Treatment for InsomniaPresentation By: JJ Wojcik

Presentation Outline

What is Insomnia?

Treatment of InsomniaNon-Pharmacological

PharmacologicalBenzodiazepines

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. SecondaryThis is based on what is causing a patient to suffer from lack of sleep

Chronic vs. AcuteThis 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 don’t routinely ask about it

Patients don’t think it’s 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 methodsNon-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

Don’t go in the bedroom unless going to sleep

Do not go to bed unless tired

Leave the bedroom if haven’t 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 AgentsBenzodiazepines

Benzodiazepine Receptor Agonists

Melatonin Receptor Agonists

Antidepressants/Antipsychotics

Some supplements are thought to help as well

BenzodiazepinesMore 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” effectsVery drowsy the following dayOccasional impaired cognition

Extremely high potential for abuse with prolonged use as well as tolerance

Drugs in this class areEstazolam, 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/Antipsychotics

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 non-prescription 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 it’s 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 FDA’s Generally Recognized as Safe List

Future TreatmentsMost 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.

ReferencesSullivan, 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