Medication Safety
Issue 13 2024
Insomnia and melatonin
Melatonin in the management of insomnia: Optimising use in adults
What is melatonin?
Melatonin is a hormone produced by the pineal gland in a circadian manner (ie. follows a predictable pattern over a 24-hour period). Melatonin is involved in both the onset of sleep, and in regulating the sleep-wake cycle. Food, stress, temperature, social environment and physical activity can impact circadian rhythms but light and darkness have the biggest influence. The evening rise in melatonin precedes onset of sleep by about two hours.
Preparations of melatonin
In Ireland, no melatonin products are licensed for long-term treatment of primary insomnia. Licensed preparations include both immediate and prolonged-release formulations. A wide variety of unlicensed formulations are also available. These products are typically imported and may rely on food-grade, rather than pharmaceutical-grade, melatonin.
In the USA, melatonin is considered a dietary supplement and is available over-the-counter, typically at strengths of 3mg and 5mg, although higher strengths can be found. In Ireland, adult prescriptions for melatonin are not reimbursed under community drug schemes (eg. medical card or drug payment scheme). Prescriptions of melatonin can be associated with considerable cost, with a 30-day supply of 2mg daily costing €30-40.
Differences in the release of melatonin from immediate and modified-release preparations are shown in Figure 1 overleaf. Modified-release preparations were developed to more closely
mimic the natural release of melatonin during sleep onset and sleep maintenance. Immediate-release preparations release melatonin more rapidly and a higher ‘peak’ blood level is achieved. The elimination half-life of melatonin is approximately 45 minutes. Thus, immediate-release preparations achieve a higher blood level quickly but are cleared from the body quickly.
Although direct comparisons are lacking, generally where melatonin treatment is indicated, modifiedrelease melatonin (e.g., Circadin®) preparations are preferable for these reasons. Modified-release melatonin needs to be taken one to two hours before desired sleep onset.
Optimising use with a limited evidence base
Numerous studies have investigated the use of melatonin in the treatment of insomnia across doses ranging from 0.1 to 10mg. Where studies
have shown melatonin to be effective, effects are generally modest. For example, in the case of adults >55 years of age, time to sleep onset was reduced by approximately 10 minutes when compared to placebo. Among adults 18 or older, a 2022 study found melatonin use to be associated with a non-significant effect on self-reported quality of sleep at four weeks compared to placebo.
The lack of evidence supporting efficacy of melatonin in the management of insomnia among adults is reflected in licensed indications. Circadin® melatonin MR 2mg tablets are licensed for shortterm treatment of primary insomnia in adults 55 year of age or older, for up to 13 weeks at a dose of 2mg. PharmaNord® melatonin 3mg tablets are licensed for use in jetlag in adults at doses of 3mg to 6mg daily for a maximum of five days.
In most groups, melatonin has not been demonstrated as an evidence-based treatment for insomnia management, including as an alternative to hypnotics. In all groups, there is an absence of evidence to support higher doses being more effective than standard doses (typically between 2mg -5mg).
Safety considerations
In short-term studies, melatonin has generally been associated with a good safety profile, with rates of adverse effects comparable to placebo.
The most common adverse effects associated with melatonin treatment include headache, vivid dreams and gastrointestinal side-effects. Use of doses in excess of 5mg may be associated with a higher risk of side-effects including daytime sedation and associated risks.
Melatonin has not been associated with discontinuation effects, including withdrawal or rebound insomnia and therefore, does not require tapering at discontinuation.
Melatonin is metabolised by CYP1a enzymes. Therefore strong inhibitors (eg. fluvoxamine) or inducers (e.g. carbamazepine) may result in clinically significant changes in melatonin plasma levels. Smoking can also decrease plasma levels through CYP1A2 induction.
Written by Margaret Brooks, Ita Fitzgerald and Jennifer Torrens, Pharmacy Department, St Patrick’s Mental Health
Figure 1: Release of melatonin from immediate and modified-release preparations