What is melatonin, anyway?

Transcription

1 DISCLOSURE & ACCREDITATION This Grand Rounds is accredited for CME by the Yale School of Medicine. If you wish to receive credit for your participation, you must: DISCLOSURE & ACCREDITATION Acknowledgement is made on behalf of the Department that: ~ There is no commercial support for this Grand Rounds. Confirmation is also made that today s lecture and faculty disclosure have been peer reviewed and: ~There are no conflicts of interest. Melatonin in Children: Panacea or Problem? Craig Canapari MD Director, Yale Pediatric Sleep Program Assistant Professor, Yale Medical School sign in complete and return the evaluation 1. What is melatonin and what does it do? 2. Why insomnia in children is challenging 3. What s the evidence for melatonin efficacy? For safety? 4. Practical notes on dosing and usage What is melatonin, anyway? Regulation of melatonin production and receptor function Regulation of melatonin production and receptor function In adults, mg of melatonin generate serum concentrations that are physiologic ( pg/ml) Pelayo and Yuen, Pediatric Sleep Pharmacology, in Sleep in Childhood Neurological Disorders, 2011 Margarita L. Dubocovich et al. Pharmacol Rev 2010;62: Copyright 2010 by The American Society for Pharmacology and Experimental Therapeutics Margarita L. Dubocovich et al. Pharmacol Rev 2010;62:

2 Development of melatonin secretion in childhood Pregnancy Secretion increases 24 weeks >term Infancy Dim Light Melatonin Onset DLMO Childhood Immature Some kids aren t ready for bed at bedtime 220 Vs Mature 165 Lower in infants 110 with abnormal development 55 0 Marked increase at 3 mo of age Bedtime is too early 1-5 y 6-11 y Teens,, In the US, melatonin sales increased from $90 million in 2007 to $260 million in 2012 CAN T SLEEP Usage of melatonin has increased drastically Jennifer Breheny Wallace, Melatonin: A Magic Sleeping Pill for Children? WSJ 6/28/13 Forster et al Eur J Clin Pharmacol Is this OK? A glowing Amazon review... From Medline Plus: Melatonin should not be used in most children. It is POSSIBLY UNSAFE. Because of its effects on other hormones, melatonin might interfere with development during adolescence. From NaturalSleep.org: Melatonin, according to more than 24 studies, is safe for children and has been used with little to no side effects. From Livestrong.com: Although the use of low doses of melatonin to help children sleep seems to be safe and effective, more research is needed to answer lingering questions. Judith Owens, Huffington Post Dec OK, yes, as parents my wife and I should do a better job starting the bedtime routine earlier, turning off the TV earlier, limiting sweets, etc., etc. Well, for whatever reason, this is not our strong suit. This 1 mg light dosage of melatonin is very helpful winding our kids down and getting them ready for bed. Quoted in the Wall Street Journal 6/28/13 Maybe it is not such a good idea parents should always be informed that (1) melatonin is not registered for use in children, (2) no rigorous long-term safety studies have been conducted in children and by the way (3) melatonin is also a registered veterinary drug used to alter the reproduction of sheep and goats. David J Kennaway J Paed and Child Health Feb

3 What makes melatonin so appealing? It s natural You can t overdose on it Readily available* Pediatric insomnia is common, occurring in 20-30% of children, across cultures. What medication treatments are available? Badin et al. Current Psych Reports, May 2016 *In the US and Canada Physicians are not well prepared to treat children with insomnia Physicians are not well prepared to treat children with insomnia Physicians are not well prepared to treat children with insomnia 20% of physicians receive formal training in sleep. There is a shortage of pediatric sleep physicians Bock DE, Sleep Medicine % of physicians receive formal training in sleep. There is a shortage of pediatric sleep physicians Bock DE, Sleep Medicine % of physicians receive formal training in sleep. There is a shortage of pediatric sleep physicians Bock DE, Sleep Medicine 2016 Mood Learning We are all ambivalent about prescribing sleep medicines in children What are the effects of insomnia on children? What effects do melatonin have on sleep in children? Relationships Behavior

4 Hypnotic effects? Ability to induce sleep when given prior to bedtime. Go to sleep earlier When you give melatonin matters Decreased Sleep Onset Latency Increased > Sleep >> Time Decreased Nocturnal Awakenings Chronobiotic effects Ability to phase shift the sleep period. Can be earlier (if dosed from 3-5 hours prior to DLMO to 1-2 hours) OR Later (5-6 hours after DLMO) Go to sleep later Max effect: 4-6 h before falling asleep 10p 7a 10p 7a Typically a minute reduction Present in about 50% of studies Generally not a major effect Chronic sleep onset insomnia* Autism* Defined as difficulty falling asleep within 30 minutes of age appropriate bedtime Melatonin in Specific Disorders ADHD* Delayed sleep phase syndrome* Neurodevelopmental Disorders Chronic insomnia Reduced difficulty falling asleep and bedtime struggles Increased sleep time Eczema* Syndromes: Angelman, Rett, Fragile X, Smith-Magenis*, Down, Prader-Willi, Sanfilippo, Williams No dose response Early dosing superior Difficulty with sleep onset and maintenance are very common in autism. Registry study of 1518 children with autism, ages % of children with ADHD have sleep problems ranging from mild to severe Autism Reduced difficulty falling asleep (60%) Increased sleep time Resolution of sleep complaints (25%) Reduction in parental stress But maybe it is less clear than it seems? 71% had abnormal score on CSHQ 30% with sleep disorder diagnosis 46% on medication (of those w sleep dx) 24% total on sleep medication ADHD Some studies report delay in DLMO with ADHD Dose ranges mg Usually given 30 m prior to bedtime KB Brown, B Malow Chest 2016 Malow et al Pediatrics 2016 Children taking medication for sleep had WORSE: Daytime behavior Quality of life Why? Melatonin decreases sleep latency and increases sleep time. It does not improve daytime symptoms

5 Delayed Sleep Phase Syndrome is a common and under-recognized condition in teenagers Later circadian melatonin phase Side effects: Short Term Neuro: headaches, dizziness, daytime sedation Alert in the evening sleep onset insomnia Morning sleepiness difficulty awakening from sleep Is melatonin safe? GI: Nausea, vomiting CV: Slight drop in BP Endocrine: Increase in glucose GU: Enuresis Delayed sleep time and reduced sleep duration during the school week Often, no side effects are reported 10 pm 1 am 6 am Usually, SE are minimal, compared with other meds There is no lethal dose that has been discovered. Long term safety data CS Lee et al, J Child Adol Psychopharm 59 Dutch children on long term melatonin for chronic insomnia Mean duration of use: 3.1 years Mean age 12 year Mean dose 2.7 mg 44 children with insomnia and developmental delay Mean duration of use: 4.3 years Mean age 9.9 year Mean dose 10.4 mg 105 Children prescribed melatonin for ADHD/Insomnia. 61 still using it daily Mean duration of use: 3.7 years Mean age 12 year Mean dose 4.2 mg Evaluation of sleep, puberty and mental health in children with long-term melatonin treatment for chronic idiopathic childhood sleep onset insomnia. Data followed: Strength and Difficulties Questionnaire CSHQ Tanner staging Long-term effectiveness outcome of melatonin therapy in children with treatment-resistant circadian rhythm sleep disorders. Phone calls to parents Chart reviews if hospitalized Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia Data followed: Parental questionnaires van Geijlsijk et al, Psychopharm, 2011 Carr et al, J Pineal Res, 2009 van Geijlsijk et al, J Pineal Res, 2009 No difference compared with published norms of Dutch children Parents happy with melatonin efficacy Few adverse events reported

6 105 Children prescribed melatonin for ADHD/Insomnia. 61 still using it daily Mean duration of use: 3.7 years Mean age 12 year Mean dose 4.2 mg Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia Data followed: Parental questionnaires van Geijlsijk et al, J Pineal Res, Children with autism on no meds Dose escalation trial 14 weeks Mean age 5.8 year Mean dose 2.8 mg Melatonin for Sleep in Children with Autism: A Controlled Trial Examining Dose, Tolerability, and Outcomes Malow et al, J Autism Dev Disord, 2012 Sleep latency improved Effective over duration of study Improvement in behavior, sleep, parenting stress Problems with these studies Lack of long term studies Long term studies based on parental reports Lack of long term biomarker data No alteration in CBC, metabolic profile, ACTH, cortisol, estrogen, testosterone, FSH, LH, or prolactin noted The Kennaway editorial parents should always be informed that (1) melatonin is not registered for use in children, (2) no rigorous long-term safety studies have been conducted in children and by the way (3) melatonin is also a registered veterinary drug used to alter the reproduction of sheep and goats. The Case Against Melatonin David J Kennaway J Paed and Child Health Feb Dubocovich Endocrine In seasonally breeding animals, it induces reproductive changes, often at doses well below those given to children.. Cause for concern Neurodevelopmentally normal Young age Functioning well Developmental or syndromic problems Older age Poor functioning of parent or child Practice pathway for insomnia in children who have ASD. Lack of long term studies. Behavioral methods only Behavioral methods + Meds Some drugs increase melatonin levels (tricyclics, citalopram, caffeine, fluvoxamine, cimetidine) Beth A. Malow et al. Pediatrics 2012;130:S106-S by American Academy of Pediatrics

7 Practice pathway for insomnia in children who have ASD. Practice pathway for insomnia in children who have ASD. Beth A. Malow et al. Pediatrics 2012;130:S106-S124 Dosing: Problems with preparations Beth A. Malow et al. Pediatrics 2012;130:S106-S124 Page 1 of 7 Amazon search, melatonin for kids : 188 results 9/4/ by American Academy of Pediatrics 2012 by American Academy of Pediatrics If used as chronobiotic, start with a low dose of mg fast release melatonin 3-4 h before bedtime; increase by mg every week as needed (maximum 3 mg; adolescents: 5 mg) until effect If no response after 1 week: increase dose by 1 mg every week until effect appears When 1 mg is effective: try lower dose Maximum dose: <40 Kg: 3 mg; >40 Kg: 5 mg Minimum age: 6 months of age Dosing Dosing Timing: 3-4 hours prior to bedtime (chronobiotic) 30 minutes prior to bedtime (hypnotic) Duration: Minimum 4 weeks Can be withdrawn prior to puberty or after puberty Stop once a year in summer Dosing If used as a sleep inductor start with 1-3 mg 30 min before sleep of before the examination (EEG, Evoked potentials or MRI) Metabolized slower: Check timing; it may be given too late oral contraceptives, cimetidine, fluvoxamine Troubleshooting Comorbidities: DSPS: consider chronotherapy first Neuropsych conditions; treat concurrently Lower may be better than higher Nightwakings may occur if dose is too high Medication interactions Summary Metabolized faster: carbamazepine, esomeprazole, omeprazole