Download guidelines for the treatment of sleep disorders

GUIDELINES FOR THE TREATMENT OF SLEEP DISORDERS
Dr. Sachln Sharma & Dr J.K.Trivedl'
INTRODUCTION
Disturbed sleep is among the most frequent health complaints physician encounter. For most, it is an
occasional night of poor sleep or daytime sleepiness. However, at least 15%-20% of adults report
chronic sleep disturbance or misalignment of circadian timing. These lead to serious impairment of
daytime functioning and may contribute to exacerbate medical psychiatric conditions.
Clinical psychiatrists and psychologists of the new millennium will need to master general basic
knowledge of sleep and chronobiology , the disorders of sleep and circadian rhythms, and their
clinical management (1,2).
Disordered sleep has protean effects on mood, attention,, memory and general sense of vigor.
Furthermore, disturbance in sleep has clear prognostic value and must be addressed to optimize
clinical come.
DIAGNOSTIC CATEGORIES
Sleep Disorders
Sleep disorder can be divided into four major categories:
1.
Dyssomnias: disorders associated with complaints of insufficient, disturbed, or non-restorative
sleep.
2.
Hypersomnias : disorders of excessive sleepiness.
3.
Disturbances of the circadian sleep-wake cycle.
4.
Parasomnias: abnormal behaviors or abnormal physiological events in sleep (1, 2).
By the definition, the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV)
limits itself to chronic disorder (at least 1 month in duration) (1). On the other hand, the International
Classification of Sleep Disorders includes sleep disorder of short-term and intermediate duration,
which in fact are more common than chronic disorders (3).
Primary sleep disorders result from conditions inherent to the mechanism by which sleep is regulated.
Sleep may be disturbed owing io pain or discomfort from medical illness, considered in term of DSMIV-TR to be secondary sleep disorders. In addition, sleep disorders may be related to other mental
disorders, general medical conditions, and substance abuse.
Following are the diagnostic criteria for the different categories:
DYSSOMNIAS:
1.
Primary Insomnia :DSM IV TR classification
a.
The predominant complaint is difficulty initiating or maintaining sleep, or non-restorative
sleep, for at least 1 month.
Department of Psychiatry, K.G. Madieal University, Lucknow
(232)
2.
b.
The sleep disturbance (or associated daytime fatigue) causes clinically significant distress
or impairment in social, occupational, or other important areas of functioning.
c.
The sleep disturbance does not occur exclusively during the course of narcolepsy, breathingrelated sleep disorder, circadian rhythm sleep disorder, or a parasomnia.
d.
The sleep disturbance does not occur exclusively during the course of another mental
disorder (e.g. major depressive disorder, generalized anxiety disorder, a delirium).
e.
The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of
abuse, a medication) or a general medical condition.
Primary Hypersomnia : DSM IV TR classification
a.
The predominant complaint is excessive sleepiness for at least 1 month (or less if recurrent)
as evidenced by either prolonged sleep episodes or daytime sleep episodes that occur
almost daily.
b.
The excessive sleepiness cause clinically significant distress or impairment in social,
occupational, or other important areas of functioning.
c.
The excessive sleepiness is not better accounted for by insomnia and does not occur
exclusively during the course of another sleep disorder (e.g., narcolepsy, breathing-related
sleep disorder, circadian rhythm sleep disorder, or a parasomnia) and cannot be accounted
for by an inadequate amount of sleep.
d.
The disturbance does not occur exclusively during the course of another mental disorder.
e.
The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of
abuse, a medication) or a general medical condition.
Specify if:
Recurrent: If there are periods of excessive sleepiness that last at least 3 days occurring several
times a year for at least 2 years.
3.
4.
Narcolepsy: DSM IV TR classification
a.
Irresistible attacks of unrefreshing sleep that occurs daily for at least 3 months.
b.
The presence of one or both of the following:
1.
Cataplexy (i.e., brief episodes of sudden bilateral loss of muscle tone, most often in
association with intense emotion)
2.
Recurrent intrusions of elements of REM sleep into the transition between the sleep and
wakefulness, as manifested by either hypnopompic or hypnagogic hallucinations or sleep
paralysis at the beginning or end of sleep episodes.
c.
The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of
abuse, a medication) or another general medical condition.
Breathing-Related Sleep Disorder: DSM IV TR classification
a.
Sleep disruption, leading to excessive sleepiness or insomnia that is judged to be due to a
sleep-related breathing condition (e.g., obstructive or central sleep apnea syndrome or
central alveolar hyperventilation syndrome).
(233)
b.
5.
The disturbance is not better accounted for by another mental disorder and is not due to
the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or
another general medical condition ( other than breathing-related disorder)
Orcadian Rhythm Sleep Disorder: DSM IV TR classification
a.
A persistent or recurrent pattern of sleep disruption leading to excessive sleepiness or
insomnia that is due to a mismatch between the sleep-wake schedule required by a person's
environment and his or her circadian sleep-wake pattern.
b.
The sleep disturbance causes clinically significant distress or impairment in social,
occupational, or other important areas of functioning.
c.
The disturbance does not occur exclusively during the course of another sleep disorder or
other mental disorder.
d.
The disturbance is not due to the direct physiological effects of a substance (e.g., a rug of
abuse, a medication) or a general medical condition.
Specify type:
Delayed sleep phase type: a persistent pattern of late sleep onset and late awakening times, with
an inability to fall asleep and awaken at a desired earlier time.
Jet lag type: sleepiness and alertness that occur at an inappropriate time of day relative to local
time, occurring after repeated travel across more than one time zone.
Shift work type: insomnia during the major sleep period or excessive sleepiness during the major
awake period associated with night shift work or frequently changing shift work.
Unspecified type
6.
Periodic Limb Movements in Sleep (PLMS) Previously called nocturnal myoclonus, is a disorder
in which repetitive, brief, and stereotyped limb movements occur during sleep, usually about
every 20 to 40 seconds. It has following features Leg kicks every 20-40s Duration of 0.5-5s
Complaints of:
•
Insomnia
•
Excessive sleepiness
•
Restless leg
•
Very cold or hot feet
•
Uncomfortable sensations in legs
PARASOMNIAS:
The parasomnias are a group of disorders characterized by disturbance of either physiological
processes or behavior associated with sleep, but not necessarily causing disturbances of sleep or
wakefulness. It includes:
1.
Nightmare Disorder (DSM-IV-TR criteria)
a.
Repeated awakenings from the major sleep period or naps with detailed recall or extended
and extremely frightening dreams, usually involving threats to survival, security, or selfesteem. The awakenings generally occur during the second half of the sleep period.
(234)
2.
b.
On awakening form the frightening dreams, the person rapidly becomes oriented and alert
(in contrast to the confusion and disorientation seen in sleep terror disorder and some
forms of epilepsy).
c.
The dream experience, or the sleep disturbance resulting from the awaking, causes clinically
significant distress or impairment in social, occupational, or other important areas of
functioning.
d.
The nightmares do not occur exclusively during the course of another mental disorder
(e.g., a delirium, posttraumatic stress disorder) and are not due to the direct physiological
effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.
Sleep Terror Disorder (DSM-IV-TR criteria)
Recurrent episodes of abrupt awakening from sleep, usually occurring during the first third
of the major sleep episodes and beginning with a panicky scream.
3.
4.
b.
Intense fear and signs of autonomic arousal, such as tachycardia, rapid breathing, and
sweating, during each episode.
c.
Relative unresponsiveness to efforts of other to comfort the person during the episode.
d.
No detailed dream is recalled and there is amnesia for the episode.
e.
The episode cause clinically significant distress or impairment in social, occupational, or
other important areas of functioning.
f.
The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of
abuse, a medication) or a general medical condition.
Sleepwalking Disorder (DSM-IV-TR criteria)
a.
Repeated episodes of rising from bed-du«ng sleep and walking about, usually occurring
during the first third of the major sleep episode.
b.
While sleepwalking, the person has a blank, staring face, is relatively unresponsive to the
efforts of others to communicate with mm or her, and can be awakened only with great
difficulty.
c.
On awakening (either from the sleepwalking episode or the next morning), the person has
amnesia for the episode.
d.
Within several minutes after awakening from the sleepwalking episode, there is no
impairment of mental activity or behavior (although there may initially be a short period of
confusion or disorientation).
e.
The sleepwalking causes clinically significant distress or impairment in social, occupational,
or other important areas of functioning.
f.
The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of
abuse, a medication) or a general medical condition.
REM Sleep Behavior Disorder
It is associated with complicated behaviors during sleep such as walking, running, singing and talking
(4). It occurs during second half of night during REM sleep.
(235)
5.
Sleep Disturbance related to Other Psychiatric Disorder
6.
Sleep Disorder in other Medical Condition
7.
Substance-Induced Sleep Disorder
REVIEW OF MANAGEMENT OF INSOMNIA
NON- PHARMACOLOGICAL MANAGEMENT
Most insomnia patients indicate that they would prefer a non*pharmacologic solution to their insomnia
(5).There are several effective treatment approaches to chronic insomnia that do not involve the use
of hypnotics ( 6), Education about normal sleep and counseling around habits for promoting good
sleep hygiene are a good but insufficient intervention when used alone ( 7, 8). Various relaxation
therapies hypnosis, meditation, deep breathing, and progressive muscle relaxation can be helpful.
These techniques in contrast to use of hypnotics, are not immediately beneficial but require several
weeks of practice to improve sleep (9). Success is dependent on high degree of motivation in patients,
who must devote considerable time to practice these techniques. Those who succeed in learning
these techniques have a greater satisfaction with maintenance treatment than do patients chronically
using hypnotics (10,5). Furthermore, responders to behavioral interventions have sustained benefits
after 6 months (11). Biofeedback can be helpful in those patients who are not sensitive to their
internal state of arousal (12). Patients are provided an external measure of a biological variable such
as an EMG or EEG that allows them a means to influence their own level of arousal. Sleep restriction
therapy is similarly aimed at reducing the amount of wake time spent in bed (13).
Cognitive Behavior Therapy (CBT)
Morin et al, 1993 (14) found the CBT was effective in reducing sleep latency, waking up, early morning
awakening and increasing sleep efficiency. Morin et al 1999 (15) found both CBT and pharmacotherapy
effective for short term management of insomnia but that improvement was better sustained over
time with CBT.
Behavioral treatments, in combination with addressing sleep hygiene, may be helpful in treating
psycho physiological and other insomnias. Relaxation training (progressive relaxation, autogenic
training, meditation, deep breathing) can all be effective if over taught to become automatic. Two
other behavioral therapies have been shown to be effective: Stimulus control and Sleep restriction
therapy (16,13, 8) both requiring more than 3 weeks to be effective.
Stimulus Control: Stimulus control behavioral modification focuses on eliminating environmental
cues associated with arousal (and aims to break the negative association of being in bed unable to
sleep (10). The goal is to remove all behaviors from bedroom except sleep and loving.
Sleep restriction Therapy is similarly aimed at reducing the amount of wake time spent in bed (13)
and is based on the observation that more time spent in bed leads to fragmented sleep.
CBT emphasizes the role of dysfunctional thoughts in maintenance of primary insomnia. Not only it
is known to improve sleep efficiency but also has been demonstrated to aid in BZD discontinuation in
older insomnia. It also imparts a greater sense of control over the problems. One may use systematic
desensitization by reciprocal inhibition aiming to desensitize the patients to the associated experience.
Other techniques, each with minimal efficacy are somatic relaxation, including muscle relaxation
procedures, Electromyographic biofeedback, paradoxical intention, cognitive focusing.
(236)
A comprehensive review of the efficacy of non-pharmacological treatment for chronic insomnia, based
on two meta-analysis and 48 individual treatment studies, showed reliable improvement in the main
outcome measures of latency to sleep and wake time after sleep onset. (17).Data consistently indicated
that 70%-80% of insomnias benefited from the treatment. Sleep latency was reduced and subjective
report of sleep quantity and quality improved. Improvements with behavioral treatments are well
maintained over at last 6 months. (8).
Relaxation and biofeedback therapies
Relaxation techniques target the cognitive or physiological arousal that interferes with sleep. A number
of relaxation therapies have been used for insomnia, including PMR and biofeedback to diminish
physiologic arousal, and imagery techniques, autogenic training, and meditation to reduce cognitive
arousal. Relaxation techniques may be most useful for sleep onset insomnia. In general, the magnitude
of improvements seen with relaxation is smaller than for other behavioral approaches. (18).
PHARMACOLOGICAL TREATMENTS FOR INSOMNIA
Several medication classes are used for the treatment of insomnia, although the strength of evidence
regarding their efficacy and tolerability varies considerably. A wide variety of sedating medication has
commonly been used as sleeping pills, which vary in pharmacokinetic properties and side effects.
The ideal sleeping pill would shorten latency to sleep, maintain normal physiological sleep all night
without blocking normal behavioral responses, leave neither hangover nor withdrawal effects the
next day; be devoid of tolerance and side effects such as Impairment of breathing, cognition, and coordination, and should not be habit forming or addictive (19).
Short life hypnotics usually produce less daytime sedation than those with longer half-life drugs, but
they often result in more rebound insomnia when they are discontinued (20). However, they relatively
cause more amnesia especially for material that is learned during the period of peak concentration of
drugs.
The major classes are benzodiazepine receptors agonists (BzRA), antidepressant drugs (AD),
antihistamines, melatonin, and various herbal remedies including valerian root extracts. Of these
medications, only BzRAs are formally approved for the indication of insomnia treatment in the United
States.
Benzodiazepine Receptor Agonists
Benzodiazepine receptor agonists (BzRAs) include the true benzodiazepines (e.g., triazolam,
temazepam, estazolam, and lorazepam) as well as a structurally dissimilar group of nonbenzodiazepine
agents, including an imidazopyridine (Zolpidem), pyrazolopyrimidine (zalpelon), and cyclopyrolone
(zopiclone). BzRAs are the only pharmacologic agents currently approved by the FDA for the treatment
of insomnia, and they are labeled for short-term use (i.e., less than 4 weeks).
In summary, these agents bind at a specific recognition site in the benzodiazepine-a-aminobutyric
acid (GABA)-chloride ion channel macromolecular complex. This binding is responsible for the hypnotic,
anxiolytic, myorelaxant, and anticonvulsants actions of BzRAs.
There is some evidence that the nonbenzodiazepine BzRAs, specifically Zolpidem, may be relatively
more specific for hypnotic effects relative to anticonvulsants and anxiolytic effects: this may be related
to greater specificity for benzodiazepine type I receptors.
(237)
Specific BzRAs differ significantly in pharmacokinetic properties, including the rate of absorption,
extent of distribution, and rate of elimination. BzRAs also range widely in elimination half-life, from 1
hour for zaleplon to 120 hours for flurazepam and its metabolities. Finally, these agents differ in terms
of active metabolities, which may have longer half-lives than the parent compound.
BzRAs are efficacious in the short-term treatment of insomnia. Recent metaanalyses examined
BzRAs effects on sleep latency, sleep duration, number of awakenings, and sleep quality (21,22). For
each of these outcomes, the effect size ranged between 0.55 and 0.75, substantiating the superiority
of these agents over placebo. Other data support a broader range of beneficial outcomes. For instance,
treatment with zopiclone for both 14 days and 8 weeks of treatment was associated with greater
improvements in quality of life measures, social activities and professional activities compared to
placebo (23). A survey of patients with untreated insomnia and those receiving benzodiazepines
showed that the later group reported fewer symptoms of feeling blue, down in the dumps, or depressed,
and being easily upset compared to the former group (24).
BzRAs have consistent effects on polysomnography (PSG) sleep measures (25). As expected, BzRAs
are associated with reduced sleep latency and wakefulness during the night, and increased sleep
duration and sleep quality ratings. Other specific PSG effects depend on the particular agent. For
instance, zaleplon, with its very short half-life, has not been demonstrated to consistently affect sleep
duration despite its effect on sleep latency. Traditional benzodiazepines reduce REM and stages 3 to
4 NREM sleep, whereas zaleplon and Zolpidem are not associated with changes in sleep stages. In
addition, BzRAs reduce the number of periodic limb movements and arousals associated with these
movements (26). BzRAs can also lead to oxyhemoglobin desaturations during sleep and can
theoretically worsen sleep apnea; however, in patients with moderate degrees of sleep apnea, the
change in number of apneas and oxyhemoglobin saturation is felt to be clinically insignificant (27).
Although BzRAs have been studied primarily for short-term treatment of insomnia, insomnia is often
a chronic condition , and many patient take their hypnotics for longer periods of time. Some patients
clearly developed tolerance with continued use of BzRAs, and some polysomnography (PSG) studies
support this phenomenon (28); however, other PSG studies show continued efficacy over several
nights of continued nightly administration. For instance, trizolam, Zolpidem, and zaleplon have shown
continued efficacy over a period of 4 to 5 weeks in double-blind, placebo controlled studies ( 29-32),
and single blind studies have shown continued efficacy by PSG for as long as 6 months (33,34).
Studies using self-ratings or observer ratings have documented efficacy for even longer amounts of
time. For instance, double-blind studies have shown continued efficacy for up to 24weeks with no
evidence of tolerance according to mean subject rating (35,36) and single blind studies have shown
efficacy for up to 1 year of treatment (37,38); however the rote of BzRAs in long-term treatment or
maintenance treatment of insomnia remains to be more clearly defined.
BzRAs can have significant adverse effects. The most common of these is a continuation of their
desired therapeutic effects, sedation during the daytime. Daytime sleepiness is clearly more severe
with longer-acting agent such as flurazepam, which has been documented in PSG studies (29, 39).
Similar PSG studies of short-acting hypnotics have not shown an increase in daytime sleepiness.
BzRAs are also associated with dose-related anterograde amnesia that may even be primarily
responsible for their therapeutic affect (40,41). BzRAs can also impair other aspects of psychomotor
performance including reaction time, recall, and vigilance. Whether or not such deficits improve with
discontinuation of the drug is more controversial, with some studies noting improvement following
discontinuation (42, 43) and other studies failing to show such improvement (44).
(238)
BzRAs are significantly related to an increased risk of injurious falls and hip fractures in elderly
people. In particular, risk seems to be increased with the use long-acting agents, high doses, multiple
agents, and cognitive impairments in patients (45, 46).
Several discontinuation phenomena have been examined in relation to BzRAs. Rebound insomnia
refers to an increase in insomnia symptoms beyond their baseline levels. Rebound is thought to be
associated primarily with short-acting BzRAs, although recent evidence for Zolpidem and zaleplon
does not show the effect. Patients who demonstrate rebound insomnia tend to have worse baseline
sleep and higher medication doses than patient without rebound (47, 48). The behavioral aspect of
taking a pill may contribute to rebound insomnia. Individuals who have shown a poor response to
treatment may show the greatest rebound (49). Withdrawal symptoms may occur in 40% to 100% of
patients treated chronically with benzodiazepines, and can persist for days or weeks following
discontinuation (50, 51). Withdrawal symptoms can include dizziness, confusion, depression, and
feeling of unreality. Cognitive and behavioral treatments can help patients discontinue chronic
benzodiazepine use (52). The prevalence of true withdrawal phenomenon in any individual treated
with one-daily hypnotic dose of BzRAs is not well known. Recurrence is another potential
discontinuance syndrome that has received little attention in insomnia. Given that insomnia tends to
be chronic, it should not be surprising that many patients complained of their original symptom after
discontinuation of an effective treatment. The role of recurrence in chronic BzRAs treatment also
remains to be well defined. Finally, abuse of BzRAs used for insomnia appears to be uncommon.
One survey showed no greater use of increased doses for BzRAs compared to antidepressants (53).
Although data are difficult to obtain, benzodiazepines may be used by 0.5% to 3% of the population
for non-medical purposes in any one year (54). Among those who wish to discontinue chronic use of
BzRAs, their pattern of use tends to suggest stability or declining doses over time as well as tendency
to intermittent rather than consistent dosing (55). Thus, among individuals with no prior substance
use history, abuse of BzRAs appears to be uncommon. Administration of Zaleplon 4 hours of more
before usual time of rising in morning does not appear to be associated with impairment in motor
performance (56)
Antidepressant Drugs
Although use of antidepressant drugs (AD) for insomnia has increased dramatically, evidence to
support their efficacy is relatively sparse. The most commonly used ADs for insomnia include trazodone,
tertiary tricyclic agents, and mirtazapine. These drugs clearly have diverse effects on
neurotransmission. In general, the sedating properties of antidepressants are related to antagonism
of serotonin 5-HT2, histamine, and a1-adrenergic receptors.
Antidepressant drugs vary widely in their effects on sleep continuity, EEG data activity and slow-?
wave sleep, and REM sleep. Sleep continuity effects are likely to be most important in the treatment
of insomnia. Some antidepressant drugs also can cause or exacerbate insomnia problems. Selective
serotonin reuptake inhibitors (SSRIs) bupropion, noradrenergic selective tricyclic drugs and strongly
serotonergic tricyclic drugs (e.g., clomipramine) are the most common agents to have such effects.
In addition, serotonergic specific antidepressants can lead to anomalous sleep stages characterized
by eye movements during NREM sleep and they can also cause or exacerbate restless leg syndrome
and periodic limb movements. Antidepressants may also be associated with slight improvements in
sleep apnea (57).
(239)
Studies with small number of subjects and diverse inclusion criteria suggested the beneficial effects
of trazodone 150 to 400 mg on sleep continuity measures, as well as a tendency to increase stages
3 to 4 sleep and improve subjective sleep quality ratings, in insomnia patients (58-60). A more recent
2-week double-blind placebo-controlled study compared the effects of trazodone 50 mg and Zolpidem
10mg to placebo among individuals with primary insomnia (61). This study showed improvements in
subjedve sleep latency and sleep duration with both active drugs although there was some evidence
for superiority of Zolpidem during the second treatment week. Both drugs were well tolerated. Other
studies involving primary insomnia have shown beneficial effects of short-term treatment with lowdose doxepine (62) and trimipramine (63) compared to placebo. Finally, a recent open-label trial of
paroxetine for primary insomnia in the elderly showed significant improvement in a multivariate
measures of sleep quantity based on both diary and polysomnography sleep measures (64). Small
improvements were noted in diary-based measures of sleep quality and PSG measures of sleep
efficiency; however, the greatest improvements were noted in daytime symptoms of mood and well
being. Thus, it may not simply be the sedating properties of antidepressants that lead to improvement
in insomnia.
Indirect evidence for the efficacy of antidepressant*, and differential effects among agents, comes
from studies in individuals with major depression. For instance, fluvoxamine has a relatively alerting
effect relative to desipramine that in turn is more alerting than amitriptyline (65, 66). A comparison of
trimipramine and imipramine found that both drugs improve sleep quality, although trimipramine was
associated with more positive effects on PSG sleep (67). A comparison of fluoxetine with trazodone
showed that the latter drug was not only associated with more improvements in insomnia symptoms,
but also with a greater percentage of sedating events during the daytime (68). A series of comparison
between fluoxetine and nefazodone has consistently shown that both drugs improve subjective sleep
quality among depressed patients, although the change appears to be larger with nefazodone (69,
70). Nefazodone also led to improvements in PSG sleep efficiency, whereas fluoxetine was associated
with mild decrements.
Antihistamines
Antihistamines such as diphenhydramine are among the most widely available over-the-counter
preparations for insomnia. The mechanism of action of these drugs involves inhibition of histamine
H1 receptors. Histaminic neurons in the posterior hypothalamus promote wakefulness through
interaction with ascending cholinergic nuclei. Inhibition of H1 receptors leads to decreased alertness
and subjective sedation. The elimination half-life of diphenhydramine range .'orm 3 to 5 hours, within
increase in elderly persons. In addition to their effect on histamine, these medications can also have
antimuscarinic anticholinergic effects.
Despite their widespread use, a large body of well-documented research does not support the efficacy
of antihistamines (71). Diphenhydramine 50 mg, improved subjective rating of sleep quality, sleep
time, sleep latency, and wakefulness after sleep onset in middle-aged subjects with insomnia (71).
Amore recent study comparing the effects of lorazepam versus a combination of lorazepam plus
diphenhydramine showed a slight advantage for the combination preparation in terms of sleep latency
and subjective sleep quality (72). On most sleep measures, the two drug preparation were fairly
similar. Studies of antihistamines in elderly people demonstrate subjective sedative properties
comparable in magnitude to those of benzodiazepines and confirmed by effects such as increased
sleep time, decreased awakening, and shorter sleep latency (73, 74).
(240)
Adverse effects of antihistamines include a range of cognitive and performance impairments (75).
The anticholinergic effects of these medications may be of particular concern in elderly subjects. The
relative safety and efficacy of antihistamine with more sustained use has not been examined.
Melatonin
Melatonin has been widely used as a "natural" sleep promoting agent. Data regarding its efficacy and
safety have been mixed. The study designs, doses, and outcome measures used in melatonin trials
have been quite variable and may contribute to inconsistent findings (76). Melatonin is secreted by
the pineal gland during hours of darkness and the secretion of melatonin may result from influence of
specific receptors in the suprachiasmatic nucleus of the hypothalamus (77). In addition, melatonin
shifts circadian rhythms according to phase response curve (78, 79). The half-life of endogenous
melatonin is less than 1 hour. Exogenous melatonin is absorbed from the gastrointestinal tract. A
wide variety of preparations are commercially available, ranging from very short-acting to very longacting agents, with half-lives ranging from several minutes to approximately 8hours. Doses greater
than 1 mg are likely to include supraphysiological concentrations. Clinical trials have employed doses
ranging from 0.1 to 80 mg.
During daytime administration, melatonin cause sleepiness and fatigue and in healthy subjects (80,81).
When administered in night to healthy subjects, melatonin decreases sleep latency (82) and the
number of awakenings, and improves sleep efficiency in an experimental insomnia paradigm (83).
Studies in insomnia patients have also yielded inconsistent findings. Single night administration seems
to produce very little effects (84). Subjective sleep ratings showed no effects in another trial of 5 mg
for 1 week (85), whereas a 14-day trial of 75 mg resulted in increased subjective sleep time (86).
Trials of melatonin in elderly people have ranged from 1 to 21 days. The most consistent effect is
reduced sleep latency with some evidence as well for reduced nighttime wakefulness using sustainedreleased preparations (87-90). In a carefully designed 14-days crossover trial, immediate- and
sustained-release melatonin were associated with shortened sleep latency, but no change in sleep
time, sleep efficiency, wakefulness, or subjective sleep measures (91).
Adverse effects associated with melatonin have not been carefully evaluated. Melatonin affects
reproductive cycles in several mammalian species, and reports have indicated the potential for
worsening of sleep apnea and impaired cognitive and psychomotor performance during daytime
administration. There are also some concerns regarding vasoconstriction as a potential side effect.
Valerian Extract
Valerian extract is one of the most widely used herbal remedies for insomnia. These extract are
derived from roots of the genus Valeriana, most often of the species V. officinelis. They contain of
number of potentially active compounds, including sesquiterpenes and valepotriates. Valerian extracts
show affinity for GABAA receptors, which may be related to the high amount of GABA itself that is
often contained in these preparations (92,93). However, GABA does not cross the blood-brain barrier,
so this is an unlikely mechanism of action. Other potential actions include affinity for serotonin and
adenosine receptors. Clinical studies with valerian extracts show mild sedative and anxiolytic effects.
In particular, four double-blind placebo-controlled studies have examined doses of 400 to 900 mg of
valerian extract over periods of time from 1 to 8 days, and in diverse subject populations ranging from
healthy young adults to elderly insomniacs (94 -97). Subjective effects include decreased sleep
latency and improved sleep quality (94, 96, 97). One study also reported decreased subjectively
(241)
rated awakenings (94). Polysomnography studies have shown an increase in stage 3 to 4 NREM
sleep and reduced stagel sleep (95), with no change in sleep onset time, a.vake time after sleep
onset, or other measures of sleep continuity (95,96). Likewise, valerian was found not to influence
the EEG power spectrum during sleep (96). Small numbers of subjects, different inclusion criteria,
and inconsistent findings hamper findings from these studies. These studies do not demonstrate the
efficacy of valerian extract in most groups of individuals with primary insomnia.
Clinical studies have suggested a generally favorable side effect profile for valerian extract; however,
the sedative effects of valerian may potentiate the effects of other CNS antidepressants (93).
Combination- Non pharmacological and Pharmacological treatment
In a randomized controlled trial conducted by Morin etal 1999(17) patients receiving cognitive behavior
therapy (CBT) alone or CBT with temazepam rated themselves as significantly less impaired than
those receiving drug treatment alone or placebos. They concluded that drug therapy gradually lost its
clinical benefits over time but behavioral therapy had more lasting effects. Kupfer and Reynolds 1997
(98) in a review article stated that to achieve treatment goals for patients with insomnia, educational,
behavioral and pharmacologic interventions should be combined. Attarian 2000 (100) concurred
with this statement when he noted that the best management for insomnia is a combination of hypnotic
medication and behavioral methods. Holbrook etal2000 (101) also advocates a three step approach
to treatment in primary care: (i) look for reversible underlying causes; (ii) non-pharmacological therapy;
and (iii) pharmacological therapy.An earlier article by Rajput and Bromley in 1999 (102) stated the
following:
•
drug therapy may be beneficial for short-term improvement
•
behavioral intervention may produce more sustained effects
•
behavioral intervention combined with pharmacologic agents may be more effective than either
approach alone.
Wohlgemuth etal2001 (103) after conducting a randomized controlled trial comparing CBT, relaxation
training (RT) and placebo treatment recommended that considering the cost, side effects and
temporary benefits of drug treatment, CBT as a first line therapy for chronic insomnia warrants
consideration.
Polysomnography -when to do?
Polysomnography is required in patients with excessive daytime sleepiness, snoring, apnea spells, a
body mass index over 35, narcolepsy, sleep walking, periodic limb movement disorders, failure of
treatment (104).
INDIAN LITERATURE
In the area of the sleep disorders Indian studies and literature is too embarrassingly scanty, primarily
being review articles and replication of western literature (105), few cases reports e.g. fluoxetine
induced augmentation of methylphenidate in primary hypersomnia (106).
PRACTICING GUIDELINES FOR INSOMNIA:
Treatment of insomnia should be directed at identifiable causes, or those factors that perpetuate the
disorders such as temperament and life style, ineffective coping and defense mechanism, inappropriate
use of alcohol or other substances maladaptive sleep wake schedules, and excessive worry about
(242)
poor sleep. Clinical management is multidimensional has psychosocial, behavioral and
pharmacological approaches.
General treatment recommendation
Clinician treating sleep disorder should attempt to determine the cause of the disorder before initiating
treatment. Secondary sleep disorders generally are best managed by treating the underlying disorder.
It is equally important to know, beforehand, the normal psychological variations in sleep structure.
Some subjects are known to require sleep of less than six hours, while some require more than nine
hours. At the extremes of ages, variations are normally seen; the elderly have gradual reduction in
sleep- both qualitatively and quantitatively. However, Kripke et al (2002) [128] found that sleep of
more than 8.5 hours or less than 3.5 hours per night had a mortality risk 15 percent higher than those
slept an average of 7 hours per night. A detailed sleep history including episodes of awakening can
assist in diagnostic clarification and treatment planning. Spouses or family members can often furnish
information on behaviors such as snoring or motor activity. Additional factors that need to be evaluated
include current stressors, medication or substances use, psychiatric history and environmental factors
that may affect sleep.
Following are the recommendations:
Practice guidelines for the use of polysomnography in the evaluation of insomnia
•
Polysomnography is not routinely indicated for transient or chronic insomnia
•
It is indicated when sleep apnea or myoclonus is suspected, particularly in the older patients.
•
It should be considered if diagnosis is uncertain and behavior or drug therapy is ineffective.
•
It is indicated for patient with confusional or violent arousals, particularly if the clinical diagnosis
is uncertain.
•
It should be considered for circadian rhythm disorder if the clinical diagnosis is uncertain.
Recommendation - Sleep diary
Among patients with insomnia, a sleep diary for 1-2 weeks should be kept to serve as a baseline
assessment of the sleep problem and to monitor the effectiveness of treatment. A sleep diary kept for
a period of 2 weeks is helpful for patients who have insomnia (98). The diary includes the patients'
usual bedtime, the total sleep time, the time until onset of sleep, number of awakenings in the night,
medications used, quality of sleep rating and daytime consequences of poor sleep. This record,
although subjective, reflects the patient's perception of the amount and quality of sleep he or she is
getting (100). This sleep diary would help the physician in determining the severity of the sleep
disturbance, the medications being used, the duration of its use and provide a glimpse into the
effectiveness of the present treatment regimens.
Insomnia involves daytime consequences such as fatigue, lack of energy, difficulty in concentrating
and irritability that cause marked distress or impairment in social, occupational or other important
areas of functioning. As such, among patients with insomnia, there should be an assessment of
daytime consequences using the scales available locally.
Therapeutic options for acute insomnia
Recommendations
Among patients with acute insomnia, appropriate action against the inciting cause would often reverse
(243)
the condition but short-term pharmacologic therapy together with behavioral intervention should be
initiated when the sleep disturbance persists and causes marked daytime impairment. The cause of
acute insomnia can often be traced to a particular inciting event. However, even brief episodes of
acute insomnia should be treated appropriately when daytime sequelae are severe. It is important to
note that untreated acute insomnia might lead to chronic insomnia (99).The recommended
pharmacologic and non-pharmacological treatment options are similar for those with chronic insomnia
and will be discussed in greater detail in the recommendations that follow.
Therapeutic options for chronic insomnia
General Recommendation
Among patients with chronic insomnia educational or behavioral intervention combined with
pharmacologic agents is more beneficial than either therapy alone .As chronic insomnia is often due
to a myriad of factors, a patient may need multiple treatment modalities.
Recommendation- Non-pharmacological treatment
The following non-pharmacologic treatment options may be employed for patients with insomnia:
Behavioral Therapies
Sleep Hygiene Education
It is the basis of preventive strategy for insomnia and is the approach of first choice once a full
assessment has eliminated primary psychiatric or medical disorder.
These are general guidelines, it is usually better to help focus one of two of these principles at a time.
Long term outcome data is still scarce to support its use.
•
Target environmental factors and health practices that may be helpful or detrimental for sleep
•
Effects: Found to be beneficial when used in combination with other non-pharmacological
insomnia treatments
•
Helps to provide interference of insomnia caused by poor hygiene
•
Sleep hygiene suggestions
•
Maintain regular hours of bedtime and arising
•
Avoid heavy meals near bedtime
•
Avoid daytime napping
•
Exercise daily, but not later in the evening
•
Minimize caffeine intake and smoking within 8 hr of bedtime
•
Do not look at clock in night
•
Make bedroom comfortable, preferably slightly cool
•
Do not use alcohol while going to sleep
•
Go to bed only when sleepy
•
Minimize light, noise and excessive temperature during sleep
•
Avoid evening stimulation: substituted radio or relaxed reading for television. Practice evening
relaxation routines
(244)
Relaxation Therapy
- Insomnia patients tend to have high levels of cognitive, physiologic, and/or emotional
arousal both day and night
•
Effects: Progressive muscle relaxation to reduce somatic arousal
•
Imagery training, meditation are used to lower presleep cognitive arousal
•
Consistent daily practice is needed over 2-4 weeks to achieve benefit
•
Professional guidance may be necessary for initial training
•
Yoga may be an effective method for relaxation when done properly (e.g. Shavasana)
Sleep Restriction Therapy
•
Goal is to decrease the amount of time in bed to increase the percentage of time spent in bed
asleep
•
Helpful for patients who have been increasing their time in bed to increase their actual sleep
time
•
Effects: Creates mild sleep deprivation which promotes shorter sleep onset and longer time
asleep
•
Patients should stay in bed only as long as their average sleep time: but no less than 5 hr*
Allowable time in bed is increased by 15-20 min as sleep efficiency improves * Time in bed is
increased over a period of weeks until optimal sleep duration is achieved. * Usually keep wakeup
time the same and adjust bedtime Instructions to be given to the patient are:
•
Stay in bed for the amount of time you think you sleep each night. (Plus 15 min)
•
Get up at the same time each day.
•
Do not nap during the day.
•
When sleep efficiency is 85% (i.e., sleeping for 85% of the time in bed), go to bed 15 min earlier.
•
Repeat this process until you are sleeping for 8 hours or the desired amount of time.
•
Example: If you report sleeping only 5h a night and you normally get up at 6 AM, you are allowed
to be in bed from 12:45 AM until 6 AM.
Stimulus Control Therapy
•
Based upon the theory that insomnia is conditioned response to temporal (bedtime) and
environmental (bedroom/bed) cues that are associated with sleep.
•
The approach is also based on the hypothesis that the sleep environment has become associated
with a state of greater arousal specific to presleep factors heard from insomniac patients that
they are able to fall asleep in the living room, but not in their bedroom.
•
Effects: Sleep onset and sleep maintenance difficulties can be reduced with stimulus control
therapy
•
Bed and bedroom should be associated with rapid onset of sleep
•
Go to bed only when sleepy
•
Use bed only for sleep (or sex)
(245)
•
Get out of bed and go to another room when unable to fall asleep and return only when sleepy
•
Keep regular morning arising regardless of duration of sleep the night before
Cognitive Therapy
•
Identify faulty beliefs and attitudes about sleep and replace them with more adaptive ones
•
Effects: Has been shown to have positive results on insomnia especially when combined with
other techniques
•
Goal is to provide reassurance to patients regarding beliefs about sleep
•
Eg 'not everyone has 8 hr of sleep', patient may feel refreshed with less, assistance in dealing
with bedtime apprehension
•
Attempt to decrease the cycle of insomnia, emotional distress, dysfunctional thoughts which
can cause further sleep disturbances
Paradoxical Intention
In paradoxical intention, the patients is asked to try not to sleep, which enables the patient recognize
the potency of homeostatic sleep regulation. Later it can be suggested to the patient that the body will
not allow missing too much sleep.
Cognitive Focusing
This breaks up the ruminating thought process that typically occurs while an insomniac lies awake in
bed. In this the patient prepares in advance a series of reassuring thoughts and images on which
patients is asked to concentrate, should they wake up during the night.
Thought suppression
Thought stopping and articulatory suppression attempt to interrupt the flow of thought. No attempt is
made to deal with thought material as such but rather to alternate thinking. With articulatory suppression
the patient is instructed to repeat, sub vocally a word every 3 seconds. Additionally, this technique
may be useful during the night to enable rapid return to sleep.
It is important that the therapist encourage the patient to take an active role in the process, rather
than passively receiving guidance (Co-scientist model). Active involvement can be encouraged by
negotiating an acceptable outcome, which also helps in dispelling unrealistic expectation.
PHARMACOLOGOCAL MANAGEMENT
Recommendation- Pharmacological treatment
Among patients with chronic insomnia, the rational prescription of medications is of utmost importance
and should follow these principles:
•
start with the lowest effective dose
•
use intermittent dosing
•
prescribe medications for short-term use
•
discontinue the medications gradually
•
be alert for rebound insomnia
(246)
Benzodiazepines
•
Most commonly prescribed agents for treatment of insomnia
•
May be used as adjunctive therapy with behavioral therapy
•
Effects: Have been proven effective for short-term insomnia treatment
•
Normal sleep patterns are altered
•
Use usually limited to a maximum 4 weeks duration
•
Long term use increase chances of habituation and withdrawal symptoms
•
Tolerance to hypnotic effects develops on repeated administration
•
Rebound Insomnia occurs
•
Alter sleep patterns least
•
Are safer than other drugs in overdose
•
Do not significantly induce drug metabolizing enzymes that cause unwanted interactions
Tolerance develops within 3-14 days. Further there are substantial problems of dependence and
withdrawal symptoms with long term usage. Hence these should be prescribed rarely and that too for
short periods (less than a month) and intermittently (107).Those who are benzodiazepine dependent
experience significant rebound insomnia on withdrawal, with vivid dreams and increased REM sleep.
Benzodiazepine-like Hypnotics
Zaleplon
•
Effects: Similar hypnotic effects to benzodiazepines but side effects tend to be less
•
Does not alter normal sleep patterns and is not associated with tolerance or rebound insomnia
Zolpidem
•
Effects: Similar hypnotics effects to benzodiazepines but side effects tend to be less
•
Does not alter normal sleep patterns and is usually not associated with rebound insomnia
•
Tolerance and dependence has occurred in some patients
•
Has been used for up to 6 month usually without withdrawal issues or rebound insomnia upon
discontinuation
Zopiclone
•
Effects: Decreases sleep latency when compared to placebo and generally increases sleep
duration without changing normal sleep patterns
•
Rebound insomnia has occurred but not as severe as with benzodiazepines
•
Recommended for short-term use limited to maximum 4 weeks duration
Guidelines for Prescribing Hypnotics
•
Use the lowest effective dose.
•
Use intermittent dosing (alternate night or less)
•
Prescribe for short term use (< 4 weeks) in the majority of cases.
•
Discontinue slowly
(247)
•
Be alert for rebound insomnia/ withdrawal symptoms
•
Advise patients of the interaction with alcohol and other sedating drugs.
•
Avoid the use of hypnotics in patients with respiratory disease or severe hepatic impairment and
in addiction prone individuals.
Caution with Hypnotics
Hypnotics are relatively contraindicated in patients with sleep disordered breathing, during pregnancy,
in substance abuse. Caution should be used fn prescribing hypnotics to patients who snore loudly, to
patients who have renal, hepatic or pulmonary disease, and to elderly.
Other Agents
Antidepressants
•
TCAs have been used in lower doses than used for depression to treat insomnia
•
Effects: The sedating antidepressants at usual doses improve insomnia when used in patients
with major depression
•
Little scientific evidence to support use in non-depressed patients
Antihistamines
•
Effects: Generally lees effective than benzodiazepines and are associated with daytime
drowsiness.
BENZODIAZEPINES LIKE-HYPNOTICS
Drug
Zaleplon
Dosage
5-10mgPOat
bedtime
Half-life: 1 hr
Zolpidem
5-10mgPOat
bedtime
Half-life-1.5-4.5hr
Zopiclone
7.5-15 mgPO at
bedtime
Half-life: 3.5-6 hr
Remarks
Adverse Reactions
"Amnesia, anxiety, dizziness, hallucinations,
somnolence,
impaired coordination, rash,
photosensitivity reactions, peripheral edema, Gl upset
etc
Special Instructions
* Has been used up to 5 week in trail settings
Adverse Reaction
"Headache, drowsiness, dizziness, lethargy, abnormal
dreams, amnesia, rash, Gl upset etc
Special Instructions
"Has been used for up 6 months usually without
withdrawal issues or rebound insomnia upon
discontinuation
Adverse Reaction
'Bitter taste, somnolence, dizziness, headache, Gl
upset, psychiatric and paradoxical reactions, amnesia,
rebound insomnia and withdrawal symptoms
Special Instructions
•Recommended for short-term use limited to maximum
4 week duration
(248)
BENZODIAZEPINES
Drug
Alprazolam
Bromazepam
Clonazepam
Dosage
Half-life: 12-15hr
Half-life: 12-32 hr
0.5mg PO at
bedtime
Half-life: 19-60 hr .
5-10 mg PO
Dipotassium
Clorzapate
at bedtime
Half-life: 6-8 h, active
metabolite:48-96 hr
Estazolam
1-2mgPOat
badtime
Half-life: 8-24 hr
Flunitrazepam 0.5-2mg PO at
bedtime
Half-life: 16-35 hr
15-30mgPOat
Flurazepam
bedtime
Half-life:2-3 hr
Lorazepam
1 -4 mg PO at
bedtime
Half-life: 8-24 hr
Remarks
Adverse Reactions
Dependence and withdrawals symptoms can occur
especially in patients with history of drug dependence
CNS effects (eg sedation, drowsiness, muscle
weakness, ataxia. Less commonly slurred speech,
vertigo, headache, confusion). Symptoms decrease
after continued use
Prolonged use of agents with longer half lives may
provide next day anxiolytic action and decrease
rebound hypertension but they can cause daytime
sleepiness cognitive impairment, and in co-ordination
Special Instruction
Elderly patients should receive lower doses
Short-term use (<4 week) to avoid dependence and
withdrawal symptoms
Drug
Remarks
Dosage
Lormetazeparr 1 -2 mg PO at
bedtime
Half-life: 11 hr
Adverse Reaction
Midazolam
7.5-15 mgPO at
bedtime
Half-life:2-7 hr
Nitrazepam
5-10 mg POat
bedtime
Half-life:24-30 hr
CNS effects (eg sedation, drowsiness, muscle
weakness, ataxia. Less commonly slurred speech,
vertigo, headache, confusion). Symptoms decrease
after continued use
Oxazepam
15-30 mg PO at
bedtime
Half-life:2.8-5.7 hr
Temazepam
20 mg PO at
bedtime
Half-life:3-25 hr
Triazolam
0.125-0.25mgPOat
bedtime
Half-life: 1.5-5 hr
Dependence and withdrawals symptoms can occur
esp in patients with history of drug dependence
Prolonged use of agents with longer half lives may
provide next day anxiolytic action and decrease
rebound hypertension but they can cause daytime
sleepiness cognitive impairment, and in co-ordination
Triazolam: Has been withdrawn from the market in
several countries because of reports of confusion,
amnesia and unusual behavior
Special Instruction
Elderly patients should receive lower doses
Short-term use (<4 week) to avoid dependence and
withdrawal symptoms.
(249)
MANAGEMENT OF OTHER SLEEP DISORDERS
Treatment of Primary Hypersomnias
Clinical management is controversial owing to the lack of controlled studies. Most widely used, and
successful of the treatment options available are the stimulant compounds. For patients intolerant of,
or insensitive to stimulants, stimulating antidepressants, MAOI or SSRI classes may be used.
Methysergide may be effective in resistant cases; however cautions regarding pleural and
retroperitoneal fibrosis should be taken.
Treatment of Narcolepsy
Major goals of treatment of narcolepsy include:
a.
To improve quality of life.
b.
To reduce excessive daytime sleepiness (EDS)
c.
To prevent cataplectic attacks
The major wake promoting medications are:
Modafinil- Preferred due to efficacy, safety, availability, and low risk of abuse and diversion (110).
Modafinil is FDA approved for EDS treatment. Usual dosing is 200-400 mg each morning.
Amphetamine and Dextroamphetamine (10 mg morning)
Methamphetamine (10-20 mg bd)
Pemoline - carries the rare risk of fatal hepatic toxicity
Pharmacological treatment of cataplexy, sleep paraoxysm, and hypnagogic hallucination include
administration of activating SSRI such as fluoxetine (10-20 mg/d) and TCA such as protriptyline (1040 mg/d) and clomipramine (25-50 mg/d)
Sodium oxybate xyrem, appears to be well tolerated and beneficial for treatment of catalepsy, EDS
and inadvertent sleep attacks (108,109)
Practice guide lines for the use of stimulants in the treatment of narcolepsy:
A polysomnogram and the Multiple Sleep Latency Test should establish the diagnosis of
narcolepsy.
Stimulants should be used to alleviate daytime sleepiness, not to maximize performance.
Pemoline, methylphenidate, dextroamphetamine, methamphetamine, and modafinil have proven
efficacy.
The recommended maximum daily dose for some of the stimulants used to treat narcolepsy are
as follows:
•
Pemoline150mg
•
Methylphendiate 100 mg
•
Dextroamphetamine 10Omg
•
Methamphetamine 80 mg
Combining short and long-acting stimulants may be indicated in some patients.
Tolerance is most likely to occur in treatment with high-dose amphetamines.
(250)
Most female patients should discontinue taking stimulants during pregnancy.
Caution is urged in prescribing stimulants to nursing mothers Adequate nocturnal sleep and
planned daytime naps (when possible) are important preventive measures (111).
Treatment of sleep apnea
It may be alleviated by weight loss, avoidance of sedatives, use of tongue retaining devices, breathing
under positive pressure through a mask- CRAP (continuous positive airway pressure), sleep position
training (112,113)
TCAs are sometimes used in sleep apnea in young adults (not in older people).
The newer shorter acting non-benzodiazepine hypnotics seem to be safer in these patients and may
be considered in those who snore.
Surgery, including pharyngoplasty; may relieve heavy snoring (114)
To date, nasal CRAP remains the initial treatment of choice for moderate to severe sleep apnea;
however discontinuation of nasal CRAP even for one night results in complete reversal of the gain
made in daytime alertness (116)
Treatment of Circadian Rhythm Sleep Disorder- Delayed and Advanced Sleep phase disorder
Primary disorder should be identified and treated. Clinical management includes choronobiological
strategies to shift the phase position of the endogenous oscillator in the appropriate direction, e.g.
exposure to bright light in the morning advances the delayed sleep phase i.e. individuals will become
sleepy earlier in evening (115) On the other hand administration of bright light in evening acts to
delay circadian rhythm, thus individuals will get sleep later in the evening. Light is usually administered
in dose of 2500 lux for 2 hours per day, although the ideal intensity and duration are yet to be
determined. For some individuals, spending more time outdoors in bright sunlight may be sufficient
to treat the sleep phase disorders.
Treatment of Shift Work
No totally satisfactory method currently exists for managing shift work problems. Appropriate exposure
to bright lights and darkness may push the circadian pacemaker in the correct direction and help
stabilize its phase position, especially in association with the use of dark glasses outside and blackout
curtains at home to maintain darkness at the appropriate times for promotion of sleep and shifting of
the circadian pacemaker (117). Naps may also be useful in reducing sleep loss. Modest amounts of
coffee may maintain alertness early in the shift but should be avoided near the end of the shift.
Treatment with melatonin has been found to be less successful than timed bright light exposure in
aiding adjustment to shift work.
Treatment of Jet Lag
Some efforts before departure may be useful to prevent or ameliorate these problems. For people
who plan to readjust their circadian clock to the new location, it may be possible to move the sleepwake and light-dark schedules appropriately before departure. Good sleep hygiene principles should
be respected before, during, and after the trip. Whereas adequate fluid intake on the plane is necessary
to avoid dehydration, alcohol consumption should be avoided or minimized because it causes diuresis
and may disrupt sleep maintenance.
(251)
On arriving at the destination, it may be.preferable to try to maintain a schedule coinciding with actual
home time if the trip is going to be short. Unfortunately, the exact protocols have not been established
in all instances yet and require further research and experimentation.
In addition to synchronizing the clock with the new environment, sleep and rest should be promoted
by good sleep hygiene principles, by avoidance of excessive caffeine and alcohol, and, possibly, by
administration of short duration hypnotics. Care should be taken, however, to avoid hangover effects
or amnesia associated with hypnotics. Because individual responses to sleeping pills vary considerably
from person to person, it is often helpful to develop experience with specific compounds and doses
before departure.
Transient Situational insomnia
This develops after a change in sleeping environment or after a significant life event. Recovery is
usually rapid (within a few weeks). Treatment is symptomatic, with intermittent use of hypnotics and
resolution of the underlying stress.
Insomnia associated with other medical disorder
Treatment of the underlying medical disorder or symptom is the most useful approach.
Substance Induced Sleep Disorder
An important aspect in evaluation of sleep disorders is to the review the use of medications and other
substances including prescription, over the counter and recreational drugs, as well as alcohol,
stimulants, narcotics, coffee and nicotine and exposures to toxins, heavy metals etc.
In general, treatment should be aimed at the primary diagnosis after management of any acute
withdrawal condition that may exist. Non-pharmacological treatment approaches include sleep hygiene
and sleep restriction, attention to general nutrition, physical health and psychosocial support. Use of
benzodiazpines or other hypnotics is not generally recommended because of cross tolerance or
deliberate or inadvertent overdose. Karam Hage and Brower et al 2000 (118) reported that the sleep
of abstinent alcoholic patients improved when treated with gabapentin.
SSRIs are associated with over arousal and insomnia in some patients, but commonly with sedation
in other (119). Co-administration of bed time trazodone in a double-blind, placebo-controlled study
was effective in managing fluoxetine induced insomnia in depressed patients (120).
General Approaches to the Clinical Management of Sleep Disorder in Psychiatric Patients
Nonspecific treatment, such a use of sleep hygiene principles, is often helpful for the both the sleep
complaints and the underlying psychiatric disorder.
In general, avoid polypharmacy. Sleeping pills should be prescribed reluctantly to patients who receive
adequate doses of antidepressants. Although co-administration of a benzodiazepine may improve
sleep during the first week of antidepressants therapy, a low dose of Zolpidem, zaleplon, trazodone,
or other sedating antidepressants at night in addition to the antidepressants may be less likely to
produce tolerance and may have additive antidepressant benefits. Antipsychotic medications should
(262)
not be administered as sleeping aids unless the patient is psychotic or otherwise unresponsive to
other medications
PARASOMNIAS: MANAGEMENT
Sleepwalking
After establishing the diagnosis advice must be given regarding making the room and surrounding
area safe. It may even be necessary for the patient to sleep on ground floor. Family reassurance is
necessary.
Attention to family and psychological uses- reduction in overall tension in house hold- may reduce
sleepwalking. Anxiety reduction techniques may be helpful.
Some patients respond to administration of benzodiazepines (BZDs) or sedating antidepressants at
bedtime (4). Schenk et al (1986) (4) reported that the long term use of BZD in adults with injurious
parasomnia, was safe and effective.
Treatment of Sleep Terror Disorder
Nocturnal administration of BZDs has been reported to be beneficial by suppressing delta sleep.
REM Sleep Behavior Disorder
Clonazepam 0.5-1 mg, bedtime, is usually remarkably successful in controlling the symptoms. Patients
and family should be educated about nature of the disorder and warned against about injuring
themselves or others. Carbamazepine has also been found to be useful (122). Treatment with the
acetylcholinesterase inhibitor Donepezil has also been found to be effective (121).
Nightmares
The disorder is usually self limited in children but can be helped sometimes with psychotherapy,
desensitization or rehearsal instruction (127). Secondary nightmares, as in PTSD, can be difficult in
treat. They are some times brought out by REM-suppressing drugs, in which case, the treatment is to
gradually discontinue the medication, if possible.
Periodic Limb Movement in Sleep (PLMS)
Because the pathogenesis of PLMS is not usually known, treatment is often symptomatic.
Dopaminergic agents such as L-Dopa (25-100mg/d), Pergolide (0.05-1mg), Pramipexole (0.250.875mg), generally provide the most effective treatment for PLMS and restless leg syndrome (123126). Clorazepam, opiates like oxycodone and propoxyphene, anticonvulsants like carbamezepine
and gabapentin (124), have also been found to be effective.
Pharmacologic Treatment Options in RLS/PLMS
(253)
Medication
Dosage Range
Side Effects
L-Dopa/carbidopa
25/100-100/400/D
Dyskinesia,Nausea
Pergolide
0.05-1 mg
Nausea
Rhinitis
Dizziness
Dyskinesia
Pramipexole
0.25-0.875mg
Dizziness
Sedation
Orthostasis
Anticonvulsants
Variable
Sedation
Opiates
Variable
Constipation
Nausea
Clonazepam
0.5-2mg
Dizziness
Sedation
Practice guidelines for the treatment of nocturnal myoclonus (NM) and restless legs
syndrome(RLS)
The diagnosis of nocturnal myoclonus or restless legs syndrome should be established by the patienfs
history, bed partner report, and possible polysomnogram.
Secondary causes of NM and RLS should be evaluated and treated.
Levodopa/carbidopa, oxycodone, propoxyphene, carbamazepine, and clonazepam have proven
efficacy. Gabapentin and clonidine have possible efficacy.
Close physician monitoring of adverse effects is required.
Iron supplementation is useful for RLS patients with iron deficiency.
Most female patients should discontinue taking medication during pregnancy.
No information is known about the use of medication in children with NM or RLS.
Scope of this document:
The guidelines are aimed to ensure uniform standards of care.The psychiatrists should consider, but
not restrict to the recommendations made, as these are neither comprehensive nor definitive. They
are also meant principally for adults patients. Owing to poverty of work in this area in India, these
guidelines must be regarded only as a preliminary effort, requiring further modification and revisions.
Hence, feedback and suggestion from all mental health professionals will be more than welcome.
(254)
An algorithm for the differential diagnosia of peraiatent aleep diaorder complainta
Step 1: Consider the role of
general medical conditions,
substance use, and other
mental disorders
Yes
A: Sleep disorder due to a general
medical disorder
B: Breathing-related sleep disorder
C: Substance-induced sleep disorder
D: Other mental disorder and/or
insomnia related to a mental
disorder
| No
Step 2: If the individual suffers
from the sleep involved in shift
work, frequently crosses over
time zones, or has abnormal
timing of sleep
Yes
A:
B:
C:
D:
E:
G:
Circadian rhythms sleep disorder
Sleep-awake schedule disorder
Delayed sleep phase
Advanced sleep phase
Shift work
Non-24-h day
4 No
Step 3: Are the symptoms
predominantly events during
sleep (i.e., abrupt awakening,
frightening dreams, walking
about while sleeping)
Yes
A:
B:
C:
D:
Nightmare disorder
Sleep terror disorder
Sleepwalking disorder
Periodic limb movements or
restless legs syndrome
E: Nocturnal panic attacks
j, No
Step 4: If the primary
complaint is insomnia (i.e.,
difficulty initiating or
maintaining sleep)
Yes
Primary Insomnia (if symptoms
persist for more than 1 month)
Dyssomnia not otherwise
specified (symptoms persist for
less than 1 month)
4, No
Step 5: If the primary
complaint is excessive
sleepiness or hypersomnia
Yes
A: Narcolepsy (sleep attacks)
B: Primary hypersomnia (prolonged
sleep episodes, regular daytime
sleep episodes)
C: Dyssomnia not otherwise
specified
D: Breathing-related sleep disorder
(see steplA)
E: Kleine-Levin syndrome
F: Menstrual cycle-associated
hypersomnia
G: Atypical or winter depression
No
Step 6: If clinically significant
criteria are not met for a
previously described specific
disorder, or if one wants to
note symptoms as a more
complete evaluation is being
conducted
Dyssomnia not otherwise specified
Yes
(255)
Diagnostic approach to Insomnia
Sleep History
Include:
? Hours of sleeping
0
Sleep and awakening times
? Sleep Position
0
Type of bed, pillows, etc
? Eating habits in evening
? Alcohol intake
Discuss sleep patterns with bed
partner
Arthritis, allergies, congestive heart
failure, and benign prostatic
hypertrophy can all affect sleep
patterns.
Any chronic medical conditions ?
T
Decongestants, beta agonists, corticosteroids,
beta blockers, diuretics, antidepressants, and
H2 blockers commonly disturb sleep.
Medication?
Any family history of sleep
dysfunction ?
T
Anxiety, depression, and panic disorder
can disrupt sleep patterns
Any psychiatric illness?
T
Any symptoms of daytime
sleepiness, excessive snoring,
apnea, or BMI>35
Referral for
Polysomnography
If Yes
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Treatment Algorithm of Insomnia
Diagnosis of insomnia
Pharmacological
treatment
Non-prescription
medications
Non-pharmacological
treatment
Prescription
medications
Non-prescription
medications
Antidepressants
1. Amitriptyline
2. Trazodone
3. Nortriptyline
Identify and treat the
associated conditions
Non-benzodiazepine
Hypnotics
1.Zolpidem
2.Zaleplon
1. Stimulus control
2.Paradoxical Intention
3.Muscle relaxation
4.Sleep restriction
5.Temporal control
6. Improving sleep hygiene
Benzodiazepines
(BZDs)
Short acting
1. Triazolam
Intermediate acting
1 Temazepam
2.Estazolam
Long-acting
1. Flurazepam
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References
1.
American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorder.
APA, Washington DC.
2.
Kryger MH, Roth T, and Dement WC (2000) Principles and Practice of Sleep Medicine. WB
Saunders. Philadelphia
3.
Diagnostic Classification Steering Committee, Thorpy MJ (chair) (1990) International classification
of sleep Disorder: Diagnostic and coding Manual, Rev. American Academy of Sleep Medicine,
Rochester.
4.
Schenk C, Bundlie S, EttingerM.et al (1986) Chronic behavioral disorders of human REM sleep:
A new category of parasomnia. Sleep 9, 293-308.
5.
Morin CM , Gaulier B.Barry T et al. Patient's acceptance of psychological and pharmacological
therapies for insomnia. Sleep 1992; 302-305
6.
Chesson AL Jr. Wise M, Davilax D, et al (1999) Practice parameters for the treatment of restless
legs syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine
Report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep
22,961-968.
7.
Hauri P: Primary insomnia, in Treatment of psychiatric Disorders, Vol 3. Washington, DC, American
Psychiatric Association, 1989, pp 2424-2433
8.
Morin CM, Stone J, Mcdonald K. Psychological management of insomnia: a clinical replication
series with 100 patients. BehavTher 1994; 25:291-309
9.
Mc dusky HY, et al 1991. Efficacy of behavioral versus triazolam treatment in persistent sleep
onset insomnia. Am J Psychiatry 148:121-126.
10. Bootzin rr, Perlis ML: Nonpharmacologic treatments of insomnia. J Clin Psychiatry 53 (suppl):
37-41,1992
11. Jacobs GD et all996. Perceived benefits in behavioral medicine insomnia program : a clinical
report. Am J Med 100:212-216
12. Hauri PJ, Esther MS: Insomnia. Mayo Clin Poc 65 :869-882,1990.
13. Spielman AJ, Saskin P, and Thorpy MJ (1987) Treatment of chronic insomnia by restriction of
time in bed. Sleep 10, 45-56.
14. Morin CM et al (1993). CBT for late-life insomnia. J Consult Clin Psychol 61,137-146
15. Morin CM, Colecchi C, Stone J, Sood R, Brink D.Behavioral and pharmacological therapies for
late-life insomnia: a randomized controlled trial. JAMA 1999; 282:991-999.
16. Bootzin RR and Nicassio PM (1978) Behavioral treatment for insomnia. In progress in Behavioral
Modification. Hersen M, Eieser RM, and Miller PM (eds). Academic Press, New Yor.pp. 1-45
17. Morin CM, Huri RT, Espie CA, et al. Non-pharmacological treatment of chronic insomnia. Sleep
1999:22:1134-1156
18. Morin CM, Culbert JP, Schwarts SM. Non-pharmacological intervention for insomnia: a metaanalysis of treatment efficacy. Am J Psychiatr 1994,151; 1172-1180
(258)
19. Gillin JC and Byerly WF (1990) The diagnosis and management of insomnia. New England
Journal of Medicine 322, 239-248.
20. Gillin JC, Spinweber CL, and Johnson LC (1989) Rebound insomnia: A critical review. J Cline
Psychopharmacol 9,161-172.
21. Nowell PD, Mazumdar S, Buysse DJ, et al. Benzodiazepines and Zolpidem for chronic insomnias
meta analysis of treatment efficacy, /aaaia 1997;278:2170-2177
22. Holbrook AM, Crowtheer R, Lotter A, et al. MetaO-analysis of benzodiazepine use in the treatment
of insomnia. CMAJ 2000; 162: 225-233.
23. Leger D, Querasalva MA, Philip P. Health related quality of life in patients with insomnia treated
with zopidem. Pharmacoeconomics 1996; 10: 39-44.
24. Baiter MB, Uhlenhuth EH, The beneficial and adverse effects of hypnotics. J Clin Psychiatry
1991;52:16-23.
25. Parrino L, Terzano MG. Polysomnographic effects of hypnotic drugs: a review.
Psychopharmacology 1996;126:1-16.
26. Henning W, Allen R, Earley C, et al. The treatment of restless legs syndrome and periodic limb
movement disorder. Sleep 1999;22:970-999.
27. Berry RB, Kouchi K, Bower J. Triazolam in patients with obstructive sleep apnea. Am J Respir
Crit Care Med 1995;151:450-454,
28. Kales A, Bixler EO, Scharf M, et al. Sleep laboratory studies of flurazepam: a model for evaluating
hypnotic drugs. Clin Pharmacol Therapent 1976;19:576-583.
29. Mitler MM, Seidel WF, Van Den Hoed J, et al. Comparative hypnotics effects of flurazepam,
triazolam, and placebo: a long term simultaneous nighttime and daytime study. J Clin
Psychopnrmacol 1984;4:2-13.
30.
Scharaf MB, Roth T, Vogal GW, et al. A multicenter, placebo-controlled study evaluating Zolpidem
in the treatment of chronic insomnia. J Clin Psychopnrmacol 1994;55:192-199.
31. Walsh JK, Vogal GW, Scharf M et al. A five week, polysomnographic assessment of zelepelon
10 mg for the treament of primary insomnia. Sleep Med 2000;1:41-49.
32. Elie R, Ruther E, Farr I, et al. Sleep latency is shortened during 4 weeks of treatment with
zaleplon, a noval non-benzodiazepine hypnotic. Zaleplon Clinical Study Group. J Clin Psychiatry
1999;60:536-544.
33. Pecknold J, Wilson R, LeMorvan P. Long term efficacy and withdrawals of zopiclone: a sleep
laboratory study. Int Clin Psychopharmacol 1990;5:57-67.
34. Kummer J, Guendel L, Linden J, et al. Long-term polysomnographic study of the efficacy and
safety of Zolpidem in elderly psychiatric in-patients with insomnia. J Int Med Res 1993;21:171184.
35. Oswald I, French C, Adam K, et al. Benzodiazepine hypnotics remain effective for 24 weeks, Br
Med J 1982;284:860-863.
36. Allen RP, Mendels J, Nevins DB, et al. Efficacy without tolerance or rebound insomnia for
midazolam and temazepam after use for one to three month, J Clin Pharmacol 1987;27:768775.
(259)
37.
Schlich D, L'Heritier C, Coquelin JP, et al. Long-term treatment of insomnia with Zolpidem: a
multi-center general practioner study of 107 patients (published erratum appears in J Int Med
Res 1993;21(6):346). J Int Med Res 1991;19:271-279.
38. Marrek L, Cramer P, Attali P, et al. The safety and efficacy of Zolpidem in insomniac patients: a
long-term open study in general practice. J Int Med Res 1992;20(2):162-170.
39. Carskadon MA, Seidel WF, Greenblatt DJ, et al. Daytime carryover of triazolam and flurazepam
in elderly insomniacs. Sleep 1982; 5:361-371.
40. Roth T, Roehrs R, Wittig R, et al. Benzodiazepines and memory. Br J Clin Pharmacol 1984;18:45S49S.
41. Perlis ML, Giles DE, Mendelson WB, et al. Psychophysiologic insomnia: the behavioural model
and a neurocognitive perspective. J Sleep Res 1997;6:179-188.
42. Tonne U, Hiltunen AJ, Vikander B, et al. Neuropsychological changes during steady states drug
use, withdrawal and abstinence in primary benzodiazepine-dependent patients. Acta Psychiatr
Scand 1995; 91:299-304.
43. Salzman C, Fisher J, Nobal K, et al. Cognitive improvement following benzodiazepine
discontinuation in elderly nursing home residents. Int J Ger Psychiatry 1992;7:89-93.
44. Tata PR, Rolling J, Collins M, et al. Lack of cognitive recovery following withdrawal from long
term benzodiazepines use. Psychol Med 1994;24:203-213.
45. Mustard CA, Mayer T. Case control study of exposure to medication and the risk of injurious falls
requiring hospitalization among nursing home residents. Am J Epidemiol 1997;145:738-745.
46. Neutal CI, Hirdes JP, Maxwell CJ, et al. New evidence on benzodiazepines use and falls: the
time factor. Age Ageing 1996;25:273-278.
47. Merlotti L, Roehers T, Zorick F, et al. Rebound insomnia: duration of use and individuals difference,
J Clin Psychopharmacol 1991; 11:368-373.
48. Roehers TA, Zorick FJ, Witting RM, et al. Dose determination of rebound insomnia. Br J Clin
Pharmacol 1986;22:143-147.
49. Hajak G, Clarebach R Fischer W et al. Rebound insomnia after hypnotic withdrawal in insomniac
outpatients. Eur Arch Psychiatry Clin Neurosci 1998;248:148-156.
50. Griffiths RR, Weerts EM. Benzodiazepines self-administration in humans and laboratory animalsImplications for problems of long-term use and abuse. Psychopharmacology 1997;134:1-37.
51. Lader M. Anxiety or depression during withdrawal of hypnotics treatments. J Psychosom Res
1994;38:113-123.
52. Morin CM, Colecchi CA, Ling WD, et al. Cognitive behavior therapy to facilitate benzodiazepine
discontinuation among hypnotic-dependent patients with insomnia. BehavTher 1995;26:733745.
53. Baiter MB, Uhlenhuth EH. Prescribing and use of benzodiazepines: an epidemiologic perspective.
J Psychoactive Drugs 1992;24:63-64.
54. Woods JH, Winger G. Current benzodiazepines issues. Psychopharmacology 1995;118:107115,118.
(260)
55. Romach M, Busto U, Somer G, et al. Clinical aspects of chronic use of alprazolam and lorazepam.
Am Psychiatry 1995; 152:1161-1167.
56. Vermeeren A, Riedel WJ, van boxtel MP, et al. (2002) Differential residual effects of zeleplon
and zopiclone on actual driving. A comparison with a low dose of alcohol. Sleep 25,224-231.
57. Buysse DJ, Reynolds CF, Hoch CC, et al. Longitudinal effects of nortriptyline on EEG sleep and
the likelihood of recurrence in elderly depressed patients. Neuropsychopharmacology
1996;14:243-252.
58. Montgomory I, Oswald I, Morgan K, et al. Trazodone enhances sleep in subjective quality but
not in objective duration. Br J Clin Pharmacol 1983;16:139-144.
59. Scharf MB, Sachais BA. Sleep laboratory evaluation of the effects and efficacy of trazodone in
depressed insomniac patients. J Clin Psychiatry 1990;51:13-17.
60. Parrino L, Spaggiari MC, Boselli M, et al. Clinical and polysomnographic effects of trazodone
CR in chronic insomnia associated with dysthymia. Psychopharmacology 1994; 116:389-395.
61. Walsh JK, Erman M, Erwin CW, et al. Subjective hypnotic efficacy of trazodone and Zolpidem in
DSMIII-R primary insomnia. Hum Psychopharmacol 1998;13:191-198.
62. Hajak G, Rodenbeck A, Adler L, et al. Nocturnal melatonin secretion and sleep after doxepin
administration in chronic primary insomnia. Pharmacopsychiatry 1996;29:187-192.
63. Hohagan F, Montero RF, Weiss E, et al. Treatment of primary insomnia with trimipramine: an
alternative to benzodiazepine hypnotics? Eur Arch Psychiatry Clin Neurosci 1994;244:65-72..
64. Nowell PD, Reynolds CF, Buysse DJ, et al. Paraxetine in the treatment of primary insomnia:
preliminary clinical and EEG sleep data. J Clin Psychiatry 1999;60:89-95.
65. Shipley JE, Kupfer DJ, Griffin SJ, et al. Comparison of effects of desipramine and amitriptyline
on EEG sleep depressed patients. Psychopharmacology 1985;85:14-22.
66. Kupfer DJ, Perel JM, Pollock BG, et al. Fluvoxamine versus desiperamine: comparative
polysomnographic effects. Biol Psychiatry 1991 ;29:23-40.
67. Ware JC, Brown FW, Moorad PJ, et al. Effects on sleep: a double-blind study comparing
trimipramine to imipramine in depressed insomniac patients. Sleep 1989;12:537-549.
68. Beasley CM, Dornseif BE, Pultz JA, et al. Fluoxetine versus trazodone: efficacy and activatingsedating effects. J Clin Psychiatry 1991;52:294-299.
69. Armitage R, Yonkers K, Cole D, et al. A multi-center, double-blind comparison of the effects of
nefazodone and fluoxetine on sleep architecture and quality of sleep in depressed outpatients.
J din Psychopharmacol 1997;17:161-168.
70. Rush AJ, Armitage R, Gillin JC, et al. Comparative effects of nafazodone and fluoxetine on sleep
in outpatients with major depressive disorder. Biol Psychiatry 1998;44:3-14.
71. Rickels K, Morris RJ, Newman H, et al. Diphenhydramine in insomniac family practice patients:
a double-blind study. J Clin Pharmacol 1983;23:234-242.
72. Saletu B, Saletu-Zyhlarz G, Anderer P, et al. Nonorganic insomnia in generalized anxiety disorder.
Neuropsychobiology 1997;36:130-152.
(261)
73. Mesulam M-M. Central cholinergic pathways: neuroanatomy and some behavioral implications.
In: Avoli M, ReaderTA, Dykes RW, et al, eds. Neurotransmitters and cortical function. New York:
Plenum Press, 1988:237-260.
74. Meuleman JR, Nelson RC, Clark RL Jr. Evaluation of temazepam and diphenhydramine as
hypnotics in a nursing-home population. Drug Intell Clin Pharm 1987;21:716-720.
75. Meltzer EC Antihistamine and decongestant-induced performance decrements. J Occup Med
1990;32:327-334.
76. Mendelson WB. A critical evaluation of the hypnotic efficacy of melatonin. Sleep 1997,20:916919.
77. Sack RL, Hughes RJ, Edgar DM, et al. Sleep-promoting effects of melatonin: at what dose, in
whom , under what conditions, and by what mechanisms? Sleep 1997;20:908-915.
78. Lewy AJ, Ahmed S, Jackson JM, etal. Melatonin shifts human circadian rhythms according to a
phase-response curve. Chronobiol Int 1992;9:380-392.
79. Deacon S, Arendt J. Melatonin-induced temperature suppression and its acute phase-shifting
effects correlate in a dose-dependent manner in humans. Brain Res 1995;688:77-85.
80. Dollins AB, Zhdanova IV, Wurtman RJ, et al. Effect of inducing nocturnal serum melatonin
concentrations in daytime on sleep, mood, body temperature and performance. Proc Ntal Acad
SciUSA 1994;91:1824-1828.
81. Tzischinsky O, Lavie P. Melatonin possesses time-dependent hypnotics effects. Sleep
1994;17:638-645.
82. Zhdanova IV, Wurtman RJ, Morabito C, et al. Effects of low oral doses of melatonin, given 2-4
hours before habitual bedtime, on sleep in normal young humans. Sleep 1996;19:423-431.
83. Waldhauser F, Saletu B, Trinchard-Lugan I, Sleep laboratory investigations on hypnotic properties
of melatonin. Psychopharmacology 1990;100:222-226.
84. James SP, Sack DA, Rosenthal NE, et al. Melatonin administration in insomnia.
Neuropsychopharmacology 1989;3:19-23.
85. Ellis CM, Lemmens G, Parkes JD. Melatonin and insomnia, J Sleep Res 1996 ;6 :61-65.
86. MacFarlane JG, Cleghom JM. Brown GM et al. The effects of exogenous melatonin on the total
sleep time and daytime alertness of chronic insomniacs: a preliminary study. Biol Psychiatry
1991;30:371-376.
87. Garfinkel D, Laudon M, Nof D, et al. Improvement of sleep quality in elderly people by controlledrelease melatonin. Lancet 1995;346:541-544.
88. Haimov I, Lavie P, Laudon M, et al. Melatonin replacement therapy of elderly insomniacs. Sleep
1995;18:598-603.
89. Wurtman RJ, Zhdanova I. Improvement of sleep quality by melatonin. Lancer 1995,346:1491.
90. Lushington K, Pollard K, Lack L, et al. Daytime melatonin administration in elderly good and
poor sleepers: effects on core body temperature and sleep latency. Sleep 1997;20:1135-1144.
91. Hughes RJ, Sack RL, Lewy AJ. The role of melatonin and circadian phase in age-related sleepmaintenance insomnia: assessment in a clinical trial of melatonin replacement. Sleep 1998;21:5268.
(262)
92. Houghton PJ. The scientific basis for the reputed activity of Valerian. J Pharm Pharmacol
1999;51:505-512.
93. Wong AH, Smith M, Boon HS. Herbal remedies in psychiatric practice. Arch Gen Psychiatry
1998;55:1033-1044.
94. Leathwood PD, Chauffard F, Heck E, et al. Aqueous extract of valerian root (Valeriana officinalis
L.) improves sleep quality in man. Pharmacol Biochem Behav 1982;17:65-71.
95. Schulz H, Stolz C, Muller J. The effects of valerian extract on sleep polygraphy in poor sleepers:
a pilot study. Pharmacopsychiatry 1994;27:147-151.
96. Balderer G, Borbely AA. Effect of valerian on human sleep. Psychopharmacology 1985;87:406409.
97. Lindahl O, Lindwall L. Double-blind study of a valerian preparation. Pharmacol Biochem Behav
1989;32:1065-1066.
98. Kupfer DJ, Reynolds CF III. Management of insomnia.N.Engl. J. MedA 997;336: 341-6.
99. NHLBI Working Group on Insomnia. Insomnia: assessment and management in primary care.
Bethesda:American Academy of Family Physicians, 1999.
100. Attarian HP. Helping patients who say they cannot sleep - practical ways to evaluate and treat
insomnia. Postgrad. /Wed.2000;107:127-42.. .
101. Holbrook AM, Crowther R, Lotter A, Cheng C, King D.What are the benefits and risks associated
with the use of benzodiazepines to treat insomnia? CMA72000; 162:225-32.
102. Rajput V, Bromley SM. Chronic insomnia: A practical review.vAm Fam. P/7ys.1999;60:1431-8.
103. Edinger J, Wohlgemuth WK, Radtke RA, Marsh GR.Quillian RE. How useful is cognitive behavioral
therapy(CBT) for the treatment of chronic insomnia? J. Fam.Pract. 2001; 285:1856-64.
104. Chesson A et al Practice parameters for the evaluation of chronic insomnia, An American
Academy of Sleep Medicine Report. Standards of Practice Committee of American Academy
of Sleep Medicine. Sleep 23:237-241, 2000.
105. Solonki RK. Sleep disorder in Textbook of Postgraduate Psychiatric 2nd ed. Jaypee publication
2003
106. Andrade C (1997); Primary hypersomnia. Response to fluoxetine and methylphenidate. Indian
J. of Psychiatry, 41(4): 377-380).
107. Puri t al 2002. Sleep disorder in Textbook of Psychiatry, 2nd ed., Churchill Livingstone
108. US Xyrem Multicenter Study Group (2002) A randomized, double-blind, placebo-controlled
multicenter trial comparing the effects of three doses of orally administered sodium oxybate
with placebo for the treatment of narcolepsy. Sleep 25, 224-231.
109. Litner M, Jhonson SF, McCall WV, et al (2001) Practice parameters for the treatment of narcolepsy:
An update for 2000. Sleep 24, 451-466.
110. Basset et al : Use of modafinil in the treatment of narcolepsy: A long-term follow-up study.
Neurophysiol Clin 23:60-66.1996.
(263)
111. Helmus et al. The alerting effects of short and long naps in narcoleptic, sleep deprived, and
alert individuals,. Sleep 20:251-257, 1997.
112. Aubert G (1992) Alternative therapeutic approaches in sleep apnea syndrome. Sleep 15 S69S72
113. Guilleminault C and Stoohs R (1990) Obstructive sleep apnea syndrome: whom toteat and how
to treat. In sleep and Respiration, Issa FG. Suratt PM, and Remmers JE (eds). Wiley-Liss, New
York, pp. 417-426.
114. Rodenstein DO (1992) Assessment of uvulopalatopharyngoplasty for the treatment of sleep
apnea syndrome. Sleep 15(6), S56-S62.
115. Rosnthal NE, Josepj-Vanderpool JR, Levendosky A, et al (1990) Phase shifting effects of bright
morning ligdht as treatment for delayed sleep phase syndrome. Sleep 13(4), 354-361.
116. Kribbs NB et al Effect one night without nasal CPAP treatment of sleep and sleepiness in patients
with obstructive sleep apnea. American Review of Respiratory Disease 147:1162-1168, 1993.
117. Czeisler CA, Kronauer RE, Allan JS, et al (1984) Bright light induction of strong (typeO) resetting
of the human circadian pacemaker. Am J Physiol 246, R161-R183
118. Karam-Hage M and Brower KJ (2000) Gabapentin treatment for insomnia associated with alcohol
dependence (letter). Am J Psychiatr 157,151.
119. Beasley et al (1991). High-dose fluoxetine efficacy and activating sedating effects in agitated
and retailed depression. J Clin Psychoparmacol 11(3), 166-174.
120. Nierenberg et al 1994. Trazodone for antidepressants-associated insomnia. Am J Psychiatr
151, 1069-1072.
121. Ringmau JM et al Treatment of REM sleep behavior disorder with donepezil: a report of three
cases. Neurology 55:870-871, 2000
122: Barnford CR, Carbamazepine in REM sleep behavior disorder. Sleep 16:33-34,1993.
123. Walter AS, Hening WA, KaveyN, et al (1988) A double-blind randomized crossover trial of
bromocriptine and placebo in restless legs syndrome. Ann Neurol 24, 455-458.
124. Heninger W, Allen R, Early C, et al (1999) The treatment of restless legs syndrome and periodic
limb movement disorder ( Review). Sleep 22, 970-999.
125. Montplaisir J, Denesle R, and Petit D (2000) Pramipexole in the treatment of restless legs
syndrome: A follow-up study. Eur J Neurol 7 (Suppl), 27-31.
126. Montplaisir J, Nicholas A, Denesle R, et al (2002) Restless legs syndrome improved by
pramipexole: A double-blind randomized trial. Neurology 52, 938-943.
127. Backwin H 1970 Sleepwalking in twins. Lancet 2, 446-447.
128. Kripke DF, Garfinkel L, Wingard DL, Klanber MR, Maries MR : Mortality associated with sleep
duration and insomnia. Arch Gen Psychiatry. 2002; 59:131.
(264)