The Secret Life of Melatonin

Clare Gray MD FRCPC Mental Health Rounds

July 21, 2016

child & youth Mental Health Series

If you are connected by videoconference:

Please mute your system while the speaker is

presenting.

Please feel free to ask questions!

By registering for today’s event…

You will have had an opportunity to apply for professional credits or a certificate of attendance You will receive an email with a link to today’s online evaluation Visit our website to download slides and view archived events Sign-up to our distribution list to receive our event notifications Questions? mentalhealthseries@cheo.on.ca

You may also want to…

Professional Credits

Disclosures

• I will be discussing “off label” use of melatonin

• I am not a sleep medicine specialist

• I am not an expert on melatonin

Learning Objectives

• At the end of this presentation, participants will be able to • Describe the role of melatonin with respect to

sleep • Appreciate the pros and cons associated with

melatonin use • Understand the importance of non-

pharmacological approaches in sleep management

Outline • Why talk about melatonin?

• Endogenous melatonin • Synthesis, secretion

• Exogenous melatonin • Dosing • Side effects • Health Canada Update

• Use of melatonin in • Primary sleep disorders – DSPS, Behavioural insomnia of childhood • Secondary – ASD, ADHD, ID

• Other potential uses for melatonin

• Non-pharmacological approaches to sleep

Why a talk about Melatonin?

• The use of melatonin is increasing rapidly

• Seems like many/most patients have already tried melatonin before seeing a health professional

• Dirk Bock (2016); Western University • Surveyed 100 physicians –67 responded • 28 pediatricians • 36 family physicians

Why a talk about Melatonin?

• Over a 6 month period • 89% had recommended OTC • 66% had recommended prescription medication

• 30% recommended OTC/prescription medication to otherwise healthy kids • 73% melatonin • 41% OTC antihistamines • 37% antidepressants • 29% benzodiazepines

Why a talk about Melatonin?

• Over a 6 month period • 89% had recommended OTC • 66% had recommended prescription medication

• 30% recommended OTC/prescription medication to otherwise healthy kids • 73% melatonin • 41% OTC antihistamines • 37% antidepressants • 29% benzodiazepines

Why a talk about Melatonin?

• D. Bock (2015) • Surveyed 350 parents in the ED • 80% of children with a medical condition had

trouble sleeping • 70% of children without • 27% taking OTC (40% melatonin) • 6% taking prescription medications for sleep

Why a talk about Melatonin?

• D. Bock (2015) • Surveyed 350 parents in the ED • 80% of children with a medical condition had

trouble sleeping • 70% of children without • 27% taking OTC (40% melatonin) • 6% taking prescription medications for sleep

Melatonin sales in the USA

0

50

100

150

200

250

300

350

400

2003 2007 2012 2014

378

90

260

$ (m

illio

ns)

62

What is Melatonin?

• A hormone

• N-acetyl-5-methoxytryptamine

• Produced by the pineal gland

Melatonin secretion

• Secretion of melatonin from the pineal gland is controlled by • Endogenous rhythmicity of cells in the

Suprachiasmatic nucleus (SCN) in the hypothalamus • Light perception by the retina

• Melatonin is secreted in the darkness in response to the release of norepinephrine from retinal photoreceptors and the resulting activation of the retino-hypothalamic-pineal system

24 Hour Melatonin Levels

•

1 pg = 0.000000001 mg

Melatonin and Age

• By 3 months of age diurnal secretion of melatonin is evident

• Melatonin output decreases with age!

Two process model

• When we sleep is driven by sleep homeostasis

• Drive for sleep • Increases throughout the day the longer we are

awake

• Circadian Rhythm • 24 hour clock • Controls alertness and tiredness throughout the

day

Health Canada

• First licensed in Canada in 2005 as a “natural health product”

• Over 500 melatonin-containing natural health products licensed in Canada – either single or multi-ingredient formulations

• 2 multi-ingredient melatonin cold remedies (>12yo) have been licensed in Canada since 2011 – not currently marketed in Canada

• Available in Canada (2016)

• GABA

• Melatonin

• 5HTP

• Snoozeberry flavour!

Health Canada

• Should not be used for more than 4 weeks without consulting a healthcare professional

• Health Canada has not authorized any melatonin –containing products for use in children 11 years and younger • Use is “off label”

• In USA, FDA deems melatonin “dietary

supplement” • In UK, Australia – requires a prescription!

Health Canada

• Consult MD especially if • Hormonal disorders, brain (CP, seizure d/o),

heart (hypertension), liver or kidney diseases, diabetes, migraine, depression

• Taking blood pressure, sedative, psychiatric or immunosuppressive medications

Other interactions • Melatonin may decrease BP

• Caution with antihypertensives

• Melatonin may increase blood sugar • Caution in diabetics

• Caffeine – may increase or decrease melatonin levels

• OCPs – may increase melatonin levels

• Melatonin – increases immune system activity – decreasing effectiveness of immunosuppressants

• Melatonin might slow blood clotting – caution with anticoagulants

Exogenous Melatonin

• T1/2 -- 40 minutes

• Extensive first pass effect for oral preparations – with bioavailability of 1 to 37%

• Peak concentrations within an hour

Melatonin interactions

• Kennaway (2015)

• CYP1A2 (to a lesser extend CYP2C19)

• Children 1 to 9 years old • Have 50 to 55% of adult levels CYP1A2 • Can lead to high levels of melatonin

• Inhibitors of CYP1A2 – raises melatonin levels • fluvoxamine, cimetidine, ciprofloxacin

• Inducers of CYP1A2 – lower melatonin levels • carbamazepine, omeprazole, smoking

Mechanism of Action

• Hypnotic –at higher doses it may induce sleep

• Chronobiotic – regulates the circadian rhythm

• DLMO – Dim light melatonin onset • Natural rise in melatonin levels 1 to 3 hours before

sleep onset • Corresponds to the end of the “wakefulness” signal

produced by the circadian system • Blue/white light exposure in the evenings can delay

DLMO

Dosing melatonin

• Peculiar drug because timing of its administration plays a critical role in the results of treatment

• The timing of when you take melatonin will determine both the magnitude and direction of effect

• The optimal timing to dose melatonin for shifting the sleep period is actually a few hours before bedtime (before DLMO)

• https://youtube/AmBSjPQ3pCM

Dosing melatonin

• The earlier the melatonin is administered before DLMO the larger the phase advance of sleep onset

• Within a window of 1 to 6 hours before DLMO, each advance intake time of 1 hour resulted in an increase in effect on sleep onset of 19 minutes

• Assess DLMO – by measuring it in saliva

• Recommended to measure DLMO before starting melatonin!

Melatonin dosing

• No evidence to indicate that extended-release melatonin has advantages over immediate-release melatonin

• If maintenance of sleep is the main problem – melatonin treatment usually is ineffective

• The administration of exogenous melatonin does not seem to affect endogenous production

Side Effects

• Morning drowsiness

• Daytime sleepiness*

• Headache*

• Dizziness*

• Hyperactivity

• Irritability

• Abdominal pain

• Diarrhea

• Rash

• Hypothermia

• Increased enuresis

• Depressed mood

• Melatonin can interact with various medications • Anticoagulants • Immunosuppressants • Diabetes medications • OCP

British survey – • Waldron (2005)

• Surveyed British pediatricians – N 148

• 1918 children prescribed melatonin (0.5 to 24 mg)

• 18% MDs reported adverse events • 2 – new seizures • 3 – increased seizure frequency • 5 – hyperactivity • 6 – agitation/behavioural changes • 6 – worse sleep • 2 – nightmares • 2 -- constipation

Health Canada 2016

• Serious neurologic AEs suspected of being associated with melatonin use have been reported in children and adolescents • Both in Canada and internationally

• Based on current evidence, a relationship between pediatric use of melatonin and the occurrence of neurological adverse reactions such as seizures could not be established

Health Canada 2016

• International reports brought to Health Canada’s attention by foreign regulators

• Neurological adverse reactions • Anxiety • Panic reactions • Visual hallucinations • Seizures

• Health Canada had conducted a review of the safety of melatonin in children and adolescents in 2011

Health Canada 2016 • At the time of the 2011 review – Health Canada had received 18

Canadian reports of adverse events suspected of being associated with melatonin

• Most frequent – daytime sleepiness

• 5/18 considered serious • 2 cases with epilepsy – 1 had a seizure and the other had increased

frequency of seizures while taking melatonin and carbamazepine • 1 with ADHD had hallucinations while taking melatonin and ADHD

medication • The other 2 – dyspnea and an increase LFTs

• Limited information – causal association not established

Health Canada 2016

• Reviewed WHO Global Individual Case Safety Reports Database System

• 163 reports of adverse reactions (8 from Canada) suspected of being associated with pediatric use of melatonin

• Most common – general fatigue, aggression, abnormal dreams, headache

Side Effects – Long Term

• Possible suppression of the hypothalamic – gonadal axis • Theoretical risk

• Kennaway (2015) • Hundreds of experiments on young and adult

animals (rodents, cats, ruminants and primates) reporting major influences on reproductive system

• melatonin is used as a veterinary drug!

Side Effects – Long Term

• Van Geijlswijk 2011 – • evaluated puberty in 51 adolescents using

melatonin for a mean duration of 3.1 years – no impact

• Case reports • Elevated endogenous melatonin levels in 7 male

patients with GNRH deficiency • Higher melatonin secretion in males with

hypogonadotropin hypogonadism and delayed puberty

Melatonin interactions

• Because melatonin my decrease blood pressure or serum glucose – • Caution in patients who receive concomitant

therapy with agents that affect BP or blood sugar

• Melatonin is safe in overdose – any excess is simply excreted

• Exogenous melatonin doesn’t seem to affect the endogenous secretion

Definitions

• SOL – sleep onset latency • Time from laying down to sleep to sleep onset • Up to 30 minutes is normal • Difference of 15 minutes is clinically important

• TST – total sleep time

• DLMO – dim light melatonin onset

Melatonin and Primary Sleep Disorders

• 2 most common causes of insomnia in children and adolescents • DSPS – Delayed Sleep Phase Syndrome • Behavioural Insomnia of Childhood

Melatonin and primary sleep disorders

• Buscemi (2005)

• Systematic review

• 2 RCTs

• N 110; 0 to 18 years old

• 5mg melatonin x 4/52

• Decrease SOL 16.7 minutes

Melatonin in Primary Sleep Disorders

• Gringras (2012) • 3 to 15 year olds • Escalating melatonin dose 45 minutes before

bedtime • Objective measurement (actigraphy) • Decreased SOL by 45 minutes • Advanced wake time by 30 minutes • Overall TST not affected

Melatonin and primary sleep disorders

• Ferraciola-Oda (2013)

• Meta-analysis

• 19 RCTs

• N 1683; adults and children

• Decrease SOL of 7 minutes

• Increase TST 8.25 minutes

• Higher doses and longer duration of treatment was associated with greater effect sizes on SOL and TST – suggesting there is no evidence of the development of tolerance*

Melatonin and primary sleep disorders

• When melatonin was administered at a time related to DLMO, meta-analyses showed that melatonin decreased SOL

• However without knowing DLMO – melatonin did not improve sleep

Melatonin and Secondary Sleep Disorders

• ADHD

• ASD

• ID

Melatonin and ADHD

• As many as 70% of children with ADHD have been reported has having mild to severe sleep problems

• Cortese (2009) • Meta-analysis • More sleep problems in kids with ADHD • Bedtime resistance • Sleep onset difficulties • Night awakenings • Difficulties with morning awakenings • Higher levels of daytime sleepiness

Melatonin and ADHD

• Pian Gi (2003) • N 27 • Open label • 3mg • Decrease SOL 135 minutes at 1 week • Decrease SOL 16 minutes at 3 months

Melatonin and ADHD

• Weiss (2006) • N 23; • RCT • 5mg melatonin, on stimulants • Decrease SOL 16 minutes • Increase TST 15 minutes

Melatonin and ADHD

• Van der Heijden (2007) • N 105; 6 to 12 years old • Double blind crossover • No stimulant treatment • 3 to 6 mg melatonin • Decrease SOL 27 minutes (increase SOL 10

minutes in placebo group) • Increase TST 20 minutes

• No change in behaviour, QOL, cognitive performance

Melatonin and ADHD

• Anderson (2008) • N 107 • 3 to 6 mg melatonin, not on stimulants • Decrease SOL 24 minutes • Increase TST 33 minutes

Melatonin and ASD

• 67% of ASD children have sleep difficulties • Reduced total sleep • Longer sleep latency • Nocturnal and early morning awakenings

• Garstang (2006) • N 11; 5 to 15 years old • DB randomized crossover design • 5mg melatonin x 4 weeks • Decrease SOL from 2.6 h to 1.06 hours • Increase TST from 8.05 h to 9.84 hours

Melatonin and ASD

• Anderson (2008) • N 107; 2 – 18 years old • Open label, based on parent response • 0.75 mg – 6 mg (30 to 60 mins before bedtime) • Followed avg. 1.8 years • 25% no sleep concerns • 60% improved sleep • 14% no response • 1% worse

Melatonin and ASD

• Cortesi (2012) • N 134; Mean age 6 years • 3 mg controlled release vs CBT vs combo vs

placebo • Melatonin alone • Decrease SOL 36 minutes • Increase TST 71 minutes

• CBT • Decreased SOL by 17 minutes • Increased TST 37 minutes

Melatonin and ASD

• Rossignol & Frye (2013)

• Meta-analysis RCT placebo controlled crossover studies • Significant improvement • Large effect size • Sleep duration and SOL • But not in nighttime awakenings • Majority responded to 1 to 3 mg given 30 minutes

before bedtime • Overall improvement rate 80%

Melatonin and ID

• Sajith (2007)

• Meta-analysis 9 RCTs

• N 183

• Melatonin decreased SOL by 34 minutes

• Increased TST 50 minutes

Melatonin and other neurological disorders

• Epilepsy • Literature is conflicting • But suggests that melatonin is unlikely to exacerbate

seizures and might even protect against them • Need more data

• Headaches • No definitive consensus • Open label trial (Miano 2008) children with primary

headache, melatonin 3mg bid • decreased number of headaches by more than 50% and

decreased the intensity and duration of headache in 14 of 21 children

Other actions of melatonin

• Antioxidant

• Anti-inflammatory

• Free radical scavenger

• Neuroprotective • ?role in minimizing neuronal damage from birth

asphyxia (animal studies)

What else can Melatonin do? (maybe)

• Cancer – breast, prostate

• Alzheimer's

• Anti-aging

• Analgesia for diagnostic procedures

• Helpful with sleep EEGs – sedation for brainstem auditory evoked potential assessments

Other potential uses

• University of Maryland Medical Center (2016) • Heart disease • Antioxidant/anti-inflammatory/lower BP

• Menopause • Sleep/prevent bone loss

• Benzodiazepine Withdrawal • Fibromyalgia and Chronic Pain • Sunburn • IBS • Sarcoidosis • Assisted reproduction

Non-pharmacological approaches to sleep

• Audience participation time

• What can we do to improve sleep without medication?

Non-pharmacoligcal approaches to sleep

• No daytime napping

• Electronics turned off 30 to 60 minutes before bed

• Limiting caffeine intake

• Exercise (but not right before bed)

• Dark room

• Comfortable bed/pillow

• Cool room (60 to 68 F)

• Good bedtime routine

• Regular bed time

• Regular wake time

Conclusions • Melatonin can be useful – timing of administration is important

• Studies in special populations provide best evidence for usefulness (ASD, ADHD)

• Adverse effects – seem to be mild and self limited

• Long term safety profile in children has yet to be established

• Use non pharmacological interventions first!

• Studies to date have serious limitations – small number of trials, small number of subjects, lack of long term studies, variations in how sleep is measured, variability in dosing and timing of dosing etc

Questions or Comments?

Video-conferencers: Unmute your system to ask a question

Webcasters: Type your question

for participating in today’s

Mental Health Series Join us again in September!

Thank you!

mentalhealthseries@cheo.on.ca