What is insomnia?

Insomnia is defined as a complaint of one or more of the following:

Difficulty falling asleep Difficulty maintaining sleep Poor quality of sleep or non-refreshing sleep

The term “sleep quality” cannot be measured objectively as it contains purely subjective aspects such as “depth” or “restful” sleep

These symptoms are associated with significant daytime distress

Diagnostic and Statistical Manual of Mental Disorders: Diagnostic Criteria for Primary Insomnia, Fourth Edition, American Psychiatric Association; 2000:597-661

Organisation WH. Tenth revision of the International Classification of Diseases, Chapter V (F): Mental and Behavioural Disorders. Clinical descriptions and diagnostic guidelines. WHO 1992; Geneva:182/184

Insomnia prevalence increases with age

Insomnia severity and age1

1. Weyerer and Dilling, Sleep.1991 Oct;14(5):392-82. Lemoine et al, Journal of Sleep Research, Vol 16 issue 4, in press

Approximately 50% of the elderly population report on insomnia and overall dissatisfaction with quality of sleep2

0

5

10

15

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15-19 20-29 30-39 40-49 50-59 60-69 70+

Age

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Mild

Moderate/severe

Clinical Perspective

Insomnia, particularly poor sleep quality is associated with:Significant daytime distress and functioningAdverse effects on psychosocial, physical and occupational functioning

characterized by Fatigue or lethargy, Mood disturbances, Cognitive impairments, Motor impairments, increased risk of falls and accidents Social discomfort, absenteesm Non-specific physical ailments

Poor Quality of life Subjective sleep quality and daytime dysfunction are the best predictors of impaired quality

of life Increased health care costs

Lemoine et al, Journal of Sleep Research, Vol 16 issue 4, in pressBrassington GS et al. J Am Geriatr Soc. 2000;48:1234-1240Leger D, et al. Sleep. 1999 May 1;22 Suppl 2:S394-401.

Why is good quality sleep necessary?

Restorative function for the brain and the body Important role in learning and memory Better daytime functioning Better quality of life Better mood Less fatigue Less accidents

Maquet P., 2001, Ohayon et al., 2001, Sateia et al., 2000, Zammit et al., 1999

American Psychiatric Association. Task Force on DSM-IV. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). Washington, DC: American Psychiatric Association;, 2000.

Twice as many road accidents in insomniacs with global sleep dissatisfaction

Insomnia car drivers with Global Sleep Dissatisfaction (GSD) had almost two times more road accidents compared to insomnia drivers without GSD

p<0.01

6.9%

13.0%

0%

5%

10%

15%

With GDS Without GDS

%

road

accid

en

ts

Ohayon et al, Sleep,2001: 24: 780-7.

Poor sleep quality has serious medical implications

Poor Sleep Quality,more than Sleep Quantity correlates to fatigue, depression, anxiety and physical morbidity

-0.2

0

0.2

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0.8

1

Co

rrela

tio

n c

oeffi

cie

nt

Sleep QualitySleep Quantity

* p<0.01

**

* *

Physical Health Anxiety Depression Fatigue

After Pilcher et al, , J Psychosom Res. 1997

Good Quality/Restorative Sleep

Clinically oriented sleep medicine has shifted from sleep quantity to sleep quality

Sleep quality is better related to health and affects balance and satisfaction with life that sleep quantity

Poor sleep quality and daytime dysfunction increase with age

The German Society of Sleep Medicine has published a formal consensus that defined non-restorative sleep to be the key syndrome in the clinical algorithm to diagnose and treat sleep disorders

Hajak G. Eur Arch Psychiatry Clin Neurosci 2001;251(2):49-56.

Riemann D FJ, Mayer G, Peter JH. The Guidelines for "Non-Restorative Sleep": Relevance for the Diagnosis and Therapy of Insomnia. Somnologie 2003;7(2):66-76.

Characteristics of an ideal hypnotic

Sedative Hypnotics:side effects

In meta-analyses, sedative hypnotics has been shown to be associated with frequent and serious adverse events (Number needed to harm= 6)

Type of adverse events versus placbo Cognitive adverse events (hangover) (p<0.01) Psychomotor adverse events (p=0.07) Residual Morning or daytime fatigue (p<0.001) Performance tasks the morning after significantly impaired Amnesia

It has been shown that use of benzodiazepines is associated with increased risk of falls and road accidents

It is widely recognised that benzodiazepines has potential to produce physical and/or psychological dependence

Glass J, Lanctot KL, et al, BMJ. 2005 Nov 19;331(7526):1169. Hallfors D and Saxe L. American Journal of public health. Sept. 1993, Vol.83, N9Leipzig RM et al, J.Am Geriatri Soc, 1999 Jan; 47 (1):30-9Barbone F et al, Lancet 1998 Oct 24;352(9137):1331-6

Issues in using hypnotics in elderly

Benzodiazepines may contribute to psychomotor impairment and increase the risk of falls and car accidents

The use of benzodiazepines among elderly patients has been associated with intellectual and cognitive impairment

Older people are more susceptible to the side effects of benzodiazepines (especially if they have additional risk factors for cognitive or psychomotor AEs), so for these patients the risk-benefit analysis might not be favourable

There is a need for a drug with a safe profile in the context of potentially long-term use and low levels of drug-drug interactions

Cumming RG, et al. CNS Drugs 825–837, 2003Gray S, et al. Drug Safety 21:101–122, 1999Glass J, et al. BMJ. 2005 Nov 19;331(7526):1169. Epub 2005 Nov 11. Review. Barbone F, et al. Lancet. 1998 Oct 24;352(9137):1331-6

Key unmet needs in treatment of insomnia

Treatments improving the next day alertness More effective in the elderly population Improvement in sleep maintenance Lack of potential for tolerance and addiction No effects on memory No rebound insomnia No psychomotor impairments (no risk of falls) Increased quality of life

Datamonitor, published 04/2007

Melatonin

An endogenous physiological sleep regulator

Secreted during night time by the pineal grand

Synchronizes the biological clock

Involved in sleep control

Zisapel. Sleep and sleep disturvances: biological basis and clinical implications. Cell. Mol.Life Sci.

Melatonin’s Natural Secretion Profile

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18 21 24 3 6 9 12

Time (h)

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(ug

/h)

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1

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1.6

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ato

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/ml)

6-SMT (ug/h)

Saliva

Plasma

urine

Arendt Bojkowski et al. J Clin Endocrinol Metab 60:1166-73.

Melatonin – one of the key components for quality sleep

An important physiological sleep regulator An important cue of the internal biological

clock Sharp increase in sleep propensity at night

occurs 2 hours after the onset of endogenous melatonin

Zisapel Cell Mol Life Sci. 2007 May;64(10):1174-86.

Melatonin production decreases with age

Circadin® - a prolonged release melatonin (2 mg) formulation

Circadin is a prolonged-release matrix tablet formulation of melatonin, which circumvents the fast clearance of the hormone by releasing the hormone in the gastro-intestinal tract over an extended period of time and thereby mimics physiological pattern of melatonin secretion

EPAR, Assessment report for Circadin. Procedure No.EMEA/H/C/695

Circadin® mimics the physiological profile of melatonin at night

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)Fast release Melatonin

Circadin

Circadin® - a prolonged release melatonin formulation

Data on file (Neurim)

Circadin® Pharmacokinetics

Cmax (pg/ml)

Tmax (hours)

Plateau time (h)

Basal state

Median

Range

51

30-126

18

16-22

6.6

4.7-9.6

Drug fasting

Median

Range

393

180-855

1.5

0.5-3

4.4

3.1-9.9

Drug with meal

Median

Range

390

205-1020

2.5

1-4

3.1

1.7-5-5

EPAR, Assessment report for Circadin. Procedure No.EMEA/H/C/695

The Circadin® equation

Poor sleep quality in 55+ years is associated with reduced melatonin production

Circadin® is formulated to mimic physiological pattern of melatonin secretion

Treatment with Circadin® restores sleep quality and consequently daytime functioning

+

=