Melatonin

Circadin dose

2mg/day

Half-life of melatonin

30-53 minutes

MENDS study result SOL

37 minutes shorter in melatonin group (45 minutes when measured with actigraphy)

Biomelatonin dose

3mg/day standard

Prevalence of sleep problems in children with ASD

40-86%, SOL and reduced sleep duration.

Sleep problems in children with ID and ASD

77-86%

Original use of melatonin as a sleep promoter

Adults with visual impairment

NHS lothian shared care protocol 2011

Age >3 years, neurodevelopmental disorder/primary sleep disorder, >6 months sleep disturbance or so severe that the family are heading for crisis, after failure of sleep hygiene. First line- biomelatonin- 3mg, 20-30 mins before bed, second line circadin 2mg, 1-2 hours before bed.

Issues identified in audit of NHS lothian melatonin prescription practice

Documentation, short term stabilisation and follow-up, improve protocol guidance including drug holidays and withdrawal, lack of standardisation in sleep hygiene strategies offered

MOA of melatonin for stabilising sleep

Hypnotic action and chronobiological facilitator

Pharmacology of melatonin's sleep regulation

Hypnotic effect controlled via its binding to melatonin MET1 receptors possibly also via GABA-A receptors, regulator melatonin can act as a zeitgebers (like photic stimulation).

Indications for melatonin treatment in adults

Jet lag, restoring rhythm to sleep in shift workers, age-related insomnia, delayed sleep phase syndrome, non-24 hour sleep-wake disorder.

Narcolepsy pathogenesis

Loss of hypocretin neurones in the hypothalamus, primary cause unknown probably autoimmune/infective insult. Secondary causes- trauma and parkinsons. Onset often in teenage years. (onset is seasonal and increased following flu)

MENDS study results TST

Mean total sleep time was 22 minutes longer in the melatonin group, say with 95% confidence that sleep time was between 0.5 and 44 minutes longer in the melatonin group.

Melatonin metabolism

Melatonin is metabolised from L-tryptophan through metabolic intermediates.

MENDS study conclusion

Melatonin puts children to sleep faster, but means that they wake up earlier. Further studies with slow-release melatonin are suggested.

Production of melatonin

Neuropeptide produced in pineal gland in response to darkness, described as the hormone of darkness.

Describe sleep being out of phase

Normal sleep phase- asleep between 'normal times' Early sleep phase- want to sleep earlier and wake up earlier leading to cranky if awake in the early evening and early morning wakings. Late sleep phase- leading to sleep onset latency and difficulty waking.

Sleep disorders

OSA etc.

Actigraphy

Physical activity monitor, differentiate wake and sleep. Good for diagnosis and treatment monitoring of circadian rhythm disturbance.

MENDS study patient population

Randomised, double blind placebo-controlled trial. 146 children from 21 centres. Children with near-developmental delay (including autism, epilepsy and genetic disorders) AND sleep onset problems OR sleep maintenance problems.

Effects of melatonin on sleep

Reduced sleep onset latency, increased total sleep time and reduced night wakenings.

MENDS study treatment

Regiment of melatonin 45 minutes before bed with doses escalated from 0.5mg to 12mg.

Sleep problems

SOL, TST etc.

Treatment of delayed sleep phase disorder

Sleep hygiene (electronics out of bedroom, establish fixed sleep onset time/age-appopriate bedtime) Chronotherapy- advance bedtime by 3 hours/day over 1 week Morning bright light therapy Melatonin used to facilitate sleep onset

Melatonin as a regulator of sleep

Sleep promoting effects and use to phase-shift sleep

Naturally occurring hypnotics

Valerian (limited evidence) and lavender oil.

Melatonin metabolism in children with ASD

abnormal melatonin circadian rhythm, decreased melatonin levels, correlation between melatonin levels and ASD behaviours.

Prescription hypnotics

antihistamines, clonidine, chloral hydrate, benzodiazepine receptor agonists ie. Zolpidem. Short term gain only, sedation alone rarely changes sleep pattern.

Melatonin physiological roles

circadian rhythm regulation, antioxidant, anti-inflammatory, immune response, regulate synaptic plasticity.

Delayed sleep phase in older children and adolescents

diurnal rhythm set by wake time not sleep onset, bright light on awakening enhances pattern, light in bedroom at night diminishes pattern.

Circadian rhythm of melatonin

high levels of melatonin at night, low levels during the day

Symptoms of narcolepsy

hyper somnolence, excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, sleep paralysis.

Central dysrhythmic breathing

immature respiratory control allows overshooting and marked drop in paCO2 and immature respiratory control leads to fall to well below paCO2 leading to reaching apnoea threshold, leading to hypoxia and increased ventilation (vicious cycle).

Melatonin circadian rhythm in individuals with visual impairment

loss of circadian rhythm to melatonin, melatonin levels run free (free running), period length >24 hours, non 24 hour sleep-wake disorder.

MENDS study early morning waking

melatonin group woke up 30 minutes earlier

MENDS study night-wakening

no difference.

Melatonin potential side effects

puberty, high dose reduce body temperature, anecdotal reports of lowering/raising epileptic seizure threshold.