Pharmacotherapy of Insomnia

History Problem statement Physiology of sleep wake cycle Pathogenesis Pharmacological management Non Pharmacological approaches Newer targets

Overview

“Insomnia is defined as repeated difficulty with sleep initiation, maintenance, consolidation, or quality that occurs despite adequate time and opportunity for sleep and that results in some form of daytime impairment.”

Definition

History of Pharmacotherapy of Insomnia Antiquity

1912

1959

19th century

•Alcoholic beverages

•Lardanum compound

•Herbal formulations COMPOUNDS

• Bromide • Chloral hydrate • Paraaldehyde • Urethane • Sulfonal

•1903- Barbital 1912- Phenobarbital

Chlordiazepoxide

Present

•Benzodiazepines •1980 Non Benzodiazepines •Melatonin and Analogues

Epidemiology

10- 50% of the population are affected.

20 % of adult population having chronic insomnia

Increases with age

Twice as common in females

•Up to 30 yrs [M/F 1:1]•> 30 years females•> 70 yrs M/F 1:2 ]

Lower educational attainment

Depression

Unemployment

Widowed, divorced

Socioeconomic Impact of Insomnia

Insomnia has a detrimental effect on health related quality of life to the same degree as chronic disorders such as depression and congestive heart failure (Katz & McHorney, 2002).

economic costs that encompass health care use, absenteeism accidents, increased alcohol consumption

(Chilcott & Shapiro, 1996; Stoller, 1994)

annual cost was estimated to be between $35 to$107 billion a year in the US

International Classification of Sleep Disorders, 2nd Edition (ICSD-2)

hAdjustment insomnia

primary insomnia

Paradoxical insomnia

Insomnia due to medical condition

Insomnia due to mental disorder

•Inadequate sleep hygiene

•Insomnia due to drug or substance abuse

•Idiopathic insomnia

•Behavioral insomnia of childhood

•Primary sleep disorders causing insomnia

Types of insomnia The National Institute of Mental Health Consensus Development Conference (1984)

1. Transient insomnia <3 days brief environmental stressor • It may respond to attention to sleep hygiene rules.• If hypnotics are prescribed ,lowest dose for 2-3 nights.

2 . Short-term insomnia lasts from 3 days to 3 weeks personal stressor such as illness, grief, or job problems

• sleep hygiene education is the first step. • Hypnotics may be used adjunctively for 7-10 nights.

3.Long-term insomnia insomnia that has lasted for >3 weeks

No specific stressor may be identifiable.

A more complete medical evaluation is necessary in these patients, but most do not need an all-night sleep study.

Physiology

Promotion of wakefulness

Areas

Medullary reticular formation Thalamus Basal forebrain

Neurotransmitters

Histamine (TMN) posterior hypothalamusNA –(LC)Serotonin – (DRN)Dopamine –(VTA)Acetylcholine – cholinergic neurons of the basal forebrain

Promotion of wakefulness

•A novel neuropeptide, orexin (also known as hypocretin),

•localized to a cluster of neurons in the lateral hypothalamus also appears to be involved in the control of wakefulness.

Promotion of sleepThe anterior hypothalamus includes the ventrolateral preoptic nucleus (VLPO), containing gamma-aminobutyric acid (GABA) and the peptide galanin, which are inhibitory and promote sleep

These project to the TMN and the brainstem arousal regions to inhibit wakefulness.

.

Melatonin and the circadian process

Melatonin synthesis is inhibited by light and stimulated by darkness

The nocturnal rise in melatonin begins between 8 and 10 pm and peaks between 2 and 4 am, then declines gradually over the morning.

Melatonin acts via 2 specific melatonin receptors:

MT1 attenuates the alerting signal, and MT2 phase shifts the SCN clock.

The suprachiasmatic nucleus (SCN) is entrained to the external environment by the cycle of light and darkness.

The retinal ganglion cells transmit light signals via the retinohypothalamic tract to stimulate the SCN.

A multisynaptic pathway from the SCN projects to the pineal gland, which produces melatonin.

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Sleep Wake Cycle___________________________

The flip-flop switch model

Stages of Sleep Non-Rapid Eye Movement (NREM) sleep◦Stage I ◦Stage II◦Stage III◦Stage IV

Rapid Eye Movement (REM) sleep

Normal Sleep Values Normal sleep per day is between 6-8 hours,

although some people can maintain a 4-6 hour cycle

4-6 NREM/REM cycles per night Sleep structure changes throughout life Wakefulness after sleep◦Less than 30 minutes

Sleep Onset Latency (SOL) ◦Less than 30 minutes

REM Sleep Latency◦70-120 minutes

PathogenesisSpielman model 3P’s of Insomnia

PredisposingAnxiety, depression

Precipitating•Sudden change in life•schedule changes, •medications, •medical conditions

Perpetuating

Poor sleep hygieneover concern

Genetic Hypothesis

  Fatal familial insomnia autosomal dominant human prion disease caused by changes in the PRNP (prion protein) gene.

Disruption sleep pattern that progresses to hallucinations, a rise in catecholamine levels,autonomic disturbancessignificant cognitive and motor deficits. .

CLOCK and Per2.

 A mutation or functional polymorphism in Per2 can lead to circadian rhythm disorders

advanced sleep phase syndromedelayed sleep phase syndrome

A mis sense mutation gene encoding the GABAA beta 3 subunit in a patients with chronic insomnia.

Objective testsSleep DiaryA sleep diary is appropriate when a patient reports an irregular sleep schedule.

Actigraphy

For actigraphy, a portable device is worn around the wrist to record gross motor activity and light/darkness over extended periods.

Polysomnography

To distinguish between other sleep disorders OSA RESTLESS LEG SYNDROME

PHARMACOTHERAPY OF INSOMNIA

BenzodiazepinesNon-benzodiazepine hypnoticsMelatonin receptor agonistsAntidepressantsAntipsychoticsAntihistaminesObsolete drugs

Benzodiazepines

Sedative hypnotic property

7 membered Diazapene ring Benzene ring

5-aryl substituent

SAR OF Diazepam

Structure 2-Keto Benzos◦ Some administered as prodrug

◦ All have active metabolites (commonly desmethyldiazepam)

◦ Long half-lives (most in excess of 60 hours) Diazepam

Chlordiazepoxide (Librium)

Flurazepam

Clonazepam Flunitrazepam

◦ No active metabolites◦ Not metabolized in the liver◦ Intermediate half-lives (most ~ 8-20 hours)

3-hydroxy Benzos

Lorazepam Oxazepam

Triazolo Benzos

Very rapid onset Very short half-life

Alprazolam Triazolam

Additional heterocyclic ring attached at the 1 and 2 positionsSome active metabolitesShort to intermediate half-lives (anywhere from 3-14 hours)

Long acting Diazepam , Flurazepam, Clonazepam, Chlordiazepoxide

Intermediate acting Alprazolam, Estazolam, Temazepam , Lorazepam Nitrazepam Short acting Triazolam , Oxazepam , Midazolam

Classification

Site and Structure of Action Site of action is the

GABAA receptor

Structure of GABAA receptor comprised of 5 subunits

o 2 α subunits (to which GABA binds)

o 2 β subunits (to which barbiturates bind)

1 γ subunit (to which benzodiazepines bind)

Thus far 16 different subunits have been identified and classified into seven subunit families: α,β,,,ε,θ,π.

six α, three β , three , and single ε,θ,π. and subunits

Benzodiazepine-sensitive ·        α1, α2, α3, α5     Benzodiazepine-insensitive ·        α4 and α6

Properties of GABAA receptor Myorelaxant, motor-impairing, and anxiolytic-

like properties thought to be mediated by α2, α3, and/or α5 subunits

Benzodiazepines acting on α2, α3, and/or α5 nonsedative, nonamnesic anxiolytic

properties

Sedative ,Anticonvulsant activity and amnesic properties are thought to be mediated by α1 receptors

Limbic system α2

Ascending RAS

MOA

The benzodiazepines do not substitute for GABA but appear to enhance GABA's effects allosterically without directly activating GABAA receptors or opening the associated chloride channels.

Benzodiazepines increase the affinity of the receptor for GABA, and thus increase Cl - conductance and hyperpolarizing current

increase in the frequency of channel-opening events

Absorption

Except for Midazolam all can be absorbed orally

Distribution

•90% Protien bound • Cross the placental barrier

Metabolism

Phase 1 reactions , metabolites are conjugated in phase 2 reactions

Phase 1 metabolites are pharmacologically active Excretion

Water souluble metabolites

BZD are the choice of drugs for treatment of insomnia Drug with most suitable pharmacokinetic profile is chosen

Treatment of insomnia

Transient insomnia ( 3 DAYS )

Rapidly acting , rapidly eliminated BZD like

Triazolam (0.125-0.25mg) HSEffective in sleep initiation problems

Temazepam 15-30mg at bed time Effective in sleep maintenance

Used intermittently

Long term insomnia > 3 weeks

Intermittent use of

Flurazepam (15-30mg) HS rebound insomnia and withdrawal effects are less Nitrazepam (5-10mg) HS

Short Term insomnia 3days -3 weeks

Tremazepam (15-30mg)HS effective in sleep maintainence Flurazepam(15-30mg)HS effective in early morning awakeningEstazolam(1-2mg) HS

Drug Peak Blood Level (hours)

Elimination Half-Life1 (hours)

Comments

Alprazolam 1-2 12-15 Rapid oral absorption

Chlordiazepoxide 2-4 15-40 Active metabolites; erratic bioavailability from IM injection

Clorazepate 1-2 (nordiazepam) 50-100 Prodrug; hydrolyzed to active form in stomach

Diazepam 1-2 20-80 Active metabolites; erratic bioavailability from IM injection

Eszopiclone 1 6 Minor active metabolites

Flurazepam 1-2 40-100 Active metabolites with long half-lives

Lorazepam 1-6 10-20 No active metabolites

Oxazepam 2-4 10-20 No active metabolites

Temazepam 2-3 10-40 Slow oral absorption

Triazolam 1 2-3 Rapid onset; short duration of action

Zaleplon <1 1-2 Metabolized via aldehyde dehydrogenase

Zolpidem 1-3 1.5-3.5 No active metabolites1Includes half-lives of major metabolites.

Pharmacokinetic properties of some benzodiazepines and newer hypnotics in humans

Effect of hypnotics on sleep architecture DRUG EFFECT ON SLEEP

CYCLE SYMPTOMS

Benzodiazepines Partial disruption of the NREM/REM ratio Slight decrease in REM

Decreased stage 1 and stage 3 and 4 Increased duration of stage 2

On withdrawal- vivid dreams Due to slight increase in REM

Sleep latency shortened

Episodes of wakeing between stage 4 and REM decreased

Non Benzodiazepines Does not interfere with sleep cycle

Decrease in stage 0 and stage 1

Increased stage 3 and 4

No increase in REM on withdrawal

Decreased sleep latencyAnd awakening

Refereshing sleep

Barbiturates Decreases the duration of REM sleep

Alters the NREM/REM RATIO

REM buildup

Severely alters the sleep cycles Decreased stage 0Decreases the stage 1 And stage 4

On withdrawal

Nightmares

Decreased sleep latency

Decreased night time awakening

1. Long-acting agents taken at bedtime

daytime sedation the following day Cognitive impacts are considerable: Inhibition of learning behaviors, academic performance,

and psychomotor functioning common

2. Short-acting agents taken at bedtime early-morning wakening rebound insomnia the following night

ADVERSE REACTIONS

3. Advancing age retards Phase 1 metabolism of BZD

4. Respiration is not seriously depressed, unless benzo is taken concurrently with another CNS depressant (i.e., alcohol)

5. Benzodiazepine Poisoning Treated with the BZD receptor antagonist

iv. Flumazenil 0.2mg/min max 5mg till the symptoms of respiratory depression , confusion lathargy , congnitive symptoms disappear .

DependenceMECHANISMDue to the gradual down regulation of the GABA receptors

Taken for prolonged periods of time Drugs with Short to medium half life

WITHDRAWAL SYMPTOMS

anxiety state, increases in rebound insomnia, restlessness, agitation, irritability, etc

Tolerence to the sedative effects developes slowly mechaniasm is unclear

May be dude to self induction of benzodiazepines

Tolerance

CYP3A4 CYP2C9 Potentiate the effects of other CNS depressants alcohol, hypnotics and neuroleptics anticonvulsants

Enzyme inhibitors like cimitidine, ketoconazole enhance BZD action Smoking and aminophylline antagonises the activity of BZD

DRUG INTERACTIONS

MOA – Benzodiazepine receptor 1 (BZ1) -- alfa 1 subunit

Antianxiety , sedative in nature Do not alter REM Sleep Pattern Minimal day time residual sleepiness Risk of tolerance and dependence is much less than BZD

Non Benzodiazepines

Drug t1/2 Action Use

Zolpidem(10-20mg)

2-3 hrs Faster onset Transient insomnia

Zaleplon(10-20mg) 3-4 hrs Shorter duration of hypnosis

Short term insomnia

Zopiclone(7.5mg) 6-8 hrs Longer acting

Eszopiclone(1-3mg)

6 hrs

Melatonin Congeners

Ramelteon

Melatonin levels in the suprachiastmatic nucleus rise and fall in a circadian fashion,

Two GPCRs for melatonin, MT1 and MT2, are found in the suprachiasmatic nucleus,

MT1 receptors promotes the onset of sleepMT2 receptors shifts the timing of the circadian system

Ramelteon binds to both MT1 and MT2 receptors with high affinity but, unlike melatonin, it does not bind appreciably to quinone reductase 2, the structurally unrelated MT3 receptor

Pharmacokinetics of ramelteon

Absorption -rapidly GI tract ,peak serum concentration obtained in 1 hr significant first-pass metabolism that occurs after oral administration, ramelteon bioavailability is <2%

Distribution In the bloodstream, ~80% of ramelteon is protein bound

Metabolism hepatic CYPs 1A2, 2C9 t1/2 of ~2 hours in humans.

Of the four metabolites, one, M-II, acts as an agonist at MT1 and MT2 receptors

Inhibitors CYP1A2- Ciprofloxacin Fluvoxamine CYP2C9- FluconazoleInducer- refampin

Indications - transient and chronic insomnia specifically sleep onset difficulties

Dosage 8-mg tablet be taken ~30 minutes before bedtime

ADVERSE REACTIONS

dizziness, somnolence, fatigue, and endocrine changes as well as ↓ testosterone and increases in prolactin.Infertility

Antidepressants

TCA

Amitriptyline doxepin

Side effects: dry mouth, urinary retention, dizziness, daytime sedation

Used at much lower doses for insomnia

Mirtazapine

Associated with weight gain, increased appetite, daytime sedation and dizziness

Trazodone- off label use at low doses

Major side effects: sedation, dizziness, dry mouth, orthostatic hypotension, priapism (rare)

No good research to support its use

Antipsychotics Called the “atypical antipsychotics” Block dopamine from binding to receptors in the

brain Examples:◦ risperidone (Risperdal)◦ olanzapine (Zyprexa)◦ quetiapine (Seroquel)◦ ziprasidone (Geodon)

Antipsychotics Not FDA approved for insomnia

Typically used at doses much lower than those for treating psychosis

Quite sedating but also associated with weight gain, increased risk for diabetes, high blood pressure, restless leg syndrome, muscle spasm or parkinson-like symptoms

Quetiapine and ziprasidone have been shown to increase total sleep time as well as sleep efficiency

Non Prescription Antihistamines Diphenhydramine Doxylamine Promethazine 25mg HS 10mg in children

Commonly used in pediatric population as sedatives

Little evidence to support their use Side effects: dry mouth, urinary retention, blurred vision, dizziness,

sedation, next day hangover

Barbiturates

Paraaldehyde Chloral hydrate Meprobamate

Obsolete drugs

BARBITURATESClassification

(1) Ultra-short-acting barbiturates: act within seconds, and their duration of action is 30min. Therapeutic use of Thiopental: anesthesia

(2) Short-acting barbiturates: have a duration of action of about 2h. The principal use of Secobarbital, : sleep-inducing hypnotics.

(3)Intermediate-acting barbiturates: effect lasting 3-5h.eg Amobarbital

(4)Long-acting barbiturates: >6h. Such as Barbital and Phenobarbital. Therapeutic uses: hypnotics and sedative, and antiepileptic agents at low doses.

BARBITURATES Barbiturates depress the CNS at all level in a dose-

dependent fashion. Now it mainly used in anaesthesia and treatment

of epilepsy; use as sedative-hypnotic agents is no longer recommended.

Reasons: (1) have a narrow therapeutic-to-toxic dosage range. (2) suppress REM sleep. (3) Tolerance develops relatively quickly. (4) have a high potential for physical dependence and abuse. (5) potent inducers of hepatic drug-metabolising enzymes

MOA Barbiturates share with benzodiazepines the ability to

enhance the action of GABA, but they bind a different site on the GABA-receptor/chloride channel, and their action seems to prolong the duration of the opening of GABA-activated chloride channels.

PK High lipid solubility cross the blood-brain barrier and results in a short onset.

redistribution to the other tissues results in short duration of action.

Metabolized by Phase 1 reaction in the liver

Barbiturates and their metabolites the excretion via the renal route.

Therapeutic uses1. Sedative-hypnotic agents(obsolete )2. convulsions as in status epilepticus.3. Anesthetic (or be given before anesthetic)4. Combination with antipyretic-analgesic5. Treatment of hyperbilirubinemia and kernicterus in

the neonate.

Adverse effectsAfter effect: hangover, automatism, amnesiaToleranceDependence: including psychologic and physiologic dependence. Depressant effect on respirationAllergic Skin eruptions and porphyria

Barbiturate poisoning Mostly sucidal

Charaterised by respiratory failure , cardiovascular collapse Coma Renal failure

Treatment

1. Gastric lavage 2. Artificial respiration 3. Forced alkaline diuresis with mannitol and sodium

bicarbonate

Chloral hydrate (obsolete )

Chloral hydrate was used for the short-term treatment of insomnia  mid-20th century.

It is also still used as a sedative prior to EEG procedures, few available sedatives that does not suppress epileptiform discharges.

Misc Drugs

Paraaldehyde(obsolete )

Paraldehyde is a polymer of acetaldehyde

It was commonly used to induce sleep in sufferers from delirium tremens

Meprobamate

Was marketed as a anxiolytic and sedative

MOA – Acts at the GABAA receptor in the limbic system

The Non-pharmacologic Approach

Cognitive Behavioral Therapy for Insomnia (CBTi)

◦Stimulus control therapy◦Sleep restriction therapy◦Relaxation training◦Cognitive therapy◦Sleep hygiene education

Sleep Hygiene Exercise earlier during the day, and no more than 4-6 hours before

sleep

Keep bedroom dark and quiet, to be used only for sleep

Curtail time in bed to only when sleepy

Fixed sleep/wake times for 365 days

Avoid naps

Avoid stimulus or stimulating activities before sleep or in bed

No alcohol at least 4 hours before sleep, no caffeine after noon, and quit smoking!!

Light snack before bedtime

Stimulus Control Use bedroom for sleep

Go to bed only when tired and sleepy

Remove clock from the bedroom to avoid constantly watching it

Regular sleep/wake times

Light therapy if required

No bright lights when you wake up at night

Sleep Restriction An effective form of treatment

Estimate the time actually asleep then limit bedtime to that amount, but no less than 5 hours

Add time in bed gradually once the patient sleeps more than 85% of that time

Cognitive therapy and relaxation therapy

The patient is educated to correct inaccurate beliefs about sleep•To reduce catastrophic thinking •excessive worrying about the consequences of failing to obtain adequate sleep.

Relaxation therapypatient is taught to recognize and control tension through a series of exercises

Biofeedback techniques can also be used. provide patients with immediate feedback regarding their level of tension and rapidly teaching them how to relax.

HERBAL MEDICATIONS

Valerian root Induction of sleep Lavender Sleeping aidsChamomile tea

Newer targets

Orexins

They excitatory neuropeptides that have a critical role in maintaining wakefulness.

Orexin receptor antagonists promote sleep in animals and humans

SB-649,868,  0rexin receptor antagonist in development by GlaxoSmithKline.

Currently in Phase 2 development,

Bettica P, "Phase I studies on the safety, tolerability, pharmacokinetics and pharmacodynamics of SB-649868, a novel dual orexin receptor antagonist". J. Psychopharmacol. (Oxford) 

Suvorexant (MK-4305) is a dual in development by Merck & Co.

Suvorexant works by turning off wakefulness rather than by inducing sleep.

It is not currently approved for commercial use, but it has completed three Phase III trials

FDA Review

Increased somnolence the next day and users of higher doses had an increased rate of suicidal ideation

Conclusions

•Treatment of insomnia requires a multimodal approach of cognitive and behavioral therapy and pharmacotherapy

•Non Benzodiazepines are the most favored hypnotics , followed by Benzodiazepines

•Looking into the future , Orexin antagonists could emerge as a new treatment for insomnia

THANK YOUTHA