Clinical relevance

Q14: Why is Circadin® only for people aged 55 and over? Can Circadin® be used in adult patients younger than 55 years?
A14: Circadin® works by increasing the levels of melatonin in the body(Ref. 1). There is a general decline in melatonin production with age(Ref.2, Ref. 3, Ref. 4). Also, insomnia sufferers have shown poorer melatonin production than people without insomnia across all age groups(Ref. 5) Therefore, the impairment in melatonin production as a result of ageing may be a cause of insomnia. Insomnia sufferers aged 55 years and older were selected to be studied in clinical trials as they would, theoretically, have poorer melatonin production (due to both age and insomnia) and were hypothesised to benefit the most from therapy with Circadin®(Ref. 1). As there are large inter-individual variations in ‘normal’ physiologic levels of melatonin across (as well as within) age groups, younger adults with insomnia may benefit from Circadin®. However, the current indication for Circadin®, as stated in the Summary of Product Characteristics (SPC), is for use in people aged 55 and over(Ref. 1 ). The physicians would need to make their own clinical judgement, in consultation with the patient, if they were to use Circadin® to treat younger adults suffering from insomnia.

Q15: How quickly will Circadin® make me fall asleep?
A15: Circadin® shortens sleep latency (time to get to sleep) by approximately 9 minutes compared with placebo, corresponding to a 40% reduction of sleep latency compared with baseline (measured objectively)(Ref. 6). Similar decreased values were seen for the Duration of Wake Prior to Sleep Onset (DWAPSO), and the percentage of Time Spent Asleep (TSA)(Ref. 7). These two parameters were improved by approximately 50%, as compared to placebo values(Ref. 6). Although the effect of Circadin® on sleep latency is comparable to that of the ‘z’-drugs(Ref. 7), Circadin® should not be considered a ‘hypnotic’ in the traditional sense due to the fact that it is not a CNS depressant. In line with this, Circadin® should not be taken on an ‘as needed’ basis, but as a course of 21 tablets(Ref. 1).

Q16: The clinical effect size does not look impressive and the placebo effect is large. What is the explanation behind this? What is the clinical effect size with other hypnotics? How does this relate to the risk:benefit ratio?
A16: Clinical trials of virtually all drugs that act on brain functions, and which are typically assessed using questionnaires, have large effects in the placebo group. Despite this, it was possible to show a statistically significant and clinically relevant effect of Circadin® on sleep quality and morning alertness in people over 55 years with primary insomnia(Ref. 8, Ref. 9). It is important to realise that Circadin® represents a new paradigm in the treatment of sleep disorders, in which quality of sleep and daytime functioning are the primary efficacy parameters for treatment. This approach is in line with recommendations from, e.g., The German Society of Sleep Medicine, which has published a formal consensus that defined non-restorative sleep - a reflection of impaired sleep quality, according to DSM-IV and ICD-10 criteria - to be the key syndrome in the clinical algorithm to diagnose and treat insomnia(Ref. 9). Therefore, the regulatory authorities requested that the clinical study efficacy parameters be demonstrated in a rather stringent way. Thus, efficacy of Circadin® needed to be demonstrated in not just one parameter (quality of sleep, or morning alertness), but two parameters combined (quality of sleep and morning alertness). The effect size on each individual parameter is, of course, higher than the effect size on combined parameters. This differs from the currently available sleep drugs, which have been approved based on their effect on quantity of sleep (sleep latency and sleep maintenance). However, very few of the trials of existing drugs have measured quality of sleep, and none have measured daytime functioning. Circadin® also has a safety profile comparable to that of placebo(Ref. 1). The current hypnotic drugs carry a high risk of adverse effects(Ref. 11). Indeed the value of current hypnotics in the vulnerable elderly population has been questioned in a recent meta-analysis (Glass et al., 2005)(Ref. 11). The authors concluded, “Improvements in sleep with sedative use are statistically significant, but the magnitude of effect is small. The increased risk of adverse events is statistically significant and potentially clinically relevant in older people at risk of falls and cognitive impairment. In people over 60, the benefits of these drugs may not justify the increased risk, particularly if the patient has additional risk factors for cognitive or psychomotor adverse events.”(Ref. 11). Circadin® has demonstrated significant improvement in quality of sleep and morning alertness(Ref. 8, Ref. 9). Combined with its safety profile, the use of Circadin® in older patients , has a good risk:benefit ratio.

Q17: Zolpidem is as good as Circadin® (and cheaper) - so why use Circadin®?
A17: Apart from the risk of dependence, 'z'-drugs such as zolpidem and zopiclone have been associated with residual sedative effects, marked rebound insomnia, strange behaviour at night and anterograde memory disturbances(Ref. 11, Ref. 12, Ref. 13). In contrast, Circadin® does not cause impairment of cognitive skills or a negative effect on next-morning vigilance(Ref. 14, Ref. 15). In fact, in clinical trials, Circadin® improved morning alertness and functioning(Ref. 8, Ref. 9, Ref. 16). Circadin® does not alter sleep architecture, and there is no evidence of dependence, rebound or withdrawal effects(Ref. 14, Ref. 9, Ref. 8). Furthermore, Circadin® shortens sleep latency to the same extent as the 'z'-drugs(Ref. 14, Ref. 8, Ref. 7). Unlike zolpidem and the other hypnotics, Circadin® improves quality of sleep, daytime functioning, and quality of life(Ref. 8, Ref. 9, Ref. 14, Ref. 16)

Q18: I am perfectly satisfied with my benzodiazepine treatment, why should I change to Circadin®?
A18: BZDs have been associated with rebound insomnia, dependence, and neuropsychiatric reactions such as hostility and depression. Also, although effective in getting patients to sleep, these hypnotics further disrupt sleep architecture and structure - primarily by reducing 'deep sleep' (NREM stages 3 and 4) as well as REM stages of sleep(Ref. 17, Ref. 18). As one of the many theories surrounding the function of sleep is memory consolidation which involves NREM/deep sleep, the reduction in the amount of this deep sleep observed with the use of hypnotics may impair the consolidation of memories. In addition, the use of sedative hypnotics has been associated with road traffic accidents and a higher risk of falls(Ref. 11, Ref. 19), especially in the elderly population. Circadin® is safe and is not associated with any of these adverse effects. Furthermore, Circadin® shortens sleep latency to the same extent as most of the 'z'-drugs but, in addition and unlike BZDs and 'z'-drugs, Circadin® improves the restorative value of sleep which translates into improved quality of sleep, daytime functioning, and quality of life(Ref. 14, Ref. 7, Ref. 9, Ref. 8).

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