Circadin and the role of melatonin in sleep

Insomnia is the most common sleep disorder, occurring in 30 – 45% of adults. It is 1.5 times more likely to occur in women than in men(Ref. 1).

Insomnia is the perception or complaint of inadequate sleep due to difficulty falling asleep, waking up frequently during night, waking up early, or of non-refreshing or poor quality of sleep. All are associated with daytime distress or poor daytime functioning(Ref. 2).

Clinical data shows that poor quality of sleep corresponds negatively to measures of health, well-being and satisfaction with life more so than quantity of sleep(Ref. 1).

It is estimated that primary insomnia (defined as insomnia with no underlying conditions as its cause) affects 1-10% of the general population, increasing to up to 25% in the elderly(Ref. 1).

Key elements for the definition of primary insomnia include difficulties in initiating or maintaining sleep and/or non-restorative sleep (inadequate sleep quality) as well as negative effects on subsequent daytime functioning as a result of a poor quality of sleep(Ref. 3).

It is not surprising that the disruption of normal sleep patterns has an influence on a patient’s life. Insomnia has a statistically significant negative impact on daily functioning, alertness and responsiveness and quality of life(Ref. 4).

Studies have shown that patients with insomnia have impaired cognitive function, with slower reaction time, worse balance and poorer memory than control patients(Ref.5, Ref. 6). These difficulties are of prime concern in older adults, who may already experience some decline in cognitive function due to natural ageing(Ref. 7).

Melatonin - A  signal of darkness and marker for circadian rhythms
Melatonin is a naturally occurring hormone that is key to sleep and the sleep-wake cycle in humans and animals(Ref. 8). In the body, melatonin is produced by the pineal gland in the brain when night falls. The retina detects failing light, and the level of melatonin gradually increases, reaching its peak in the middle of the night in natural circumstances(Ref. 9).

Our circadian rhythm (or ‘body clock’) is influenced by melatonin, as it acts as a ‘time cue’, anticipating sleep. It is also an important physiological regulator of the sleep-wake cycle(Ref. 8).

Melatonin is not a sedative, but a sign of darkness or night-time, and is a cue for innate night-time behaviour. In the morning when plasma levels of melatonin decrease, sleep ends and wakefulness begins(Ref. 8).

In humans, melatonin induces heat loss, reduces arousal and related brain activity and delays production of cortisol, which increases blood pressure and blood sugar, in preparation for sleep(Ref. 1).

The rise in prevalence of sleep disorders associated with age is concomitant with the decrease in melatonin levels that occur with age(Ref. 12).

Fig.1

About Circadin®
Circadin® is a novel, first in class prolonged-release melatonin tablet formulation, which releases melatonin and mimics the physiological pattern of melatonin secretion.

Mode of Action
Because of its novel formulation, Circadin® releases melatonin gradually over 8-10 hours thereby mimicking the body’s natural release of melatonin and resulting in the re-setting of natural circadian rhythms and the encouragement of natural, restorative sleep(Ref. 13).

Circadin® has been demonstrated to preserve the natural sleep architecture. In Fig 2, the dark line (baseline) represents natural deep sleep which is maintained by Circadin®, in contrast to the hypnotic, zolpidem(Ref. 13).

Fig. 2

Circadin® is different from ordinary preparations of melatonin and is the first melatonin-containing prescription drug approved in the EU. It is also the first drug active on melatonin receptors to be licensed in the EU. Without the prolonged-release matrix formulation, melatonin levels would peak and then rapidly fall due to short half-life (40-50 minutes) of melatonin, and this would not provide levels of melatonin throughout the sleeping period that mimic the natural profile and therefore would not reset the natural rhythms(Ref. 13).

Fig 3 compares the melatonin concentration in blood plasma over time seen with Circadin® and immediate-release melatonin.

Fig.3

Circadin® shortens sleep latency (time to get to sleep) but more importantly Circadin® has been shown to significantly improve sleep quality (see Fig 4) and morning alertness (the behaviour following awakening). These are the pre-conditions for normal daily performance and productivity, leading to better quality of life(Ref. 14, Ref. 15).

These features distinguish Circadin® from other available treatments. Circadin® is indeed the first sleep agent to demonstrate improvements in quality of life(Ref. 14, Ref. 15).

Fig. 4

Safety and Tolerability
Unlike other sleep medications, Circadin® does not impair memory, daytime vigilance, or driving performance. Because Circadin® works via the natural sleep pathway, there are no rebound and withdrawal effects – the side effect profile is benign and there is no evidence of dependency(Ref. 15).

Who can use Circadin?
Circadin is indicated as monotherapy for the short-term treatment of primary insomnia characterised by poor quality of sleep in patients who are aged 55 or over.

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References

1. Wade AG, Zisapel N, Lemoine P. Prolonged-release melatonin for the treatment of insomnia: targeting quality of sleep and morning alertness. Ageing Health 2008; 4(1): 11-12

2. Diagnostic and statistical manual of mental disorders for primary insomnia, fourth edition, American Psychiatric Association, 2000: 597-661

3. Wade et al. 2008 (in press)

4. Zammit GK, Weiner J, Damato N et al. Quality of life in people with insomnia. Sleep 1999; 22 Suppl 2: S379-85

5. Hauri PJ. Cognitive deficits in insomnia patients. Acta Neurol Belg. 1997; 97(2): 113-7

6. Crenshaw MC, Edinger JD. Slow-wave sleep and waking cognitive performance among older adults with and without insomnia complaints. Physiol Behav. 1999; 66(3): 485-92

7. Szuba MP et al. Insomnia: principles and management. Cambridge University Press, 2003. ISBN 0-521-01076-4.

8. Zisapel, N. Sleep and sleep disturbances: biological basis and clinical implications. Cell Mol Life Sci 2007; 64: 1174-1186

9. Lewy AJ. Light suppresses melatonin secretion in humans. Science 1980; 210 (4475): 1267-1269

10. Zisapel N. Daily scheduling of the golden spiny mouse under photoperiodic and social cues. J Expol Zool. 1999; 284 (1): 100-106

11. Smolensky M, Lamberg C. Henry Holt and publishers The body clock guide to better health. 2000

12. Mahlberg R et al. Normative data on the daily profile of urinary 6-sulfatoxymelatonin in healthy subjects between the ages of 20 and 84. Psychoneuroendocrinology. 2006 Jun;31(5):634-41. Epub 2006 Apr 3.

13. Circadin Summary of Product Characteristics, http://www.emea.europa.eu/ humandocs/PDFs/EPAR/circadin/H-695-en6.pdf, last accessed 16 April 2008

14. Wade AG, Ford I, Crawford G et al. Efficacy of prolonged release melatonin in insomnia patient aged 55-80years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin 2007; 23(10): 2597-2605

15. Lemoine P, Nir T, Laudon M et al. Prolonged-release melatonin improves sleep quality and morning alertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res 2007; 16: 372-380