Treatment for

Insomnia
Presentation By: JJ Wojcik

Presentation Outline
What is Insomnia?
Treatment of Insomnia
Non-Pharmacological
Pharmacological
Benzodiazepines
Benzodiazepine Receptor Agonists
Melatonin-Receptor Agonists
Anti-Depressants

Future Treatments

What is Insomnia?
Classified as the inability to get
enough sleep despite adequate time.
Symptoms Include:
Delayed Sleep Onset
Early Morning Wake-Ups
Unrefreshing Sleep
Trouble Maintaining Sleep

Causes many problems in daytime

functioning

Classifications of
Insomnia
Primary vs. Secondary
This is based on what is causing a
patient to suffer from lack of sleep

Chronic vs. Acute

This is based on how long the patient
suffers from symptoms of insomnia

Primary Insomnia
Also referred to as Idiopathic
This is diagnosed when a patient has
no other cause of insomnia other
than the fact they cannot sleep
Also been known to be patient
confusion and misconception around
what is meant and understood to be
sleep

Secondary Insomnia
This is also more commonly referred
to as Comorbid Insomnia
When insomnia is being caused by some
other outside factor, illness, or
disorder including:
Drug Abuse
Psychiatric Disorders
Medical Problems
Other Sleep Disorders disruptive to
sleep

Acute Insomnia
This is when a patient suffers from
insomnia fewer than 3 times a week
for less than a month
Typically stems from changes in the
environment and a short illness the
patient might have had

Chronic Insomnia
This will be diagnosed when a
patient suffers from symptoms more
than 3 times a week for a period
longer than a month
When insomnia becomes a chronic
problem, it is typically said to be
comorbid insomnia

Causes of Insomnia
Often caused by depression
or other psychiatric
problems
Also caused by excess,
lasting stress or racing
thoughts at bedtime
Symptoms of insomnia also
could be cause by other
sleeping disorders such
as:
Restless Leg Syndrome
Sleep Apnea
Somnolence

Diagnosing Insomnia
The diagnosis of insomnia can often be
difficult and is a prolonged process
Sleep logs
Watching symptoms for weeks at a time

It is often very underdiagnosed due to

both patient and physician
misunderstandings
Doctors dont routinely ask about it
Patients dont think its important
enough to bring up in a normal check up
Goes overlooked

Treatment of
Insomnia
Insomnia is not a disorder that can
necessarily be cured
Symptoms treated in order to relieve
patient of distress
Treated by two different methods
Non-Pharmacological Treatment
Pharmacological Treatment

Non-Pharmacological
Treatment
This is attempted before the use of
pharmacological treatment, typically
for at least 2-3 weeks
This mainly has to do with
attempting to improve sleep habits
The different methods used are:
Improving Sleep Hygiene
Stimulus Control Therapy
Restrictive Sleep Therapy

Improving Sleep Hygiene

Basically improving comfort when
sleeping
Decrease Ambient Noise
Go to bed/wake up at a constant time
Reduce Lighting
Think Positively

Not shown to be particularly effective

on its own, though has been seen to be
very critical to improving the efficacy
of other non-pharmacological treatments

Stimulus Control
Therapy
Learn to associate the bedroom with sleep
alone
Dont go in the bedroom unless going to sleep
Do not go to bed unless tired
Leave the bedroom if havent fallen asleep in 15
minutes
Be completely relaxed when in bed

This method has been seen to be very effective

if used for over a prolonged period of time
Improved efficacy if sleep hygiene is also
managed

Sleep Restriction
Therapy
Restricting sleep during the day
Cutting sleep short during certain
nights
Goal is to be excessively tired when
time to sleep at night
Shown the most promising results of
all the non-pharmacological therapies
and even more effective when sleep
hygiene is improved

Pharmacological
Treatment
This is the treatment of insomnia with
the use of pharmacological agents
Most often prescription agents
Some supplements used

4 Classes of Prescription Agents

Benzodiazepines
Benzodiazepine Receptor Agonists
Melatonin Receptor Agonists
Antidepressants/Antipsychotics

Some supplements are thought to help

as well

Benzodiazepines
More than 45 years old and are potent hypnotics
and anxolytics
Improve sleep time, but not usually sleep
latency (often one of the more desired effects)
Disrupt normal sleep cycles
Tend to cause bad hangover effects
Very drowsy the following day
Occasional impaired cognition
Extremely high potential for abuse with
prolonged use as well as tolerance
Drugs in this class are
Estazolam, Flurazepam, Quazepam, Temazepam,
and Triazolam

Triazolam Mechanism
Interacts with the GABAA receptor to bind
at the post synaptic membrane and induce
chloride permeability to inhibit excitation
By doing so, hypnotic effects are induced,
and inducing sleep is therefore achieved
Improves sleep onset, but not necessarily
sleep maintenance
Bad reported rebound insomnia with
discontinued use

Pharmacokinetics
This has a very short half-life, as
many of the other benzodiazepines,
staying in the system about 2-5
hours
The amount in the system (AUC) is
proportional the dose
Clearance and time for elimination
are not dose dependent

Other
Benzodiazpeines
Flurazepam

Quazepam

Temezepam

Benzodiazepine Receptor
Agonists
Fewer hangover symptoms than benzodiazepines
Claim amore restful night sleep
Fewer problems with dependency, though still an
issue
Do not show deleterious effects to the sleep cycle
Longer half-life than benzodiazepines so help with
sleep maintenance
Some drugs are dose dependent (Eszopiclone)
Few are approved for long-term use: Eszopiclone
Drugs in the class include:
Zolpidem, Zaleplon, and Eszopiclone

Eszopiclone (Lunesta)
Mechanism
Binds at the omega subunit of the
GABAA receptor to increase chloride
permeability and decrease
excitation of the neuron
This subunit is found more in the
brain as opposed to the spine where
the other class of the GABA
receptors are found
Thought to be safer than
benzodiazepines, but still have
serious potential for abuse, and
reported rebound insomnia with
discontinued use
Effectiveness of the drug is dose
dependent

Pharmacokinetics
This drug does have a relatively fast
half-life and elimination time but
can be delayed after a high fat meal
Both the AUC and the Cmax were seen to
be dose dependent in the patients
examined
CYP 3A4 and 2E1 were involved in the
metabolism of the drug
Mean elimination time was 5.8 hours

Melatonin Receptor
Agonists
Newer class of drug
Far less potential for abuse and dependency
and is the only hypnotic that is not
classified as a controlled substance
Approved for long-term use more readily than
other medications
There have been complains of drowsiness,
dizziness, and fatigue in the following days
after use
Only drug in this class thus far is Ramelteon

Ramelteon Mechanism
This works by selectively binds the
Melatonin Receptors (MT)1 and MT2,
that are thought to regulate the
sleepiness and readjustment of the
circadian rhythms, respectively
Does not show any addictive or
dependency in patients because it
does not, nor do any of its
metabolites, bind to any large
ligand group receptors

Pharmacokinetics
Undergoes extensive first pass
metabolism
Half-life ranged from 1-3 hours
All pharmacokinetic properties have
been seen to be dose proportional

Antidepressants/Antip
sychotics
Some physicians prefer this mode of
treatment over benzodiazepines because
of the far less potential for dependency
Can produce anticholinergic effects if
used too long:
Constipation
Weight Gain

This is mostly used in patients who

suffer from comorbid insomnia as a
result from depression

Non-Prescription
Supplements
There are certain different nonprescription supplements that are
also used an thought to be effective
These include:
Antihistamines
Melatonin
Valerian

Antihistamines
Used because many people will
experience sleep inducing side
effects from this kind of medicine
Typically in patients with acute
insomnia who need a quick fix for
a restless night here and there
Tolerance can and most often will be
gained if used too much

Melatonin
Naturally produced hormone in the
pineal gland
This hormone keeps the circadian
rhythm
There has not been a minimum dose
established
Not shown to be necessarily
effective

Valerian
This is an herb that is thought to
interact at the GABAA receptor
because of its sedative properties
similar to other drugs that act at
that receptor
Can cause some nausea, upset stomach,
dizziness, and long-lasting fatigue
Is included on the FDAs Generally
Recognized as Safe List

Future Treatments
Most future treatments have to do with other
stimulations of the GABA receptor
Some facing problems for their problems in
pregnant women and their abuse/dependency issues

There are also trials being done to assess the

efficacy of the 5-HT receptor in treating
insomnia
Different agonists have shown to improve sleep
onset and sleep maintenance

Many other Melatonin Receptor Agonists are also

being researched to go alongside Ramelteon in
this class of drug

Assigned Reading
Monti, Jaime M. Primary and
secondary insomnia: Prevalence,
causes and current therapeutics.
Current Medicinal Chemistry: Central
Nervous System Agents (2004),
4(2), 127-134.

Homework Question
Explain the mechanismm of action of
the benzodiazepam class of hypnotic
agent.

References
Sullivan, Shannon S.; Guilleminault, Christian.
Emerging
drugs
for insomnia : new
frontiers for old and novel
targets.
Expert Opinion on Emerging Drugs (2009), 14(3), 411-422
Passarella, Stacy; Duong, Minh-Tri.
Diagnosis and treatment
of insomnia.
American Journal of Health-System Pharmacy
(2008), 65(10), 927-934
Hair, Philip I.; McCormack, Paul L.; Curran, Monique P.
Eszopiclone : a review of its use in the treatment of insomnia.
Drugs (2008), 68(10), 1415-1434
Silvestri, R.; Ferrillo, F.; Murri, L.; Massetani, R.; Perri, R.
Di; Rosadini, G.; Montesano, A.; Borghi, C.; Giclais, B. De La.
Rebound insomnia after abrupt discontinuation of hypnotic
treatment: Double-blind randomized comparison of zolpidem
versus
triazolam.
Human Psychopharmacology (1996), 11(3),
225-233
Nguyen, Nancy N.; Yu, Susan S.; Song, Jessica C.
Ramelteon : a
novel melatonin receptor agonist for the treatment of insomnia.
Formulary (2005), 40(5), 146-150, 152-155