EU_Psych_Zisapel.qxp 24/6/08 04:17 Page 40
Insomnia
Efficacy and Safety of Circadin
®
in the Treatment of Primary Insomnia
a report by
Nava Zisapel
1
and Patrick Lemoine
2
1. Department of Neurobiology, Faculty of Life Sciences, Tel Aviv University, and Neurim Pharmaceuticals Ltd, Tel Aviv;
2. International Medical Director, CLINEA-ORPEA
Circadin
®
(Neurim Pharmaceuticals) is a prolonged-release formulation of health-related quality of life.
13–17
More so than poor sleep quantity, poor
2mg melatonin (PR-melatonin 2mg) that, when taken before bedtime, sleep quality corresponds negatively to physical and mental measures of
mimics the physiological pattern of melatonin excretion during the night. It health, wellbeing, activities of daily living, driving skills, memory, productivity
was approved by the European Medicines Agency (EMEA) in June 2007 for and satisfaction with life.
10,11,18–23
the short-term treatment of primary insomnia characterised by poor quality
of sleep in patients over 55 years of age. PR-melatonin 2mg is a first-class The management of insomnia involves non-pharmacological and
medicine that goes beyond the facilitation of sleep onset of other widely pharmacological approaches, and traditionally focuses on alleviating
used drugs for insomnia. This is due to its ability to improve sleep quality difficulties in initiating or maintaining sleep. The most commonly
and next-day alertness and quality of life. No significant adverse events prescribed drugs for insomnia are benzodiazepines (e.g. temazepam) and
were found with PR-melatonin 2mg compared with placebo, and it can be non-benzodiazepine (e.g. zopiclone, zolpidem) hypnotics, which potentiate
used concomitantly with most medications. In contrast to traditional the central nervous system (CNS)-suppressant activity of brain gamma-
sedative hypnotics, it has shown no evidence of impairing cognitive or aminobutyric acid (GABA–A) receptors.
24
None of these improve subsequent
psychomotor skills, or of dependence or abuse potential. daytime functioning and they are all associated with a higher risk of driving
accidents, falls and fractures, overdose and cognitive impairment, along with
Insomnia – Symptoms, Daytime Disturbances and the potential for abuse and dependence;
25
therefore, their use is
Treatment Options discouraged, particularly in elderly patients.
26
An unmet medical need
Insomnia is the common complaint of difficulty initiating or maintaining sleep remains for a drug that improves quality of sleep. Thus, treatment focus has
and/or experiencing poor quality of sleep (also termed non-restorative sleep, shifted to re-establishing restorative sleep, improving daytime functioning
a subjective complaint about tiredness on waking and throughout the day, and quality of life and avoiding withdrawal symptoms.
26–28
feeling rested and restored on waking and the number of awakenings
experienced during the night) over at least one month and with negative Melatonin – A Physiological Sleep Regulator
effects upon subsequent daytime functioning.
1–3
Patients may suffer Melatonin (N-acetyl-5-methoxytryptamine) is produced by the pineal gland
immensely from a poor quality of sleep while their sleep quantity is within the in a process that is regulated by the internal biological clock, which is
normal limits.
1,2
Insomnia is a very common disorder, and its prevalence localised in the suprachiasmatic nuclei (SCN) of the hypothalamus and
increases with age
4–7
and is 1.5 times higher in women than in men.
8,9
The inhibited by light perceived by the retina.
29
Normally, endogenous melatonin
disorder may be primary, namely not attributable to any known physical or levels rise soon after the onset of darkness, peak in the middle of the night
mental condition or environmental cause, or secondary, resulting from an and gradually decline towards the morning.
30
Melatonin serves as a
existing physical or mental condition. The prevalence of poor sleep quality physiological signal of darkness to re-set the biological clock in order to
increases with age.
10–12
Insomnia also has negative consequences on match the environmental day–night cycle and regulate the sleep–wake
and other circadian rhythms (e.g. temperature, blood pressure and
hormones).
31–33
Melatonin undergoes first-pass hepatic metabolism (half-life
Nava Zisapel is a Professor at Tel Aviv University specialising in
neurobiology and biological clocks. She is the incumbent of the
in human serum is ca. 40 minutes)
34
and over 80% is excreted exclusively in
Michael Gluck Chair in neuropharmacology and amyotrophic
the urine as 6-sulfatoxymelatonin (6-SMT).
35
Melatonin is thought to act via
lateral sclerosis research. In 1991 she founded Neurim
its own receptors (MT1, MT2), which are members of the G protein-linked
Pharmaceuticals in Tel Aviv, and she serves as Chief Scientific
Officer of the company. With her colleagues she has written receptor family.
36
The presence of MT1 and MT2 receptors in the SCN,
over 170 papers in peer-reviewed journals. Dr Zisapel holds a
hippocampus and other brain areas, and melatonin’s physiological activities
BSc in chemistry, an MSc in biochemistry and a PhD in
biochemistry from Tel Aviv University.
in these areas, implicates these receptors in the regulation of sleep and
circadian rhythms and, perhaps, memory consolidation.
37–42
E:
navazis@post.tau.ac.il
Patrick Lemoine is International Medical Director of CLINEA-
Circadin – A Prolonged-release Melatonin Formulation
ORPEA, a group that includes 20 psychiatric institutions in The production of melatonin decreases with age.
43–45
Lower production of
France, Switzerland and Italy. Previously, he was Medical
melatonin was found in patients above 55 years of age who suffered from
Director of Unité Clinique de Psychiatrie Biologique (UCPB) at
Vinatier Hospital in Lyon, and was a Research Fellow at
poor sleep quality than in healthy elderly people without such a
Stanford University and a Research Associate at Montreal
complaint.
44–48
Melatonin therapy may replenish the deficiency in the
(Philippe Pinel Research Center) between 1996 and 1999. Dr
Lemoine has published 20 books and over 300 papers.
endogenous sleep-regulating hormones to improve sleep quality and
reinforce the functioning of the circadian clock such that the increase in
sleep propensity is in tune with the societal activity cycle.
49
Due to its short
40 © TOUCH BRIEFINGS 2008
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