dr. Agung Wiwiek Indrayani, M.

Kes
Pharmacology Department
Medical Faculty, Udayana University
2012
 INSOMNIA is a major public health problem

Many medications are used in insomnia

Different pharmacologic effects

To facilitate a better overall understanding

Mismatch between potential life-long nature

of insomnia and the longest clinical trials

National Institutes of Health Statement Regarding the

Treatment of Insomnia. Sleep. 2005;28:1049-1057.
 • Maximize synchrony between
Biological Clock biological clock activity and desired
sleep/wake schedule

Homeostatic • Maximize homeostatic sleep drive

Sleep Drive • Limit daytime napping

• Minimize external sleep-disruptive

factors and maximize external
External/Internal
sleep-inducing factors
Factors
• Maximize treatment of
medical/psychiatric illnesses
 Primarily clinical – history

Look for psychiatric illnesses and intrinsic

sleep disorders
Depression, anxiety
Circadian rhythm, obstructive sleep apnea,
restless legs syndrome

Sleep Diary
Co-investigator

Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. Philadelphia,
Pa: Elsevier Saunders; 2005.
Sleep Hygiene

Sleep Restriction

Stimulus Control

Cognitive Behavioral Therapy

Relaxation

Paradoxical Intention
 Insomnia Treatment Algorithm
Insomnia Complaint

Acute Chronic
•Review Sleep Hygiene
• Short-acting Chronic Chronic/Persistent
Benzodiazepine Receptor Intermittent Insomnia
Agonist Insomnia
Medical/Psychological No associated
Associated
Sleep Disorder Medical/Psycholo
gical Conditions
* Sleep hygiene
•

A* Anticipatory Behavioral Rx Treat Medical/

•

• Short-acting Benzodiazepine Psychological

Receptor Agonist Sleep Disorder Need to provide
Prompt Relief
N Y Insomnia
No Yes
• • Short-acting
No • Behavioral
Yes • Sleep Hygiene
– Sleep restriction •
– Sleep restriction
* Sleep hygiene • – Stimulus control
Short acting benzodiazepine agonist
• Behavioral (sleep restriction,• stimulus • Sleep hygiene
control, relaxation, cognitive) •• Behavioral (sleep restriction, stimulus
• Consider benzodiazepine receptor control, relaxation, cognitive)
Adapted from Simon RD. Postgraduate agonist or SSRI or other antidepressant • Tapper benzodiazepine after several
Medicine. 2003 weeks of good sleep
Sleep Disorder Class or Disorder Medications Used for
Treatment
Insomnia BRZA sedative- Zolpidem, zaleplon,
hypnotics espoziclone, zopiclone
BZD sedative hypnotics Flurazepam, quazepam,
estazolam, temazepam,
triazolam
Hypnotics Ramelteon

Chronobiotics Melatonin

Sedating Trazodone, amytriptiline,

antidepresants doxepine
Others- approved for Xyrem, Gabatril, Mirtazapine,
others indications Quatiapine
Triazolam & temazepam have significantly higher
activity at the α1 compared to alprazolam and
diazepam  superior sedative hypnotics associated
with sedation, motor-impairment, respiratory
depression, amnesia, ataxia and reinforcing behaviour

Alprazolam & diazepam higher activity at the α2

compared triazolam & temazepam  superior
anxiolytics agents associated with anxiolytic
activity and disinhibition
 can help initiate sleep and increase sleep time, but
decrease deep sleep and increase light sleep

Hypnotic benzodiazepines such as temazepam, flunitrazepam,

triazolam, flurazepam, midazolam, nitrazepam and quazepam
better suited to treat insomnia

These drugs can lead to tolerance, physical dependence and the

benzodiazepine withdrawal syndrome upon discontinuation
Side effects : long acting drugs have a very high rate of residual daytime
drowsiness associated with a significantly increased risk for automobile
accidents and falls in elderly particulary in the first week after taking
them

Memory loss, sleep walking, sleep driving, eating while asleep may occur,
and enhanced by alcohol

Elderly people are more susceptible to side effects

Contraindication for pregnant women and nursing mothers
Have been associated with the development of cleft lip in newborns
 Withdrawal symptoms : usually after prolonged use and indicates
dependency. They can last 1-3 weeks after stopping the drug and may
include : GI stress, sweating, disturbed heart rhythm, severe cases
hallucinate or experience seizures

Rebound insomnia often occurs after withdrawal , typically includes 1-2

nights of sleep, disturbance, daytime sleepiness and anxiety
Newer short acting non benzodiazepines can induce sleep with fewer side
effects than benzodiazepines

Zolpidem is more selective and zaleplone is highly selective for α1

subunit on GABAA receptors an advantage over benzodiazepines in
terms of sleep architecture and a reduction in side effects

Zopiclone and eszopiclone binds unselectivity to α1, α2, α3,and α5

GABAA benzodiazepine receptors.

In general these drugs are recommended in short term use (7-10 days)
and treatment should not exceed 4 weeks. Zolpidem, zopiclone and
eszopiclone mild to moderate insomnia
 Treatment Considerations

 All non benzodiazepine carry label warning: these

drugs can cause sleep related behaviour including
sleep driving, making phone calls, preparing and
eating food while asleep
 Most cases cases of sleep walking and sleep
driving likely occur when patients use zolpidem
along with alcohol or take more than recommended
dose
 In addition severe allergic reraction (anaphylaxis)
and facial swelling (angioedema) can occur even the
first time taken
 Treatment Considerations

 Interactions : alcohols, rifampin, ketoconazole,

cimetidine

 Dependency, withdrawal symptoms and rebound

insomnia : lower than benzodiazepin drugs
 Treatment Considerations

 Interactions : alcohols, rifampin, ketoconazole,

cimetidine
 Dependency, withdrawal symptoms and rebound
insomnia : lower than benzodiazepin drugs
 Duration of therapy: Very little data
◦ Zolpidem: 35 days,1 3 months,2 6 months3
◦ Eszopiclone: 6 months4,5
◦ Indiplon: 12 months6

1.Ambien [prescribing information]. New York, NY: Sanofi-Synthelabo Inc;2004.

2. Perlis ML, McCall WV, Krystal AD, Walsh JK. J Clin Psych. 2004;65:128-137.
3. Schenck CH, Mahowald MW, Sack RL. JAMA. 2003;289(19):2475-2479.
4. Krystal AD, Walsh JK, Laska E, et al. Sleep. 2003;26:793-799.
5. Roth T, Walsh J, Krystal A, et al. Sleep Med. 2005;6:487-495.
6. Indiplon APA data at: http://abstractsonli
 A placebo-controlled, double-blind, parallel-group
study evaluated the efficacy and safety of various
doses of zolpidem
 Recommended doses of zolpidem (up to 10 mg)
decreased sleep latency and increased sleep
duration and maintenance while showing no
significant effect on next day psychomotor
performance
 Doses at higher than recommended levels did not
improve sleep efficiency
◦ May result in increased incidence of side effects

Roth T, Roehrs T, Vogel G. Sleep. 1995;18(4):246-251.

*Significantly different from placebo (p<0.05).
Vogel G, et al. Sleep Res. 1989;18:30. Abstract.
NS=No significant difference from placebo (p>0.05).
Data on file, Searle.
 Dose T1/2 Residual Sedation
Flurazepam 15-30 mg 47-100 h High
Quazepam 7.5-15.0 mg 39-73 h High

Estazolam 0.1-2.0 mg 10-24 h Medium/High

Temazepam 7.5-20.0 mg 3.5-18.4 h Medium/High

Eszopiclone 1-3 mg 6h Low/Medium

Triazolam 0.125-0.25 mg 1.5-5.5 h Low/Medium

Zolpidem 5-10 mg 1.4-4.4 h Low

Zaleplon 5-10 mg 1h Low/None

1. Murray L, Kelly G, eds. Physicians’ Desk Reference. Montvale, NJ: Thomson PDR; 2005.
2. Benzodiazepine receptor agonists. Up-to-date Web site available at: www.uptodate.com. Accessed March
29, 2006.
 Indication : insomnia that is caused by depression (secondary
insomnia)

Trazodone, doxepin, amitryptiline, mirtazapine have a very strong

sedative effect

Many side effects :

Amitryptiline &doxepine both have antihistaminergic,

anticholinergic and antiadrenergic properties
Mirtazapine side effects are primarily antihistaminergic and
trazodone side effects are primarily antiadrenergic
Withdrawal effects, rebound insomnia
 Effective in several types of insomnia,can treat insomnia without
altering the sleep pattern and it does not impair performance related
skills

Good effect for the treatment of insomnia due to jet leg and the
chronic circadian rhythm disorders

Melatonine has demostrated effectiveness equivalent to zopiclone in

inducing sleep and regulating the sleep/ waking cycle,Ramelteon and
tasimelteon lack the potential for dependence
  Probably not a good hypnotic when used
at night
 Some elderly may benefit
 Blind people
 May be useful when trying to sleep during
periods of high biological clock activity
(shift work, etc)
 Some side effects (vasoconstriction)

Brzezinsk A. NEJM 1997;336(3):186-195.

Roth T, Stubbs C, Walsh JK. Sleep. 2005;28:303-307.
The antihistamine diphenhydramine is widely used in non prescription
sleep aids

The effectiveness of these agents may decrease over time and the
incidence of next day sedation is higher than the newer
prescription drugs

Crytoheptadine enhances sleep quality and quantity whereas

benzodiazepine tend to decrease sleep quality
 Anticholinergic side effects may occurred
 These drugs can induce dependence and rebound
effects
 Residual sedation is common
 Typically long half life
 Minimal efficacy data
Hydrocodone, oxycodone & morphine are used for insomnia that
associated with pain due to their analgesic and hypnotics effects

Opioid can fragment sleep and decrease REM and stage 2

sleep

Appropiate in carefully selected patients with pain

associated insomnia
 Medical and psychological causes must be
identified or ruled out before deciding on the
treatment for insomnia

 Non-pharmacologic treatment must be

considered before any pharmacological
approach is applied

 Pharmacological treatments have been used

mainly to reduce symptoms in acute insomnia
but their role in the management of chronic
insomnia remains unclear
THANK YOU