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Modified-release (m/r) melatonin (Circadin®) was recently launched by Lundbeck for the short-term monotherapy treatment of primary insomnia in patients aged 55 years or older. The recommended dose is 2 mg, 1-2 hours before bedtime and after food, for 3 weeks. [1]
Melatonin (Circadin) is available in a 21-tablet blister pack, and is priced at £10.77 for a 3-week treatment course.
Action
- Practitioners who consider m/r melatonin for an older person need to ensure that the patient has primary insomnia, through robust questioning and physical and mental assessment. This is a minority of insomnia patients.
- Before considering medication, all patients with insomnia should review their life-style and behaviour to improve “sleep hygiene” – see ‘The Good Sleep Guide’
- Only a small proportion of patients are likely to benefit from m/r melatonin and its effects appear small.
- Due to the short-term nature of the trials, m/r melatonin is not suitable for repeat prescription. Sleep hygiene measures should be continued after the 3-week course of m/r melatonin.
- It is difficult to place m/r melatonin in the current management of primary insomnia because of the lack of comparative data with other treatments, including prescription hypnotics.
What is the background to this?
Melatonin is a human hormone produced by the pineal gland. It regulates circadian rhythms and sleep, but production decreases with age and older people are particularly liable to suffer from insomnia [2]. Primary insomnia is sleeplessness that is not attributable to a medical, psychiatric or environmental cause [3]. Current prescription hypnotics, such as benzodiazepines, can have residual effects the next day causing psychomotor impairment. In addition, tolerance, dependence and withdrawal can occur [4].
What do these studies claim?
The effects of m/r melatonin were assessed using the Leeds Sleep Evaluation Questionnaire. This uses visual analogue scales for getting to sleep, quality of sleep (QOS) and behaviour following wakening (BFW), a measure of morning awakeness. Diagnoses of primary insomnia were made using a sleep history questionnaire and a physical examination. To rule out psychiatric disorders, patients underwent detailed psychological assessment, including depression and anxiety scales and the Mini Mental State test. Both studies were sponsored by the manufacturer, Neurim Pharmaceuticals [2, 5].
What are the details of these studies?
Wade et al
This randomised, double-blind, placebo-controlled trial comprised 3 weeks of treatment [2]. Exclusions included jet-lag and sleep problems related to shift work. 354 patients were studied (mean age 65.7 years).
The primary end-point was improvements of 10mm or more on both QOS and BFW. Both scales are 100mm in total. Sleep latency (time to falling asleep) was included as a secondary end-point. Intention-to-treat analysis showed 25% of patients in the m/r melatonin group met the primary end-point vs. 14% in the placebo group (odds ratio 2.01, 95% CI 1.17 to 3.46, P=0.011). Sleep latency was 8.8 minutes shorter for melatonin patients compared to placebo (95% CI 1.0 to 16.7, P=0.028). Quality of life was assessed using the WHO’s Wellbeing index, which covers positive mood and vitality. There was a statistically significant better outcome for the m/r melatonin patients (P=0.034). 70% of patients who responded to m/r melatonin showed an improvement in quality of life compared to 24% of the non-responders. There were no significant differences in quality of days, quality of nights or in the Clinical Global Improvement score. Similar numbers reported adverse events in each group.
Lemoine et al
This was a similar study with a 3-week treatment period but then 2 weeks of placebo (run-out) [5]. 82 patients were randomised to m/r melatonin and 88 to placebo (mean age 68.5 years). The mean QOS improvement was 22.5 for melatonin vs. 16.5mm in placebo patients (P=0.047). Mean improvement in BFW was 15.7mm in melatonin patients vs. 6.8mm in the placebo group (P=0.002). Secondary outcomes, ease of getting to sleep and awakening from sleep, were not significantly different in the two groups. Withdrawal effects were assessed by questionnaire at the end of the run-out period and there appeared to be no evidence of significant rebound insomnia or withdrawal, or the study was not large enough to show a difference. Adverse events were again similar in each group. Sleep latency was not measured in this trial.
So what?
These two trials have demonstrated that some older people treated with m/r melatonin for 3 weeks will have an improvement in quality of sleep and morning awakeness, but only a minority will benefit (number needed to treat (NNT) of 9 or 5 over 3 weeks [2,5]). A small improvement in sleep latency (about 9 minutes) was found, as a secondary end-point, which is a similar magnitude to that found in trials of benzodiazepines, Z-drugs and ramelteon (not yet licensed).
Day-time functioning, fatigue, mood and quality of life are important to patients who are suffering from insomnia, however, these two trials provide little or no evidence that m/r melatonin produces a significant improvement on these patient-oriented outcomes. The Wade et al trial did show a statistically significant improvements in quality of life, as a secondary end-point. However, the effect appears small.
Currently, a lack of evidence demonstrating clinically significant benefits over prescription hypnotics makes it difficult to comment on the place in therapy of m/r melatonin. Longer-term studies will be necessary to demonstrate that m/r melatonin does not cause any sort of dependence. It must be remembered that m/r melatonin is licensed for primary insomnia only and as a 3-week course.
References
- Circadin. Summary of Product Characteristics. Accessed from http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=20878 on 3rd June 2008
- Wade AG, Ford I, Crawford G, et al. Efficacy of prolonged release melatonin in insomnia patients aged 55–80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opinion 2007;23:2597-605
- European Medicines Agency. Assessment report for Circadin. Accessed from URL: http://www.emea.europa.eu/humandocs/Humans/EPAR/circadin/circadin.htm on 21 May 2008
- National Institute for Health and Clinical Excellence. Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia. Technology Appraisal 77. April 2004. Available from URL: http://www.nice.org.uk/nicemedia/pdf/TA077fullguidance.pdf
- 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;16:372-80
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