INSOMNIA

1
INSOMNIA
2
Definitions and epidemiology Insomnia refers
to difficulty in falling asleep or staying
asleep, or to lack of refreshment from
sleep Complains of poor sleep increase with
increasing age and are twice as common in women
as in men By the age of 50 years a quarter of
the population are dissatisfied with their
sleep The proportion rising to 30-40
(two-thirds of them women) among individuals over
65 years
3

• SLEEP SYSTEM
• The phenomenon of sleep is actively induced and
  maintained by neural mechanisms in several brain
  areas
• The lower brainstem
• Pons
• Parts of the limbic system
• These mechanisms have reciprocal inhibitory
  connections with arousal systems
• Activation of sleep systems at the same time
  inhibits waking, and vice versa
• Normal sleep includes two distinct levels of
  consciousness Orthodox sleep
• Paradoxical sleep
• They are promoted from separate neural centers

4
Cortex
5
Orthodox sleep normally takes up about 75 of
sleeping time It is divided into four stages
(1-4) which merge into each other, forming a
continuum of decreasing cortical and behavioral
arousal Stages 3 and 4 are associated with
increasing amounts of high-voltages d slow waves
(1-3 Hz) shown on electroencephalograph (EEG)
These later stages represent the deepest level
of sleep and are also termed slow-wave sleep (SWS)
6
Paradoxical sleep (rapid eye movement sleep,
REMS) normally takes up 25 of sleeping time and
has quite different characteristics. The EEG
shows unsynchronized fast activity similar to
that found in the alert conscious state, and the
eyes show rapid jerky movements. Peripheral
autonomic activity is increased during REMS, and
there is an increased output of catecholamines
and free fatty acids. Vivid dreams and
nightmares most often occur in REMS Brief
frightening dreams (hypnagogic hallucinations)
can occur in orthodox sleep, especially at the
transition between sleeping and waking
7
Stage 4 sleep occurs mostly in the first few
hours, while REMS is most prominent towards the
morning Brief awaking during the night are
normal Both SWS and REMS are thought to be
essential for brain function.
8
Etiology and clinical manifestations Insomnia
may be caused by any factor which increases
activity in arousal systems or decreases activity
in sleep systems. Many causes act on both
systems. Increased sensory stimulation activates
arousal systems, resulting in difficulty in
falling asleep. Common causes include pain or
discomfort and external stimuli such as noise,
bright lights and extremes of temperature.
Anxiety may also delay sleep onset as a result
of increased emotional arousal.
9
Drugs are an important cause of insomnia.
Difficulty in falling asleep may result
directly from the action of stimulants, including
caffeine, theophylline, sympathomimetic amines
and some antidepressants. Drugs withdrawal
after chronic use of CNS depressants, including
hypnotics, anxiolytics and alcohol, commonly
cause rebound insomnia with delayed or
interrupted sleep, increases REMS and nightmares.
With rapidly metabolized drugs, such as alcohol
or short-acting BZDs, this rebound may occur in
the latter part of the night, resulting in early
waking. Certain drugs, including neuroleptics,
TCAs and propranolol, may occasionally cause
nightmares.
10
Difficulty in staying asleep is characteristic of
depression. Alteration of sleep stages,
increased dreaming and nightmares may also occur
in schizophrenia, while recurring nightmares are
a feature of PTSD. Interference with circadian
rhythms, as in shift work or rapid travel across
time zones, can cause difficulty in falling
asleep or early waking. Reversal of the sleep
pattern, with a tendency to poor nocturnal sleep
but a need for daytime naps, is common in the
elderly, in whom it may be associated with
cerebrovascular disease or dementia.
11
Investigations, differential diagnosis
Many patients complaining of insomnia
overestimate their sleep requirements. Although
most people sleep for 7-8 hours daily, some
healthy subjects require as little as 3 hours of
sleep, and sleep requirements decline with age.
Such physiological insomnia does not usually
cause daytime fatigue, although the elderly may
take daytime naps.
12
If insomnia is causing distress, primary causes
such as pain, drugs which disturb sleep,
psychiatric disturbance including anxiety and
depression, organic causes such as sleep apnea
should be identified and treated before
hypnotic therapy is prescribed. There is
growing concern that sleepiness resulting from
insomnia increases the risk of industrial,
traffic and other accidents.
13
Treatment Hypnotic drugs provide only
symptomatic treatment for insomnia. Although
often efficacious in the short term, they do
little to alter the underlying cause which should
be sought and treated where possible. The ideal
hypnotic would gently suppress all arousal
systems while simultaneously stimulating the
systems for deep and satisfying sleep. It would
allow a natural return of normal sleep patterns
and would be suitable for long-term use.
14
Unfortunately, no such hypnotic exists All
presently available hypnotics are general CNS
depressants which inhibit both arousal and sleep
mechanism. They do not induce normal sleep and
often have adverse effects including daytime
sedation hangover and rebound insomnia on
withdrawal. They are unsuitable for long-term
use because of the development of tolerance and
dependence.
15
Benzodiazepines By far the most commonly
prescribed hypnotics are the BZDs. Theses drug
differ considerably in potency (equivalent
dosage) and in rate of elimination but only
slightly in clinical effects. All BZDs have
sedative/hypnotic, anxiolytic, amnesic, muscular
relaxant and anticonvulsant actions with minor
differences in the relative potency of these
effects.
16
Pharmacokinetics Most BZDs marketed as hypnotics
are well absorbed and rapidly penetrate the
brain, producing hypnotic effects within half an
hour after oral administration. Rates of
elimination, however, vary, with elimination
half-lives of from 6 to 100 hours The drugs
undergo hepatic metabolism via oxidation or
conjugation, and some form pharmacologically
active metabolites with even longer elimination
half-lives. Oxidation of BZDs is decreased in
the elderly, in patients with hepatic impairment
and in the presence of some drugs including
alcohol.
17
Pharmacokinetics characteristics are important in
selecting a hypnotic drug. A rapid onset of
action combined with a medium duration of action
(elimination half-life about 6-8 hours) is
usually desirable (temazepam, loprazolam). Too
short a duration of action may lead to, or fail
to control, early morning waking While a long
duration of action (nitrazepam) may produce
residual effects the next day and may lead to
cumulation if the drug used regularly. However,
frequency of use and dosage are important.
18
For example, diazepam (5-10 mg) produces few
residual effects when used occasionally, despite
its slow elimination, although chronic use
impairs daytime performance. Large doses of
short-acting drugs may produce hangover effects,
while small doses of longer-acting drugs may
cause little or no hangover.
19
Effects on sleep A major site of the hypnotic
action of BZDs is the brainstem reticular
formation which, is of central importance in
arousal The reticular formation is extremely
sensitive to depression by BZDs which decrease
both spontaneous activity and responses to
afferent stimuli. Similar depression of limbic
arousal systems adds to hypnotic efficacy in
patients with insomnia due to anxiety. Active
sleep mechanisms are also suppressed, and this
effects lead to disruption of the normal sleep
patterns.
20
BZDs are effective hypnotics they hasten sleep
onset decrease nocturnal awakenings increase
total sleeping time and often impart a sense of
deep, refreshing sleep. They produce changes in
the relative proportion of different sleep
stages. Stage 2 (light sleep) is prolonged and
mainly accounts for the increased sleeping time.
By contrast, the duration of SWS and REMS are
decreased. The latency to the first REMS
episode is prolonged and dreaming is diminished.
21
This abnormal sleep profile probably arises
because of the unselective depression of both
arousal and sleep mechanisms. The suppression of
REMS may be an important factor in determining
rebound effects on drug withdrawal. Mechanism of
action Most of the effects of BZDs result
from their interaction with specific binding
sites associated with postsynaptic GABAA
receptors in the brain.
22
Profile of some hypnotic drugs
23
Adverse effect of hypnotic use Tolerance
Tolerance to the hypnotic effects of BZDs
develops rapidly. Sleep latency, Stage 2
sleep, SWS, REMS, Dreaming and Intrasleep
awakenings All tend to return to pretreatment
levels after few weeks of regular use.
24
Rebound insomnia It is common on withdrawal of
BZDs Sleep is poorer than before drug
treatment Sleep latency is prolonged Intrasleep
wakenings become more frequent REMS duration and
intensity is increased, with vivid dreams or
nightmares which may add to frequent awakening.
These symptoms are most marked when the drugs
have been taken in high doses or for long
periods But can occur after only a weak of low
dose administration. They are conspicuous with
moderately rapidly eliminated BZDs (temazepam,
lorazepam) and may last for several weeks.
25
Oversedation, hangover effects Many BZDs used
as hypnotics can give rise to a subjective
hangover. After most of them, even those with
short elimination half-lives, psychomotor
performance and memory may be impaired on the
following day. Oversedation is most likely with
slowly eliminated BZDs, especially if used
chronically. Most marked in the elderly in whom
drowsiness, incoordination and ataxia, leading to
falls and fractures, and acute confusional states
may result even from small doses.
26
Some BZDs in hypnotic doses may decrease
alveolar ventilation and depress the
respiratory response to hypercapnia, increasing
the risk of cerebral hypoxia, especially in the
elderly and in patients with chronic respiratory
disease.
27
Drug interactions BZDs have additive effects
with other CNS depressants. Combinations of
BZDs with alcohol, other hypnotics, sedative
TCAs, anti-histamines or opioids can cause
marked sedation and may lead to accidents or
severe respiratory depression.
28
Pregnancy and lactation The regular use of BZDs
is contraindicated in pregnancy The drugs are
concentrated in fetal tissues where hepatic
metabolism is minimal. They also enter breast
milk Long-acting BZDs are contraindicated during
lactation, Short to medium-acting BZDs appear
to be safe.
29
Zopiclone Zopiclone is a cyclopyrrolone It is a
non- BZD that binds to BZD receptors. It has
hypnotic effects similar to BZDs and carries the
same potential for adverse effects including
dependence and abstinence effects on withdrawal.
Psychiatric reactions, including hallucinations
and behavioral disturbances, have been reported
to occur shortly after the first dose. This
drug appears to have no particular advantages
over BZDs, although it may cause less alteration
of sleep stages.
30
Zolpidem Zolpidem is an imidazopyridine It
binds preferentially to one BZD receptor subtype
(BZD-1) thought to mediate hypnotic effects. It
is an effective hypnotic with only weak
anticonvulsant and myorelaxant properties. In
contrast, BZDs bind to three known subtypes and
zopiclone to two. Because of its short
elimination half-life (2 hours) hangover effects
are rare But rebound effects may occur in the
later part of the night, causing early morning
waking and daytime anxiety. With high doses,
brief psychotic episodes, tolerance and
withdrawal effects have been reported.
31
Zaleplon Zaleplon is a pyrazolopyrimidine It
binds selectively to BZD-1 receptor. It is an
effective hypnotic at a dose of 5-10 mg It has a
very short elimination half-life (1 hour), and
appears to cause minimal residual effects on
psychomotor or cognitive function after 5 hours.
No tolerance or rebound insomnia were observed
after 4 weeks treatment The drug appears
suitable for use in the elderly.
32
Chloral derivatives (chloral hydrate, triclofos,
dichloralphenazone) Chloral derivatives
still have some use as hypnotics in general
practice. They are all metabolized to
trichlorethanol, which has an elimination
half-life of 8 hours. These drugs are
moderately effective as hypnotics and their
effects on sleep are similar to those of BZDs.
They can produce hangover effects, dependence,
and an abstinence syndrome on withdrawal and may
cause gastrointestinal disturbance.
33
Chloral derivatives (chloral hydrate, triclofos,
dichloralphenazone)
The mechanism of action (on GABAA receptors) is
similar to that of BZDs, But respiratory and
cardiovascular depression occurs on overdose.
34
Clomethiazole Clomethiazole has hypnotic and
anticonvulsant properties and a mode of action on
GABAA receptors similar to that of BZDs. It is
fairly rapidly eliminated (half-life of 4 hours)
and produces little respiratory depression at
therapeutic doses. For these reasons it has
been advocated for use in the elderly and
sometimes used in alcohol and narcotic
detoxification. It has a low therapeutic index,
produces a profound respiratory depression in
overdose, and carries an appreciable risk of
dependence, especially in combination with
alcohol.
35
Promethazine Promethazine is one of the few drugs
with useful hypnotic properties which does not
act on GABA-BZD receptors. It is a sedative
antihistamine with antagonistic effect on H1
receptors in the brain. Promethazine is related
to the phenothiazines, and has additional slight
neuroleptic and anticholinergic effects.
Hangover effects are common, and it
occasionally produces excitement rather than
sedation. It is sometimes of value in pediatrics
practice and in cases where other hypnotics are
contraindicated. Other antihistamines with
similar effects include diphenhydramine and
chlorpheniramine.
36
Other drugs used as hypnotics TCAs with
sedative effects and neuroleptic drugs in low
dosage are being increasingly used as hypnotic
alternatives to BZDs. Such drugs are not
recommended for general hypnotic use since they
have potentially serious adverse effects.
37
Rational drug treatment of insomnia A hypnotic
drug may be indicated for insomnia when it is
Severe Disabling Unresponsive to other
measures Likely to be temporary In choosing an
appropriate agent, individual variables relating
to the patient and to the drug need to be
considered
38
Drug treatment in insomnia
39
Patient care The duration of insomnia is
important in deciding on a hypnotic
regimen. Transient insomnia may be caused by
changes of routine such as overnight travel,
change in time zone, alteration of shift work or
temporary admission to hospital. In these
circumstances a hypnotic with rapid onset of
action and medium duration of action and few
residual effects could be used on one or two
occasions.
40
Short-term insomnia May result from temporary
environmental stress. In this case a hypnotic
may occasionally be indicated, But should be
prescribed in low dosage for 1 or 2 weeks
only Preferably intermittently on alternate
nights or one night in three.
41
Chronic insomnia Is usually secondary to other
conditions (organic or psychiatric) at which
treatment should initially be aimed. In
selected cases a hypnotic may be helpful but it
is recommended that such drugs should be
prescribed at the minimal effective dosage and
administered intermittently (one night in three)
or temporarily (not more than 2 or 3
weeks). Occasionally it is necessary to repeat
short, intermittent courses at intervals of a few
months. Hypnotics should be taken 20 minutes
before retiring in order to allow dissolution in
the stomach and absorption to commence before the
patient lies down in bed.
42
In the elderly Hypnotics can improve the quality
of life but the dosage should be adjusted
Usually half the recommended adult
dose Hypnotics with long elimination half-lives
should be avoided. In the
children Hypnotics are generally contraindicated
for children. Where sedation is required,
sedative antihistamines are usually
recommended. A single dose of a BZD (with
appropriate dosage reduction) may be more
effective
43
Hypnotics are contraindicated in patients with
acute pulmonary insufficiency, significant
respiratory depression, obstructive sleep apnea
or severe hepatic impairment. In patients with
chronic pain or terminal conditions suitable
analgesics including non-steroidal
anti-inflammatory agents or opiates, sometimes
combined with neuroleptics, usually provide
satisfactory sedation.