue distribution after a single dose (e.g., lipophilicity)
(Zammit, 2009a). The duration of effect is impacted by the half-life when the recommended
doses are administered (Zammit, 2009b). The drugs with longer half-lives can accumulate
with chronic use, causing accumulation and residual sedation therefore, they are not
recommended for older patients due to the increased risk of side effects (Dailly and Bourin,
2008). Theoretically, benzodiazepines with a long half-life may accumulate and produce
augmenting sedation; at the same time, tolerance to benzodiazepines may occur, which
reduces these effects. However, data on the issue of tolerance were found to be limited and
conflicting.
Anterograde amnesia, or memory for information presented following administration of the
drug, has the potential to occur with any drug which exhibits sedative activity, including the
BzRAs, and barbiturates (Möhler et al., 2002). Benzodiazepines prevent the processing of
new information and potentially unpleasant experiences, causing anterograde amnesia (AJHP,
2002). The degree of severity of the amnesia depends on the plasma concentration of the
benzodiazepine (Roth et al., 1990; Verwey et al., 2005). The higher the dose (the higher the
plasma concentration), the greater the degree of severity of amnesia, leading to a higher
frequency of amnesiac events (Roehrs & Roth, 2003). A number case report studies have
demonstrate that anterograde amnesia is associated with the use of zolpidem and this
behaviour ceased after discontinuation of the zolpidem (Tsai et al., 2007; Hoque & Chesson,
2009). Furthermore, benzodiazepines are vital supplemental drugs in anaesthetics. These
drugs can relieve anxiety and prevent the patient from recalling the events of a surgical
procedure (Saari et al., 2011). Benzodiazepines have been demonstrated to be far more
efficient than other sedative-hypnotic drugs used in anaesthetics, giving better degrees of
sedation, reliable amnesia, respiratory and hemodynamic function (Saari et al., 2011).
Benzodiazepines (midazolam) also appear to be capable of reducing nausea and vomiting
post-surgery (Bauer et al., 2004).A major beneficial use of benzodiazepines is their amnesic
52
effect in the treatment of nausea and emesis (vomiting), particularly in patients (more notably
children) who experience anxiety and anticipatory nausea and emesis linked to chemotherapy
(Greenberg et al., 1987; Mori et al., 1993; Potanovich et al., 1993). Kris et al (1985) found
the adjunct efficacy of lorazepam used in conjuction with metoclopromide or dexamethasone
for the treatment of chemotherapy-induced nausea is equivalent to that of diphenhydramine
used with these same drugs, however, the treatment of anticipatory anxiety symptoms using
lorazepam is superior. Bishop et al (1984) conducted a randomised, double-blind, crossover
study whereby lorazepam was demonstrated to exhibit an enhanced efficacy over placebo
when used in conjunction with prochlorperazine for chemotherapy-induced nausea. However,
there is no published evidence to advocate the use of benzodiazepines as single or primary
anti-emetics (National Cancer Institute, 2011). In addition, there are no definitive guidelines
of benzodiazepine doses given in the literature for the treatment of emesis.
The most commonly documented effect which occurs with the discontinuation of BzRAs is
rebound insomnia (Pinto et al., 2010). Rebound insomnia is a decline in the quality of sleep as
compared to the insomnia experienced by the patient before being treated with BzRAs.
Rebound insomnia only lasts for approximately 1-2 nights, after discontinuation of the drug
(Zammit, 2009a). Rebound insomnia is different to a withdrawal syndrome, that is, the
development of a series of symptoms which were absent before treatment (Zammit, 2009a).
Withdrawal symptoms usually last a few days to a few weeks instead of the 1- 2 nights for
rebound insomnia. Roehrs et al (1990) reported that rebound insomnia becomes apparent
when a hypnotic drug is suddenly stopped after 1 or 2 nights of drug use; however, there is no
evidence that it increases in severity with the number of repeated nights of use (Merlotti et al.,
1991; Roehrs et al., 1990). The frequency of rebound insomnia increases with high doses of
short- and intermediate-acting benzodiazepines, but it can be reduced by steadily lowering the
dose over a period of a few nights and by decreasing the administration frequency (Budur et
al., 2007). Rebound insomnia does not seem to happen with long-acting hypnotics due to the
steady decline in plasma concentration, an intrinsic part of the pharmacology of these drugs
(Woods et al., 1992). New non-benzodiazepines have been developed which do not appear to
produce rebound insomnia, even though the duration of their action is short to intermediate.
Silvestri et al (1996) showed that rebound insomnia occurred after the abrupt discontinuation
of triazolam but not zolpidem, two short-acting non-benzodiazepines, demonstrating that
when administered at an appropriate dose, short-acting non-benzodiazepines may not cause
rebound insomnia. Walsh et al (2000) did not find any evidence suggesting that rebound
53
insomnia occurs when zolpidem 10 mg was self-administered as required over an 8-week
period, as subjects’ total sleep time did not change on nights when no medication was taken
that immediately followed a night when medication was taken. In an investigation comparing
zolpidem-CR to a placebo, rebound insomnia was not detected on the 3 nights after
discontinuation of the drug (Erman et al., 2007a; Erman et al., 2007b). Furthermore, other
studies have demonstrated that sudden discontinuation of zaleplon does not cause rebound
insomnia in adult (Fry et al., 2000; Walsh et al., 2000) or elderly (Ancoli-Israel et al., 1999)
patients following time periods of up to 5 weeks of nightly use. One study showed that 2 mg
of eszopiclone resulted in rebound insomnia only on the first night after discontinuation of the
treatment (Zammit et al., 2004), however another study found that no rebound insomnia
(Krystal et al., 2006).
The major concern with using BzRA hypnotics is dependence (Ebert et al., 2006).
Epidemiologic data suggests that most insomnia patients do not continue treatment with
hypnotics for extended time periods, with approximately 70% using these drugs for up to 2
weeks (Mellinger et al., 1985; Roehrs et al., 2002). Of patients taking prescription hypnotics,
approximately 36% report regular use, that is, longer than one month, (Johnson et al., 1998)
however it is improbable that this persistent use as reported in this study reflects physical or
psychological drug dependence. Studies examining the self-administration of hypnotics by
patients with insomnia suggest that these patients do not increase the dose of the drug (Roehrs
et al., 1996), daytime use is uncommon (Roehrs et al., 2002a) and the frequency of selfadministration changes depending on the severity of the insomnia (Roehrs et al., 2002b).
Other investigations demonstrate that BzRAs have a low-to-moderate behavioural
dependence liability, indicating that hypnotic self-administration in patients suffering from
insomnia is best explained as therapy-seeking behaviour, instead of drug dependence (Roehrs
et al., 2002; Roehrs et al., 1996; Roehrs et al., 1992) .
Several studies have examined the risk of incurring a fall in elderly patients being treated with
a BzRA (Joester et al., 2010; Rhalimi et al., 2009; Wang et al., 2001). However, it is difficult
to attribute any increased risk of falling to this class of drugs alone, as these patients exhibit
other physical or psychiatric conditions which may affect their risk of falling. Moreover, the
clinical studies that have been conducted have a small sample size. However, a few studies
suggest that insomnia and sleep disturbance, but not the use of hypnotic such as BzRAs, lead
to an increased risk of incurring a fall in elderly individuals (Brassington et al., 2000; Latimer
et al., 2007; Avidan et al., 2005), although these findings cannot be taken as definitive
54
evidence. This is due to the fact that these studies did not use sufficient sample size, did not
adjust for the large number of potential covariates, and did not employ a longitudinal design.
Individual side effects have been reported following treatment with BzRA hypnotics,
including somnambulism and sleep-related eating disorders (AMH, 2012). Zolpidem is the
only documented BzRA to cause both of these conditions (Hoque and Chesson, 2009; Sharma
and Dewan, 2005; Sansone and Sansone, 2008). Somnambulism (Liskow and Pikalov, 2004;
Yang et al., 2005) and sleep-related eating disorder (Morgenthaler and Silber, 2002; Vetrugno
et al., 2006) occurs when zolpidem was administered at two to three times the clinical dose.
The first reported a case of sleepwalking following administration of zolpidem was recorded
by Mendelson (1994). Since then, several cases of somnambulism after zolpidem intake for
treatment of insomnia have been reported (Harazin & Berigan, 1999; Morgenthaler and
Silber, 2002; Sansone and Sansone, 2008; Sattar et al., 2003; Sharma and Dewan, 2005; Yang
et al., 2005). These behaviours were not apparent in patients before commencement of
treatment with zolpidem. Furthermore, those with a history of childhood sleepwalking or
alcohol abuse or have incurred previous brain injury, seem to be more susceptible to
sleepwalking following administration of zolpidem (Mendelson, 1994; Yang et al., 2005).
Melatonin Receptor Agonist
The first melatonin receptor agonist officially approved by the FDA to treat insomnia was
ramelteon (Pandi-Perumal et al., 2011). However, it is not available in Australia. Ramelteon
is used to treat insomnia characterized by sleep-onset difficulty and is rapidly absorbed by and
eliminated from the body (Hibberd and Stevenson, 2004; Karim et al., 2006). Ramelteon is
1,000 times more selective for the melatonin-1 (MT1) receptor than for the MT2receptor,
suggesting that ramelteon may be more effective for insomnia characterized by difficulty
falling asleep (Hirai et al., 2003) as (MT1) receptors impede the wake-promoting activity of
the SCN, thereby inducing sleep (Mitchell and Weinshenker, 2010). MT2 receptors appear to
be involved in sleep-wake cycling (Dubocovich et al., 2003; von Gall et al., 2002).
Data from polysomnographic and subjective reports show that ramelteon at doses between 4
and 32 mg decreases sleep latency in adult (Erman et al., 2006) and elderly (Roth et al.,
2006; Roth et al., 2007) primary insomniacs. Ramelteon efficacy studies show that
improvements in sleep latency are sustained following 5 weeks (8 and 16 mg) (Zammit et al.,
2007), 6 months (8 mg) (Mayer et al., 2009), and 1 year (8 and 16 mg) (DeMicco et al., 2006)
of treatment. There are only small improvements in total sleep time and sleep efficiency
55
which may be explained by the decrease in sleep latency, without disrupting other sleep
maintenance variables including wake after sleep onset (Roth et al., 2007). One study
suggests that ramelteon may exhibit chronobiotic properties when administered at doses from
1-4 mg, allowing a shift in the phase of the circadian rhythm, determined as melatonin offset
following morning awakening, when individuals experienced a 5-hour phase advance in their
sleep-wake cycles (Richardson et al., 2008). Despite the data suggesting that ramelteon may
be successful in the treatment of insomnia, there are no published studies which directly
compare the effectiveness and safety of ramelteon with other sleep-inducing drugs, nor has it
been assessed in clinical settings (Sateia et al., 2008).
The most frequent adverse effects which occur when taking ramelteon are headache,
somnolence, dizziness, fatigue, and nausea (Borja and Daniel, 2006). Several clinical trials
have tested different doses to determine whether residual sedation or cognitive impairment
occurs, finding no evidence of either (Erman et al., 2006; Griffiths et al., 2005; Roth et al.,
2005). Furthermore, no evidence has been found of the development of rebound insomnia or
withdrawal symptoms following discontinuation of ramelteon (Roth et al., 2006; Zammit et
al., 2005). Due to the low potential for abuse of the substance (Griffiths et al., 2005; Johnson
et al., 2006), ramelteon may be a suitable candidate for the treatment of insomnia in patients
who exhibit a history of chemical dependence. However, there is no evidence to support this
claim.
Antihistamines
Antihistamines are expansive class of pharmacologic agents including the first-generation,
central acting histamine H1 receptor antagonists. Antihistamines act as competitive
antagonists at histamine receptors, thus lessening congestion, sneezing, coughing, and allergy
symptoms. Histamine is one of the most important alerting central neurotransmitters which
promote wakefulness, and inactivation of histamine in the central nervous system has been
shown to cause sedation and disturbed wakefulness patterns (Mignot et al., 2002).
Antihistamines also have a sedative effect and thus are commonly used as non-prescription
sleep aids in Australia as they can be purchased in a community pharmacy without a
prescription. The evidence gathered from the literature seems to suggest that antihistamines
may be effective in the short-term treatment of insomnia, for a period of 1–2 nights, but is not
effective in the treatment of chronic insomnia (Richardson et al, 2002). First-generation H1
antihistamines, also known as sedating antihistamines, obtain their sedative ability as they are
56
capable of penetrating the blood–brain barrier (BBB) to cause their effects (Mahdy and
Webster, 2011). Thus, they are used as non-prescription sleeping aids. Conversely, secondgeneration H1 antihistamines lack sedative activity as they are unable to cross the BBB
(Mahdy and Webster, 2011).
Diphenhydramine
In 1982, the FDA approved diphenhydramine hydrochloride and diphenhydramine citrate as
active ingredients in non-prescription sleep aids (Randall et al., 2008). Also,
diphenhydramine hydrochloride is approved by the TGA as a temporary sleep aid
(Theraeputic Goods Adminstation, 2012). Diphenhydramine is also used for a range of other
medical problems such as alleviating allergies, and motion sickness (Simons and Simons,
2011). When used to treat sleep problems, diphenhydramine is administered in doses ranging
between 25–50 mg which should be taken 30–60 minutes before bedtime (Bender et al.,
2003; Kudo and Kurihar, 1990). While its primary intended use is for the relief of allergies,
diphenhydramine is frequently used as a sleep aid (Randall et al., 2008). Diphenhydramine
products often contain an analgesic such as paracetamol or ibuprofen (Morin and Benca,
2012), which can be used to provide pain relief and assist sleep induction if the insomnia is
due to pain (Morin and Benca, 2012).
Despite the common use of diphenhydramine, the number controlled studies published in the
literature providing evidence in support of its efficacy is limited, and they lack objective data
(Estivill et al., 2003; Nichols et al., 2007). Many studies demonstrate that diphenhydramine
exhibits sedative properties (Kudo and Kurihara, 1990; Meuleman et al., 1987; Rickels et al.,
1983).
Diphenhydramine is an ethanolamine which has anticholinergic activity (Skidgel & Erdos,
2006). Its half-life is 3-12 hours (Husain et al., 2010; Lippmann et al., 2001). As a result,
diphenhydramine is commonly associated with the development of mild-to-moderate side
effects the following day, most notably residual morning sedation, dry mouth, grogginess, and
malaise (Bender et al., 2003; Kudo and Kurihar, 1990). Even though diphenhydramine
produces mild-to-moderate side effects, it is the active ingredient in multiple Australian overthe-counter products marketed as sleep aids.
Rickels et al (1983) conducted a double blind, placebo-controlled, crossover study into the
use of diphenhydramine (50 mg) as a treatment for insomnia. A symptom shared by all
57
patients was a difficulty in sleep-initiation (Rickels et al, 1983). Result showed that
diphenhydramine was more effective than placebo at enhancing all sleep parameters,
including sleep latency, frequency of awakenings, wake time, sleep duration, and quality of
sleep, based on self-completed daily sleep-log responses (Rickels et al., 1983).
In a double-blind study conducted by Kudo and Kurihara (1990), 144 psychiatric patients
complaining of symptoms characteristic of insomnia were randomly allocated to receive
either a particular dose of diphenhydramine (12.5 mg, 25 mg, and 50 mg) or placebo for 2
weeks. Several self-reported sleep measures were improved such as sleep quality, duration of
sleep and severity of insomnia symptoms (Kudo and Kurihara, 1990). Enhanced sleep was
considerably better in patients who had not previously been treated for insomnia (Kudo and
Kurihara, 1990). This implies drug tolerance, cross-drug tolerance or treatment resistance.
Significant increases in daytime sleepiness measured by Multiple Sleep Latency Tests has
been demonstrated to occur with diphenhydramine (50 mg 3 times daily) versus a placebo
(6.7 ± 2.6 vs 10.3 ± 3.3; P< .02) (Roth et al., 1987). This is not surprising because the dose
used in this study exceeded the recommendations for sedative use which 50 mg at night.
(AMH, 2012).
Shapiro et al (1969) collated observational data from a program which monitored drug use in
order to assess the effectiveness of four hypnotics (chloral hydrate, diphenhydramine
hydrochloride, secobarbital, and pentobarbital). This study examined 4177 patients and found
that 2405 (58%) were given one or more of these drugs when admitted to hospital (Shapiro et
al, 1969). Diphenhydramine was administered to 512 patients, however of these, 213 (42%)
were concurrently given one or more of the other hypnotics (Shapiro et al, 1969). Patients
were administered different diphenhydramine dosages (Shapiro et al, 1969). The authors did
not specify how these doses were determined (Shapiro et al, 1969). 46 patients were given
100 mg, 440 patients were given 50 mg, 24 patients were given 25 mg while 2 patients
received a dose other than those mentioned (Shapiro et al, 1969). Physicians rated the
effectiveness of these drugs and found dose related effects (Shapiro et al, 1969). Specifically,
in 259 patients, efficacy rated ‘good’ (50.6%), ‘fair’ in 42 patients (8.2%), ‘poor’ in 54
patients (10.5%), and ‘undetermined’ in 157 patients (30.7%) (Shapiro et al, 1969). What was
not examined in this study was the possibility of an additive effect when a combination of
hypnotic agents was taken.
58
Derbez and Grauer (1967) found no difference in total hourly observational wake versus sleep
recordings in elderly patients with insomnia who were either administered a placebo or 25 mg
diphenhydramine hydrochloride. However, a drastic improvement was observed in patients
who were given MandraxTM (methaqualone base and diphenhydramine), chloral hydrate, and
methaqualone base (Derbez and Grauer, 1967). However, it must be noted that all participants
suffered from psychiatric disturbances (Derbez and Grauer, 1967). Therefore, the concurrent
use of hypnotics, neuroleptics, or antidepressants may have confounded the results obtained.
A randomised, double-blind, crossover study investigated the efficacy of temazepam 15 mg,
diphenhydramine 50 mg, and placebo for 5 nights and found that insomniacs experienced
shorter sleep latency when administered diphenhydramine than the placebo (Meuleman et al.,
1987). On the fifth night diphenhydramine was more effective at prolonging the duration
spent asleep than temazepam (Meuleman et al., 1987).
Richardson et al (2002) found tolerance to diphenhydramine’s hypnotic effects in both
objective and subjective sleep measures following 3-4 days of taking diphenhydramine. Thus
only short-term use of diphenhydramine is recommended due to the development of tolerance
(Mumford et al., 1996; Richardson et al., 2002).
In the series of trials conducted by Shapiro et al (1969), adverse effects to diphenhydramine
were reported in 9 out of 512 participants (1.8%) while treatment was discontinued in 8 of the
512 participants (1.6%). These side effects included vomiting and depression (Shapiro et al,
1969). Most of the participants received a dose of 50 mg diphenhydramine, and two were
given 100 mg (Shapiro et al, 1969).
In a study conducted by Kudo and Kurihara (1990), the authors demonstrated that the
occurrence of these side effects may be dose-dependent. In the group taking 12.5 mg
diphenhydramine, no adverse side effects were reported in 95.8% of participants, while this
percentage decreased in the group given 25 mg diphenhydramine (88%) and the group given
50 mg diphenhydramine (82.6%) (Kudo and Kurihara, 1990). Diphenhydramine may also
cause drowsiness, dizziness, grogginess, dry mouth, tiredness and weakness (Rickels et al.,
1983).
Agostini et al (2001) conducted a study involving elderly hospitalised patients suffering from
disturbed sleep, prophylaxis for blood transfusions, or allergic reactions in which 27% of
patients received diphenhydramine. They found that diphenhydramine-treated patients
59
exhibited a 70% increase in the risk of developing impaired cognition, which may be dosedependent (Agostini et al., 2001).
In children, the only reported adverse side effect from use of diphenhydramine hydrochloride
was mild drowsiness (Kudo et al., 1990). The potential for abuse for dimenhydrinate, a
combination of diphenhydramine and 8-chlorotheophylline, is high due to the hallucinogenic
and excitatory properties it causes on the CNS when taken at a higher dosage than prescribed
(Halpert, et al., 2002). Other side effects which act on the CNS are sedation, dizziness,
stimulation, euphoria, nervousness, and extrapyramidal reactions (Cirillo and Tempero,
1976). Other studies demonstrate that gastrointestinal complaints, voiding difficulties,
impotence, and headaches may also occur (Cirillo and Tempero, 1976). Antihistamines have
been shown to increase intraocular pressure and therefore antihistamines should not be
prescribed to patients with narrow angle glaucoma (Tripathi et al., 2003). These reported side
effects are not surprising as antihistamines are well documented to produce anticholinergic
effects (Yanai, 2012). Overdosages of antihistamines causehallucinations, tachcardia, and
convulsions (Worthley, 2002). In more severe cases, coma may occur followed by death
usually as a result of hypotension or cardiac arrest (Cirillo and Tempero, 1976).
Doxylamine
Doxylamine succinate is an FDA and TGA approved active ingredient in over-the-counter
sleep aids (AMH, 2012; Neubauer, 2007). Doxylamine succinate mediates its activity through
histamine antagonism at H1 receptors (AMH, 2012). Doxylamine has a slow onset of action
as it requires a relatively long time period to reach maximum plasma concentration (Randall
et al., 2008). Following oral administration, sleep is achieved after 45-60 minutes (Randall et
al., 2008). To reach the peak plasma concentration, doxylamine requires 2-3 hours after
administration (Krystal et al., 2006). Rickel et al (1984) found that sleep latency was
significantly decreased following administration of doxylamine at a dose of 25 mg for 1
week. Also, they found that ratings given by the patient were more in favour of doxylamine in
terms of sleep latency, nocturnal awakenings, sleep duration, sleep quality and morning
restfulness (Rickel et al., 1984).
Mizoguchi et al (2007) conducted a randomized, double-blind, placebo-controlled, multicenter, parallel design study on 432 subjects (224 in test group, 208 in placebo group). A
single night dose of syrup containing 7.5 mg doxylamine, 600 mg paracetamol, 15 mg
dextromethorphan and 8 mg ephedrine sulfate was administered (Mizoguchi et al., 2007).
60
Subjects were asked to complete night-time symptom relief and sleep satisfaction assessments
(Mizoguchi et al., 2007). The results confirmed that subjects who took test syrup had better
control of cold symptoms and 25-68 % confirmed better quality of sleep, indicating that the
sedative effects of doxylamine could give better quality of sleep for patients with common
cold (Mizoguchi et al., 2007).
This combination has different active ingredients as ephedrine was used to relief nasal
congestion, dextromethorphan as an antitussive, paracetamol as an analgesic and doxylamine
as a sedating agent.
The elimination half-life of doxylamine is 10 hours (Krystal et al., 2006). Therefore, upon
waking, doxylamine is still present in plasma and can cause residual daytime sedation, a wellknown side effect (Neubauer, 2007). Other potentially serious side effects following
doxylamine overdose include rhabdomyolysis and secondary acute renal failure, exhibiting a
frequency of 19% (Young-Il et al., 2007). Therefore, patients at greater risk of these side
effects (eg. elderly) taking doxylamine should be carefully monitored as early identification
and treatment of side effects is important (Leybishkis et al., 2001). Due to possible
anticholinergic properties, H1 antihistamines are not recommended for use by the elderly
which may cause or worsen mental confusion, urinary retention and constipation (Fick et al.,
2003). The mechanism of action of doxylamine is the same as diphenhydramine and there is
also the potential for tolerance to the sedative effects of doxylamine to develop (Randall et al,
2008).
Doxepin
Low-dose doxepin (3 mg and 6 mg) has recently (2010) received FDA approval for use in the
treatment of insomnia characterized by difficulty in sleep maintenance. Doxepin has long
been used as an antidepressant (doses from 10-150 mg) and an off-label sleep aid (Neubauer,
2008). When administered at extremely low doses, the primary pharmacologic activity of
doxepin appears to be antagonism of H-1 receptors (Krystal et al., 2010; Weber et al., 2010).
The issues regarding the safety of doxepin taken in high doses do not appear to apply when
administered at these very low doses (Krystal et al., 2010). This is primarily due to the fact
that the anticholinergic activity of this drug at low doses is negligible (Lankford et al., 2012;
Roth et al., 2007).
61
There are few published studies regarding the use of low dose doxepin in the treatment of
insomnia (Owen, 2009; Roth et al., 2007; Scharf et al., 2008). These studies are acute
administration PSG studies, and show that, in adult and elderly patients suffering from
primary insomnia, that 3 mg and 6 mg doses are capable of significantly reducing wakenings
after sleep onset (WASO) during the sleep period and increase the total sleep time (TST)
(Owen, 2009; Roth et al., 2007; Scharf et al., 2008). The 6 mg dose of doxepin is effective at
decreasing sleep latency (Roth et al., 2007; Scharf et al., 2008). Even though there was a
decrease in WASO, residual sedation did not occur (Roth et al., 2007; Scharf et al., 2008). It
is thought that this is related to the circadian pattern of histamine release within the body,
with elevated histamine levels at approximately the time of awakening, thus prevailing over
the antagonistic effect of doxepin (Roth et al., 2007). The findings deduced from PSG studies
are supported by subjective data (Roth et al., 2007). The type and prevalence of detrimental
side effects were more or less similar to those reported in placebo groups within these trials
(Owen, 2009; Roth et al., 2007; Scharf et al., 2008). Studies involving administration of
nightly doxepin for three months demonstrate a similar reduction in WASO and increase in
TST, without observed tolerance or safety concerns (Owen, 2009).
The longest clinical study conducted to assess the safety of doxepin lasted 3 months. More
than 2% of patients taking doxepin complained of mild to moderate side effects including
somnolence/sedation, nausea, and upper respiratory tract infection (Weber et al., 2010).
Tolerance of doxepin appears to be better at hypnotic doses of between 3 mg and 6 mg, than
at antidepressant doses ranging from 50 to 300 mg per day (Goforth, 2009; Roth et al., 2007;
Scharf et al., 2008). However, there are no published studies in the literature that directly
compare to two dose ranges. Furthermore, psychomotor function, measured using DigitSymbol Substitution Test (DSST) and Symbol- Copying Task (SCT), and sedation the
following day, measured using Visual Analogue Scale (VAS), was the same for both patients
receiving hypnotic doses of doxepin and those receiving placebo (Krystal et al., 2010; Roth,
2007). One study recorded significant differences SCT and VAS when 6 mg of doxepin was
taken (Roth et al., 2010).
Withdrawal and rebound insomnia were investigated in a randomized, double-blind, parallelgroup, placebo-controlled trial lasting 35 days conducted on adults suffering from chronic
insomnia (Krystal et al., 2011). After discontinuation of 3 mg and 6 mg of doxepin, no signs
of withdrawal syndrome have been recorded (Krystal et al., 2011).
62
Aims
The aims of this study were to determine:
The characteristics of patients requesting antihistamines as sleep aids; and
The actual usage and perceived efficacy of antihistamine therapy for insomnia in a subsample of the study population.
63
64
Chapter 2: Methodology
OVERVIEW
This study was conducted to determine the characteristics of consumers who received an
antihistamine for the treatment of a sleep condition in a community pharmacy,and a more
detailed exploration in these consenting to a follow-up telephone interview. The study period
was February to April 2012.
PROJECT DESIGN
Project Site
Community pharmacies located throughout the Australian Capital Territory were approached
to participate in this study. Written agreement to participate was obtained from each
participating pharmacy.
Participants
The study was based on a convenience sample of community pharmacy clients seeking an
antihistamine product as a sleep aid. It was conducted in 7 community pharmacies around the
Australian Capital Territory (ACT) metropolitan area. Patientsattending a participating
pharmacy requesting or recommended an antihistamine for insomnia and aged 18 years or
older were eligible for recruitment. Eligible patients were asked by the pharmacist or
pharmacy assistant (using a standardised script) if they would participate in the study and
complete an anonymous written survey regarding their treatment of insomnia. Verbal
informed consent was obtained from all participants before the survey form was provided.
The bottom of the survey form contained an optional part where patients could choose to
provide their first name and a contact telephone number.
This option was to allow a
researcher (FA) to contact these patients after two weeks to conduct a telephone follow-up
survey regarding the effectiveness of the antihistamine and other factors for their insomnia.
The survey form was placed in a locked box in the pharmacy upon completion. A researcher
(FA) visited each pharmacy to empty the locked box once per week during the study period.
Individuals who provided their contact details were contacted approximately 2 weeks after
completing the initial survey.
Informed verbal consent was obtained from each participant
before commencing the telephone interview. A second survey instrument was used to collect
data on other factors affecting insomnia and subjective data related to the effectiveness of the
antihistamine for the patient’s insomnia.
65
Pharmacy staff
The researcher visited each pharmacy to provide training on the study protocols. Inclusion
criteria were described and a sample script (Appendix A) provided to assist in recruiting
patients into the study.
Instruments
This study consisted of two phases: 1) recruitment and in-pharmacy survey (Appendix B);
and 2) follow-up telephone interview (Appendix C). The questions in both the survey and
telephone interview were adapted from the COPSAT sleep survey tool developed at the
University of Queensland.
COPSAT is a sleep survey tool developed at the University of Queensland which is based on
the Insomnia Severity Index (ISI) and Epworth Sleepiness Scale (ESS) which are validated
instruments to quantify perceived insomnia severity. The COPSAT survey not included in the
appendix because it is currently an unpublished tool, uncovered through peer networks.
Phase 1: Recruitment and in-pharmacy survey
A single page in-pharmacy survey was used as the initial data-gathering instrument for this
study. This survey assessed a number of sociodemographic characteristics of respondents that
have been examined in previous studies of risk factors for insomnia. These include age,
gender and highest education level. Other questions explored previously used insomnia
treatments and participant characterisation of their insomnia. Tick boxes were used to guide
patient categorisation and limit investigator interpretation of open patient comments.
Phase 2: Follow-up telephone survey
The follow-up telephone survey consisted of 17 open-ended questions to assess the
effectiveness of the antihistamine used in the treatment of insomnia, and other factors related
to causes of insomnia, such as caffeine and/or alcohol consumption and smoking status. The
researcher (FA) collated participants’ open responses into the categories used in the COPSAT
for ease of data analysis.
66
Data Processing and Analysis
All the completed in-pharmacy survey responses were tabulated and depicted graphically.
Statistical analyses were performed using Microsoft ExcelTM computer software and SPSS
19software. The Pearson chi-square test was then used for cross-tabulated variables. For all
statistical tests, the a priori value for statistical significance was set at p < 0.05.
Ethics
Ethical approval for this study was obtained from the Committee for Ethics in Human
Research, Faculty of Health, University of Canberra (Approval number 11-132).
67
68
Chapter 3: Results
Seventy-three people completed in the Pharmacy questionnaire of whom 48 agreed to
participate in a more detailed telephone follow-up survey 2 weeks after the pharmacy
questionnaire to assess efficacy of the antihistamine provided.
Part 1: Pharmacy Questionnaire
Seventy-three participants (47 (63.5%) female) over 18 years of age completed a brief
questionnaire administered by pharmacy staff. The initial survey contained questions about
the individual’s demographic characteristics (age, gender, and education level), sleep patterns
and treatments already tried. All subjects identified symptoms of insomnia.
Age distribution
Age was categorized into 10-year bands from 18 -66 years or more, except the 18-25 and 66+
groups. The age distribution is shown in Figure 1. If the 18-25 age group is removed, the
remaining distribution appears to approximate a normal distribution. However, this sample is
not normally distributed because it is a self-selected group who sought treatment for selfidentified symptoms of insomnia in a community pharmacy.
Figure 1. Age group of participants
The study sample consisted of 47 women (63.5%) and 26 men (36.5%). All subjects were
seeking treatment for insomnia in a community pharmacy.
69
The age-gender breakdown (Tables 4&5) show an inversion in the male/female split between
those participants aged 18-35 years (60.7% male) and those over 35 years (80.0% female)
(p= 0.00021).
Table 4. Age and Gender Cross tabulation
Age
18-25
26-35
36-45
46-55
56-65
66+
Total
Gender n (%)
Male
Female
10
9
(22.6%)
(47.4%)
7
2
(77.8%)
(22.2%)
3
10
(23.1%)
(76.9%)
4
10
(28.6%)
(71.4%)
2
10
(16.7%)
(83.3%)
0
6
(0.0%)
(100.0%)
26
47
(35.6%)
(64.4%)
Table 5. Condensed Age and Gender Cross tabulation
Gender n (%)
Male
Female
Age
17
11
18-35
(60.7%)
(39.3%)
9
36
36+
(20.0%)
(80.0%)
26
47
Total
(35.6%)
(64.4%)
Total
19
9
13
14
12
6
73
Total
28
45
73
Education Level
Participants were asked to indicate the highest education level they had achieved: diploma or
less, bachelor degree, and postgraduate study. The largest group of participants had achieved
a diploma or less (Figure 2), suggesting those with a higher education level either may have
less trouble with insomnia, are less likely to seek assistance in a community pharmacy, or are
less likely to participate in point of care research. No differences were found in the gender
mix between education levels (Figure 2) (p=0.443).
70
Figure 2. Education levels of participants
The gender distribution by education level was quite even (Figure 3).
Figure 3. Distribution of highest education level by gender
How often do you think you have difficulties falling asleep?
Almost one third of participants (30.1%) identified difficulty initiating sleep 5-7 times per
week with equal proportions of 23.3% each identifying difficulty falling asleep less than once
per week,1-2 times per week and 3-4 times per week
71
When cross-tabulated with age, the maximum frequency of difficulty falling asleep increased
with increasing age (shaded cells, Table 6) (p=0.006). A higher proportion of older
participants reported more frequent difficulty falling asleep.
Table 6. Difficulty falling asleep and age cross tabulation
Age
Difficulty falling asleep
Less than once per
week
1-2 times per week
3-4 times per week
5-7 times per week
Total
Count
18-25
5
26-35
3
35-45
5
46-55
4
56-65
0
66-+
0
Total
17
%
Count
29.4%
9
17.6%
4
29.4%
2
23.5%
0
0%
2
0%
0
23.3%
17
%
52.9%
23.5%
11.8%
0%
11.8%
.0%
23.3%
Count
2
0
3
6
4
2
17
%
Count
11.8%
3
0%
2
17.6%
3
35.3%
4
23.5%
6
11.8%
4
23.3%
22
%
Count
13.6%
19
9.1%
9
13.6%
13
18.2%
14
27.3%
12
18.2%
6
30.1%
73
26%
12.3%
17.8%
19.2%
16.4%
8.2%
100%
%
How often do you think you have difficulty staying asleep?
The largest proportion (32.9%) of participants reported interrupted sleep 5-7 times per week
(Table 7). It is not known if an answer of 7 times per week was an occurrence of each night
or more awakenings on fewer nights.
Interestingly, the second most frequent response
(30.1%) was less than once per week. Recall bias could be a factor in these data.
Table 7. Frequency of staying asleep
Frequency
%
Less than once per week
30.1
1-2 times per week
13.7
3-4 times per week
23.3
5-7 times per week
Total
32.9
100.0
Similar to the “difficulty falling asleep” above, the maximum frequency of difficulty staying
asleep also increased with increasing age (shaded cells, Table 8) when cross-tabulated
(p=0.004).
72
Table 8. Difficulty staying asleep and age cross tabulation
Age
Difficulty staying asleep
Less than once per
week
1-2 times per week
3-4 times per week
5-7 times per week
Total
Count
18-25
9
26-35
5
36-45
3
46-55
4
56-65
1
66-+
0
Total
22
%
40.9%
27.2%
13.6
18.2
4.5%
0%
30.1%
Count
6
1
2
1
0
0
10
%
Count
60%
2
10%
1
20%
2
10
6
0%
5
0%
1
13.7%
17
%
Count
11.8%
2
5.9%
2
11.8%
6
35.3%
3
29.4%
6
5.9%
5
23.3%
24
%
Count
8.3%
19
8.3%
9
25%
13
12.5%
14
25%
12
20.8%
6
32.9%
73
%
26%
12.3
17.8%
19.2%
16.4%
8.2%
100%
How often do you think you have frequent awakening from sleep?
Maintenance of sleep, once established, followed a similar pattern to the previous question of
difficulty staying asleep (Table 9), with the largest proportion reporting 5-7 times per week
(34.2%) followed by less than once per week (26.0%). This is not surprising given the
similarity in the two questions. There was a trend towards increased incidence of this factor
with increasing age (shaded cells, Table 10), however, it did not quite reach statistical
significance (p=0.083).
Table 9. Frequency of awakening from sleep
Frequency
Percent
Less than once per week
1-2 times per week
3-4 times per week
5-7 times per week
Total
26.0
16.4
23.3
34.2
100.0
Table 10. Awakening from sleep and age cross tabulation
Age
Awakening
from sleep
Less than
once per
week
1-2 times
per week
Count
18-25
8
26-35
4
36-45
3
46-55
3
56-65
0
66+
1
Total
19
%
42.1%
21.1%
15.8%
15.8%
0%
5.3%
100%
5
0
2
1
4
0
12
41.7%
0%
16.7%
8.3%
33.3%
0%
100%
3-4 times
per week
Count
3
3
3
5
2
1
17
%
Count
17.6%
3
17.6%
2
17.6%
5
29.4%
5
11.8%
6
5.9%
4
100%
25
%
Count
12%
19
8%
9
20%
13
20%
14
24%
12
16%
6
100%
73
%
26%
12.3%
17.8%
19.2%
16.4%
8.2%
100%
5-7 times
per week
Total
Count
%
73
How often do you feel that your sleep is refreshing?
Over one third of respondents (37.0%) stated their sleep was not refreshing on most nights
(Table 11). This complements the results above, and is not surprising, given the population
for this study is those people seeking a sleep aid in a community pharmacy. When the nature
of the population is considered (ie seeking a sleep aid), this result could be considered low.
Table 11. Frequency of self-reported refreshing sleep
Frequency
%
Less than once per week
37.0
1-2 times per week
27.4
3-4 times per week
19.2
5-7 times per week
16.4
Total
100.0
No significant association was found between the frequency of refreshing sleep and age
(Table 12) (p=0.332).
Table 12. Refreshing sleep and Age Cross tabulation
Age
Refreshing sleep
Less than once per
week
1-2 times per week
3-4 times per week
5-7 times per week
Total
Count
18-25
5
26-35
4
36-45
7
46-55
6
56-65
3
66-+
2
Total
27
%
Count
18.5%
8
14.8%
2
25.9%
2
22.2%
5
11.1%
2
7.4%
1
37.0%
20
%
Count
40%
5
10%
1
10%
2
25%
1
10%
4
5%
1
27.4%
14
%
Count
35.7%
1
7.1%
2
14.3%
2
7.1%
2
28.6%
3
7.1%
2
19.2%
12
%
Count
8.3%
19
16.7%
9
16.7%
13
16.7%
14
25%
12
16.7%
6
16.4%
73
%
26%
12.3%
17.8%
19.2%
16.4%
8.2%
100%
Have you tried any other treatment?
Almost 80% of participants (79.5 %) had previously tried at least one different type of
treatment before seeking the treatment that qualified them for inclusion in this study.
Which product(s) have you tried for insomnia?
More than half the respondents reported using a herbal and/or an over the counter product and
(52.1% and 50.6% respectively) (Table 13). Approximately one quarter used a prescription
medication (26.0%) and almost one-fifth had used alcohol as a sleep aid (19.2%). Natural
74
activities were also taken in consideration, having 12.3% for behavior therapy, 32.9% for
relaxation, and 37.0% for exercise.
Table 13. Product (s) previously used for insomnia
Product that has been used Percentage*
Herbal
52.1%
OTC
50.7%
Exercise
37.0%
Relaxation
32.9%
Prescription Medicine
26.0%
Alcohol
19.2%
Behavior
12.3%
*Participants could indicate more than one choice
Relaxation (11.0%), over the counter products (8.2%) and exercise (8.2%) were more
commonly used by younger participants (18-25 years) while prescribed medications were
rarely used (1.37%) (Table 14). In the 26-35 year age group, over the counter medication was
the most commonly used sleep aid (5.5%). Herbal remedies were commonly used by
participants aged 36-45 (12.3%). Over the counter medication was the most common sleep
aid (13.7%) used by patients aged 46-55. Equal proportions of 11.0% of participants aged 5665 years had used either over the counter and/or herbal products.
Table 14. Other treatments used by participants by age group
Age Range
OTC
18-25
26-35
36-45
46-55
56-65
66+
Total
6.9%
5.5%
9.6%
13.7%
10.9%
4.1%
50.7%
Herbal
Alcohol
Behavior
Prescription
Relaxation
8.2%
5.5%
2.7%
1.4%
8.2%
4.1%
2.7%
1.4%
2.7%
4.1%
12.3%
2.7%
1.4%
4.1%
8.2%
12.3%
4.1%
4.1%
5.5%
9.6%
10.9%
4.1%
2.7%
6.9%
1.4%
4.1%
0%
0%
5.5%
1.4%
52.1% 19.2%
12.3%
26.1%
32.9%
Highest result in each row (by age)
Highest result in each column (by treatment)
Result if highest in a particular row & column together
Exercise
11%
2.8%
5.5%
12.3%
1.4%
4.1%
37.1%
How often you have used antistamine as a sleep aid?
The majority of respondents (60.2%) identified that they had previously used an antihistamine
as a sleep aid (Figure 4).Of the 44 respondents who had previously used an antihistamine,
75
almost three quarters (72.8%) had used it on an as required basis, 13.6% once weekly and
13.6% used it a couple of times a week.
Figure 4. Frequency of using Antihistamine
Which product was recommended for treatment of your insomnia?
All participants (100%) used doxylamine for the treatment of insomnia complaints.
Part 2: Telephone interview survey
Forty-eight of the original 73 participants opted to complete a follow up telephone interview
to evaluate the effectiveness after using antihistamine by providing contact details.
Participants who elected to participate in this additional interview were asked more detailed
questions about other factors which might impact on their sleep patterns.
Participant demographics
Three quarters of this sub-sample (36, 75.0%) were women. The age distribution for this part
was skewed to the 36-65 bracket (Figure 5), however, the education distribution was similar
to the total study population with half the participants in this part of the study (50.0%) having
achieved a diploma or less (Figure 6).
76
Figure 5. Age group for Part 2 telephone survey
Figure 6. Education level of respondents for Part 2 telephone survey
77
Effect of caffeine consumption on falling asleep
Participants were asked about their caffeine consumption (tea, coffee or soft drink beverage)
to explore the association between daily caffeine intake and patient’s ability to fall asleep.
The majority of respondents (61.2%) stated that they consumed caffeine 2 to 3 times a day
(Table 15), with a further 26.5% having caffeine once a day. Only 4.1% of participants stated
they did not consume caffeine.
Table 15. Frequency of caffeine consumption
Caffeine Consumption
Never
Less than once a day
Once a day
2 to 3 times a day
More than 4 times a day
Total
Percent
4.1
2.0
26.5
61.2
6.1
100.0
No significant relationship was found between caffeine consumption and difficulty falling
asleep variables, however,there was a trend towards increased incidence of difficulties falling
asleep with increasing caffeine consumption (shaded cells, Table 16) (p=0.063).
Table 16. Caffeine consumption and difficulty falling asleep Cross tabulation
Caffeine Consumption
Never
Less than once a day
Once a day
2 to 3 times a day
More than 4 times a day
Total
Count
Difficulty Falling Asleep Frequency
Less
1-2
than
times
once per
per
3-4 times 5-7 times
week
week
per week per week
1
0
0
1
Total
2
%
Count
50%
0
0%
1
0%
0
.5
0
4.2%
1
%
Count
0%
2
100%
3
0%
6
0%
1
2.1%
12
%
Count
16.7%
3
25%
5
50%
9
8.3%
13
25.0%
30
%
Count
10%
0
16.7%
0
30%
0
43.3%
3
62.5%
3
%
Count
0%
6
0%
9
0%
15
100%
18
6.3%
48
12.5%
18.8%
31.3%
37.5%
100%
%
Most respondents consumed caffeine containing beverages 1-3 times a day with highest
proportion was seen within age group 36-55 consuming caffeine two to three times a day
(Table 17).
78
Table 17. Caffeine consumption with age group Cross tabulation
Age
Caffeine consumption
Never
Less than once a day
Once a day
2 to 3 times a day
More than 4 times a day
Total
Count
18-25
1
26-35
0
36-45
0
46-55
1
56-65
0
66+
0
%
Count
50%
1
0%
0
0%
0
50%
0
0%
0
0%
0
4.2%
1
%
Count
100%
3
0%
1
0%
3
0%
1
0%
4
0%
0
2.1%
12
%
Count
25%
2
8.3%
2
25%
8
8.3%
8
33.4%
6
0%
4
25.0%
30
%
Count
6.7%
0
6.7%
0
26.7%
0
26.7%
0
20%
1
13.3%
2
62.5%
3
%
Count
0%
7
0%
3
0%
11
0%
10
33.3%
11
66.7%
6
6.3%
48
14.6%
6.3%
22.9%
20.8%
22.9%
12.5%
100%
%
Total
2
Alcohol Consumption
Respondents were asked about their alcohol consumption status and frequency (Table 18).
Sixty percent stated that they drank alcohol 2-3 times a week, with 25.0% drinking more than
4 times a week.
Table 18. Frequency of alcohol drinking per week
Alcohol Drinking Frequency
Never
Once a week
2 to 3 times a week
More than 4 times a week
Total
Percent
10.4
4.2
60.4
25.0
100.0
No statistically significant relationship was found between frequency of alcohol consumption
and difficulties falling asleep. However, consuming alcohol 2-3 times a week appears to
increase the incidence of all frequencies of difficulty falling asleep. The amount of alcohol
consumed was not requested.
79
Table 19. Difficulties Falling Asleep and Alcohol Consumption Cross
tabulation
Alcohol Consumption
2 to 3 times a
Once a week
week
0
3
Difficulties Falling Asleep
Less than once per
week
1-2 times per week
3-4 times per week
5-7 times per week
Total
Total
More than 4
times a week
3
6
Count
Never
0
%
Count
0%
1
0%
0
50%
4
50%
3
12.5%
8
%
Count
12.5%
3
0%
1
50%
8
37.5%
4
16.7%
16
%
Count
18.8%
1
6.3%
1
50%
14
25%
2
33.3%
18
%
Count
5.6%
5
5.6%
2
77.8%
29
11.1%
12
37.5%
48
10.45%
4.2%
60.4%
25%
100%
%
Smoking status
Participants were classified as smokers if they reported smoking of any kind (cigarette, pipe
or cigar) and as non-smokers otherwise. A narrow majority of respondents (47.9%) were
smokers (Table 20).Smokers were significantly more likely than non-smokersto report more
frequent difficulties falling asleep (p=0.003).
Table 20. Smoking and Difficult falling asleep Cross tabulation
Frequency of difficulties falling asleep
Smoking status
Non smoker
Smoker
Total
Less than once per
week
Count
6
1-2 times
per week
6
%
Count
26.1%
0
26.1%
2
21.7%
10
26.1%
13
47.9%
25
0%
8%
40%
52%
52.1%
6
8
15
19
48
12.5%
16.7%
31.3
39.6%
100%
%
Count
%
3-4 times
per week
5
5-7 times per
week
6
Total
23
Effects of antihistamine on sleep latency
Table 21 shows a clear difference in sleep latency between pre- and post-antihistamine use
(p=0.002). When the respondents were not using an antihistamine, the sleep latencies were
higher than when using antihistamines. Given antihistamines are used for sleep disturbances,
this finding shows their efficacy.
80
Table 21. Sleep latency time before and after using antihistamine
Sleep latency time
Before using antihistamine
%
After using antihistamine
%
Less than 1/2 hour
0
77.1
1/2 - 1 hour
0
18.8
1 - 2 hours
39.6
4.2
2 - 3 hours
47.9
0
More than 3 hours
12.5
0
Total
100
100
Quality of sleep before and after using antihistamine
Participants were asked to assess the quality of their sleep before and after antihistamine use
(Table 22). Before treatment, the vast majority rated their sleep quality as “poor” or “very
poor” (85.5%), whereas after (or during) treatment with an antihistamine, 93.7% rated their
sleep as “good” or “very good”.
Table 22. Quality of sleep before and after using antihistamine
Quality of sleep before using
antihistamine
%
Quality of sleep after Using
antihistamine
%
Very poor
29.2
0.0
Poor
56.3
Average
12.5
6.3
Good
2.1
35.4
Very good
0.0
58.3
Total
100.0
100.0
85.5
0.0
93.7
Nap time before and after using Antistamine
The responses to the question about napping did not change with antihistamine use (Table
23), therefore, antihistamine use was not associated with any change in day time subjective
sleepiness.
81
Table 23. Nap length time before and after using antihistamine
Nap length time
How long do you nap during the day
before antihistamine?
%
How long do you nap during the day
after antihistamine?
%
I do not nap
79.2
79.2
0-15 minutes
0.0
0.0
16-30 minutes
14.6
20.8
6.3
0.0
100.0
100.0
Longer than 30 minutes
Total
Effect of Antihistamine on awakening after sleep onset
Participants were asked about fragmentation characteristics include mid-sleep awakening,
wakening after sleep onset and time delay to fall asleep again after awakening.
Table 24, shows a significant impact of antihistamine usage where 95.8% of participants who
experienced awakening before antihistamine (of varying duration) did not wake after using an
antihistamine (p=0.017).
Table 24. Wake time after sleep onset before and after using antihistamine Cross
tabulation
How long does it take fall asleep again when
you wake you up at night before antihistamine?
less than half hour
Between 1/2-1 hour
1 to 2 hours
2 to 3 hours
More than 3 hours
Total
How long does it take fall asleep again when
you wake you up at night after antihistamine?
Count
No awaking
15
Between 1/2-1 hour
0
Total
15
%
Count
100%
14
0%
0
31.3%
14
%
Count
100%
14
0%
1
29.2%
15
%
Count
93.3%
1
6.7%
1
31.3%
2
%
Count
50%
2
50%
0
2.1%
2
%
Count
100%
46
0%
2
2.1%
48
%
95.8%
4.2%
100%
How long and you how often you have used an antihistamine as a sleep aid?
The range of time participants used an antihistamine as a sleep aid was 2 to 14 days with a
mean of 5 days.
82
Respondents were also asked about how frequently they have used antihistamine as a sleep
aid. Half (50.0%) reported using an antihistamine every night while 33.3% reported using
one on a “when necessary” basis and 16.7% used one more regularly, rated as “a couple of
times a week” (Figure 7).
Figure 7. Frequency of taking antihistamine
Effect of Antihistamine on daytime sleepiness
Respondents were asked if using an antihistamine was associated with daytime sleepiness.
Almost three-quarters (72.9%) reported no chance (Table 25), 20.8% reported slight chance
and 6.3% a moderate chance of daytime drowsiness. These data correlate well with the
daytime napping question (Table 26).
Table 25. Effect of antihistamine on daytime sleepiness
Antihistamine
effects
No chance
%
72.9
Slight chance
20.8
Moderate chance
6.3
Total
100.0
Effect of Antihistamine on ability to stay awake during the day
Respondents were asked if using an antihistamine affected their ability to stay awake during
the day. Similar to table 25 above, 72.9% stated not at all (Table 26), 16.7% a little, 4.2%
somewhat affected and 6.3% reported they were very much affected.
83
Table 26. Effect of Antihistamine on ability to stay awake during the day
Antihistamine effect
Not at all
%
72.9
A little
16.7
Somewhat
4.2
Very much
6.3
Total
100.0
Effect of antihistamine on work performance
When asked if using an antihistamine has affected their ability to perform their work, more
impact was reported (Table 27). In response to this question, the “Not at all” response
(39.6%) almost half nthat of the previous question (72.9%, Table 27))%.
Table 27. Effect of antihistamine on work performance
Antihistamine effect
Not at all
%
39.6
A little
18.8
Somewhat
18.8
Much
16.7
Very much
6.3
Total
100.0
Side effects of antihistamines
Almost one third (31.1%) stated that an antihistamine did not cause any side effects (table
28).
Over half the respondents reported drowsiness (54.2%), 12.6% dry mouth and only
2.1% said that antihistamine caused nausea.
Table 28. Side effects of antihistamine
Side effects
No side effects
%
31.1
Drowsiness
54.2
Dry mouth
12.6
Nausea
2.1
Total
100.0
84
Patient's opinion on antihistamines as a sleep aid
As an overall subjective assessment, 97.9% of respondents reported that an antihistamine was
helpful for treating their sleep problem.
85
86
Chapter 4: Discussion and Conclusion
This study recruited a range of people seeking treatment for insomnia in community
pharmacies in the Australian Capital Territory. The collated data showed that younger people
(18-25 years) exhibited a high frequency of seeking a sleep aid in a community pharmacy
compared to other age groups. A possible explanation for this observation is the fact that
older patients can experience a range of other health issues that require medical attention,
compared to younger individuals (Australian Institute of Health and Welfare [AIHW], 2010).
It is logical to extrapolate that older individuals experiencing one or more other health issues
are more likely to seek medical treatment and therefore could be more likely to seek medical
treatment of insomnia rather than self-medication in a community pharmacy.
Overall, this study concurs with the findings of several previous studies (Arber et al, 2009;
Groeger et al, 2004; Lindberg et al. 1997; Middelkoop et al, 1996) which reported a higher
frequency of insomnia in females than males independent of age. One age category was an
exception to this (26-35 years), where males had a higher incidence of insomnia than females.
After the age of 35 years, the difference between men and women becomes more apparent
which is consistent with Polish study findings that the incidence of insomnia increased with
age more rapidly in women aged 35 years and over than men (Kiejna et al, 2003). Johnson et
al (2006) found that the rate of insomnia was the same for boys and girls until a girl’s menses,
when the risk of developing insomnia increased almost three-fold and continued to increase
throughout life. Although our participants were aged over 18, these data support the reported
higher incidence of insomnia in females than males. Hormones (Kravitz et al, 2005),
pregnancy (Santiago et al, 2001), menopause, stress, medical conditions, and complex home
life (Meltzer & Mindell, 2006) may all be factors which contribute to the higher prevalence of
insomnia in females. Furthermore, Ohayon (2006) reported that 80% of women experiencing
severe hot flashes also reported chronic insomnia.
One of the aims of this study was to explore the symptoms and frequency of insomnia in
those receiving antihistamine treatments in a community pharmacy. While difficulty initiating
sleep, difficulty maintaining sleep and frequent awakening all increased with increasing age,
subjective expression of restorative sleep did not show a clear age-related pattern. These
findings are supported in the literature (Hoffmann, 1999; Klink et al, 1992; Ohayon &
Smirne, 2002; Ancoli-Israel & Roth, 1999) where non-restorative sleep is usually reported by
87
younger individuals (Ohayon & Bader, 2010; Ohayon & Smirne, 2002). The higher rate of
insomnia observed in the older participants involved in this study could be due to multiple
medical problems which they are more likely to experience, polypharmacy, and
environmental factors such as institutionalisation and the absence of a daily schedule,
however, these issues were not explored. Older adults who are healthy and active with a good
social life have been reported to not have higher rates of insomnia (Benca et al, 2004; Foley
et al, 1999; Janson et al, 2001; Ohayon et al, 2001).
The findings of the present study suggest that the relationship between age and insomnia may
be explained by various other factors. In recent years, the relationship between increasing age
and the risk of developing insomnia has been investigated and a positive correlation found
(Komada et al, 2011; Morphy et al, 2007; Paparrigopoulos et al, 2010; Klink & Quan, 1987;
Ohayon, 1996; Weyerer & Dilling, 1991). Foley et al. (1999) showed that in a 3-year
longitudinal study involving 6,800 older people, increasing age was not linked with insomnia
in healthy individuals. Foley et al. (1999) suggested that other factors such as chronic disease,
physical disability, depressed mood, poor perceived health, widowhood, and use of sedatives
were more likely explanations for the incident insomnia. Comorbidities were not investigated
in this study; therefore it is difficult to draw a comparison with Foley et al’s (1999) work.
However, future research could investigate the causal links in more detail.
However, other studies have determined that there is not a clear correlation between
increasing age and the development of insomnia. (Liljenberg et al, 1988; Ohayon et al, 1997).
The results of this study concur with that published by Palleson et al. (2001) who showed that
problems maintaining sleep were more frequent in the elderly participants, with daytime
impairment less common.
Education Status
Education level was found to have an inverse relationship with the risk in experiencing
insomnia with no difference found between genders. This result is supported in the literature
where individuals of lower education status were significantly more likely to experience
insomnia compared to more highly educated individuals (Frisoni et al, 1993; Gellis et al,
2005; Hartz et al, 2007). The explanation of this association could be that the higher the
education level achieved by an individual, the greater their knowledge concerning sleep
hygiene practices and how improved sleep can be achieved. Hislop & Arber (2003) also
suggested that more educated individuals may be more willing to be involved in attempts to
88
use various strategies to overcome their insomnia symptoms, and also recognise the benefits
of sleep for health and well-being (e.g. through awareness from media sources).
Treatments for Insomnia
The results of this study suggest that the use of both pharmacological and nonpharmacological treatments for insomnia is a relatively common practice among participants.
Herbal-based supplements were the most commonly used treatment reported (52.1%), with
prescription medicines used by 26.0%. This appears to be much greater than the prescription
hypnotic use in other countries such as France (9.8%), the US (8%) the UK (3.6%) and
Germany (2.4%) (Ohayon, 2001; Roehrs et al, 2002). However, the international hypnotic use
rates are sourced from the general population, whereas this study interviewed people who
self-identified insomnia and were seeking treatment in a community pharmacy, therefore a
higher rate of hypnotic use is not unexpected.
The proportion of individuals surveyed who used OTC medications was 50.7%. This result is
much higher rate than USA where 10% OTC sleep aid use has been reported (Roehrs et al,
2002). Also, alcohol use was almost double (19.2%) that of insomniacs in the USA (10%)
(Roehrs et al, 2002). The AIHW reported that 7.2% of the Australian population over 12
years of age consumed alcohol daily in 2010 (AIHW, 2011) this is just less than half the rate
found for respondents with a sleep problem. Whether these clear differences between
countries in the use of medications or a healthcare intervention reveal differences in cultural
or economic status is unclear and requires further investigation. Finally, 82.2% of individuals
surveyed in this study used a range of self-help methods to treat insomnia including
relaxation, exercise or other behavioural strategies. This result shows that insomniacs may use
a variety of such self-help remedies for a considerable period of time before seeking
professional help. This result is consistent with the findings of Morin et al (2006).
A majority of participants (60.2%) had used an antihistamine previously (at the time of
survey) as a sleep aid. Pillitteri et al (1994) found that among college students who reported
sleep problems, 6.4% of men and 11.4% of women reported using OTC sleep aids, although
this is a younger age group, and almost 20 years old. The age of these data is important as
restrictions on pharmaceuticals have been eased over this timeframe, making antihistamines
more accessible now than they were in 1994.
89
Of the respondents who had previously used an antihistamine, the majority (72.7%) reported
using it as required, with 13.6% each reporting once weekly use or “a couple of times a
week”. High proportions of individuals who experience transient insomnia self-medicate for
short periods of time (less than 1 week) with OTC products (Johnson et al, 1998). Ohayon et
al (1998) showed that most of the subjects used antihistamine at least 3 days per week
(53.7%) and had been doing so for over 1 month (57.6%). These results appear conflicted,
however, countries place different restrictions on antihistamines – for example, they require a
prescription in the USA. Self medication of antihistamine could be enhanced by the low cost
and ease of obtaining OTC medication in Australia rather than visiting a physician.
Diminished physician involvement in the prescription of OTC medication and freedom to
move between community pharmacies reduces patient follow-up and may lead to the misuse
of these medications, potentially leading to dependence. Ancoli-Israel (1999) and Roth (1999)
reported that it is rare for insomniacs to see a physician about their sleep problem with 40% of
insomniacs preferring to self-medicate with either OTC medications or alcohol.
Caffeine consumption
There was a trend towards an increased incidence of difficulty falling asleep with increasing
caffeine consumption; however, the results were not statistically significant. The timing,
nature and amount of caffeine consumption were not investigated and these could also be
reasons for the spread of results. This concurs with Youngberg et al (2011) who found that
low to moderate caffeine consumption during the morning hours has little effect on subjective
or polysomnographic sleep measures in individuals with primary insomnia.
Smoking Status
Smoking was also linked to an increased frequency of difficulty falling asleep compared to
non-smokers. This is consistent with several studies which have found a strong relationship
between smoking and insomnia (Peters et al., 2011; Pomerleau et al., 2000; Soldatos et al.,
1980; Wetter and Young, 1994; Zhang et al, 2006). Furthermore, people who smoke during
the night have greater sleep disturbance than those who do not (Peters et al., 2011). This is not
surprising given that nicotine acts as a stimulant in the central nervous system (Saint-Mleux et
al, 2004).
90
Alcohol consumption
No statistically significant difference between frequency of alcohol consumption and
difficulties falling asleep were found. However, 77.8% of the respondents reported problems
falling asleep 5-7 times per week after consuming 2 to 3 units of alcohol within the same
period. Studies into this issue have varied findings. In the Medical Outcomes Study, there was
no significant association between insomnia and alcohol use in patients with a chronic disease
(Katz & McHorney, 1998; Kuppermann et al, 1995). However, several studies have shown
that moderate alcohol consumption detrimentally effects sleep (Tsutsumi et al, 2000; Young
et al, 2002).
Doxylamine
The most frequently administered nonprescription medications are doxylamine and
diphenhydramine, two sedating antihistamines (Ramakrishnan & Scheid, 2007; Ringdahl et
al, 2004). Doxylamine has been shown to induce sedation (AMH, 2012), leading to its use as
a sleep aid.
In this study carried out on patients seeking treatment for insomnia in community pharmacies,
doxylamine was the antihistamine used by all respondents. It produced significantly more
improvement than previous treatment in several sleep parameters, including sleep-onset
latency (which is the target symptom for OTC products), maintenance of sleep and quality of
sleep as measured by patient’s subjective reports. Comparing pre- and post-treatment
responses, 97.9% stated that the antihistamine they received (doxylamine) was helpful in
treating their insomnia symptoms. To my knowledge, there is little published literature in
English addressing the use of doxylamine as a sleep aid. Rickels et al (1984) concur by
concluding that doxylamine consistently produced a significant improvement in sleep.The
results in this study are from a smaller sample size and only subjective appraisals of efficacy.
Side effects reported included anticholinergic effect of dry mouth, nausea, sluggishness, and a
hangover effect. These were not unexpected as they are common side effects of doxylamine
(AMH, 2012), which was the product taken by all participants in this study. Doxylamine is
effective at inducing drowsiness when taken at before going to sleep, however, having a halflife of up to 10 hours, doxylamine is still present in plasma on awakening, causing residual
daytime sedation (Krystal et al., 2006). This poses a risk to elderly patients and those taking
other anticholinergic medications (antidepressants, antipsychotics) (Neubauer, 2007). One
91
such risk of an anticholinergic-based antihistamine is tachycardia and other cardiac effects
which may aggravate angina (Hayes et al, 2007). Furthermore, concurrent use of
antihistamines with any of phenothiazines, nitroglycerin, nifedipine, prazosin, and diuretics
significantly impairs responsiveness and sensitivity of baroreceptors, leading to an increased
risk in developing postural hypotension (Hayes et al, 2007).
The answers to the question regarding how long participants nap did not change with
antihistamine use indicating no change in subjective day time sleepiness. The reason for this
lack of napping may be due to participants’ professional duties or perhaps it was advised by
healthcare professionals to avoid napping during the day. Alternatively, a possible reason is
because napping is not a strong part of Australian culture, few people actually nap. The exact
reasons are uncertain as the survey did not address this question.
Respondents were asked about the period of time in which they used doxylamine as a sleep
aid and the frequency. The duration was between 2 to 14 days with a mean of 5 days. In
regards to the frequency of use, half (50%) reported using an antihistamine every night. The
development of tolerance to the sedative effects of antihistamines is possible (Richardson et
al, 2002). It is the responsibility of pharmacists to ensure that patients do not extend this
period of use. Pharmacists should discuss the risks of misusing antihistamines.
This study also examined the association between using antihistamines (doxylamine) and the
reports of excessive sleepiness, tiredness, or drowsiness. Few patients reported residual
effects such as sleepiness, tiredness or drowsiness following antihistamine use. To my
knowledge, these associations have never been examined in past general population surveys.
Almost three-quarters of the surveyed individuals (72.9%) who used an antihistamine
reported no daytime sleepiness, 20.8% reported slight chance while 6.3% a moderate chance
(Table 26). The respondents were also asked whether antihistamine use affected their ability
to stay awake during the day with 72.9% stating “not at all”. Respondents were also asked
whether antihistamine use affected their ability to perform their work duties. These results
were different with 39.6% reporting not at all, indicating a possible low grade of drowsiness,
or affect on mental alertness. Since doxylamine is a potent sedative with a long half-life it is
not surprising to find that some users experienced these effects.
Comparing before and after treatment, 97.9% of patients rated an antihistamine as helpful as a
sleep aid for the treatment of insomnia. For those people who rated it not helpful, a possible
92
explanation that may develop tolerance as tolerance can develop (Richardson et al, 2002) and
abrupt withdrawal can lead to rebound insomnia (Morin & Benca, 2012).
The main strength of this study is that the data are reliable in terms of what the researcher can
control; it was collated from a survey distributed to patients exhibiting symptoms of insomnia
and followed up by the researcher with one-on-one telephone interviews rather than surveying
individuals who do not present such symptoms. As Hajak states that, strict diagnostic criteria
are required to ensure that the study sample ‘undoubtedly (requires) treatment’ (Hajak, 2001).
This study used participant self diagnosis as this criterion, leading to potential misdiagnosis
and also over diagnosis.
However, there are also some limitations to this study. Firstly, the collated data was selfreported and therefore may have been affected by recall and other biases. Secondly, as the
study was conducted in community pharmacies, this requires participants to be able to reach
these locations and as such, the data collated may be biased against the frail, ill or
institutionalised. Thirdly, the sample size employed in this study was not large enough to
ensure the data were completely robust and the short data collection window would not
account for any seasonal variation in presentations. Finally, the data collated was of a
subjective nature, that is, data was not objective as it explored opinions and beliefs.
This study has linked some of the individual research processes previously used in sleep
disorder and insomnia research into a practical study reflective of real world practice and
issues. The findings show that antihistamines are used as a sleep aid with quite good efficacy.
Conclusion
Despite the limitation of the study, the prevalence of insomnia complaints associated with
many factors. Increasing age affected sleep patterns. The findings of this study showed that
antihistamine (Doxylamine) is effective for primary insomnia. This treatment leads to
significant improvementsin subjective sleep parameters.
93
94
References
Access Economics (2004).Wake Up Australia: The Value of Healthy Sleep. http://www.sleep.org.au. retrieved
20 September 2011.
Achermann, P. (2004). The two-process model of sleep regulation revisited. Aviation, Space, and Environmental
Medicine,75(Suppl.3):A37–43.
Adam, K. (1980). Sleep as a restorative process and a theory to explain why. Progress In Brain Research,
53289-305.
Adams, J. (2006). Socioeconomic position and sleep quantity in UK adults. Journal Of Epidemiology And
Community Health, 60(3), 267-269.
Adrien, J., Alexandre, C., Boutrel, B., & Popa, D. (2004). Contribution of the "knock-out" technology to
understanding the role of serotonin in sleep regulations. Archives Italiennes De Biologie, 142(4), 369-377.
Agarwal, R. (2007). Relationship between circadian blood pressure variation and circadian protein excretion
in CKD. American Journal Of Physiology. Renal Physiology, 293(3), F655-F659.
Agostini, J., Leo-Summers, L., & Inouye, S. (2001). Cognitive and other adverse effects of diphenhydramine use
in hospitalized older patients. Archives Of Internal Medicine, 161(17), 2091-2097.
Altena, E., Van Der Werf, Y., Sanz-Arigita, E., Voorn, T., Rombouts, S., Kuijer, J., & Van Someren, E. (2008).
Prefrontal hypoactivation and recovery in insomnia. Sleep, 31(9), 1271-1276.
Alvarez, G., & Ayas, N. (2004). The impact of daily sleep duration on health: a review of the literature. Progress
In Cardiovascular Nursing, 19(2), 56-59.
American Academy of Sleep Medicine. (2005). The international classification of sleep disorders, 2nd
edn.Westchester, IL: American Academy of Sleep Medicine.
American Sleep Disorders Association. (1990). International classification of sleep disorders: Diagnostic and
coding manual. Rochester, MN: Author.
American Psychiatric Association. (1994). Diagnostic and statistical manual of mental disorders (4th
ed.).Washington, DC: Author.
Amzica, F. (2002). Physiology of sleep and wakefulness as it relates to the physiology of epilepsy. Journal Of
Clinical Neurophysiology: Official Publication Of The American Electroencephalographic Society, 19(6), 488503.
Ancoli-Israel, S. (2000). Insomnia in the elderly: a review for the primary care practitioner. Sleep, 23 Suppl
1S23–S30; discussion S36–S38.
Ancoli-Israel, S. (2005). Sleep and aging: prevalence of disturbed sleep and treatment considerations in older
adults. The Journal Of Clinical Psychiatry, 66 Suppl 9,24-30.
Ancoli-Israel, S. (2006). The impact and prevalence of chronic insomnia and other sleep disturbances
associated with chronic illness. The American Journal Of Managed Care, 12(8 Suppl), S221-S229.
Ancoli-Israel, S., & Ayalon, L. (2006). Diagnosis and treatment of sleep disorders in older adults. The
American Journal Of Geriatric Psychiatry: Official Journal Of The American Association For Geriatric
Psychiatry, 14(2), 95-103.
Ancoli-Israel, S., Cole, R., Alessi, C., Chambers, M., Moorcroft, W., & Pollak, C. (2003). The role of
actigraphy in the study of sleep and circadian rhythms. Sleep, 26(3), 342-392.
95
Ancoli-Israel, S., Richardson, G., Mangano, R., Jenkins, L., Hall, P., & Jones, W. (2005). Long-term use of
sedative hypnotics in older patients with insomnia. Sleep Medicine, 6(2), 107-113.
Ancoli-Israel, S., & Roth, T. (1999). Characteristics of insomnia in the United States: results of the 1991
National Sleep Foundation Survey. I. Sleep, 22 Suppl 2S347-S353.
Ancoli-Israel, S., Walsh, J.K., Mangano, R.M., & Fujimori, M.(1999). Zaleplon, a novel nonbenzodiazepine
hypnotic, effectively treats insomnia in elderly patients without causing rebound effects. Primary Care
Companion to The Journal of Clinical Psychiatry ,1(4),114–120.
Anderer, P., Moreau, A., Woertz, M., Ross, M., Gruber, G., Parapatics, S., & ... Dorffner, G. (2010).
Computer-assisted sleep classification according to the standard of the American Academy of Sleep
Medicine: validation study of the AASM version of the Somnolyzer 24 × 7. Neuropsychobiology, 62(4), 250264.
Arber, S., Bote, M., & Meadows, R. (2009). Gender and socio-economic patterning of self-reported sleep
problems in Britain. Social Science & Medicine (1982), 68(2), 281-289.
Arendt, J., Van Someren, E., Appleton, R., Skene, D., & Akerstedt, T. (2008). Clinical update: melatonin and
sleep disorders. Clinical Medicine (London, England), 8(4), 381-383.
Attarian, H. (2000). Helping patients who say they cannot sleep. Practical ways to evaluate and treat
insomnia. Postgraduate Medicine, 107(3), 127.
Australian Government Department of Health and Ageing, Therapeutic Goods Administration. (2011). Poisons
Standard 2011. Retrieved from http://www.tga.gov.au/industry/scheduling-poisons-standard.htm .
Australian Institute Of Health And Welfare. (2010). Australia’s health 2010, The twelfth biennial health report
of
the
Australian
Institute
of
Health
and
Welfare,
Retrieved
from
http://www.aihw.gov.au/WorkArea/DownloadAsset.aspx?id=6442452962.
Australian Institute of Health and Welfare. ( 2011). Drugs in Australia 2010: Tobacco, alcohol and other drugs.
Canberra: Australian Institute of Health and Welfare
Avidan, A., Fries, B., James, M., Szafara, K., Wright, G., & Chervin, R. (2005). Insomnia and hypnotic use,
recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. Journal Of
The American Geriatrics Society, 53(6), 955-962.
Balderer, G., & Borbély, A. (1985). Effect of valerian on human sleep. Psychopharmacology, 87(4), 406-409.
Balter, M., & Uhlenhuth, E. (1991). The beneficial and adverse effects of hypnotics. The Journal Of Clinical
Psychiatry, 52 Suppl16-23.
Barnes, J., Anderson, L., & Phillipson, J. (2001). St John's wort (Hypericum perforatum L.): a review of its
chemistry, pharmacology and clinical properties. The Journal Of Pharmacy And Pharmacology, 53(5), 583-600.
Barone, G., Gurley, B., Ketel, B., Lightfoot, M., & Abul-Ezz, S. (2000). Drug interaction between St. John's
wort and cyclosporine. The Annals Of Pharmacotherapy, 34(9), 1013-1016.
Bartlett, D., Marshall, N., Williams, A., & Grunstein, R. (2008). Predictors of primary medical care consultation
for sleep disorders. Sleep Medicine, 9(8), 857-864.
Bartlett, D., Marshall, N., Williams, A., & Grunstein, R. (2008). Sleep health New South Wales: chronic sleep
restriction and daytime sleepiness. Internal Medicine Journal, 38(1), 24-31.
Baskett, J., Broad, J., Wood, P., Duncan, J., Pledger, M., English, J., & Arendt, J. (2003). Does melatonin
improve sleep in older people? A randomised crossover trial. Age And Ageing, 32(2), 164-170.
96
Bastien, C. H., Vallieres, A., & Morin, C. M. (2001). Validation of the Insomnia Severity Index as an outcome
measure for insomnia research. Sleep Medicine, 2, 297–307.
Bastien, C. M., Valli`eres, A. & Morin, C.M. (2004). Precipitating Factors of Insomnia. Behavioral Sleep
Medicine, 2(1), 50-62.
Bauer, K., Dom, P., Ramirez, A., & O'Flaherty, J. (2004). Preoperative intravenous midazolam: benefits beyond
anxiolysis. Journal Of Clinical Anesthesia, 16(3), 177-183.
Beck, A. T, Rush, A. J., Shaw, B. F., & Emery, G. (1979). Cognitive therapy of depression. New York: Guilford
Press.
Bélanger, L., Belleville, G., & Morin, C.(2009). Management of Hypnotic Discontinuation in Chronic
Insomnia.Sleep Medicine Clinics,4(4), 583–592.
Belanger, L., Savard, J., & Morin, C. (2006). Clinical management of insomnia using cognitive therapy.
Behavioral Sleep Medicine, 4(3), 179-198.
Belongia, E.A., Hedberg, C.W., Gleich, G.J., White, K.E., Mayeno, A.N., Loegering, D.A., et al. (1990). An
investigation of the cause of the eosinophilia myalgia syndrome associated with tryptophan use.The New
England journal of medicine, 323(6), 357–65.
Benca, R. (2005). Mood disorders. In M.Kryger ,T. Roth & W. Dement (Eds.), Principles and practice of
sleep disorders medicine (pp. 1311-1326). Philadelphia, PA: W.B. Saunders Company
Benca, R., Ancoli-Israel, S., & Moldofsky, H. (2004). Special considerations in insomnia diagnosis and
management: depressed, elderly, and chronic pain populations. The Journal Of Clinical Psychiatry, 65 Suppl
826-35.
Benca, R., & Quintas, J. (1997). Sleep and host defenses: a review. Sleep, 20(11), 1027-1037.
Bender, B., Berning, S., Dudden, R., Milgrom, H., & Tran, Z. (2003). Sedation and performance impairment of
diphenhydramine and second-generation antihistamines: a meta-analysis. The Journal Of Allergy And Clinical
Immunology, 111(4), 770-776.
Benke, D., Barberis, A., Kopp, S., Altmann, K., Schubiger, M., Vogt, K., & ... Möhler, H. (2009). GABA A
receptors as in vivo substrate for the anxiolytic action of valerenic acid, a major constituent of valerian root
extracts. Neuropharmacology, 56(1), 174-181.
Bent, S., Padula, A., Moore, D., Patterson,M., & Mehling, W. (2006). Valerian for Sleep: A Systematic Review
and Meta-Analysis. The American Journal of Medicine, 119(12), 1005–1012.
Bilia, A., Gallon, S., & Vincieri, F. (2002). Kava-kava and anxiety: growing knowledge about the efficacy and
safety. Life Sciences, 70(22), 2581-2597.
Bishop, J., Olver, I., Wolf, M., Matthews, J., Long, M., Bingham, J., & ... Cooper, I. (1984). Lorazepam: a
randomized, double-blind, crossover study of a new antiemetic in patients receiving cytotoxic chemotherapy and
prochlorperazine. Journal Of Clinical Oncology: Official Journal Of The American Society Of Clinical
Oncology, 2(6), 691-695.
Bjorvatn, B., & Pallesen, S. (2009). A practical approach to circadian rhythm sleep disorders. Sleep Medicine
Reviews, 13(1), 47-60.
Bjorvatn, B., & Ursin, R. (1998). Changes in sleep and wakefulness following 5-HT1A ligands given
systemically and locally in different brain regions. Reviews In The Neurosciences, 9(4), 265-273.
Black, J., Saini, B., Wong, K. (2007). The role of pharmacists in improving the management of sleep disorders
in the community. Respirology, 12(1), A24.
97
Blackwell, T., Redline, S., Ancoli-Israel, S., Schneider, J., Surovec, S., Johnson, N., & ... Stone, K. (2008).
Comparison of sleep parameters from actigraphy and polysomnography in older women: the SOF study.
Sleep, 31(2), 283-291.
Blasi, A., Jo, J., Valladares, E., Morgan, B., Skatrud, J., & Khoo, M. (2003). Cardiovascular variability after
arousal from sleep: time-varying spectral analysis. Journal Of Applied Physiology (Bethesda, Md.: 1985),
95(4), 1394-1404.
Bonnet, M., & Arand, D. (1995). 24-Hour metabolic rate in insomniacs and matched normal sleepers. Sleep,
18(7), 581-588.
Bootzin, R. (1972). A stimulus control treatment for insomnia. Proceedings of the American Psychological
Association, 7, 395–396.
Bootzin, R. R. (1977). Effects of self-control procedures for insomnia. In R. B. Stuart (Ed.), Behavioral selfmanagement (pp. 176–195). New York: Brunner/Mazel.
Bootzin, R. R., & Epstein, D. R. (2000). Stimulus control. In K. L. Lichstein, & C. M. Morin (Eds.), Treatment
of late-life insomnia (pp. 167–184). Thousand Oaks, CA: Sage.
Bootzin, R., & Epstein, D. (2011). Understanding and treating insomnia. Annual Review Of Clinical Psychology,
7,435-458.
Bootzin, R.R., Epstein, D., Engle-Friedman, M. & Salvio, M. (1996). Sleep disturbances. In L.L. Carstensen,
B.A. Edelstein, & L .Dornbrand (Eds.), The Practical Handbook ofClinical Gerontology (pp. 398–420).
Thousand Oaks, CA: Sage.
Borbély, A., & Achermann, P. (1999). Sleep homeostasis and models of sleep regulation. Journal Of Biological
Rhythms, 14(6), 557-568.
Borja, N., & Daniel, K. (2006). Ramelteon for the treatment of insomnia. Clinical Therapeutics, 28(10),
1540-1555.
Born, J., & Wagner, U. (2009). Sleep, hormones, and memory. Obstetrics And Gynecology Clinics Of North
America, 36(4), 809.
Bove, G. (1998). Acute neuropathy after exposure to sun in a patient treated with St John's Wort. Lancet,
352(9134), 1121-1122.
Brainard, G. C., Sliney, D., Hanifin, J. P., Glickman, C., Byrne, B., Greeson, J. M., et al. (2008). Sensitivity of
the human circadian system to short-wavelength (420 nm) light. Journal of Biological Rhythms, 23(5), 379–386.
Braithwaite, D., Emery, J., De Lusignan, S., & Sutton, S. (2003). Using the Internet to conduct surveys of health
professionals: a valid alternative?. Family Practice, 20(5), 545-551.
Brandenberger, G., Gronfier, C., Chapotot, F., Simon, C., & Piquard, F. (2000). Effect of sleep deprivation on
overall 24 h growth-hormone secretion. Lancet, 356(9239), 1408.
Brassington, G., King, A., & Bliwise, D. (2000). Sleep problems as a risk factor for falls in a sample of
community-dwelling adults aged 64-99 years. Journal Of The American Geriatrics Society, 48(10), 1234-1240.
Breidenbach, T., Hoffmann, M., Becker, T., Schlitt, H., & Klempnauer, J. (2000b). Drug interaction of St John's
wort with cyclosporin. Lancet, 355(9218), 1912.
Breidenbach, T., Kliem, V., Burg, M., Radermacher, J., Hoffmann, M., & Klempnauer, J. (2000a). Profound
drop of cyclosporin A whole blood trough levels caused by St. John's wort (Hypericum perforatum).
Transplantation, 69(10), 2229-2230.
98
Breslau, N., Roth, T., Rosenthal, L., & Andreski, P. (1996). Sleep disturbance and psychiatric disorders: a
longitudinal epidemiological study of young adults. Biological Psychiatry, 39(6), 411-418.
Brockmöller, J., Reum, T., Bauer, S., Kerb, R., Hübner, W., & Roots, I. (1997). Hypericin and pseudohypericin:
pharmacokinetics and effects on photosensitivity in humans. Pharmacopsychiatry, 30 Suppl 294-101.
Brower, K., Aldrich, M., Robinson, E., Zucker, R., & Greden, J. (2001). Insomnia, self-medication, and relapse
to alcoholism. The American Journal Of Psychiatry, 158(3), 399-404.
Budur, K., Rodriguez, C., & Foldvary-Schaefer, N. (2007). Advances in treating insomnia. Cleveland Clinic
Journal Of Medicine, 74(4), 251.
Burgos, I., Richter, L., Klein, T., Fiebich, B., Feige, B., Lieb, K., & ... Riemann, D. (2006). Increased nocturnal
interleukin-6 excretion in patients with primary insomnia: a pilot study. Brain, Behavior, And Immunity, 20(3),
246-253.
Buscemi, N., Vandermeer, B., Hooton, N., Pandya, R., Tjosvold, L., Hartling, L., & ... Vohra, S. (2005). The
efficacy and safety of exogenous melatonin for primary sleep disorders. A meta-analysis. Journal Of General
Internal Medicine, 20(12), 1151-1158.
Buscemi, N., Vandermeer, B., Pandya, R., Hooton, N., Tjosvold, L., Hartling, L., & ... Klassen, T. (2004).
Melatonin for treatment of sleep disorders. Evidence Report/Technology Assessment (Summary), (108), 1-7.
Buysse, D. (2008). Chronic insomnia. The American Journal Of Psychiatry, 165(6), 678-686.
Buysse, D., Germain, A., & Moul, D. (2005). Diagnosis, epidemiology, and consequence of insomnia. Primary
Psychiatry, 12(8), 37-44.
Buysse, D., Hall, M., Strollo, P., Kamarck, T., Owens, J., Lee, L., & ... Matthews, K. (2008). Relationships
between the Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and
clinical/polysomnographic measures in a community sample. Journal Of Clinical Sleep Medicine: JCSM:
Official Publication Of The American Academy Of Sleep Medicine, 4(6), 563-571.
Buysse, D., Reynolds, C., Monk, T., Berman, S., & Kupfer, D. (1989). The Pittsburgh Sleep Quality Index: a
new instrument for psychiatric practice and research. Psychiatry Research, 28(2), 193-213.
Buxton, O. M., Spiegel, K., & van Cauter, E. (2002). Modulation and endocrine function and metabolism by
sleep and sleep loss. In T. L. Lee-Chiong, M. J. Sateia, & M. A. Carskadon (Eds.), Sleep medicine (pp. 59-69).
Philadelphia: Hanley & Belfus.
Carey, T., Moul, D., Pilkonis, P., Germain, A., & Buysse, D. (2005). Focusing on the experience of insomnia.
Behavioral Sleep Medicine, 3(2), 73-86.
Carrier, J., Land, S., Buysse, D., Kupfer, D., & Monk, T. (2001). The effects of age and gender on sleep EEG
power spectral density in the middle years of life (ages 20-60 years old). Psychophysiology, 38(2), 232-242.
Carrier, J., Paquet, J., Morettini, J., & Touchette, E. (2002). Phase advance of sleep and temperature circadian
rhythms in the middle years of life in humans. Neuroscience Letters, 320(1-2), 1-4.
Carskadon, M. A., & Dement, W. C. (2005). Normal human sleep: An overview. In M. H. Kryger, T. Roth & W.
C. Dement (Eds.), Principles and practice of sleep medicine (4th ed., pp. 13Y23). Philadelphia: Elsevier
Saunders.
Cassaglia, P., Griffiths, R., & Walker, A. (2009). Cerebral sympathetic nerve activity has a major regulatory role
in the cerebral circulation in REM sleep. Journal Of Applied Physiology (Bethesda, Md.: 1985), 106(4), 10501056.
Catcheside, P., Chiong, S., Mercer, J., Saunders, N., & McEvoy, R. (2002). Noninvasive cardiovascular markers
of acoustically induced arousal from non-rapid-eye-movement sleep. Sleep, 25(7), 797-804.
99
Centers for Disease Control and Prevention. Hepatic toxicity possibly associated with kava-containing products-United States, Germany, and Switzerland, 1999-2002. (2003). JAMA: The Journal Of The American Medical
Association, 289(1), 36-37.
Cespuglio, R., Faradji, H., Gomez, M., & Jouvet, M. (1981). Single unit recordings in the nuclei raphe dorsalis
and magnus during the sleep-waking cycle of semi-chronic prepared cats. Neuroscience Letters, 24(2), 133-138.
Cespuglio, R., Gomez, M.E., Walker, E. & Jouvet, M. (1979) Effect of cooling and electrical stimulation of
nuclei of raphe system on states of alertness in cat. Electroencephalography and clinical neurophysiology,
47(3):289-308.
Cespuglio, R., Sarda, N., Gharib, A., Chastrette, N., Houdouin, F., Rampin, C., & Jouvet, M. (1990).
Voltammetric detection of the release of 5-hydroxyindole compounds throughout the sleep-waking cycle of the
rat. Experimental Brain Research. Experimentelle Hirnforschung. Expérimentation Cérébrale, 80(1), 121-128.
Charles, J., Harrison, C., & Britt, H. (2009). Insomnia. Australian Family Physician, 38(5), 283.
Chen, M., Lin, L., Wu, S., & Lin, J. (1999). The effectiveness of acupressure in improving the quality of sleep of
institutionalized residents. The Journals Of Gerontology. Series A, Biological Sciences And Medical Sciences,
54(8), M389-M394.
Cheng, T.(2000). St. John’s wort interaction with digoxin. Archive of Internal Medicine,160(16), 2548.
Chokroverty ,S. (2009). Sleep disorders medicine: Basic science, technical considerations and clinical aspects
(3rd ed.). Philadelphia: Elsevier.
Chokroverty, S. (2010). Overview of sleep & sleep disorders. The Indian Journal Of Medical Research, 131126140.
Choudhary, S., & Choudhary, S. (2009). Sleep effects on breathing and respiratory diseases. Lung India: Official
Organ Of Indian Chest Society, 26(4), 117-122.
Cirillo, V., & Tempero, K. (1976). Pharmacology and therapeutic use of antihistamines. American Journal Of
Hospital Pharmacy, 33(11), 1200-1207.
Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. (2002).
American Journal Of Health-System Pharmacy: AJHP: Official Journal Of The American Society Of HealthSystem Pharmacists, 59(2), 150-178.
Colrain, I., Crowley, K., Nicholas, C., Afifi, L., Baker, F., Padilla, M., & ... Trinder, J. (2010). Sleep evoked
delta frequency responses show a linear decline in amplitude across the adult lifespan. Neurobiology Of Aging,
31(5), 874-883.
Cohen, S., Doyle, W., Alper, C., Janicki-Deverts, D., & Turner, R. (2009). Sleep habits and susceptibility to the
common cold. Archives Of Internal Medicine, 169(1), 62-67.
Cole, M., & Dendukuri, N. (2003). Risk factors for depression among elderly community subjects: a systematic
review and meta-analysis. The American Journal Of Psychiatry, 160(6), 1147-1156.
Cooke, J., & Ancoli-Israel, S. (2006). Sleep and its disorders in older adults. The Psychiatric Clinics Of North
America, 29(4), 1077.
Cook, N. (2008). A fine balance: the physiology of sleep. Practice Nursing, 19(2), 73-76.
Cover, H., & Irwin, M. (1994). Immunity and depression: insomnia, retardation, and reduction of natural killer
cell activity. Journal Of Behavioral Medicine, 17(2), 217-223.
Coxeter, P., Schluter, P., Eastwood, H., Nikles, C., & Glasziou, P. (2003). Valerian does not appear to reduce
symptoms for patients with chronic insomnia in general practice using a series of randomised n-of-1 trials.
Complementary Therapies In Medicine, 11(4), 215-222.
100
Curry, D., Eisenstein, R., & Walsh, J. (2006). Pharmacologic management of insomnia: past, present, and future.
The Psychiatric Clinics Of North America, 29(4), 871.
Czisch, M., Wehrle, R., Kaufmann, C., Wetter, T., Holsboer, F., Pollmächer, T., & Auer, D. (2004). Functional
MRI during sleep: BOLD signal decreases and their electrophysiological correlates. The European Journal Of
Neuroscience, 20(2), 566-574.
Dailly, E., & Bourin, M. (2008). The use of benzodiazepines in the aged patient: clinical and pharmacological
considerations. Pakistan Journal Of Pharmaceutical Sciences, 21(2), 144-150.
Daley, M., Morin, C., LeBlanc, M., Grégoire, J., Savard, J., & Baillargeon, L. (2009). Insomnia and its
relationship to health-care utilization, work absenteeism, productivity and accidents. Sleep Medicine, 10(4), 427438.
Danel, T., & Touitou, Y. (2004). Chronobiology of alcohol: from chronokinetics to alcohol-related alterations of
the circadian system. Chronobiology International, 21(6), 923-935.
Danker-Hopfe, H., Kunz, D., Gruber, G., Klösch, G., Lorenzo, J., Himanen, S., & ... Dorffner, G. (2004).
Interrater reliability between scorers from eight European sleep laboratories in subjects with different sleep
disorders. Journal Of Sleep Research, 13(1), 63-69.
da Silva, J., Nakamura, M., Cordeiro, J., & Kulay, L. r. (2005). Acupuncture for insomnia in pregnancy -- a
prospective, quasi-randomised, controlled study. Acupuncture In Medicine, 23(2), 47-51.
Datta, S. & MacLean, R.R. (2007.)Neurobiological mechanisms for the regulation of mammalian sleep-wake
behavior: reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence.
Neuroscience & Biobehavioral Reviews, 31(5), 775–824.
Deloitte Access Economics. (2011). Re-awakening Australia: The economic cost of sleep disorders in Australia,
2010. Retrived from http://www.sleephealthfoundation.org.au/pdfs/news/Reawakening%20Australia.pdf.
DeMicco, M., Wang-Weigand, S., Zhang, J.(2006). Long-term therapeutic effects of ramelteon treatment in
adults with chronic insomnia: a 1 year study. Sleep, 29 (Abstract Suppl),A234.
Derbez, R., & Grauer, H. (1967). A sleep study and investigation of a new hypnotic compound in a geriatric
population. Canadian Medical Association Journal, 97(23), 1389-1393.
Di, Y., Li, C., Xue, C., & Zhou, S. (2008). Clinical drugs that interact with St. John's wort and implication in
drug development. Current Pharmaceutical Design, 14(17), 1723-1742.
Diekelmann, S., & Born, J. (2010). The memory function of sleep. Nature Reviews. Neuroscience, 11(2), 114126.
Dietz, B., Mahady, G., Pauli, G., & Farnsworth, N. (2005). Valerian extract and valerenic acid are partial
agonists of the 5-HT5a receptor in vitro. Brain Research. Molecular Brain Research, 138(2), 191-197.
Dijk, D., Duffy, J., & Czeisler, C. (2000). Contribution of circadian physiology and sleep homeostasis to agerelated changes in human sleep. Chronobiology International, 17(3), 285-311.
Döble, A., Canton, T., Malgouris, C., Stutzmann, J., Piot, O., Bardone, M., & ... Blanchard, J. (1995). The
mechanism of action of zopiclone. European Psychiatry: The Journal Of The Association Of European
Psychiatrists, 10 Suppl 3117s-128s.
Doghramji, K. (2006). The epidemiology and diagnosis of insomnia. The American Journal Of Managed
Care, 12(8 Suppl), S214-S220.
Dollman, W., LeBlanc, V., & Roughead, E. (2003). Managing insomnia in the elderly - what prevents us
using non-drug options?. Journal Of Clinical Pharmacy And Therapeutics, 28(6), 485-491.
Dominguez, R., Bravo-Valverde, R., Kaplowitz, B., & Cott, J. (2000). Valerian as a hypnotic for Hispanic
patients. Cultural Diversity & Ethnic Minority Psychology, 6(1), 84-92.
Donath, F., Quispe, S., Diefenbach, K., Maurer, A., Fietze, I., & Roots I. (2000) Clinical evaluation of the
effects of valerian extract on sleep structure and sleep quality. Pharmacopsychiatry, 33(2),47-53.
101
Douglas, N. (2005). Respiratory physiology: Control of ventilation. In M.Kryger, T.Roth, & W.Dement, (Eds.),
Principles and practice of sleep medicine (4th ed., pp. 224–229). Philadelphia: Elsevier/Saunders.
Drake, C., Roehrs, T., & Roth, T. (2003). Insomnia causes, consequences, and therapeutics: an overview.
Depression And Anxiety, 18(4), 163-176.
Dubocovich, M., Delagrange, P., Krause, D., Sugden, D., Cardinali, D., & Olcese, J. (2010). International Union
of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G proteincoupled melatonin receptors. Pharmacological Reviews, 62(3), 343-380.
Dubocovich, M., Rivera-Bermudez, M., Gerdin, M., & Masana, M. (2003). Molecular pharmacology, regulation
and function of mammalian melatonin receptors. Frontiers In Bioscience: A Journal And Virtual Library,
8d1093-d1108.
Dugovic, C. (1992). Functional activity of 5-HT2 receptors in the modulation of the sleep/wakefulness states.
Journal of sleep research,1(3):163-168.
Dündar, Y., Dodd, S., Strobl, J., Boland, A., Dickson, R., & Walley, T. (2004). Comparative efficacy of newer
hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis. Human
Psychopharmacology, 19(5), 305-322.
Dürr, D., Stieger, B., Kullak-Ublick, G., Rentsch, K., Steinert, H., Meier, P., & Fattinger, K. (2000). St John's
Wort induces intestinal P-glycoprotein/MDR1 and intestinal and hepatic CYP3A4. Clinical Pharmacology
And Therapeutics, 68(6), 598-604.
Ebben, M., & Spielman, A. (2009). Non-pharmacological treatments for insomnia. Journal Of Behavioral
Medicine, 32(3), 244-254.
Ebbens, M. M., & Verster J.C. (2010).Clinical evaluation of zaleplon in the treatment of insomnia.Nature and
Science of Sleep,2, 115-126.
Ebert, B. & Wafford, K. A.(2006a). Benzodiazepine receptor agonists and insomnia: is subtype selectivity lost in
translation? . Drug Discovery Today: Therapeutic Strategies ,3(4), 547–554 .
Ebert, B., Wafford, K., & Deacon, S. (2006b). Treating insomnia: Current and investigational pharmacological
approaches. Pharmacology & Therapeutics, 112(3), 612-629.
Edinger, J., & Sampson, W. (2003). A primary care "friendly" cognitive behavioral insomnia therapy. Sleep,
26(2), 177-182.
Edinger, J., & Wohlgemuth, W. (1999). The significance and management of persistent primary insomnia: the
past, present and future of behavioral insomnia therapies. Sleep Medicine Reviews, 3(2), 101-118.
Edinger J. D.,Wohlgemuth,W. K., Radtke, R. A., Marsh, G. R., & Quilian, R. E. (2001). Cognitive behavioral
therapy for treatment of chronic primary insomnia: A randomized controlled trial. Journal of the American
Medical Association, 285(14),1856–1864.
Eggermann, E., Serafin, M., Bayer, L., Machard, D., Saint-Mleux, B., Jones, B., & Mühlethaler, M. (2001).
Orexins/hypocretins excite basal forebrain cholinergic neurones. Neuroscience, 108(2), 177-181.
Ellis, C., Lemmens, G., & Parkes, J. (1996). Melatonin and insomnia. Journal Of Sleep Research, 5(1), 61-65.
Epstein, D.R., & Dirksen, S.R. (2007). Randomized trial of cognitive-behavioral intervention for insomnia in
breast cancer survivors. Oncology Nursing Forum, 34(5), E51–59.
Erman, M., Krystal, A., Zammit, G., Soubrane, C., & Roth, T.(2007). Long-term efficacy of zolpidem extendedrelease in the treatment of sleep maintenance and sleep onset insomnia with improvements in next-day
functioning. Sleep,30, A241–2.
102
Erman, M., Krystal, A., Zammit, G.,(2007). No evidence of rebound insomnia in patients with chronic insomnia
treate with zolpidem extended-release 12.5 mg administered ‘‘as needed’’ 3-7 nights/week for 6 months, Sleep,
30, Suppl,A241-2
Erman, M., Seiden, D., Zammit, G., Sainati, S., & Zhang, J. (2006). An efficacy, safety, and dose-response study
of Ramelteon in patients with chronic primary insomnia. Sleep Medicine, 7(1), 17-24.
Espie, C. A. ( 2002). Insomnia: conceptual issues in the development, persistence, and treatment of sleep
disorder in adults. Annual Review of Psychology,53, 215–243.
Espie, C., Broomfield, N., MacMahon, K., Macphee, L., & Taylor, L. (2006). The attention-intention-effort
pathway in the development of psychophysiologic insomnia: a theoretical review. Sleep Medicine Reviews,
10(4), 215-245.
Espie, C. A., Inglis, S. J., & Harvey, L. (2001). Predicting clinically significant response to cognitive behavior
therapy for chronic insomnia in general medical practice: Analysis of outcome data at 12 months posttreatment.
Journal of Consulting and Clinical Psychology, 69, 58–66.
Espie, C., MacMahon, K., Kelly, H., Broomfield, N., Douglas, N., Engleman, H., & ... Wilson, P. (2007).
Randomized clinical effectiveness trial of nurse-administered small-group cognitive behavior therapy for
persistent insomnia in general practice. Sleep, 30(5), 574-584.
Estivill, E., Bové, A., García-Borreguero, D., Gibert, J., Paniagua, J., Pin, G., & ... Cilveti, R. (2003). Consensus
on drug treatment, definition and diagnosis for insomnia. Clinical Drug Investigation, 23(6), 351-385.
Feige, B., Gann, H., Brueck, R., Hornyak, M., Litsch, S., Hohagen, F., & Riemann, D. (2006). Effects of alcohol
on polysomnographically recorded sleep in healthy subjects. Alcoholism, Clinical And Experimental Research,
30(9), 1527-1537.
Fetveit, A. (2009). Late-life insomnia: a review. Geriatrics & Gerontology International, 9(3), 220-234.
Fick, D., Cooper, J., Wade, W., Waller, J., Maclean, J., & Beers, M. (2003). Updating the Beers criteria for
potentially inappropriate medication use in older adults: results of a US consensus panel of experts [corrected]
[published erratum appears in ARCH INTERN MED 2004 Feb 9;164(3):298]. Archives Of Internal Medicine,
163(22), 2716-2724.
Foley, D., Monjan, A., Brown, S., Simonsick, E., Wallace, R., & Blazer, D. (1995). Sleep complaints among
elderly persons: an epidemiologic study of three communities. Sleep, 18(6), 425-432.
Foley, D., Monjan, A., Simonsick, E., Wallace, R., & Blazer, D. (1999). Incidence and remission of insomnia
among elderly adults: an epidemiologic study of 6,800 persons over three years. Sleep, 22 Suppl 2S366-S372.
Ford, D., & Kamerow, D. (1989). Epidemiologic study of sleep disturbances and psychiatric disorders. An
opportunity for prevention?. JAMA: The Journal Of The American Medical Association, 262(11), 1479-1484.
Friedman, L., Benson, K., Noda, A., Zarcone, V., Wicks, D., O'Connell, K., & ... Yesavage, J. (2000). An
actigraphic comparison of sleep restriction and sleep hygiene treatments for insomnia in older adults. Journal Of
Geriatric Psychiatry And Neurology, 13(1), 17-27.
Friedman, E., Love, G., Rosenkranz, M., Urry, H., Davidson, R., Singer, B., & Ryff, C. (2007). Socioeconomic
status predicts objective and subjective sleep quality in aging women. Psychosomatic Medicine, 69(7), 682-691.
Frisoni, G. B., De Leo, D., Rozzini, R., Bernardini, M., Dello Buono, M., & Trabucchi, M. (1993). Night sleep
symptoms in an elderly population and their relation with age, gender, and education. Clinical Gerontologist, 13,
50– 67.
103
From the Centers for Disease Control and Prevention. Hepatic toxicity possibly associated with kava-containing
products--United States, Germany, and Switzerland, 1999-2002. (2003). JAMA: The Journal Of The American
Medical Association, 289(1), 36-37.
Fry, J., Scharf, M., Mangano, R., Fujimori, M. (2000). Zaleplon improves sleep without producing rebound
effects in outpatients with insomnia. Zaleplon Clinical Study Group. International Clinical
Psychopharmacology, 15(3),141-152.
Fuller, P., Gooley, J., & Saper, C. (2006). Neurobiology of the sleep-wake cycle: sleep architecture, circadian
regulation, and regulatory feedback. Journal Of Biological Rhythms, 21(6), 482-493.
Fullerton, D. (2006). The economic impact of insomnia in managed care: a clearer picture emerges. The
American Journal Of Managed Care, 12(8 Suppl), S246-S252.
Gangwisch, J., Heymsfield, S., Boden-Albala, B., Buijs, R., Kreier, F., Pickering, T., & ... Malaspina, D. (2006).
Short sleep duration as a risk factor for hypertension: analyses of the first National Health and Nutrition
Examination Survey. Hypertension, 47(5), 833-839.
Garfinkel, D., Laudon, M., Nof, D., & Zisapel, N. (1995). Improvement of sleep quality in elderly people by
controlled-release melatonin. Lancet, 346(8974), 541-544.
Goforth, H. (2009). Low-dose doxepin for the treatment of insomnia: emerging data. Expert Opinion On
Pharmacotherapy, 10(10), 1649-1655.
Gellis, L. A., Lichstein, K. L., Scarinci, I. C., Durrence, H., Taylor, D. J., Bush, A. J., & Riedel, B. W. (2005).
Socioeconomic Status and Insomnia. Journal Of Abnormal Psychology, 114(1), 111-118.
Gemma, C., Imeri, L., de Simoni, M., & Mancia, M. (1997). Interleukin-1 induces changes in sleep, brain
temperature, and serotonergic metabolism. The American Journal Of Physiology, 272(2 Pt 2), R601-R606.
Giedke, H., & Breyer-Pfaff, U. (2000). Critical evaluation of the effect of valerian extract on sleep structure and
sleep quality. Pharmacopsychiatry, 33(6), 239.
Goldstein, T., Bridge, J., & Brent, D. (2008). Sleep disturbance preceding completed suicide in adolescents.
Journal Of Consulting And Clinical Psychology, 76(1), 84-91.
Gottlieb, D., Punjabi, N., Newman, A., Resnick, H., Redline, S., Baldwin, C., & Nieto, F. (2005). Association of
sleep time with diabetes mellitus and impaired glucose tolerance. Archives Of Internal Medicine, 165(8), 863867.
Grandner, M., Patel, N., Gehrman, P., Xie, D., Sha, D., Weaver, T., & Gooneratne, N. (2010). Who gets the best
sleep? Ethnic and socioeconomic factors related to sleep complaints. Sleep Medicine, 11(5), 470-478.
Greenberg, D., Surman, O., Clarke, J., & Baer, L. (1987). Alprazolam for phobic nausea and vomiting related to
cancer chemotherapy. Cancer Treatment Reports, 71(5), 549-550.
Greenblatt, D.J., Harmatz, J.S., Sharpiro, L., Engelhardt, N., Gouthro, T.A., & Shader, R.I.(1991). Sensitivity to
triazolam in the elderly. The New England journal of medicine,324(24),1691-8.
Greeson, J., Sanford, B., & Monti, D. (2001). St. John's wort (Hypericum perforatum): a review of the current
pharmacological, toxicological, and clinical literature. Psychopharmacology, 153(4), 402-414.
Griffiths, R., Suess, P., Johnson, M. (2005). Ramelteon and triazolam in humans: behavioral effects and abuse
potential. Sleep,28, A44.
Groeger, J., Zijlstra, F., & Dijk, D. (2004). Sleep quantity, sleep difficulties and their perceived consequences in
a representative sample of some 2000 British adults. Journal Of Sleep Research, 13(4), 359-371.
104
Grozinsky-Glasberg, S., Fichman, S., & Shimon, I. (2010). Metastatic bronchial neuroendocrine tumor to the
pineal gland: a unique manifestation of a rare disease. Hormones (Athens, Greece), 9(1), 87-91.
Gurley, B., Swain, A., Williams, D., Barone, G., & Battu, S. (2008). Gauging the clinical significance of Pglycoprotein-mediated herb-drug interactions: comparative effects of St. John's wort, Echinacea, clarithromycin,
and rifampin on digoxin pharmacokinetics. Molecular Nutrition & Food Research, 52(7), 772-779.
Hagan, J., Price, G., Jeffrey, P., Deeks, N., Stean, T., Piper, D., & ... Thomas, D. (2000). Characterization of SB269970-A, a selective 5-HT(7) receptor antagonist. British Journal Of Pharmacology, 130(3), 539-548.
Hajak, G. (2000). Insomnia in primary care. Sleep, 23 Suppl 3S54-S63.
Hajak, G. (2001). Epidemiology of severe insomnia and its consequences in Germany. European Archives Of
Psychiatry And Clinical Neuroscience, 251(2), 49-56.
Hajak, G., Rodenbeck, A., & Rutber, E. (1994). Sleep-Inducing effects of l-tryptopban. In W. Kocben & H.
Steinbart (Eds), L-tryptophan Current Prospects in Medicine and Drug Safety (63-83). New York, NY: Waiter
de Gruyter & Company.
Hale, L. (2005). Who has time to sleep?. Journal Of Public Health (Oxford, England), 27(2), 205-211.
Hall, M. (2010). Behavioral medicine and sleep: Concepts, measures and methods. In A.Steptoe (Ed.),
Handbook of behavioral medicine: Methods and applications (pp. 749–768). Berlin: Springer.
Hall, M., Matthews, K., Kravitz, H., Gold, E., Buysse, D., Bromberger, J., & ... Sowers, M. (2009). Race and
financial strain are independent correlates of sleep in midlife women: the SWAN sleep study. Sleep, 32(1), 7382.
Hall, M., Okun, M. L., Atwood, C. W., Buysse, D. J., & Strollo, P. J. (2008). Measurement of sleep by
polysomnography. In L. L.Luecken & L. C.Gallo (Eds.), Handbook of physiological research methods in health
psychology (pp. 341–367).London: Sage Publications.
Hall-Porter, J., Curry, D., & Walsh, J. (2010). Pharmacologic Treatment of Primary Insomnia . Sleep Medicine
Clinics, 5(4), 609-625.
Halpert, A., Olmstead, M., & Beninger, R. (2002). Mechanisms and abuse liability of the anti-histamine
dimenhydrinate. Neuroscience And Biobehavioral Reviews, 26(1), 61-67.
Harazin, J., & Berigan, T. (1999). Zolpidem tartrate and somnambulism. Military Medicine, 164(9), 669-670.
Harrer, G., Schmidt, U., Kuhn, U., & Biller, A. (1999). Comparison of equivalence between the St. John's wort
extract LoHyp-57 and fluoxetine. Arzneimittel-Forschung, 49(4), 289-296.
Harsora, P., & Kessmann, J. (2009). Nonpharmacologic management of chronic insomnia. American Family
Physician, 79(2), 125-130.
Hartmann, E., Lindsley, J., & Spinweber, C. (1983). Chronic insomnia: effects of tryptophan, flurazepam,
secobarbital, and placebo. Psychopharmacology, 80(2), 138-142.
Hartz, A., Daly, J., Kohatsu, N., Stromquist, A., Jogerst, G., & Kukoyi, O. (2007). Risk factors for insomnia in a
rural population. Annals Of Epidemiology, 17(12), 940-947.
Harvey, A. (2002). A cognitive model of insomnia. Behaviour Research And Therapy, 40(8), 869-893.
Harvey, A. G. (2005). A Cognitive Theory and Therapy for Chronic Insomnia. Journal Of Cognitive
Psychotherapy, 19(1), 41-59.
105
Harvey, A., Murray, G., Chandler, R., & Soehner, A. (2011). Sleep disturbance as transdiagnostic: consideration
of neurobiological mechanisms. Clinical Psychology Review, 31(2), 225-235.
Harvey, A., Sharpley, A., Ree, M., Stinson, K., & Clark, D. (2007). An open trial of cognitive therapy for
chronic insomnia. Behaviour Research And Therapy, 45(10), 2491-2501.
Harvey, A., & Tang, N. (2003). Cognitive behaviour therapy for primary insomnia: can we rest yet?. Sleep
Medicine Reviews, 7(3), 237-262.
Hauri, P. (1991). Case studies in insomnia. New York: Plenum Press.
Hayes, B., Klein-Schwartz, W., & Barrueto, F. (2007). Polypharmacy and the geriatric patient. Clinics In
Geriatric Medicine, 23(2), 371.
Hedlund, P., Huitron-Resendiz, S., Henriksen, S., & Sutcliffe, J. (2005). 5-HT7 receptor inhibition and
inactivation induce antidepressantlike behavior and sleep pattern. Biological Psychiatry, 58(10), 831-837.
Henderson, L. L., Yue, Q. Y., Bergquist, C. C., Gerden, B. B., & Arlett, P. P. (2002). St John's wort (Hypericum
perforatum ): drug interactions and clinical outcomes. British Journal Of Clinical Pharmacology, 54(4), 349356.
Hennessy, M. M., Kelleher, D. D., Spiers, J. P., Barry, M. M., Kavanagh, P. P., Back, D. D., & ... Feely, J. J.
(2002). St John's Wort increases expression of P-glycoprotein: Implications for drug interactions. British Journal
Of Clinical Pharmacology, 53(1), 75-82.
Hepatic toxicity possibly associated with kava-containing products--United States, Germany, and Switzerland,
1999-2002. (2002). MMWR. Morbidity And Mortality Weekly Report, 51(47), 1065-1067.
Herxheimer, A., & Petrie, K. (2002). Melatonin for the prevention and treatment of jet lag. Cochrane Database
Of Systematic Reviews (Online), (2), CD001520.
Hetta, J., Broman, J., & Mallon, L. (1999). Evaluation of severe insomnia in the general population-implications for the management of insomnia: insomnia, quality of life and healthcare consumption in Sweden.
Journal Of Psychopharmacology (Oxford, England), 13(4 Suppl 1), S35-S36.
Hillman, D., Murphy, A., & Pezzullo, L. (2006). The economic cost of sleep disorders. Sleep, 29(3), 299-305.
Himanen, S., & Hasan, J.(2000). Limitations of Rechtschaffen and Kales. Sleep Medicine Reviews, 4 (2), 149–
167.
Hibberd, M., Stevenson, S.J.(2004).Aphase-I open-label study of the absorption, metabolism, and excretion of
(14C)-ramelteon (TAK-375) following a single oral dose in healthy male subjects. Sleep, 27, A54.
Hirai, K., Kato, K., Nishiyama, K., Hinuma, S., Uchikawa, O., Ohkawa, S., and Miyamoto, M. (2003). TAK-375
and its metabolites are selective agonists at ML1 receptors. Sleep, 26:A79.
Hislop, J., & Arber, S. (2003). Understanding women's sleep management: beyond medicalizationhealthicization?. Sociology Of Health & Illness, 25(7), 815-837.
Hoffmann, G. (1999). Evaluation of severe insomnia in the general population--implications for the management
of insomnia: focus on results from Belgium. Journal Of Psychopharmacology (Oxford, England), 13(4 Suppl 1),
S31-S32.
Holbrook, A., Crowther, R., Lotter, A., Cheng, C., & King, D. (2000). Meta-analysis of benzodiazepine use in
the treatment of insomnia. CMAJ: Canadian Medical Association Journal = Journal De L'association Medicale
Canadienne, 162(2), 225-233.
106
Holbrook, A., Crowther, R., Lotter, A., & Endeshaw, Y. (2001). The role of benzodiazepines in the treatment of
insomnia: meta-analysis of benzodiazepine use in the treatment of insomnia. Journal Of The American
Geriatrics Society, 49(6), 824-826.
Hoque, R., & Chesson, A. (2009). Zolpidem-induced sleepwalking, sleep related eating disorder, and sleepdriving: fluorine-18-flourodeoxyglucose positron emission tomography analysis, and a literature review of other
unexpected clinical effects of zolpidem. Journal Of Clinical Sleep Medicine: JCSM: Official Publication Of The
American Academy Of Sleep Medicine, 5(5), 471-476.
Huang, L., Wang, D., Wang, C., Hu, Y., Zhou, J., & Li, N. (2009). The needle-rolling therapy for treatment of
non-organic chronic insomnia in 90 cases. Journal Of Traditional Chinese Medicine = Chung I Tsa Chih Ying
Wen Pan / Sponsored By All-China Association Of Traditional Chinese Medicine, Academy Of Traditional
Chinese Medicine, 29(1), 19-23.
Humberston, C., Akhtar, J., & Krenzelok, E. (2003). Acute hepatitis induced by kava kava. Journal Of
Toxicology. Clinical Toxicology, 41(2), 109-113.
Husain, Z., Hussain, K., Nair, R., & Steinman, R. (2010). Diphenhydramine induced QT prolongation and
torsade de pointes: An uncommon effect of a common drug. Cardiology Journal, 17(5), 509-511.
Iber, C., Ancoli-Israel, S., Chesson, A. L., & Quan, S. F. (2007). The AASM Manual for the Scoring of Sleep and
Associated Events: Rules, Terminology, and Technical Specifications. Westchester, IL: American Academy of
Sleep Medicine.
Imeri, L., Bianchi, S., & Opp, M. (2005). Antagonism of corticotropin-releasing hormone alters serotonergicinduced changes in brain temperature, but not sleep, of rats. American Journal Of Physiology. Regulatory,
Integrative And Comparative Physiology, 289(4), R1116-R1123.
Imeri, L., Mancia, M., Bianchi, S., & Opp, M. (2000). 5-Hydroxytryptophan, but not L-tryptophan, alters sleep
and brain temperature in rats. Neuroscience, 95(2), 445-452.
Irwin, M., Wang, M., Campomayor, C., Collado-Hidalgo, A., & Cole, S. (2006). Sleep deprivation and
activation of morning levels of cellular and genomic markers of inflammation. Archives Of Internal Medicine,
166(16), 1756-1762.
Irwin, M., McClintick, J., Costlow, C., Fortner, M., White, J., & Gillin, J. (1996). Partial night sleep deprivation
reduces natural killer and cellular immune responses in humans. The FASEB Journal: Official Publication Of
The Federation Of American Societies For Experimental Biology, 10(5), 643-653.
Issa, F., & Sullivan, C. (1982). Alcohol, snoring and sleep apnea. Journal Of Neurology, Neurosurgery, And
Psychiatry, 45(4), 353-359.
Izzo, A., & Ernst, E. (2009). Interactions between herbal medicines and prescribed drugs: an updated systematic
review. Drugs, 69(13), 1777-1798.
Jacobs, B., Bent, S., Tice, J., Blackwell, T., & Cummings, S. (2005). An internet-based randomized, placebocontrolled trial of kava and valerian for anxiety and insomnia. Medicine, 84(4), 197-207.
Jacobs, G., Pace-Schott, E., Stickgold, R., & Otto, M. (2004). Cognitive behavior therapy and pharmacotherapy
for insomnia: a randomized controlled trial and direct comparison. Archives Of Internal Medicine, 164(17),
1888-1896.
Janson, C., Lindberg, E., Gislason, T., Elmasry, A., & Boman, G. (2001). Insomnia in men-a 10-year prospective
population based study. Sleep, 24(4), 425-430.
107
Jarrett, M., Heitkemper, M., Cain, K., Burr, R., & Hertig, V. (2000). Sleep disturbance influences
gastrointestinal symptoms in women with irritable bowel syndrome. Digestive Diseases And Sciences, 45(5),
952-959.
Jasser, S. A., Blask, D. E., & Brainard, G. C. (2006). Light during darkness and cancer: Relationships in
circadian photoreception and tumor biology. Cancer Causes Control, 17(4), 515–523.
Jindal, R. D. (2009). Insomnia in Patients with Depression: Some Pathophysiological and Treatment
Considerations. CNS Drugs, 23(4), 309-329.
Joester, J., Vogler, C., Chang, K., & Hilmer, S. (2010). Hypnosedative use and predictors of successful
withdrawal in new patients attending a falls clinic: a retrospective, cohort study. Drugs & Aging, 27(11), 915924.
Johne, A., Schmider, J., Brockmöller, J., Stadelmann, A., Störmer, E., Bauer, S., & ... Roots, I. (2002).
Decreased plasma levels of amitriptyline and its metabolites on comedication with an extract from St. John's
wort ( Hypericum perforatum ). Journal Of Clinical Psychopharmacology, 22(1), 46-54.
Johns, M. (1991). A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep, 14(6),
540-545.
Johnson, E., Roehrs, T., Roth, T., & Breslau, N. (1998). Epidemiology of alcohol and medication as aids to sleep
in early adulthood. Sleep, 21(2), 178-186.
Johnson, E., Roth, T., Schultz, L., & Breslau, N. (2006). Epidemiology of DSM-IV insomnia in adolescence:
lifetime prevalence, chronicity, and an emergent gender difference. Pediatrics, 117(2), e247-e256.
Johnson, M., Suess, P., & Griffiths, R. (2006). Ramelteon: a novel hypnotic lacking abuse liability and sedative
adverse effects. Archives Of General Psychiatry, 63(10), 1149-1157.
Jones, B. (2005). From waking to sleeping: neuronal and chemical substrates. Trends In Pharmacological
Sciences, 26(11), 578-586.
Jouvet, M. (1999). Sleep and serotonin: an unfinished story. Neuropsychopharmacology: Official Publication Of
The American College Of Neuropsychopharmacology, 21(2 Suppl), 24S-27S.
Kamel, N., & Gammack, J. (2006). Insomnia in the elderly: cause, approach, and treatment. The American
Journal Of Medicine, 119(6), 463-469.
Kan, C., Hilberink, S., & Breteler, M. (2004). Determination of the main risk factors for benzodiazepine
dependence using a multivariate and multidimensional approach. Comprehensive Psychiatry, 45(2), 88-94.
Karim, A., Tolbert, D., & Cao, C. (2006). Disposition kinetics and tolerance of escalating single doses of
ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia.
Journal Of Clinical Pharmacology, 46(2), 140-148.
Karlen, W., Mattiussi, C., & Floreano, D.(2009). Sleep and Wake Classification With ECG and Respiratory
Effort Signals., IEEE Transactions on Biomedical Circuits and Systems , 3(2), 71-78.
Karliova, M., Treichel, U., Malago, M., Frilling, A., Gerken, G., & Broelsch C.(2000). Interaction of
Hypericum perforatum (St. John’s wort) with cyclosporin A metabolism in a patient after liver transplantation
.Journal of Hepatology,33(5), 853-855.
Kashyap, K., Nissen, L., Smith, S., & Kyle, G. (2012). Supply of non-prescription “pharmacist-only”
doxylamine tablets in Australian community pharmacies: a simulated patient study.Paper contributed to the
108
Treatment of insomnia and insomnia associated with psychiatric disorders, 21st Congress of the European Sleep
Research Society Paris, France 04.09.2012 - 08.09.2012.
Kato, K., Hirai, K., Nishiyama, K., Uchikawa, O., Fukatsu, K., Ohkawa, S., & ... Miyamoto, M. (2005).
Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist.
Neuropharmacology, 48(2), 301-310.
Katz, D., & McHorney, C. (1998). Clinical correlates of insomnia in patients with chronic illness. Archives Of
Internal Medicine, 158(10), 1099-1107.
Kaufmann, C., Wehrle, R., Wetter, T., Holsboer, F., Auer, D., Pollmächer, T., & Czisch, M. (2006). Brain
activation and hypothalamic functional connectivity during human non-rapid eye movement sleep: an
EEG/fMRI study. Brain: A Journal Of Neurology, 129(Pt 3), 655-667.
Kiejna, A. A., Wojtyniak, B. B., Rymaszewska, J. J., & Stokwiszewski, J. J. (2003). Prevalence of insomnia in
Poland — results of the National Health Interview Survey. Acta Neuropsychiatrica, 15(2), 68-73.
Kim, J., S. Tofade, S. T., & Peckman, H.(2009).Caring for the Elderly in an Inpatient Setting: Managing
Insomnia and Polypharmacy. Journal of Pharmacy Practice, 22(5), 494-506.
Kippist, C., Wong, K., Bartlett, D., & Saini, B. (2011). How do pharmacists respond to complaints of acute
insomnia? A simulated patient study. International Journal Of Clinical Pharmacy, 33(2), 237-245.
Klink, M., & Quan, S. (1987). Prevalence of reported sleep disturbances in a general adult population and their
relationship to obstructive airways diseases. Chest, 91(4), 540-546.
Klink, M., Quan, S., Kaltenborn, W., & Lebowitz, M. (1992). Risk factors associated with complaints of
insomnia in a general adult population. Influence of previous complaints of insomnia. Archives Of Internal
Medicine, 152(8), 1634-1637.
Komada, Y., Nomura, T., Kusumi, M., Nakashima, K., Okajima, I., Sasai, T., & Inoue, Y. (2011). Correlations
among insomnia symptoms, sleep medication use and depressive symptoms. Psychiatry And Clinical
Neurosciences, 65(1), 20-29.
Komori, T., Matsumoto, T., Motomura, E., & Shiroyama, T. (2006). The sleep-enhancing effect of valerian
inhalation and sleep-shortening effect of lemon inhalation. Chemical Senses, 31(8), 731-737.
Kravitz, H., Janssen, I., Santoro, N., Bromberger, J., Schocken, M., Everson-Rose, S., & ... Powell, L. (2005).
Relationship of day-to-day reproductive hormone levels to sleep in midlife women. Archives Of Internal
Medicine, 165(20), 2370-2376.
Krieger, J. (2000). Respiratory physiology: Breathing in normal subjects. In M. H. Kryger, T. Roth & W. C.
Dement (Eds), Principles and practice of sleep medicine (pp. 229–241). Philadelphia: WB Saunders.
Kris, M., Gralla, R., Clark, R., Tyson, L., Fiore, J., Kelsen, D., & Groshen, S. (1985). Consecutive dose-finding
trials adding lorazepam to the combination of metoclopramide plus dexamethasone: improved subjective
effectiveness over the combination of diphenhydramine plus metoclopramide plus dexamethasone. Cancer
Treatment Reports, 69(11), 1257-1262.
Krueger, J., Obál, F., Fang, J., Kubota, T., & Taishi, P. (2001). The role of cytokines in physiological sleep
regulation. Annals Of The New York Academy Of Sciences, 933211-221.
Krystal, A., Durrence, H., Scharf, M., Jochelson, P., Rogowski, R., Ludington, E., & Roth, T. (2010). Efficacy
and Safety of Doxepin 1 mg and 3 mg in a 12-week Sleep Laboratory and Outpatient Trial of Elderly Subjects
with Chronic Primary Insomnia. Sleep, 33(11), 1553-1561.
109
Krystal, A., Edinger, J., Wohlgemuth, W., & Marsh, G. (2002). NREM sleep EEG frequency spectral correlates
of sleep complaints in primary insomnia subtypes. Sleep, 25(6), 630-640.
Krystal, A., Erman, M., Zammit, G., Soubrane, C., & Roth, T. (2008). Long-term efficacy and safety of
zolpidem extended-release 12.5 mg, administered 3 to 7 nights per week for 24 weeks, in patients with chronic
primary insomnia: a 6-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter study.
Sleep, 31(1), 79-90.
Krystal, A., Lankford, A., Durrence, H., Ludington, E., Jochelson, P., Rogowski, R., & Roth, T. (2011). Efficacy
and safety of doxepin 3 and 6 mg in a 35-day sleep laboratory trial in adults with chronic primary insomnia.
Sleep, 34(10), 1433-1442.
Krystal, A., Rogers, S., & Fitzgerald, M. (2006). Long-term pharmacotherapy in the management of chronic
insomnia. Journal For Nurse Practitioners, 2(9), S621-32.
Krystal, A., Walsh, J., Laska, E., Caron, J., Amato, D., Wessel, T., & Roth, T. (2003). Sustained efficacy of
eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study
in adults with chronic insomnia. Sleep, 26(7), 793-799.
Krystal, A., Walsh, J.K., Rubens, R.(2006). Efficacy and safety of six-months of nightly eszopiclone in patients
with primary insomnia: a second long term placebo-controlled study. Sleep, 29(Suppl):A249.
Kudo, Y., & Kurihara, M. (1990). Clinical evaluation of diphenhydramine hydrochloride for the treatment of
insomnia in psychiatric patients: a double-blind study. Journal Of Clinical Pharmacology, 30(11), 1041-1048.
Kühlwein, E., Hauger, R., & Irwin, M. (2003). Abnormal nocturnal melatonin secretion and disordered sleep in
abstinent alcoholics. Biological Psychiatry, 54(12), 1437-1443.
Kummer, J., Guendel, L., Linden, J., Eich, F.X., Attali, P., Coquelin, J.P., & Kyrein, H.J. (1993). Long-term
polysomnographic efficacy and safety of zolpidem in elderly psychiatric in-patients with insomnia. The Journal
of International Medical Research, , 21(4),171-184.
Kuppermann, M., Lubeck, D., Mazonson, P., Patrick, D., Stewart, A., Buesching, D., & Fifer, S. (1995). Sleep
problems and their correlates in a working population. Journal Of General Internal Medicine, 10(1), 25-32.
Kushida, C., Littner, M., Morgenthaler, T., Alessi, C., Bailey, D., Coleman, J., & ... Wise, M. (2005). Practice
parameters for the indications for polysomnography and related procedures: an update for 2005. Sleep, 28(4),
499-521.
Lacks, P. (1987). Behavioral treatment for persistent insomnia. New York: Pergamon Press.
Lande, R., & Gragnani, C. (2010). Nonpharmacologic approaches to the management of insomnia. The Journal
Of The American Osteopathic Association, 110(12), 695-701.
Lane-Brown, M. (2000). Photosensitivity associated with herbal preparations of St John's wort (Hypericum
perforatum). The Medical Journal Of Australia, 172(6), 302.
Lankford, D., Corser, B., Zheng, Y., Li, Z., Snavely, D., Lines, C., & Deacon, S. (2008). Effect of gaboxadol on
sleep in adult and elderly patients with primary insomnia: results from two randomized, placebo-controlled, 30night polysomnography studies. Sleep, 31(10), 1359-1370.
Lankford, A., Rogowski, R., Essink, B., Ludington, E., Heith Durrence, H., & Roth, T. (2012). Efficacy and
safety of doxepin 6mg in a four-week outpatient trial of elderly adults with chronic primary insomnia. Sleep
Medicine, 13(2), 133-138.
110
Latimer Hill, E., Cumming, R., Lewis, R., Carrington, S., & Le Couteur, D. (2007). Sleep disturbances and falls
in older people. The Journals Of Gerontology. Series A, Biological Sciences And Medical Sciences, 62(1), 62-66.
Lantz, M., Buchalter, E., & Giambanco, V. (1999). St. John's wort and antidepressant drug interactions in the
elderly. Journal Of Geriatric Psychiatry And Neurology, 12(1), 7-10.
Lauderdale, D., Knutson, K., Yan, L., Rathouz, P., Hulley, S., Sidney, S., & Liu, K. (2006). Objectively
measured sleep characteristics among early-middle-aged adults: the CARDIA study. American Journal Of
Epidemiology, 164(1), 5-16.
Leathwood, P., & Chauffard, F. (1985). Aqueous extract of valerian reduces latency to fall asleep in man. Planta
Medica, (2), 144-148.
Leathwood, P., Chauffard, F., Heck, E., & Munoz-Box, R. (1982). Aqueous extract of valerian root (Valeriana
officinalis L.) improves sleep quality in man. Pharmacology, Biochemistry, And Behavior, 17(1), 65-71.
Lee, K., & Birring, S. (2010). Cough and sleep. Lung, 188 Suppl 1S91-S94.
Léger, D., & Bayon, V. (2010). Societal costs of insomnia. Sleep Medicine Reviews, 14(6), 379-389.
Leger, D., Guilleminault, C., Dreyfus, J., Delahaye, C., & Paillard, M. (2000). Prevalence of insomnia in a
survey of 12,778 adults in France. Journal Of Sleep Research, 9(1), 35-42.
Léger, D., Massuel, M., & Metlaine, A. (2006). Professional correlates of insomnia. Sleep, 29(2), 171-178.
Lehrl, S. (2004). Clinical efficacy of kava extract WS 1490 in sleep disturbances associated with
anxietydisorders.Results of a multicenter, randomized, placebo-controlled, double-blind clinical trial. Journal of
Affective Disorders, 78(2),101-110.
Lemoine, P., Garfinkel, D., Laudon, M., Nir, T., & Zisapel, N. (2011). Prolonged-release melatonin for insomnia
- an open-label long-term study of efficacy, safety, and withdrawal. Therapeutics And Clinical Risk
Management, 7301-311.
Lemoine, P., Nir, T., Laudon, M., & Zisapel, N. (2007). Prolonged-release melatonin improves sleep quality and
morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. Journal Of Sleep
Research, 16(4), 372-380.
Liljenberg, B., Almqvist, M., Hetta, J., Roos, B., & Agren, H. (1988). The prevalence of insomnia: the
importance of operationally defined criteria. Annals Of Clinical Research, 20(6), 393-398.
Livingston, G., Blizard, B., & Mann, A. (1993). Does sleep disturbance predict depression in elderly people? A
study in inner London. The British Journal Of General Practice: The Journal Of The Royal College Of General
Practitioners, 43(376), 445-448.
Levitan, R., Shen, J., Jindal, R., Driver, H., Kennedy, S., & Shapiro, C. (2000). Preliminary randomized doubleblind placebo-controlled trial of tryptophan combined with fluoxetine to treat major depressive disorder:
antidepressant and hypnotic effects. Journal Of Psychiatry & Neuroscience: JPN, 25(4), 337-346.
Leybishkis, B., Fasseas, P., & Ryan, K. (2001). Doxylamine overdose as a potential cause of rhabdomyolysis.
The American Journal Of The Medical Sciences, 322(1), 48-49.
Lichstein, K., Wilson, N., & Johnson, C. (2000). Psychological treatment of secondary insomnia. Psychology
And Aging, 15(2), 232-240.
Lichstein, K., Riedel, B., Wilson, N., Lester, K., & Aguillard, R. (2001). Relaxation and sleep compression for
late-life insomnia: a placebo-controlled trial. Journal Of Consulting And Clinical Psychology, 69(2), 227-239.
111
Lim, J., & Dinges, D. (2008). Sleep deprivation and vigilant attention. Annals Of The New York Academy Of
Sciences, 1129305-322.
Lindahl, O., & Lindwall, L. (1989). Double blind study of a valerian preparation. Pharmacology Biochemistry
and Behavior , 32(4),1065-1066.
Lindberg, E., Janson, C., Gislason, T., Björnsson, E., Hetta, J., & Boman, G. (1997). Sleep disturbances in a
young adult population: can gender differences be explained by differences in psychological status?. Sleep,
20(6), 381-387.
Lindsley, J.G., Hartmann, E.L., & Mitchell, W.(1983). Selectivity in response to L-tryptophan among insomniac
subjects: a preliminary report. Sleep, 6(3), , 247-256.
Lippmann, S., Mazour, I., & Shahab, H. (2001). Insomnia: Therapeutic Approach. Southern Medical Journal,
94(9), 866.
Liskow, B., & Pikalov, A. (2004). Zaleplon overdose associated with sleepwalking and complex behavior.
Journal Of The American Academy Of Child And Adolescent Psychiatry, 43(8), 927-928.
Lu, J., Sherman, D., Devor, M., & Saper, C. (2006). A putative flip-flop switch for control of REM sleep.
Nature, 441(7093), 589-594.
Luthringer, R., Muzet, M., Zisapel, N., & Staner, L. (2009). The effect of prolonged-release melatonin on sleep
measures and psychomotor performance in elderly patients with insomnia. International Clinical
Psychopharmacology, 24(5), 239-249.
Lydic, R., McCarley, R., & Hobson, J. (1987). Serotonin neurons and sleep. I. Long term recordings of dorsal
raphe discharge frequency and PGO waves. Archives Italiennes De Biologie, 125(4), 317-343.
Maarek, L., Cramer, P., Attali, P., Coquelin, J.P., & Morselli, P.L. (1992). The safety and efficacy of zolpidem
in insomniac patients: a long-term open study in general practice. Journal of International Medical Research,
20(2), 162-170.
MacFarlane, J., Cleghorn, J., Brown, G., & Streiner, D. (1991). The effects of exogenous melatonin on the total
sleep time and daytime alertness of chronic insomniacs: a preliminary study. Biological Psychiatry, 30(4), 371376.
Madsen, P., Schmidt, J., Wildschiødtz, G., Friberg, L., Holm, S., Vorstrup, S., & Lassen, N. (1991a). Cerebral
O2 metabolism and cerebral blood flow in humans during deep and rapid-eye-movement sleep. Journal Of
Applied Physiology (Bethesda, Md.: 1985), 70(6), 2597-2601.
Madsen, P., Holm, S., Vorstrup, S., Friberg, L., Lassen, N., & Wildschiødtz, G. (1991b). Human regional
cerebral blood flow during rapid-eye-movement sleep. Journal Of Cerebral Blood Flow And Metabolism:
Official Journal Of The International Society Of Cerebral Blood Flow And Metabolism, 11(3), 502-507.
Mahendran, R., Subramaniam, M., & Chan, Y. (2007). Psychiatric morbidity in patients referred to an insomnia
clinic. Singapore Medical Journal, 48(2), 163-165.
Mahdy, A., & Webster, N. (2011). Histamine and antihistamines. Anaesthesia and intensive care
medicine,12(7), 324–329.
Mannel, M. (2004). Drug interactions with St John's wort : mechanisms and clinical implications. Drug Safety:
An International Journal Of Medical Toxicology And Drug Experience, 27(11), 773-797.
112
Markowitz, J., DeVane, C., Boulton, D., Carson, S., Nahas, Z., & Risch, S. (2000). Effect of St. John's wort
(Hypericum perforatum) on cytochrome P-450 2D6 and 3A4 activity in healthy volunteers. Life Sciences, 66(9),
PL133-PL139.
Martins, A. C., & Gloria, M. B. (2010). Changes on the levels of serotonin precursors –tryptophan and 5hydroxytryptophan – during roasting of Arabica and Robusta coffee. Food Chemistry, 118(3), 529–533.
Mayer, G., Wang-Weigand, S., Roth-Schechter, B., Lehmann, R., Staner, C., & Partinen, M. (2009). Efficacy
and safety of 6-month nightly ramelteon administration in adults with chronic primary insomnia. Sleep, 32(3),
351-360.
McCall, W. (2005). Diagnosis and management of insomnia in older people. Journal Of The American
Geriatrics Society, 53(7 Suppl), S272-S277.
McCarley, R. (2007). Neurobiology of REM and NREM sleep. Sleep Medicine, 8(4), 302-330.
McCurry, S., Logsdon, R., Teri, L., & Vitiello, M. (2007). Evidence-based psychological treatments for
insomnia in older adults. Psychology And Aging, 22(1), 18-27.
McGinty, D., & Harper, R. (1976). Dorsal raphe neurons: depression of firing during sleep in cats. Brain
Research, 101(3), 569-575.
Mellinger, G.D., Balter, M.B., & Uhlenhuth, E.H.(1985). Insomnia and Its Treatment: Prevalence and
Correlates. Archives of General Psychiatry, 42(3),225-232.
Meltzer, L., & Mindell, J. (2006). Impact of a child's chronic illness on maternal sleep and daytime functioning.
Archives Of Internal Medicine, 166(16), 1749-1755.
Mendelson, W. (1994). Sleepwalking associated with zolpidem. Journal Of Clinical Psychopharmacology,
14(2), 150.
Mendelson, W., Thompson, C., & Franko, T. (1996). Adverse reactions to sedative/hypnotics: three years'
experience. Sleep, 19(9), 702-706.
Meisinger, C., Heier, M., Löwel, H., Schneider, A., & Döring, A. (2007). Sleep duration and sleep complaints
and risk of myocardial infarction in middle-aged men and women from the general population: the
MONICA/KORA Augsburg cohort study. Sleep, 30(9), 1121-1127.
Meolie, A., Rosen, C., Kristo, D., Kohrman, M., Gooneratne, N., Aguillard, R., & ... Mahowald, M. (2005). Oral
nonprescription treatment for insomnia: an evaluation of products with limited evidence. Journal Of Clinical
Sleep Medicine: JCSM: Official Publication Of The American Academy Of Sleep Medicine, 1(2), 173-187.
Merlotti, L., Roehrs, T., Zorick, F., & Roth, T. (1991). Rebound insomnia: duration of use and individual
differences. Journal Of Clinical Psychopharmacology, 11(6), 368-373.
Meuleman, J., Nelson, R., & Clark, R. (1987). Evaluation of temazepam and diphenhydramine as hypnotics in a
nursing-home population. Drug Intelligence & Clinical Pharmacy, 21(9), 716-720.
Milner, C.E., & Belicki, K. (2010). Assessment and Treatment of Insomnia in Adults: A Guide for Clinicians.
Journal Of Counseling & Development, 88(2), 236-244.
Michelson, D., Page, S., Casey, R., Trucksess, M., Love, L., Milstien, S., & ... Hallett, M. (1994). An
eosinophilia-myalgia syndrome related disorder associated with exposure to L-5-hydroxytryptophan. The
Journal Of Rheumatology, 21(12), 2261-2265.
Middelkoop, H., Smilde-van den Doel, D., Neven, A., Kamphuisen, H., & Springer, C. (1996). Subjective sleep
characteristics of 1,485 males and females aged 50-93: effects of sex and age, and factors related to self-
113
evaluated quality of sleep. The Journals Of Gerontology. Series A, Biological Sciences And Medical Sciences,
51(3), M108-M115.
Mignot, E., Taheri, S., & Nishino, S. (2002). Sleeping with the hypothalamus: emerging therapeutic targets for
sleep disorders. Nature Neuroscience, 5 Suppl1071-1075.
MIMS Medicines Database. [Retrieved] March 12, 2012 MIMS Medicines Database [database].
Mitchell, H., & Weinshenker, D. (2010). Good night and good luck: norepinephrine in sleep pharmacology.
Biochemical Pharmacology, 79(6), 801-809.
Mizoguchi, H., Wilson, A., Jerdack, G., Hull, J., Goodale, M., Grender, J., & Tyler, B. (2007). Efficacy of a
single evening dose of syrup containing paracetamol, dextromethorphan hydrobromide, doxylamine succinate
and ephedrine sulfate in subjects with multiple common cold symptoms. International Journal Of Clinical
Pharmacology And Therapeutics, 45(4), 230-236.
Möhler, H., Fritschy, J., & Rudolph, U. (2002). A new benzodiazepine pharmacology. The Journal Of
Pharmacology And Experimental Therapeutics, 300(1), 2-8.
Montakab, H. (1999). [Acupuncture and insomnia]. Forschende Komplementärmedizin, 6 Suppl 129-31.
Montes,L., Uribe,M., Sotres, J. and Martin, G. (2003). Treatment of primary insomnia with melatonin: a
double-blind, placebo-controlled, crossover study. Journal Of Psychiatry & Neuroscience, 28(3), 191.
Monti, J. (2011). Serotonin control of sleep-wake behavior. Sleep Medicine Reviews, 15(4), 269-281.
Moore, L., Goodwin, B., Jones, S., Wisely, G., Serabjit-Singh, C., Willson, T., & ... Kliewer, S. (2000). St.
John's wort induces hepatic drug metabolism through activation of the pregnane X receptor. Proceedings Of The
National Academy Of Sciences Of The United States Of America, 97(13), 7500-7502.
Morgenthaler, T., Kramer, M., Alessi, C., Friedman, L., Boehlecke, B., Brown, T., & ... Swick, T. (2006).
Practice parameters for the psychological and behavioral treatment of insomnia: an update. An american
academy of sleep medicine report. Sleep, 29(11), 1415-1419.
Morgenthaler, T., & Silber, M. (2002). Amnestic sleep-related eating disorder associated with zolpidem. Sleep
Medicine, 3(4), 323-327.
Mori, K., Saito, Y., & Tominaga, K. (1993). Antiemetic efficacy of alprazolam in the combination of
metoclopramide plus methylprednisolone. Double-blind randomized crossover study in patients with cisplatininduced emesis. American Journal Of Clinical Oncology, 16(4), 338-341.
Morin, C.M. (1993). Insomnia: Psychological assessment and management. New York: Guilford.
Morin, C. (2004). Cognitive-behavioral approaches to the treatment of insomnia. The Journal Of Clinical
Psychiatry, 65 Suppl 1633-40.
Morin, C., Bastien, C., Guay, B., Radouco-Thomas, M., Leblanc, J., & Vallières, A. (2004). Randomized clinical
trial of supervised tapering and cognitive behavior therapy to facilitate benzodiazepine discontinuation in older
adults with chronic insomnia. The American Journal Of Psychiatry, 161(2), 332-342.
Morin, C., & Benca, R. (2012). Chronic insomnia. Lancet, 379(9821), 1129-1141.
Morin, C., Bootzin, R., Buysse, D., Edinger, J., Espie, C., & Lichstein, K. (2006). Psychological and behavioral
treatment of insomnia:update of the recent evidence (1998-2004). Sleep, 29(11), 1398-1414.
114
Morin, C., Colecchi, C., Stone, J., Sood, R., & Brink, D. (1999 b). Behavioral and pharmacological therapies for
late-life insomnia: a randomized controlled trial. JAMA: The Journal Of The American Medical Association,
281(11), 991-999.
Morin, C., & Espie, C. (Eds.). (2003). Insomnia: A clinical guide to assessment and treatment. New York:
Kluwer Academic.
Morin, C., Hauri, P., Espie, C., Spielman, A., Buysse, D., & Bootzin, R. (1999 a). Nonpharmacologic treatment
of chronic insomnia. An American Academy of Sleep Medicine review. Sleep, 22(8), 1134-1156.
Morin, C., LeBlanc, M., Daley, M., Gregoire, J., & Mérette, C. (2006). Epidemiology of insomnia: prevalence,
self-help treatments, consultations, and determinants of help-seeking behaviors. Sleep Medicine, 7(2), 123-130.
Morin, C., Koetter, U., Bastien, C., Ware, J., & Wooten, V.(2005). Valerian-hops combination and
diphenhydramine for treating insomnia: a randomized placebocontrolled clinical trial. Sleep, 28(11), 1465-1471.
Morphy, H., Dunn, K., Lewis, M., Boardman, H., & Croft, P. (2007). Epidemiology of insomnia: a longitudinal
study in a UK population. Sleep, 30(3), 274-280.
Morrow, J., Vikraman, S., Imeri, L., & Opp, M. (2008). Effects of serotonergic activation by 5hydroxytryptophan on sleep and body temperature of C57BL/6J and interleukin-6-deficient mice are dose and
time related. Sleep, 31(1), 21-33.
Moser, D., Anderer, P., Gruber, G., Parapatics, S., Loretz, E., Boeck, M., & ... Dorffner, G. (2009). Sleep
classification according to AASM and Rechtschaffen & Kales: effects on sleep scoring parameters. Sleep, 32(2),
139-149.
Mulcahy, D., Wright, C., Sparrow, J., Cunningham, D., Curcher, D., Purcell, H., & Fox, K. (1993). Heart rate
and blood pressure consequences of an afternoon SIESTA (Snooze-Induced Excitation of Sympathetic Triggered
Activity). The American Journal Of Cardiology, 71(7), 611-614.
Müller, C., Schumacher, B., Brattström, A., Abourashed, E., & Koetter, U. (2002). Interactions of valerian
extracts and a fixed valerian-hop extract combination with adenosine receptors. Life Sciences, 71(16), 19391949.
Müller, W., Rolli, M., Schäfer, C., & Hafner, U. (1997). Effects of hypericum extract (LI 160) in biochemical
models of antidepressant activity. Pharmacopsychiatry, 30 Suppl 2102-107.
Mumford, G. K., Silverman, K., & Griffiths, R. R. (1996). Reinforcing, subjective, and performance effects of
lorazepam and diphenhydramine in humans. Experimental And Clinical Psychopharmacology, 4(4), 421-430.
doi:10.1037/1064-1297.4.4.421
Münch, M., Knoblauch, V., Blatter, K., Schröder, C., Schnitzler, C., Kräuchi, K., & ... Cajochen, C. (2005).
Age-related attenuation of the evening circadian arousal signal in humans. Neurobiology Of Aging, 26(9), 13071319.
National Cancer Institute. Prevention of Acute/Delayed Nausea and Vomiting (Emesis). Health Professional
Version. Available at: www.cancer.gov/cancertopics/pdq/supportivecare/nausea/HealthProfessional. Accessed
March 2, 2012.
National Institutes of Health State of the Science Conference statement on Manifestations and Management of
Chronic Insomnia in Adults, June 13-15, 2005. (2005). Sleep, 28(9), 1049-1057.
Nau, S., McCrae, C., Cook, K., & Lichstein, K. (2005). Treatment of insomnia in older adults. Clinical
Psychology Review, 25(5), 645-672.
115
Neikrug, A., & Ancoli-Israel, S. (2010). Sleep disorders in the older adult - a mini-review. Gerontology, 56(2),
181-189.
Neubauer, D. (2003). Pharmacologic approaches for the treatment of chronic insomnia. Clinical Cornerstone,
5(3), 16-27.
Neubauer, D. (2007). The evolution and development of insomnia pharmacotherapies. Journal Of Clinical Sleep
Medicine: JCSM: Official Publication Of The American Academy Of Sleep Medicine, 3(5 Suppl), S11-S15.
Neubauer, D. (2008). New directions in the pharmacologic treatment of insomnia. CNS Spectrums, 13(12 Suppl
17), 10-12.
Neubauer, D. (2009). New directions in the pharmacologic treatment of sleep disorders. Primary Psychiatry,
16(2), 52-58.
NHLBI (National Heart, Lung, and Blood Institute). (2003). Sleep, Sleep Disorders, and Biological Rhythms:
NIH Curriculum Supplement Series, Grades 9-12. Colorado Springs, CO: Biological Sciences Curriculum
Study.
Nichols, J., Alper, C., & Milkin, T. (2007). Strategies for the management of insomnia: an update on
pharmacologic therapies. Formulary, 42(2), 86.
Nishino, S., Okuro, M., Kotorii, N., Anegawa, E., Ishimaru, Y., Matsumura, M., & Kanbayashi, T. (2010).
Hypocretin/orexin and narcolepsy: new basic and clinical insights. Acta Physiologica (Oxford, England), 198(3),
209-222.
Nofzinger, E.A., Buysse, D.J., Germain, A., Price, J.C., Miewald, J.M. & Kupfer, D.J.(2004). Insomnia:
functional neuroimaging evidence for hyperarousal. American Journal of Psychiatry, 161(11), 2126-2129.
Nofzinger, E.A. (2005). Neuroimaging and sleep medicine. Sleep Medicine Reviews. 9 (3),157–72.
Nordio, M., & Romanelli, F. (2008). Efficacy of wrists overnight compression (HT 7 point) on insomniacs:
possible role of melatonin?. Minerva Medica, 99(6), 539-547.
Nowell, P., Mazumdar, S., Buysse, D., Dew, M., Reynolds, C., & Kupfer, D. (1997). Benzodiazepines and
zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA: The Journal Of The American
Medical Association, 278(24), 2170-2177.
Nutt, D. (2006). GABAA receptors: subtypes, regional distribution, and function. Journal Of Clinical Sleep
Medicine: JCSM: Official Publication Of The American Academy Of Sleep Medicine, 2(2), S7-S11.
Nutt, D., & Stahl, S. (2010). Searching for perfect sleep: the continuing evolution of GABAA receptor
modulators as hypnotics. Journal Of Psychopharmacology (Oxford, England), 24(11), 1601-1612.
Ohayon, M. (1996). Epidemiological study on insomnia in the general population. Sleep, 19(3 Suppl), S7-S15
Ohayon,M. M. (2001). Prevalence, diagnosis and treatment of chronic insomnia in the general population.
Proceedings of the Satellite Symposium New Developments in the Treatment of Insomnia—Do They Really Have
Any Impact on the Primary Health Care Setting? Zeist, the Netherlands: Medical Forum International.
Ohayon, M. (2002). Epidemiology of insomnia: what we know and what we still need to learn. Sleep Medicine
Reviews, 6(2), 97-111.
Ohayon, M. (2006). Severe hot flashes are associated with chronic insomnia. Archives Of Internal Medicine,
166(12), 1262-1268.
116
Ohayon, M., & Bader, G. (2010). Prevalence and correlates of insomnia in the Swedish population
aged 19-75 years. Sleep Medicine, 11(10), 980-986.
Ohayon, M., Carskadon, M., Guilleminault, C., & Vitiello, M. (2004). Meta-analysis of quantitative sleep
parameters from childhood to old age in healthy individuals: developing normative sleep values across the
human lifespan. Sleep, 27(7), 1255-1273.
Ohayon, M., Caulet, M., Arbus, L., Billard, M., Coquerel, A., Guieu, J., & ... Vespignani, H. (1999). Are
prescribed medications effective in the treatment of insomnia complaints?. Journal Of Psychosomatic Research,
47(4), 359-368.
Ohayon, M., Caulet, M., & Guilleminault, C. (1997). How a general population perceives its sleep and how this
relates to the complaint of insomnia. Sleep, 20(9), 715-723.
Ohayon, M., Caulet, M., Priest, R., & Guilleminault, C. (1997). DSM-IV and ICSD-90 insomnia symptoms and
sleep dissatisfaction. The British Journal Of Psychiatry: The Journal Of Mental Science, 171382-388.
Ohayon, M., Caulet, M., Priest, R., & Guilleminault, C. (1998). Psychotropic medication consumption patterns
in the UK general population. Journal Of Clinical Epidemiology, 51(3), 273-283.
Ohayon,M., Shapiro,M., Kennedy,H. (2000). Differentiating DSM-IV anxiety and depressive disorders in
general population: comorbidity and treatment consequences. The Canadian Journal of Psychiatry, 45(2,166172.
Ohayon, M., & Smirne, S. (2002). Prevalence and consequences of insomnia disorders in the general population
of Italy. Sleep Medicine, 3(2), 115-120.
Ohayon, M., Zulley, J., Guilleminault, C., Smirne, S., & Priest, R. (2001). How age and daytime activities are
related to insomnia in the general population: consequences for older people. Journal Of The American
Geriatrics Society, 49(4), 360-366.
Okun, M. L. (2011). Biological consequences of disturbed sleep: Important mediators of health?. Japanese
Psychological Research, 53(2), 163–176.
Okun, M., Hanusa, B., Hall, M., & Wisner, K. (2009). Sleep complaints in late pregnancy and the recurrence of
postpartum depression. Behavioral Sleep Medicine, 7(2), 106-117.
O'Malley, P. (2007). The risks of pharmacological therapy for insomnia (part 2): update for the clinical nurse
specialist. Clinical Nurse Specialist CNS, 21(5), 231-233.
Orff, H., Drummond, S., Nowakowski, S., & Perils, M. (2007). Discrepancy between subjective
symptomatology and objective neuropsychological performance in insomnia. Sleep, 30(9), 1205-1211.
Oswald, I., French, C., Adam, K., & Gilham, J. (1982). Benzodiazepine hypnotics remain effective for 24 weeks.
British Medical Journal (Clinical Research Ed.), 284(6319), 860-863.
Owen, R. (2009). Selective histamine H(1) antagonism: a novel approach to insomnia using low-dose doxepin.
Drugs Of Today (Barcelona, Spain: 1998), 45(4), 261-267.
Owens, J., & Matthews, K. (1998). Sleep disturbance in healthy middle-aged women. Maturitas, 30(1), 41-50.
Ozminkowski, R., Wang, S., & Walsh, J. (2007). The direct and indirect costs of untreated insomnia in adults in
the United States. Sleep, 30(3), 263-273.
117
Pallesen, S., Hilde, I., Havik, O. E., & Nielsen, G. (2001). Clinical assessment and treatment of insomnia.
Professional Psychology: Research And Practice, 32(2), 115-124.
Pallesen, S., Nordhus, I., Kvale, G., Nielsen, G., Havik, O., Johnsen, B., & Skjøtskift, S. (2003). Behavioral
treatment of insomnia in older adults: an open clinical trial comparing two interventions. Behaviour Research
And Therapy, 41(1), 31-48.
Pallesen, S., Nordhus, I., Nielsen, G., Havik, O., Kvale, G., Johnsen, B., & Skjøtskift, S. (2001). Prevalence of
insomnia in the adult Norwegian population. Sleep, 24(7), 771-779.
Pandi-Perumal, S., Srinivasan, V., Spence, D., & Cardinali, D. (2007). Role of the melatonin system in the
control of sleep: therapeutic implications. CNS Drugs, 21(12), 995-1018.
Paquet, J., Kawinska, A., & Carrier, J. (2007). Wake detection capacity of actigraphy during sleep. Sleep,
30(10), 1362-1369.
Paparrigopoulos, T., Tzavara, C., Theleritis, C., Psarros, C., Soldatos, C., & Tountas, Y. (2010). Insomnia and its
correlates in a representative sample of the Greek population. BMC Public Health, 10531.
Paredes, S., Barriga, C., Reiter, R., & Rodríguez, A. (2009). Assessment of the Potential Role of Tryptophan as
the Precursor of Serotonin and Melatonin for the Aged Sleep-wake Cycle and Immune Function: Streptopelia
Risoria as a Model. International Journal Of Tryptophan Research: IJTR, 223-36.
Parker, K.P., & Dunbar, S.B. (2005). Cardiac nursing. In: S.L. Woods, E.S. Froelicher, S.U. Motzer & E.
Bridges (Eds.), Sleep (5th ed pp. 197–219). Philadelphia: Lippincott Williams and Wilkins.
Passarella, S., & Duong, M. (2008). Diagnosis and treatment of insomnia. American Journal Of Health-System
Pharmacy, 65(10), 927-934.
Patel, S. (2007). Social and demographic factors related to sleep duration. Sleep, 30(9), 1077-1078.
Paul, M., Gray, G., Sardana, T., & Pigeau, R. (2004). Melatonin and zopiclone as facilitators of early circadian
sleep in operational air transport crews. Aviation, Space, And Environmental Medicine, 75(5), 439-443.
Perlis, M.L., Giles, D.E., Buysse, D.J., Tu, X., Kupfer, D.J.(1997). Self-reported sleep disturbance as a
prodromal symptom in recurrent depression. Journal of Affective Disorders ,42(2-3),209–12.
Perlis, M. L., Giles, D. E., Mendelson, W. B., Bootzin, R. R. and Wyatt, J. K. (1997). Psychophysiological
insomnia: the behavioural model and a neurocognitive perspective. Journal of Sleep Research, 6(3), 179–188.
Perlis, M., McCall, W., Krystal, A., & Walsh, J. (2004). Long-term, non-nightly administration of zolpidem in
the treatment of patients with primary insomnia. The Journal Of Clinical Psychiatry, 65(8), 1128-1137.
Peters, E., Fucito, L., Novosad, C., Toll, B., & O'Malley, S. (2011). Effect of night smoking, sleep disturbance,
and their co-occurrence on smoking outcomes. Psychology Of Addictive Behaviors: Journal Of The Society Of
Psychologists In Addictive Behaviors, 25(2), 312-319.
Petit, L., Azad, N., Byszewski, A., Sarazan, F., & Power, B. (2003). Non-pharmacological management of
primary and secondary insomnia among older people: review of assessment tools and treatments. Age And
Ageing, 32(1), 19-25.
Phillips, B., & Mannino, D. (2007). Do insomnia complaints cause hypertension or cardiovascular disease?.
Journal Of Clinical Sleep Medicine: JCSM: Official Publication Of The American Academy Of Sleep Medicine,
3(5), 489-494.
Pigeon, W. (2010). Treatment of adult insomnia with cognitive-behavioral therapy. Journal Of Clinical
Psychology, 66(11), 1148-1160.
118
Pigeon, W. R., & Perlis, M. L. (2007). Insomnia and depression: “Birds of a feather?”International Journal of
Sleep Disorders, 3, 82–91
Pigeon, W., Hegel, M., Unützer, J., Fan, M., Sateia, M., Lyness, J., & ... Perlis, M. (2008). Is insomnia a
perpetuating factor for late-life depression in the IMPACT cohort?. Sleep, 31(4), 481-488.
Pigeon, W., & Perlis, M. (2006). Sleep homeostasis in primary insomnia. Sleep Medicine Reviews, 10(4), 247254.
Pigeon, W. (2010). Diagnosis, prevalence, pathways, consequences & treatment of insomnia. The Indian Journal
Of Medical Research, 131321-332.
Pillitteri, J., Kozlowski, L., Person, D., & Spear, M. (1994). Over-the-counter sleep aids: widely used but rarely
studied. Journal Of Substance Abuse, 6(3), 315-323.
Pinto Jr, L., Alves, R., Caixeta, E., Fontenelle, J., Bacellar, A., Poyares, D., & ... Tavares, S. (2010). New
guidelines for diagnosis and treatment of insomnia. Arquivos De Neuro-Psiquiatria, 68(4), 666-675.
Piscitelli, S., Burstein, A., Chaitt, D., Alfaro, R., & Falloon, J. (2000). Indinavir concentrations and St John's
wort. Lancet, 355(9203), 547-548.
Pittler, M., & Ernst, E. (2000). Efficacy of kava extract for treating anxiety: systematic review and metaanalysis. Journal Of Clinical Psychopharmacology, 20(1), 84-89.
Pomerleau, C., Marks, J., & Pomerleau, O. (2000). Who gets what symptom? Effects of psychiatric cofactors
and nicotine dependence on patterns of smoking withdrawal symptomatology. Nicotine & Tobacco Research:
Official Journal Of The Society For Research On Nicotine And Tobacco, 2(3), 275-280.
Portas, C., Bjorvatn, B., Fagerland, S., Grønli, J., Mundal, V., Sørensen, E., & Ursin, R. (1998). On-line
detection of extracellular levels of serotonin in dorsal raphe nucleus and frontal cortex over the sleep/wake cycle
in the freely moving rat. Neuroscience, 83(3), 807-814.
Portas, C., & McCarley, R. (1994). Behavioral state-related changes of extracellular serotonin concentration in
the dorsal raphe nucleus: a microdialysis study in the freely moving cat. Brain Research, 648(2), 306-312.
Potanovich, L., Pisters, K., Kris, M., Tyson, L., Clark, R., Baltzer, L., & Gralla, R. (1993). Midazolam in
patients receiving anticancer chemotherapy and antiemetics. Journal Of Pain And Symptom Management, 8(8),
519-524.
Poyares, D., Guilleminault, C., Ohayon, M., & Tufik, S. (2002). Can valerian improve the sleep of insomniacs
after benzodiazepine withdrawal?. Progress In Neuro-Psychopharmacology & Biological Psychiatry, 26(3),
539-545.
Punyahotra, S., Dennerstein, L., & Lehert, P. (1997). Menopausal experiences of Thai women. Part 1: Symptoms
and their correlates. Maturitas, 26(1), 1-7.
Ramakrishnan, K., & Scheid, D. (2007). Treatment options for insomnia. American Family Physician, 76(4),
517-526.
Randall, S., Roehrs, T. A., & Roth, T. (2008). Over-the-Counter Sleep Aid Medications and Insomnia. Primary
Psychiatry, 15(5), 52-58.
Rechtschaffen, A., & Kales, A. (1968). A manual of standardized terminology, techniques, and scoring system
for sleep stages of human subjects.Washington, D.C:Public Health Service, U.S. Government PrintingOffice.
119
Redwine, L., Hauger, R., Gillin, J., & Irwin, M. (2000). Effects of sleep and sleep deprivation on interleukin-6,
growth hormone, cortisol, and melatonin levels in humans. The Journal Of Clinical Endocrinology And
Metabolism, 85(10), 3597-3603.
Reimold, M., Batra, A., Knobel, A., Smolka, M., Zimmer, A., Mann, K., & ... Heinz, A. (2008). Anxiety is
associated with reduced central serotonin transporter availability in unmedicated patients with unipolar major
depression: a [11C]DASB PET study. Molecular Psychiatry, 13(6), 606.
Reiter, R., Tan, D., & Fuentes-Broto, L. (2010). Melatonin: a multitasking molecule. Progress In Brain
Research, 181127-151.
Rhalimi, M., Helou, R., & Jaecker, P. (2009). Medication use and increased risk of falls in hospitalized elderly
patients: a retrospective, case-control study. Drugs & Aging, 26(10), 847-852.
Richardson, G., Roehrs, T., Rosenthal, L., Koshorek, G., & Roth, T. (2002). Tolerance to daytime sedative
effects of H1 antihistamines. Journal Of Clinical Psychopharmacology, 22(5), 511-515.
Rickels, K., Ginsberg, J., Morris, R.J., Newman, H. M., Schiller, H. M., Weinstock, R. M., & Schilling, A.
E.(1984). Doxylamine succinate in insomniac family practice patients: a double-blind study. Current
Therapeutic Research, 35(4),532-540.
Rickels, K., Morris, R., Newman, H., Rosenfeld, H., Schiller, H., & Weinstock, R. (1983). Diphenhydramine in
insomniac family practice patients: a double-blind study. Journal Of Clinical Pharmacology, 23(5-6), 234-242.
Riedel, B. W. (2000). Sleep hygiene. In K. L.Lichstein & C. M.Morin (Eds.), Treatment of late-life insomnia
(pp. 125–146). Thousand Oaks, CA: Sage.
Riedel, B., Lichstein, K., & Dwyer, W. (1995). Sleep compression and sleep education for older insomniacs:
self-help versus therapist guidance. Psychology And Aging, 10(1), 54-63.
Riedel, B., Lichstein, K., Peterson, B., Epperson, M., Means, M., & Aguillard, R. (1998). A comparison of the
efficacy of stimulus control for medicated and nonmedicated insomniacs. Behavior Modification, 22(1), 3-28.
Richardson, G., Roehrs, T., Rosenthal, L., Koshorek, G., & Roth, T. (2002). Tolerance to daytime sedative
effects of H1 antihistamines. Journal Of Clinical Psychopharmacology, 22(5), 511-515.
Richardson, G., Zee, P., Wang-Weigand, S., Rodriguez, L., & Peng, X. (2008). Circadian phase-shifting effects
of repeated ramelteon administration in healthy adults. Journal Of Clinical Sleep Medicine: JCSM: Official
Publication Of The American Academy Of Sleep Medicine, 4(5), 456-461.
Riemersma-van der Lek, R. F., Swab, D. F., Twisk, J., Hol, E. M., Hoogendijk, W. G., & Van Someren, E.
(2009). Melatonin in elderly patients. Biological Rhythm Research, 40(1), 83-84.
Ringdahl, E., Pereira, S., & Delzell, J. (2004). Treatment of primary insomnia. The Journal Of The American
Board Of Family Practice / American Board Of Family Practice, 17(3), 212-219.
Robertson, J. A., Broomfield, N. M., & Espie, C. A. (2007). Prospective comparison of subjective arousal during
the pre-sleep period in primary sleep-onset insomnia and normal sleepers. Journal Of Sleep Research, 16(2),
230-238.
Roby, C., Anderson, G., Kantor, E., Dryer, D., & Burstein, A. (2000). St John's Wort: effect on CYP3A4
activity. Clinical Pharmacology And Therapeutics, 67(5), 451-457.
Rocha, F., Guerra, H., & Lima-Costa, M. (2002). Prevalence of insomnia and associated socio-demographic
factors in a Brazilian community: the Bambuí study. Sleep Medicine, 3(2), 121-126.
120
Roehrs, T., Bonahoom, A., Pedrosi, B., Rosenthal, L., & Roth, T. (2002). Disturbed sleep predicts hypnotic selfadministration. Sleep Medicine, 3(1), 61-66.
Roehrs, T., Bonahoom, A., Pedrosi, B., Zorick, F., & Roth, T. (2002). Nighttime versus daytime hypnotic selfadministration. Psychopharmacology, 161(2), 137-142.
Roehrs, T., Hollebeek, E., Drake, C., & Roth, T. (2002). Substance use for insomnia in Metropolitan Detroit.
Journal Of Psychosomatic Research, 53(1), 571-576.
Roehrs, T., Merlotti, L., Zorick, F., & Roth, T. (1992). Rebound insomnia and hypnotic self administration.
Psychopharmacology, 107(4), 480-484.
Roehrs, T., Papineau, K., Rosenthal, L., & Roth, T. (1999). Ethanol as a hypnotic in insomniacs: self
administration and effects on sleep and mood. Neuropsychopharmacology: Official Publication Of The
American College Of Neuropsychopharmacology, 20(3), 279-286.
Roehrs, T., Pedrosi, B., Rosenthal, L., & Roth, T. (1996). Hypnotic self administration and dose escalation.
Psychopharmacology, 127(2), 150-154.
Roehrs, T., & Roth, T. (2001). Sleep, sleepiness, and alcohol use. Alcohol Research & Health: The Journal Of
The National Institute On Alcohol Abuse And Alcoholism, 25(2), 101-109.
Roehrs, T., & Roth, T. (2003). Hypnotics: an update. Current Neurology And Neuroscience Reports, 3(2), 181184.
Roehrs, T., Vogel, G., & Roth, T. (1990). Rebound insomnia: its determinants and significance. The American
Journal Of Medicine, 88(3A), 39S-42S.
Rohers, T., Carskadon, M. A., Dement, W. C., & Roth, T. (2005). Daytime sleepiness and alertness. In M. H.
Kryger, T. Roth, & W. C. Dement (Eds.), Principles and practice of sleep medicine (4th ed., pp. 39–50).
Philadelphia: Elsevier.
Rossi, S (Editor), (2012), Australian Medicines Handbook 2012, Adelaide.:Australian Medicines Handbook Pty
Ltd.
Roth, T. (2001). The relationship between psychiatric diseases and insomnia. International Journal Of Clinical
Practice. Supplement, (116), 3-8.
Roth, T. (2009). Comorbid insomnia: current directions and future challenges. The American Journal Of
Managed Care, 15 SupplS6-S13.
Roth, T., & Ancoli-Israel, S. (1999). Daytime consequences and correlates of insomnia in the United States:
results of the 1991 National Sleep Foundation Survey. II. Sleep, 22 Suppl 2S354-S358.
Roth, T., Franklin, M., & Bramley, T. (2007). The state of insomnia and emerging trends. The American Journal
Of Managed Care, 13(5 Suppl), S117-S120.
Roth, T., Heith Durrence, H., Jochelson, P., Peterson, G., Ludington, E., Rogowski, R., & ... Lankford, A.
(2010). Efficacy and safety of doxepin 6 mg in a model of transient insomnia. Sleep Medicine, 11(9), 843-847.
Roth, T., & Roehrs, T. (1992). Issues in the use of benzodiazepine therapy. The Journal Of Clinical Psychiatry,
53 Suppl14-18.
Roth, T., & Roehrs, T. (2003). Insomnia: epidemiology, characteristics, and consequences. Clinical
Cornerstone, 5(3), 5-15.
121
Roth, T., Roehrs, T., Koshorek, G., Sicklesteel, J., & Zorick, F. (1987). Sedative effects of antihistamines. The
Journal Of Allergy And Clinical Immunology, 80(1), 94-98.
Roth, T., Roehrs, T., Stepanski, E., & Rosenthal, L. (1990). Hypnotics and behavior. The American Journal Of
Medicine, 88(3A), 43S-46S.
Roth, T., Roehrs, T., Zorick, F., Conway, W. (1985). Pharmaological effects of sedative-hypnotics, narcotic
analgesics and alcohol during sleep. The Medical Clinics of North America, 69(6),1281-8.
Roth, T., Rogowski, R., Hull, S., Schwartz, H., Koshorek, G., Corser, B., & ... Lankford, A. (2007). Efficacy and
safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep, 30(11), 1555-1561.
Roth, T., Seiden, D., Sainati, S., Wang-Weigand, S., Zhang, J., & Zee, P. (2006). Effects of ramelteon on
patient-reported sleep latency in older adults with chronic insomnia. Sleep Medicine, 7(4), 312-318.
Roth, T., Seiden, D., Wang-Weigand, S., & Zhang, J. (2007). A 2-night, 3-period, crossover study of ramelteon's
efficacy and safety in older adults with chronic insomnia. Current Medical Research And Opinion, 23(5), 10051014.
Roth, T., Stubbs, C., & Walsh, J. (2005). Ramelteon (TAK-375), a selective MT1/MT2-receptor agonist, reduces
latency to persistent sleep in a model of transient insomnia related to a novel sleep environment. Sleep, 28(3),
303-307.
Roth, T., Walsh, J., Krystal, A., Wessel, T., & Roehrs, T. (2005). An evaluation of the efficacy and safety of
eszopiclone over 12 months in patients with chronic primary insomnia. Sleep Medicine, 6(6), 487-495.
Rubinstein, M. L., Rothenberg, S. A., Maheswaran, S., Tsai, J. S., Zozula, R., & Spielman, A. J. (1990).
Modified sleep restriction therapy in middle-aged and elderly chronic insomniacs. Sleep Research, 19, 276.
Rubinstein, M., & Selwyn, P. (1998). High prevalence of insomnia in an outpatient population with HIV
infection. Journal Of Acquired Immune Deficiency Syndromes And Human Retrovirology: Official Publication
Of The International Retrovirology Association, 19(3), 260-265.
Ruschitzka, F. (2000). Acute heart transplant rejection due to Saint John's wort. Lancet, 355(9203), 548.
Ruschitzka, F., Meier, P., Turina, M., Lüscher, T., & Noll, G. (2000). Acute heart transplant rejection due to
Saint John's wort. Lancet, 355(9203), 548-549.
Russo, S., Kema, I., Bosker, F., Haavik, J., & Korf, J. (2009). Tryptophan as an evolutionarily conserved signal
to brain serotonin: molecular evidence and psychiatric implications. The World Journal Of Biological
Psychiatry: The Official Journal Of The World Federation Of Societies Of Biological Psychiatry, 10(4), 258268.
Rybarczyk, B., Lopez, M., Benson, R., Alsten, C., & Stepanski, E. (2002). Efficacy of two behavioral treatment
programs for comorbid geriatric insomnia. Psychology And Aging, 17(2), 288-298.
Saari, T., Uusi-Oukari, M., Ahonen, J., & Olkkola, K. (2011). Enhancement of GABAergic activity:
neuropharmacological effects of benzodiazepines and therapeutic use in anesthesiology. Pharmacological
Reviews, 63(1), 243-267.
Saddichha, S. (2010). Diagnosis and treatment of chronic insomnia. Annals Of Indian Academy Of Neurology,
13(2), 94-102.
Sadeh, A. (2011). The role and validity of actigraphy in sleep medicine: an update. Sleep Medicine Reviews,
15(4), 259-267.
122
Sagawa, Y., Kondo, H., Matsubuchi, N., Takemura, T., Kanayama, H., Kaneko, Y., & ... Shimizu, T. (2011).
Alcohol has a dose-related effect on parasympathetic nerve activity during sleep. Alcoholism, Clinical And
Experimental Research, 35(11), 2093-2100.
Saint-Mleux, B., Eggermann, E., Bisetti, A., Bayer, L., Machard, D., Jones, B., & ... Serafin, M. (2004).
Nicotinic enhancement of the noradrenergic inhibition of sleep-promoting neurons in the ventrolateral preoptic
area. The Journal Of Neuroscience: The Official Journal Of The Society For Neuroscience, 24(1), 63-67.
Sakurai, T. (2007). The neural circuit of orexin (hypocretin): maintaining sleep and wakefulness. Nature
Reviews. Neuroscience, 8(3), 171-181.
Sansone, R., & Sansone, L. (2008). Zolpidem, somnambulism, and nocturnal eating. General Hospital
Psychiatry, 30(1), 90-91.
Santiago, J., Nolledo, M., Kinzler, W., & Santiago, T. (2001). Sleep and sleep disorders in pregnancy. Annals Of
Internal Medicine, 134(5), 396-408.
Saper, C., Chou, T., & Scammell, T. (2001). The sleep switch: hypothalamic control of sleep and wakefulness.
Trends In Neurosciences, 24(12), 726-731.
Sari, I., Davutoglu, V., Ozbala, B., Ozer, O., Baltaci, Y., Yavuz, S., & Aksoy, M. (2008). Acute sleep
deprivation is associated with increased electrocardiographic P-wave dispersion in healthy young men and
women. Pacing And Clinical Electrophysiology: PACE, 31(4), 438-442.
Sarrazin, S., Etain, B., Vederine, F., d'Albis, M., Hamdani, N., Daban, C., & ... Houenou, J. (2011). MRI
exploration of pineal volume in bipolar disorder. Journal Of Affective Disorders, 135(1-3), 377-379.
Sateia, M., Kirby-Long, P., & Taylor, J. (2008). Efficacy and clinical safety of ramelteon: an evidence-based
review. Sleep Medicine Reviews, 12(4), 319-332.
Sateia, M., & Pigeon, W. (2004). Identification and management of insomnia. The Medical Clinics Of North
America, 88(3), 567.
Sattar, S., Ramaswamy, S., Bhatia, S., & Petty, F. (2003). Somnambulism due to probable interaction of valproic
acid and zolpidem. The Annals Of Pharmacotherapy, 37(10), 1429-1433.
Scanlan, M.F., Roebuck, T., Little, P.J., Redman, J.R., & Naughton, M.T. (2000).Effect of moderate alcohol
upon obstructive sleep apnoea. The European respiratory journal, 16(5), 909-913.
Scharf, M., Black, J., Hull, S., Landin, R., & Farber, R. (2007). Long-term nightly treatment with indiplon in
adults with primary insomnia: results of a double-blind, placebo-controlled, 3-month study. Sleep, 30(6), 743752.
Scharf, M., Rogowski, R., Hull, S., Cohn, M., Mayleben, D., Feldman, N., & ... Roth, T. (2008). Efficacy and
safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind,
placebo-controlled crossover study. The Journal Of Clinical Psychiatry, 69(10), 1557-1564.
Scharf, M., Roth, T., Vogel, G., & Walsh, J. (1994). A multicenter, placebo-controlled study evaluating
zolpidem in the treatment of chronic insomnia. The Journal Of Clinical Psychiatry, 55(5), 192-199.
Schlich, D., L'Heritier, C., Coquelin, J., Attali, P., & Kryrein, H. (1991). Long-term treatment of insomnia with
zolpidem: a multicentre general practitioner study of 107 patients. The Journal Of International Medical
Research, 19(3), 271-279.
123
Schneider-Helmert, D., & Spinweber, C. (1986). Evaluation of L-tryptophan for treatment of insomnia: a review.
Psychopharmacology, 89(1), 1-7.
Schulz, H., Stolz, C., & Muller. J.(1994). The effects of valerian extract on sleep polygraphy in poor sleepers: a
pilot study. Pharmacopsychiatry, 27(4),147-151.
Schulz, V. (2001). Incidence and clinical relevance of the interactions and side effects of Hypericum
preparations. Phytomedicine: International Journal Of Phytotherapy And Phytopharmacology, 8(2), 152-160.
Schutte-Rodin, S., Broch, L., Buysse, D., Dorsey, C., & Sateia, M. (2008). Clinical guideline for the evaluation
and management of chronic insomnia in adults. Journal Of Clinical Sleep Medicine: JCSM: Official Publication
Of The American Academy Of Sleep Medicine, 4(5), 487-504.
Shapiro, S., Slone, D., Lewis, G., & Jick, H. (1969). Clinical effects of hypnotics. II. An epidemiologic study.
JAMA: The Journal Of The American Medical Association, 209(13), 2016-2020.
Sharma, A., & Dewan, V. (2005). A case report of zolpidem-induced somnambulism. Primary Care Companion
To The Journal Of Clinical Psychiatry, 7(2), 74.
Sharpley, A. L., McGavin, C. L., Whale, R. R., & Cowen, P. J. (1998). Antidepressant-like effect of Hypericum
perforatum (St John's wort) on the sleep polysomnogram. Psychopharmacology, 139(3), 286.
Shibui, K., Uchiyama, M., Kim, K., Tagaya, H., Kuriyama, K., Suzuki, H., & ... Takahashi, K. (2003).
Melatonin, cortisol and thyroid-stimulating hormone rhythms are delayed in patients with delayed sleep phase
syndrome. Sleep & Biological Rhythms, 1(3), 209–214.
Shinar, Z., Akselrod, S., Dagan, Y., & Baharav, A. (2006). Autonomic changes during wake-sleep transition: a
heart rate variability based approach. Autonomic Neuroscience: Basic & Clinical, 130(1-2), 17-27.
Shochat, T., Umphress, J., Israel, A., & Ancoli-Israel, S. (1999). Insomnia in primary care patients. Sleep, 22
Suppl 2S359-S365.
Silber, M., Ancoli-Israel, S., Bonnet, M., Chokroverty, S., Grigg-Damberger, M., Hirshkowitz, M., & ... Iber, C.
(2007). The visual scoring of sleep in adults. Journal Of Clinical Sleep Medicine: JCSM: Official Publication Of
The American Academy Of Sleep Medicine, 3(2), 121-131.
Silber, B., & Schmitt, J. (2010). Effects of tryptophan loading on human cognition, mood, and sleep.
Neuroscience And Biobehavioral Reviews, 34(3), 387-407.
Silvestri, R., Ferrillo, F., Murri, L., Massetani, R., Di Perri, R., Rosadini, G., Montesano, A., Borghi, C. and De
La Giclais, B. (1996). Rebound Insomnia After Abrupt Discontinuation of Hypnotic Treatment: Double-Blind
Randomized Comparison of Zolpidem Versus Triazolam. Human Psychopharmacology: Clinical &
Experimental, 11(3), 225-233.
Simon, P.M., Landry, S.H., & Leifer, J.C.(2002). Respiratory control during sleep. In: T.K.Lee-Chiong,
M.J.Sateia, & M.A Carskadon (Eds.), Sleep Medicine (pp. 41–51). Philadelphia: Hanley and Belfus.
Simons, F., & Simons, K. (2011). Histamine and H1-antihistamines: celebrating a century of progress. The
Journal Of Allergy And Clinical Immunology, 128(6), 1139-1150.
Simon, G., & VonKorff, M. (1997). Prevalence, burden, and treatment of insomnia in primary care. The
American Journal Of Psychiatry, 154(10), 1417-1423.
Sivertsen, B., Krokstad, S., Mykletun, A., & Overland, S. (2009). Insomnia symptoms and use of health care
services and medications: the HUNT-2 study. Behavioral Sleep Medicine, 7(4), 210-222.
124
Skidgel, R. A., & Erdos, E. G. (2006). Histamine, bradykinin, and their antagonists. In L. L. Brunton (Ed.),
Goodman & Gilman’s the pharmacological basis of therapeutics (11th ed.). New York, NY: McGraw-Hill.
Smith, M., Perlis, M., Park, A., Smith, M., Pennington, J., Giles, D., & Buysse, D. (2002). Comparative metaanalysis of pharmacotherapy and behavior therapy for persistent insomnia. The American Journal Of Psychiatry,
159(1), 5-11.
Sok, S., Erlen, J., & Kim, K. (2003). Effects of acupuncture therapy on insomnia. Journal Of Advanced Nursing,
44(4), 375-384.
Soldatos, C., Kales, J., Scharf, M., Bixler, E., & Kales, A. (1980). Cigarette smoking associated with sleep
difficulty. Science (New York, N.Y.), 207(4430), 551-553.
Somers, V., Dyken, M., Mark, A., & Abboud, F. (1993). Sympathetic-nerve activity during sleep in normal
subjects. The New England Journal Of Medicine, 328(5), 303-307.
Spence, D., Kayumov, L., Chen, A., Lowe, A., Jain, U., Katzman, M., & ... Shapiro, C. (2004). Acupuncture
increases nocturnal melatonin secretion and reduces insomnia and anxiety: a preliminary report. The Journal Of
Neuropsychiatry And Clinical Neurosciences, 16(1), 19-28.
Spiegel, K., Leproult, R., & Van Cauter, E. (1999). Impact of sleep debt on metabolic and endocrine function.
Lancet, 354(9188), 1435-1439.
Spiegel, K., Sheridan, J., & Van Cauter, E. (2002). Effect of sleep deprivation on response to immunization.
JAMA: The Journal Of The American Medical Association, 288(12), 1471-1472.
Spiegel, K., Tasali, E., Penev, P., & Van Cauter, E. (2004). Brief communication: Sleep curtailment in healthy
young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite.
Annals Of Internal Medicine, 141(11), 846-850.
Spielberger, C. D. (Ed.). (1972). Anxiety: Current trends in theory and research (Vols. 1-2). New York:
Academic Press.
Spielman, A.(1986). Assessment of insomnia. Clinical Psychology Review, 6(1),11–26.
Spielman, A., Saskin, P., & Thorpy, M. (1987). Treatment of chronic insomnia by restriction of time in bed.
Sleep, 10(1), 45-56.
Spielman, A. J., & Glovinsky, P. B. (1991). The varied nature of insomnia. In P. J.Hauri (Ed.), Case studies in
insomnia (pp. 1–15). New York: Plenum.
Spinweber, C. (1986). L-tryptophan administered to chronic sleep-onset insomniacs: late-appearing reduction of
sleep latency. Psychopharmacology, 90(2), 151-155.
Srinivasan, V., Pandi-Perumal, S., Trahkt, I., Spence, D., Poeggeler, B., Hardeland, R., & Cardinali, D. (2009).
Melatonin and melatonergic drugs on sleep: possible mechanisms of action. The International Journal Of
Neuroscience, 119(6), 821-846.
Stahl, S.(2008). Stahl’s essential psychopharmacology: neuroscientific basis and practical applications (3rd
ed.).New York: Cambridge University Press.
Stein, M., & Friedmann, P. (2005). Disturbed sleep and its relationship to alcohol use. Substance Abuse: Official
Publication Of The Association For Medical Education And Research In Substance Abuse, 26(1), 1-13.
Stepanski, E., & Wyatt, J. (2003). Use of sleep hygiene in the treatment of insomnia. Sleep Medicine Reviews,
7(3), 215-225.
125
Stevinson, C., Ernst, E.(2000). Valerian for insomnia: a systematic review of randomised clinical trials. Sleep
Medicine, 1(2), 91–99.
Stewart, R., Besset, A., Bebbington, P., Brugha, T., Lindesay, J., Jenkins, R., & ... Meltzer, H. (2006). Insomnia
comorbidity and impact and hypnotic use by age group in a national survey population aged 16 to 74 years.
Sleep, 29(11), 1391-1397.
Streitberger, K., & Kleinhenz, J. (1998). Introducing a placebo needle into acupuncture research. Lancet,
352(9125), 364-365.
Stricker, J., Brown, G., Wetherell, L., & Drummond, S. (2006). The impact of sleep deprivation and task
difficulty on networks of fMRI brain response. Journal Of The International Neuropsychological Society: JINS,
12(5), 591-597.
Stickgold, R. (2005). Sleep-dependent memory consolidation. Nature, 437(7063), 1272-1278.
Suka, M., Yoshida, K., & Sugimori, H. (2003). Persistent insomnia is a predictor of hypertension in Japanese
male workers. Journal Of Occupational Health, 45(6), 344-350.
Szelenberger, W., & Niemcewicz, S. (2000). Severity of insomnia correlates with cognitive impairment. Acta
Neurobiologiae Experimentalis, 60(3), 373.
Taheri, S., & Mignot, E. (2002). The genetics of sleep disorders. Lancet Neurology, 1(4), 242-250.
Taibi, D., Landis, C., Petry, H., & Vitiello, M. (2007). A systematic review of valerian as a sleep aid: safe but
not effective. Sleep Medicine Reviews, 11(3), 209-230.
Tank, J., Diedrich, A., Hale, N., Niaz, F., Furlan, R., Robertson, R., & Mosqueda-Garcia, R. (2003).
Relationship between blood pressure, sleep K-complexes, and muscle sympathetic nerve activity in humans.
American Journal Of Physiology. Regulatory, Integrative And Comparative Physiology, 285(1), R208-R214.
Taylor, D., & Roane, B. (2010). Treatment of insomnia in adults and children: a practice-friendly review of
research. Journal Of Clinical Psychology, 66(11), 1137-1147.
Taylor, D., Lichstein, K., Durrence, H., Reidel, B., & Bush, A. (2005). Epidemiology of insomnia, depression,
and anxiety. Sleep, 28(11), 1457-1464.
Teschke, R. (2010). Kava hepatotoxicity: pathogenetic aspects and prospective considerations. Liver
International: Official Journal Of The International Association For The Study Of The Liver, 30(9), 1270-1279.
Terzano, M., Rossi, M., Palomba, V., Smerieri, A., & Parrino, L. (2003). New drugs for insomnia: comparative
tolerability of zopiclone, zolpidem and zaleplon. Drug Safety: An International Journal Of Medical Toxicology
And Drug Experience, 26(4), 261-282.
Therapeutic Goods Administration. (2001) Twenty-eighth meeting of the Complementary Medicines Evaluation
Committee, retrieved from http://www.tga.gov.au/pdf/archive/cmec-minutes-28.pdf.
Touitou, Y. (2001). Human aging and melatonin. Clinical relevance. Experimental Gerontology, 36(7), 10831100.
Therapeutic Goods Administration. (2005). Kava fact sheet. Retrieved from http://www.tga.gov.au/safety/alertsmedicine-kava-050421.htm
Therapeutic Goods Administration. (2005). Information for sponsors: safety of kava-containing medicines.
Retrieved from http://www.tga.gov.au/safety/alerts-medicine-kava-020826.htm
126
Trinder, J., Kleiman, J., Carrington, M., Smith, S., Breen, S., Tan, N., & Kim, Y. (2001). Autonomic activity
during human sleep as a function of time and sleep stage. Journal Of Sleep Research, 10(4), 253-264.
Tripathi, R., Tripathi, B., & Haggerty, C. (2003). Drug-induced glaucomas: mechanism and management. Drug
Safety: An International Journal Of Medical Toxicology And Drug Experience, 26(11), 749-767.
Trulson, M., & Jacobs, B. (1979). Raphe unit activity in freely moving cats: correlation with level of behavioral
arousal. Brain Research, 163(1), 135-150.
Tsai, M., Tsai, Y., & Huang, Y. (2007). Compulsive activity and anterograde amnesia after zolpidem use.
Clinical Toxicology (Philadelphia, Pa.), 45(2), 179-181.
Tsuno, N., Besset, A., & Ritchie, K. (2005). Sleep and depression. The Journal Of Clinical Psychiatry, 66(10),
1254-1269.
Tsutsumi, W., Miyazaki, S., Itasaka, Y., & Togawa, K. (2000). Influence of alcohol on respiratory disturbance
during sleep. Psychiatry & Clinical Neurosciences, 54(3), 332-333.
Ursin, R. (2002). Serotonin and sleep. Sleep Medicine Reviews, 6(1), 55-69.
Van Cauter, E.(2000). Endocrine Physiology. In: M. H. Kryger, T. Roth and W. C. Dement (Eds.), Principles
and Practice of Sleep Medicine (4th ed pp. 266–278). Philadelphia: Elsevier/Saunders.
U.S. Food and Drug Administration. (2002). Consumer advisory: kava-containing dietary supplements may be
associated with severe liver injury. Retrieved from
http://www.fda.gov/Food/ResourcesForYou/Consumers/ucm085482.html. Accessed December 25, 2011.
Vashadze, S. (2007). [Insomnia, serotonin and depression]. Georgian Medical News, (150), 22-24.
Verwey, B., Muntendam, A., Ensing, K., Essink, G., Pasker-de Jong, P., Willekens, F., & Zitman, F. (2005).
Clinically relevant anterograde amnesia and its relationship with blood levels of benzodiazepines in suicide
attempters who took an overdose. Progress In Neuro-Psychopharmacology & Biological Psychiatry, 29(1), 4753.
Vermeeren, A. (2004). Residual Effects of Hypnotics: Epidemiology and Clinical Implications. CNS Drugs,
18(5), 297-328.
Vetrugno, R., Manconi, M., Ferini-Strambi, L., Provini, F., Plazzi, G., & Montagna, P. (2006). Nocturnal eating:
sleep-related eating disorder or night eating syndrome? A videopolysomnographic study. Sleep, 29(7), 949-954.
Vgontzas, A., Zoumakis, E., Bixler, E., Lin, H., Follett, H., Kales, A., & Chrousos, G. (2004). Adverse effects of
modest sleep restriction on sleepiness, performance, and inflammatory cytokines. The Journal Of Clinical
Endocrinology And Metabolism, 89(5), 2119-2126.
Vgontzas, A., Zoumakis, M., Papanicolaou, D., Bixler, E., Prolo, P., Lin, H., & ... Chrousos, G. (2002). Chronic
insomnia is associated with a shift of interleukin-6 and tumor necrosis factor secretion from nighttime to
daytime. Metabolism: Clinical And Experimental, 51(7), 887-892.
Vitiello, M. V. (2009). Recent Advances in Understanding Sleep and Sleep Disturbances in Older Adults:
Growing Older Does Not Mean Sleeping Poorly. Current Directions In Psychological Science (WileyBlackwell), 18(6), 316-320.
127
Voderholzer, U., Al-Shajlawi, A., Weske, G., Feige, B., & Riemann, D. (2003). Are there gender differences in
objective and subjective sleep measures? A study of insomniacs and healthy controls. Depression And Anxiety,
17(3), 162-172.
von Gall, C., Stehle, J., & Weaver, D. (2002). Mammalian melatonin receptors: molecular biology and signal
transduction. Cell And Tissue Research, 309(1), 151-162.
Walsh, J., & Engelhardt, C. (1999). The direct economic costs of insomnia in the United States for 1995. Sleep,
22 Suppl 2S386-S393.
Walsh, K. “Efficacy of Benzodiazepine Receptor Agonists in the Treatment of Chronic Insomnia.” NIH Stateof-the-Science Conference on Manifestations and Management of Chronic Insomnia in Adults [conference].
Bethesda, Maryland. June 13–15, 2005.
Walsh, J., Krystal, A., Amato, D., Rubens, R., Caron, J., Wessel, T., & ... Roth, T. (2007). Nightly treatment of
primary insomnia with eszopiclone for six months: effect on sleep, quality of life, and work limitations. Sleep,
30(8), 959-968.
Walsh, J., Roth, T., Randazzo, A., Erman, M., Jamieson, A., Scharf, M., & ... Ware, J. (2000). Eight weeks of
non-nightly use of zolpidem for primary insomnia. Sleep, 23(8), 1087-1096.
Walsh, J.K., Vogel, G.W., Scharf, M., Erman, M., William Erwin, C., Schweitzer, P.K., Mangano, R.M., Roth,
T. (2000). A five week, polysomnographic assessment of zaleplon 10 mg for the treatment of primary
insomnia.Sleep Medicine, 1(1),41-49.
Wang, P., Bohn, R., Glynn, R., Mogun, H., & Avorn, J. (2001). Zolpidem use and hip fractures in older people.
Journal Of The American Geriatrics Society, 49(12), 1685-1690.
Wang, X., Yuan, S., Yang, H., Sun, Y., Cheng, F., Zhang, C., & Huang, X. (2008). Abdominal acupuncture for
insomnia in women: a randomized controlled clinical trial. Acupuncture & Electro-Therapeutics Research, 33(12), 33-41.
Ward, S., & Ward, L. (2006). The evaluation and management of insomnia in primary care. Patient Care, 40(7),
46-55.
Weber, J., Siddiqui, M., Wagstaff, A., & McCormack, P. (2010). Low-dose doxepin: in the treatment of
insomnia. CNS Drugs, 24(8), 713-720.
Weissman, M., Greenwald, S., Niño-Murcia, G., & Dement, W. (1997). The morbidity of insomnia
uncomplicated by psychiatric disorders. General Hospital Psychiatry, 19(4), 245-250.
Wetter, D., & Young, T. (1994). The relation between cigarette smoking and sleep disturbance. Preventive
Medicine, 23(3), 328-334.
Weyerer, S., & Dilling, H. (1991). Prevalence and treatment of insomnia in the community: results from the
Upper Bavarian Field Study. Sleep, 14(5), 392-398.
Wheatly, D. (2001). Stress-induced insomnia treated with kava and valerian: singly and in combination. Human
Psychopharmacology: Clinical & Experimental, 16(4), 353-356.
Wheatley, D. (2005). Medicinal plants for insomnia: a review of their pharmacology, efficacy and tolerability.
Journal Of Psychopharmacology (Oxford, England), 19(4), 414-421.
White, P., Lewith, G., Hopwood, V., & Prescott, P. (2003). The placebo needle, is it a valid and convincing
placebo for use in acupuncture trials? A randomised, single-blind, cross-over pilot trial. Pain, 106(3), 401-409.
128
Wickwire, E., & Collop, N. (2010). Insomnia and sleep-related breathing disorders. Chest, 137(6), 1449-1463.
Wills, L., & Garcia, J. (2002). Parasomnias: epidemiology and management. CNS Drugs, 16(12), 803-810.
Wilson, K., Eriksson, M., D'Eon, J., Mikail, S., & Emery, P. (2002). Major depression and insomnia in chronic
pain. The Clinical Journal Of Pain, 18(2), 77-83.
Wilson, S., & Nutt, D. (2011). Insomnia: guide to diagnosis and recommended management. Prescriber, 22(10),
13-20.
Winkelman, J. (2009). The diagnosis and work-up of insomnia. CNS Spectrums, 14(12 Suppl 13), 4-6.
Woelk, H. (2000). Comparison of St. John’s wort and imipramine for treating depression: randomized controlled
trial. British Medical Journal, 321, (7620), 536-539.
Woelk, H., Burkard, G., & Grünwald, J. (1994). Benefits and risks of the hypericum extract LI 160: drug
monitoring study with 3250 patients. Journal Of Geriatric Psychiatry And Neurology, 7 Suppl 1S34-S38.
Wohlgemuth, W.K., & Edinger, J.D. (2000). Sleep restriction therapy. In K.L. Lichstein & C.M. Morin (Eds.),
Treatment of late-life insomnia (pp. 147–166). Thousand Oaks, CA: Sage.
Wolk, R., Gami, A., Garcia-Touchard, A., & Somers, V. (2005). Sleep and cardiovascular disease. Current
Problems In Cardiology, 30(12), 625-662.
Wolkove, N., Elkholy, O., Baltzan, M., & Palayew, M. (2007). Sleep and aging: 1. Sleep disorders commonly
found in older people. CMAJ: Canadian Medical Association Journal = Journal De L'association Medicale
Canadienne, 176(9), 1299-1304.
Wolkove, N., Elkholy, O., Baltzan, M., & Palayew, M. (2007). Sleep and aging: 2. Management of sleep
disorders in older people. CMAJ: Canadian Medical Association Journal = Journal De L'association Medicale
Canadienne, 176(10), 1449-1454.
Woods, J., Katz, J., & Winger, G. (1992). Benzodiazepines: use, abuse, and consequences. Pharmacological
Reviews, 44(2), 151-347.
Worthley, L. (2002). Clinical toxicology: part I. Diagnosis and management of common drug overdosage.
Critical Care And Resuscitation: Journal Of The Australasian Academy Of Critical Care Medicine, 4(3), 192215.
Wyatt, J.K., Dijk, D.J., Ritz-de Cecco. A., Ronda. J.M. & Czeisler, C.A.( 2006) . Sleep-facilitating effect of
exogenous melatonin in healthy young men and women is circadian-phase dependent. Sleep, 29 (5),609–618.
Yanai, K. (2012). Anticholinergic activity of antihistamines. Clinical Neurophysiology,123,(4) ,633–634.
Yang, C., Lin, S., Hsu, S., & Cheng, C. (2010). Maladaptive sleep hygiene practices in good sleepers and
patients with insomnia. Journal Of Health Psychology, 15(1), 147-155.
Yang, W., Dollear, M., & Muthukrishnan, S. (2005). One rare side effect of zolpidem--sleepwalking: a case
report. Archives Of Physical Medicine And Rehabilitation, 86(6), 1265-1266.
Yeo, B., Perera, I., Kok, L., & Tsoi, W. (1996). Insomnia in the community. Singapore Medical Journal, 37(3),
282-284.
Yeung, W., Chung, K., Zhang, S., Yap, T., & Law, A. (2009). Electroacupuncture for primary insomnia: a
randomized controlled trial. Sleep, 32(8), 1039-1047.
129
Young-Il, J., Jong-Oh, S., Jung-Hwan, P., Soon-Young, K., Seung-Min, L., Tae-Ho, S., & Jong-Ho, L. (2007).
Risk factors for rhabdomyolysis following doxylamine overdose. Human & Experimental Toxicology, 26(8),
617-621.
Young, T., Peppard, P., & Gottlieb, D. (2002). Epidemiology of obstructive sleep apnea: a population health
perspective. American Journal Of Respiratory And Critical Care Medicine, 165(9), 1217-1239.
Young, T., Rabago, D., Zgierska, A., Austin, D., & Laurel, F. (2003). Objective and subjective sleep quality in
premenopausal, perimenopausal, and postmenopausal women in the Wisconsin Sleep Cohort Study. Sleep,
26(6), 667-672.
Youngberg, M., Karpov, I., Begley, A., Pollock, B., & Buysse, D. (2011). Clinical and physiological correlates
of caffeine and caffeine metabolites in primary insomnia. Journal Of Clinical Sleep Medicine: JCSM: Official
Publication Of The American Academy Of Sleep Medicine, 7(2), 196-203.
Yue, G., Bergquist, C., & Gerden, B.(2000). Safety of St. John’s wort (Hypericum perforatum). Lancet,
355(9203),576-7.
Zammit, G. (2009a). Understanding the impact of insomnia. Psychiatric Times, 2-5.
Zammit, G. (2009b). Comparative tolerability of newer agents for insomnia. Drug Safety: An International
Journal Of Medical Toxicology And Drug Experience, 32(9), 735-748.
Zammit, G., Erman, M., Wang-Weigand, S., Sainati, S., Zhang, J., & Roth, T. (2007). Evaluation of the efficacy
and safety of ramelteon in subjects with chronic insomnia. Journal Of Clinical Sleep Medicine: JCSM: Official
Publication Of The American Academy Of Sleep Medicine, 3(5), 495-504.
Zammit, G., McNabb, L., Caron, J., Amato, D., & Roth, T. (2004). Efficacy and safety of eszopiclone across 6weeks of treatment for primary insomnia. Current Medical Research And Opinion, 20(12), 1979-1991.
Zammit, G., Roth, T., Erman, M., Sainati, S., Weigand, S., Zhang, J. (2005). Double blind, placebo-controlled
polysomnography and outpatient trial to evaluate the efficacy and safety of ramelteon in adult patients with
chronic insomnia. Sleep, 28:A228-A229.
Zee, P., & Manthena, P. (2007). The brain's master circadian clock: implications and opportunities for therapy of
sleep disorders. Sleep Medicine Reviews, 11(1), 59-70.
Zhang, L., Samet, J., Caffo, B., & Punjabi, N. (2006). Cigarette smoking and nocturnal sleep architecture.
American Journal Of Epidemiology, 164(6), 529-537.
Zhang, B., & Wing, Y. (2006). Sex differences in insomnia: a meta-analysis. Sleep, 29(1), 85-93.
Zhdanova, I. (2005). Melatonin as a hypnotic: pro. Sleep Medicine Reviews, 9(1), 51-65.
Zhdanova, I., Wurtman, R., Regan, M., Taylor, J., Shi, J., & Leclair, O. (2001). Melatonin treatment for agerelated insomnia. The Journal Of Clinical Endocrinology And Metabolism, 86(10), 4727-4730.
Zisapel, N. (2007). Sleep and sleep disturbances: biological basis and clinical implications. Cellular And
Molecular Life Sciences: CMLS, 64(10), 1174-1186.
Zoccoli, G., Walker, A., Lenzi, P., & Franzini, C. (2002). The cerebral circulation during sleep: regulation
mechanisms and functional implications. Sleep Medicine Reviews, 6(6), 443-455.
130
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Appendix A
Recruitment script for Pharmacy Staff
This pharmacy is participating in a University of Canberra study for people who are taking
this antihistamine as a sleep aid.
The study involves you completing this anonymous 1 page survey about your sleep (show
questionnaire). If you want to, you can add your first name and phone number so a
researcher from the University can contact you to see how well this product worked.
No-one from the pharmacy will see your completed form because I will ask you to put it in
this locked box (show box). Only the University researcher has the key.
If you have any questions about the study, the researcher’s phone number is here on the form
(show phone number).
.
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133
Appendix B
Using Antihistamines as a sleep Aid Questionnaire
University contact: Greg Kyle (02) 6201 2567
-Age Range:
-Gender
□ 18 - 25
□ Male
□ 26 – 35
□36 – 45
□ 46 – 55
□ 56 – 65
□ 66+
□ Female
-What is your highest education level?
□ High School or less
□ Diploma
□ Bachelor degree
□ Postgraduate study
-Which product was recommended today for your insomnia?
…………………..……………………………………
-Have you tried any other treatments for your insomnia?
□ Yes
□ No
-If so which one(s) have you used: (tick as many as apply).
□ Over The Counter medicine
□ Behavior therapy (eg counseling)
□ Prescribed medication
□ Relaxation therapy (eg yoga)
□ Exercise
□ Alcohol
□ Herbal products
-Please tick the appropriate box for your opinion on the following statements:
Less
than
once
per
week
1–2
times
per
week
3–4
times
per
week
5–7
times
per
week
1-How often do you think you have difficulty falling asleep?
2- How often do you think you have difficulty staying
asleep?
3- How often do you think you have frequent awakenings
from sleep?
4- How often do you feel that your sleep is refreshing?
- Have you ever used an Antihistamine for sleep before?
-How often have you have used antihistamine as a sleep aid?
□ Once weekly
□ Couple of times a week

□ Yes
□ No
□ Whenever you need
*The researcher would like to telephone you in two weeks to ask about factors that influence
your sleep and how effective this treatment has been. The telephone interview has 15 questions
about the effectiveness of the treatment and should only take a maximum of 10-15 minutes. If
you are happy to be contacted, please include your first name and telephone number below.
*You do NOT need to provide your name and phone number if you do not want to be contacted.
Do you wish to complete the second part of this survey? □ Yes
□ No
Contact phone number……………………………….. First name……………………………………
Thank you for taking the time to contribute to this research
This study has been approved by the Human Ethics Research Committee at the University of Canberra
(Approval No.: 11-132)
134
Appendix C
Q1.How often (if ever) do you consume caffeine?
-Never
-Less than once a day
-Once a day
-2-3 times a day
-4+ times a day
Q2. When you consume caffeine, what do you drink and how much?
..................................................................................................................................
..................................................................................................................................
Q3.How often (if ever) do you drink alcohol?
-Never
-Less than once a week
-Once a week
-2-3 times a week
-4+ times a week
Q4. When you consume alcohol, what do you drink and how much?
..................................................................................................................................
..................................................................................................................................
Q5.How often (if ever) do you smoke tobacco/ cigar/ pipe?
-Never
-Rarely
-1-10 cigarettes a day
-11-20 cigarettes a day
135
Q6. How long does it usually take you to fall asleep on the nights you have a problem falling
asleep?
Before antihistamine
After antihistamine
< ½ hour
½ - 1 hour
1-2 hours
2-3 hours
>3 hours
Q7. How would you rate your sleep quality overall?
Before antihistamine
Very poor
Poor
Average
Good
Very good
Q8.On a typical day, how long do you nap for in total?
Before antihistamine
I don't take naps
0-15mins
16-30mins
Longer than 30mins
After antihistamine
After antihistamine
Q9.How much time do you usually spend awake at night on the nights you have trouble
sleeping?
Before antihistamine
After antihistamine
< ½ hour
Between 1/2 – 1 hour
One to two hours
2 – 3 hours
More than 3 hours
Q10.How long does it usually take you to get back to sleep once you wake up at night?
Before antihistamine
After antihistamine
< ½ hour
Between 1/2 – 1 hour
One to two hours
2 – 3 hours
More than 3 hours
136
Q11. How long you have used Antihistamine as a sleep aid? ( Total time= days or weeks)
..................................................................................................................................
..................................................................................................................................
Q12. How often you have used Antihistamine as a sleep aid?
- Once weekly
-Couple of times a week
- Every night
- Whenever you need
Q13. How much do you think taking the sleep aid has affected your ability to fall asleep during
the daytime without intending to, or that you would struggle to stay awake while you were doing
things?
-No chance
-Slight chance
-Moderate chance
-High chance
Q14. How much do you think taking the sleep aid has affected your ability to stay awake during
the day?
-Not at all
-A little
-Somewhat
-Very much
137
Q15. How much do you think taking the sleep aid has affected your ability to get through your
work?
-Not at all
-A little
-Somewhat
-Much
-Very much
Q16. Do you think the sleep aid is causing any side effects? If yes what are these effects?
..................................................................................................................................
..................................................................................................................................
Q17. What do you think of this product as a sleep aid?
..................................................................................................................................
..................................................................................................................................
..................................................................................................................................
..................................................................................................................................
138