ADHD: Melatonin er både sikkert, effektivt og anbefalet.

Jævnligt ser vi overskrifterne i aviserne om at ‘danske børns forbrug af sovemedicin er eksploderet’ og lignende. Men i sandhed skyldes udviklingen i forbruget af Melatonin, der ikke er sovemedicin i øvrigt, at flere og flere har forstået, at ADHD medfører søvnforstyrrelser hos mange, og til disse viser videnskabelig evidens, at Melatonin er både sikkert, effektivt og anbefalet til behandling af søvnforstyrrelser ved både ADHD og Autisme.

Resumé

Søvnforstyrrelser er en gruppe af tilstande, der påvirker evnen til at sove godt på jævnlig basis, og kan medføre signifikante funktionsnedsættelser i sociale og arbejdsmæssige sammenhænge.

Resultatet af dårlig nattesøvn er meget udtalt hos børn med udviklingsforstyrrelser (f.eks. ADHD og autisme); disse børn har svært ved at falde i søvn, forblive sovende og har ofte natlige opvågninger, hvilket påvirker barnets adfærdsmæssige udfordringer i dagstiden.

Tilstrækkelig nattesøvn er af kritisk vigtighed for udvikling af normalt niveau af nødvendige synapser i hjernen, samt for hjernens aldersmæssige modenhed. Ringe søvnkvalitet kan have en uoprettelig negativ effekt på barnets kognitive opmærksomhed, hukommelse, følelsesmæssige selvregulering og adfærdsmæssige funktioner.

Melatonin er et hormon der produceres i Pineal Gland og har en vigtig rolle i regulering af søvn og døgnrytme, såvel som en mulig forbindelse til gut-brain funktionaliteten. Den primære fysiologiske funktion for Melatonin er, at give kroppen information om den daglige dag- og natterytme, således at hormonet kan medvirke til at regulerer vigtige funktioner, såsom metabolismen.

Mange børn der lider af udviklingsforstyrrelser, såsom autisme, ADHD eller mental retardering, lider ofte også af søvnforstyrrelser, og disse børn kan have god effekt af behandling med Melatonin. Melatonin forkorter indsovningsproblemer, og forlænger den samlede tid for sammenhængende søvn, men reducerer ikke natlige opvågninger.

Et meta-studie af Melatonin viser at, melatonin forbedrede søvnkvaliteten mest hos børn med autisme eller andre udviklingsforstyrrelser, og i mindre grad også i børn og unge med indsovningsproblemer.

Indtagelse af Melatonin viste generelt favorabel virkning på sikkerhedsprofilen (effekt målt imod bivirkninger), med nogle få undtagelser. De fleste bivirkninger kan undgåes såfremt doseringen og indtagelsen af medicinen, følger den normale døgn rytme.

Det er fundet genetisk bevis for at ADHD påvirker ens søvn negativt ved at forstyrre det naturlige neurobiologiske indre ur der styrer vores døgnrytme, hvilket gør medicinsk behandling af søvnforstyrrelser ved ADHD, til et naturligt valg, f.eks. melatonin.

Især for børn med ADHD, der oplever søvnforstyrrelser i forbindelse med behandling med Methylfenidat (Ritalin Concerta, Medikinet m.v.), er melatonin være en både sikker, effektiv og anbefalet behandling, uanset køn, alder og komorbide lidelser. Det samme gælder for børn med autisme, hvor melatonin ligeledes anses for at en både sikker og vel-tolereret behandling af søvnforstyrrelser. Der findes ligeledes studier der viser at melatonin også har en både sikker og god effekt hos børn med hjerneskade (TBI).

Konklusion

Den opfattende hysteri omkring forbruget af Melatonin til behandling af søvnforstyrrelser hos børn, er ikke begrundet i videnskabelige evidens, men nok nærmere på endnu en misforståelse af den medicin som ADHD kræver, præcis som vi kender det fra den normale ADHD-medicin.

Jeg har kigget på udviklingen af forbruget af Melatonin for børn mellem 0 – 17 år i Danmark fra 2008 til 2017, og den viser følgende:

Kilde: Lægemiddelstyrelsen

Som det fremgår af grafikken, så er antallet af børn og unge der er i behandling for søvnforstyrrelser, steget over de seneste 10 år. Men ser vi på forbruget af antidepressive midler (mellem 55-80% af alle børn med ADHD lider også af angst og/eller depression) så kan vi se at antallet er nærmest halveret i samme periode. Ser vi på ADHD-medicinen, ja så ligger den konstant på samme niveau (ca. 15.000 personer) over det meste af perioden.

Det fortæller os, at fordi man er begyndt at forbyde børn at blive udredt for ADHD, fordi det er for dyrt for samfundet (holdning, ikke fakta), og samtidigt har sat en stopper for brug af antidepressiv medicin til børn og unge, ja så har de blot flyttet problemet til et andet sted, nemlig til melatonin, for nu kan børnene hverken få behandlet da ADHD symptomer, deres angst, deres depression og resultatet af det? Søvnforstyrrelser!

Når et barn ikke kan få anerkendt deres medfødte psykiske lidelse, og dermed ej heller få den medicinske hjælp som vi ved virker, sikkert og godt, så udvikler de angst og depression, hvilket så igen forværrer deres søvnforstyrrelser (som vi lige har lært er neurobiologiske, ikke psykosociale!), og resultatet er så at den dårlige nattesøvn og søvnkvalitet så igen forværrer deres ADHD symptomer i løbet af dagen, hvilket så igen påvirker deres angst- og depressionssymptomer, hvilket så igen leder til yderligere forværring af deres søvnforstyrrelse!

Peter ‘ADDspeaker’ Vang, 2019

Så, som altid, desværre, er det uvidenheden der har magten i Danmark, når det kommer til forståelse og indsigt i medicinsk behandling i forbindelse med ADHD. Selvom vi har vist siden 2015 at ADHD medfører en overdødelighed på 50% i forhold til samfundet bredt set og i 2018 fik bevis for at ADHD forkorter den forventede middellevetid med 12,7 år, set i forhold til befolkningen bredt set, så holder vi stadigt og stædigt fast på vores principper her i Danmark, for det er jo mere interessant at skrive om alt det dårlige som medicin til børn og unge gør, frem for at forholde sig til virkeligheden og se på den markante, både umiddelbare og langvarige, positive effekt af korrekt medicinering i barndommen, kan medføre.

Jeg håber at ‘nogen’ en dag får hovedet ud af røven og lytter lidt til hvad vi der lever med ADHD har erfaret (i samarbejde med videnskaben og deres evidens), frem for blot at være arrogant afvisende overfor ethvert synspunkt der ikke går med på den gluten-fornægtende, laktose-frie, anti-vaccinerende og helt igennem hjernedøde offentlige forståelse, der hersker herhjemme!

/ADDspeaker

Hvad er en søvnforstyrrelse?

Sleep disorders are a group of conditions that affect the ability to sleep well on a regular basis and cause significant impairments in social and occupational functions. Although currently approved medications are efficacious, they are far from satisfactory. Benzodiazepines, antidepressants, antihistamines and anxiolytics have the potential for dependence and addiction. Moreover, some of these medications can gradually impair cognition. Melatonin (N-acetyl-5-methoxytryptamine) is an endogenous hormone produced by the pineal gland and released exclusively at night. Exogenous melatonin supplementation is well tolerated and has no obvious short- or long-term adverse effects. Melatonin has been shown to synchronize the circadian rhythms, and improve the onset, duration and quality of sleep. It is centrally involved in anti-oxidation, circadian rhythmicity maintenance, sleep regulation and neuronal survival. This narrative review aims to provide a comprehensive overview of various therapeutic functions of melatonin in insomnia, sleep-related breathing disorders, hypersomnolence, circadian rhythm sleep-wake disorders and parasomnias. Melatonin offers an alternative treatment to the currently available pharmaceutical therapies for sleep disorders with significantly less side effects. (1)

Hvad skyldes søvnforstyrrelser?

Adequate sleep is of critical need for a typical synaptic development and brain maturation, a poor quality sleep can have detrimental effects on children’s’ cognitive attention, memory, mood regulation, and behavior functions. Great concern has been voiced out regarding the high prevalence of poor sleep in children worldwide, the effects of poor sleep may be even more pronounced in children with neurodevelopmental disorders; these children often have difficulties with falling and staying asleep and with night awakenings, this has a strong association with daytime behavior problems. The purpose of this article is to provide an overview of the state of the science of sleep in children with a neurodevelopmental disorder. In this context, it is important to take the circadian cycle into account, a genetically encoded clock that drives cellular rhythms of transcription, translation and metabolism. The circadian clock interacts with the diurnal and nocturnal environment that also drives transcription and metabolism during light/dark, sleep/wake, hot/cold and feast/fast daily and seasonal cycles In conclusion, the sleep problems are a conditioning factor in the evolution and quality of life of children with neurodevelopmental disorders that must be taken into account in all cases and occupy a preferential place in both the diagnostic and the therapeutic stages. (2)

Hvad er Melatonin?

Melatonin is the hormone produced by the pineal gland that plays a role in regulating sleep and circadian rhythm as well as a possible role in gut-brain signaling. It is a normal component of breastmilk, with concentrations higher during nighttime than daytime. Some authors suggest that mothers should nurse in the dark at night in order to avoid reductions in the melatonin content of breastmilk, which could disturb infant sleep patterns. (3)

Hvordan virker Melatonin?

Melatonin is a methoxyindole synthesized and secreted principally by the pineal gland at night under normal light/dark conditions. The endogenous rhythm of secretion is generated by the suprachiasmatic nuclei and entrained to the light/dark cycle. Light is able to either suppress or synchronize melatonin production according to the light schedule. The nycthohemeral rhythm of this hormone can be evaluated by repeated measurement of plasma or saliva melatonin or urine sulfatoxymelatonin, the main hepatic metabolite. The primary physiological function of melatonin, whose secretion adjusts to night length, is to convey information concerning the daily cycle of light and darkness to body structures. This information is used for the organisation of functions, which respond to changes in the photoperiod such as the seasonal rhythms. Seasonal rhythmicity of physiological functions in humans related to possible alteration of the melatonin message remains, however, of limited evidence in temperate areas under field conditions. Also, the daily melatonin secretion, which is a very robust biochemical signal of night, can be used for the organisation of circadian rhythms. Although functions of this hormone in humans are mainly based on correlations between clinical observations and melatonin secretion, there is some evidence that melatonin stabilises and strengthens coupling of circadian rhythms, especially of core temperature and sleep-wake rhythms. The circadian organisation of other physiological functions depend also on the melatonin signal, for instance immune, antioxidant defences, haemostasis and glucose regulation. The difference between physiological and pharmacological effects of melatonin is not always clear but is based upon consideration of dose and not of duration of the hormone message. It is admitted that a “physiological” dose provides plasma melatonin levels in the same order of magnitude as a nocturnal peak. Since the regulating system of melatonin secretion is complex, following central and autonomic pathways, there are many pathophysiological situations where melatonin secretion can be disturbed. The resulting alteration could increase the predisposition to disease, add to the severity of symptoms or modify the course and outcome of the disorder. Since melatonin receptors display a very wide distribution in the body, putative therapeutic indications of this compound are multiple. Great advances in this field could be achieved by developing multicentre trials in a large series of patients, in order to establish efficacy of melatonin and absence of long-term toxicity. (4)

Hvad siger den kliniske anbefaling?

The best evidence for efficacy is in sleep onset insomnia and delayed sleep phase syndrome. It is most effective when administered 3-5 h before physiological dim light melatonin onset. There is no evidence that extended-release melatonin confers advantage over immediate release. Many children with developmental disorders, such as autism spectrum disorder, attention-deficit/hyperactivity disorder and intellectual disability have sleep disturbance and can benefit from melatonin treatment. Melatonin decreases sleep onset latency and increases total sleep time but does not decrease night awakenings. Decreased CYP 1A2 activity, genetically determined or from concomitant medication, can slow metabolism, with loss of variation in melatonin level and loss of effect. Decreasing the dose can remedy this. Animal work and limited human data suggest that melatonin does not exacerbate seizures and might decrease them. Melatonin has been used successfully in treating headache. Animal work has confirmed a neuroprotective effect of melatonin, suggesting a role in minimising neuronal damage from birth asphyxia; results from human studies are awaited. Melatonin can also be of value in the performance of sleep EEGs and as sedation for brainstem auditory evoked potential assessments. No serious adverse effects of melatonin in humans have been identified. (5)

Evidensen for Melatonin?

Sleep problems are common in children, especially those with neurodevelopmental disorders, and can lead to consequences in behavior, functioning, and quality of life. We systematically reviewed the efficacy and harms of pharmacologic treatments for sleep disorders in children and adolescents. We searched MEDLINE, Cochrane library databases, and PsycINFO through June 2018. We included 22 placebo-controlled randomized controlled trials (1-13 weeks’ duration), involving 1758 children (mean age 8.2 years). Single randomized controlled trials of zolpidem and eszopiclone in children with attention-deficit/hyperactivity disorder (ADHD) showed no improvement in sleep or ADHD ratings. Clinical Global Impression Improvement/Severity scores significantly improved with zolpidem ( P = .03 and P = .006, respectively). A single, small randomized controlled trial of diphenhydramine reported small improvements in sleep outcomes (8-10 minutes’ better sleep latency and duration) after 1 week. In 19 randomized controlled trials, melatonin significantly improved sleep latency (median 28 minutes; range 11-51 minutes), sleep duration (median 33 minutes; range 14-68 minutes), and wake time after sleep onset (range 12-43 minutes), but not number of awakenings per night (range 0-2.7). Function and behavior improvement varied. Improvement in sleep was greatest in children with autism or other neurodevelopmental disorders, and smaller in adolescents and children with chronic delayed sleep onset. Adverse events were infrequent with melatonin, but more frequent than placebo in children taking eszopiclone or zolpidem. These findings show that melatonin was useful in improving some sleep outcomes in the short term, particularly those with comorbid ASD and neurodevelopmental disorders. Other drugs and outcomes are inadequately studied. (6)

Melatonin og bivirkninger

While melatonin was once thought of simply as a sleep-inducing hormone, recent research has resulted in development of a deeper understanding of the complex physiological activity of melatonin in the human body. Along with this understanding has come widespread, increasing use of melatonin supplementation, extending beyond its traditional use as a sleep aid into novel fields of application. This increased use often involves off-label and self-prescription, escalating the importance of safety data. In order to examine the current knowledge relating to safety of the exogenous neurohormone, we conducted a comprehensive, critical systematic review of clinical evidence. We examined controlled studies of oral melatonin supplementation in humans when they presented any statistical analysis of adverse events. Of the fifty articles identified, twenty-six found no statistically significant adverse events, while twenty-four articles reported on at least one statistically significant adverse event. Adverse events were generally minor, short-lived and easily managed, with the most commonly reported adverse events relating to fatigue, mood, or psychomotor and neurocognitive performance. A few studies noted adverse events relating to endocrine (e.g. reproductive parameters, glucose metabolism) and cardiovascular (e.g. blood pressure, heart rate) function, which appear to be influenced by dosage, dose timing and potential interactions with antihypertensive drugs. Oral melatonin supplementation in humans has a generally favourable safety profile with some exceptions. Most adverse effects can likely be easily avoided or managed by dosing in accordance with natural circadian rhythms. Further research is required to explore the potential for melatonin to interact with endogenous hormones and pharmaceuticals. (7)

ADHD og Melatonin

Reports of sleep disturbances in attention deficit hyperactivity disorder (ADHD) are common in both children and adults; however, the aetiology of such disturbances is poorly understood. One potentially important mechanism which may be implicated in disrupted sleep in ADHD is the circadian clock, a known key regulator of the sleep/wake cycle. In this systematic review, we analyse the evidence for circadian rhythm changes associated with ADHD, as well as assessing evidence for therapeutic approaches involving the circadian clock in ADHD. We identify 62 relevant studies involving a total of 4462 ADHD patients. We find consistent evidence indicating that ADHD is associated with more eveningness/later chronotype and with phase delay of circadian phase markers such as dim light melatonin onset and delayed sleep onset. We find that there is evidence that melatonin treatment may be efficacious in addressing ADHD-related sleep problems, although there are few studies to date addressing other chronotherapeutic approaches in ADHD. There are only a small number of genetic association studies which report linkages between polymorphisms in circadian clock genes and ADHD symptoms. In conclusion, we find that there is consistent evidence for circadian rhythm disruption in ADHD and that such disruption may present a therapeutic target that future ADHD research might concentrate explicitly on. (8)

Methylphenidate (MPH), the first-line medication in children with attention-deficit/hyperactivity disorder (ADHD), is associated with increased risk of sleep disorders. Melatonin has both hypnotic and chronobiotic properties that influence circadian rhythm sleep disorders. This study explores the effectiveness of melatonin in children with ADHD who developed sleep problems after starting MPH. This study, based on a clinical database, included 74 children (69 males, mean age 11.6±2.2 years) naturalistically treated with MPH (mean dosage 33.5±13.5 mg/d). The severity of sleep disorder (sleep onset delay) was recorded at baseline and after a follow-up of at least 4 weeks using a seven-point Likert scale according to the Clinical Global Impression Severity score. Effectiveness of melatonin on sleep (mean dosage 1.85±0.84 mg/d) after 4 weeks was assessed using a seven-point Likert scale according to the Clinical Global Impression Improvement (CGI-I) score, and patients who scored 1 (very much improved) or 2 (much improved) were considered responders. Clinical severity of sleep disorders was 3.41±0.70 at the baseline and 2.13±1.05 after the follow-up (P<0.001). According to the CGI-I score, 45 patients (60.8%) responded to the treatment with melatonin. Gender and age (children younger and older than 12 years) did not affect the response to melatonin on sleep. Patients with or without comorbidities did not differ according to sleep response. Specific comorbidities with disruptive behavior disorders (oppositional defiant disorder or conduct disorder), affective (mood and anxiety) disorders and learning disabilities did not affect the efficacy of melatonin on sleep. Treatment was well tolerated, and no side effects related to melatonin were reported. In children with ADHD with sleep problems after receiving MPH treatment, melatonin may be an effective and safe treatment, irrespective of gender, age and comorbidities. (9)

Autisme og Melatonin

We describe our experience in using melatonin to treat insomnia, a common sleep concern, in children with autism spectrum disorders. One hundred seven children (2–18 years of age) with a confirmed diagnosis of autism spectrum disorders who received melatonin were identified by reviewing the electronic medical records of a single pediatrician. All parents were counseled on sleep hygiene techniques. Clinical response to melatonin, based on parental report, was categorized as (1) sleep no longer a concern, (2) improved sleep but continued parental concerns, (3) sleep continues to be a major concern, and (4) worsened sleep. The melatonin dose varied from 0.75 to 6 mg. After initiation of melatonin, parents of 27 children (25%) no longer reported sleep concerns at follow-up visits. Parents of 64 children (60%) reported improved sleep, although continued to have concerns regarding sleep. Parents of 14 children (13%) continued to report sleep problems as a major concern, with only 1 child having worse sleep after starting melatonin (1%), and 1 child having undetermined response (1%). Only 3 children had mild side-effects after starting melatonin, which included morning sleepiness and increased enuresis. There was no reported increase in seizures after starting melatonin in children with pre-existing epilepsy and no new-onset seizures. The majority of children were taking psychotropic medications. Melatonin appears to be a safe and well-tolerated treatment for insomnia in children with autism spectrum disorders. Controlled trials to determine efficacy appear warranted. (10)

Hjerneskade (TBI) og Melatonin

Traumatic brain injury (TBI) is common; however, effective treatments of the secondary brain injury are scarce. Melatonin is a potent, nonselective neuroprotective and anti-inflammatory agent that is showing promising results in neonatal brain injury. The aim of this study was to systematically evaluate the pre-clinical and clinical literature on the effectiveness of melatonin in improving outcome after TBI. Using the systematic review protocol for animal intervention studies (SYRCLE) and Cochrane methodology for clinical studies, a search of English-language articles was performed. Eligible studies were identified and data were extracted. Quality assessment was performed using the SYRCLE risk of bias tool. Meta-analyses were performed using standardized mean differences (SMD). Seventeen studies (15 pre-clinical, 2 clinical) met inclusion criteria. There was heterogeneity in the studies, and all had moderate-to-low risk of bias. Meta-analysis of pre-clinical data revealed an overall positive effect on neurobehavioural outcome with SMD of 1.51 (95% CI: 1.06-1.96). Melatonin treatment had a favorable effect on neurological status, by an SMD of 1.35 (95% CI: 0.83-1.88), and on cognition by an SMD of 1.16 (95% CI: 0.4-1.92). Melatonin decreased the size of the contusion by an SMD of 2.22 (95% CI: 0.8–3.59) and of cerebral edema by an SMD of 1.91 (95% CI: 1.08-2.74). Only two clinical studies were identified. They were of low quality, were used for symptom management, and were of uncertain significance. In conclusion, there is evidence that melatonin treatment after TBI significantly improves both behavioral outcomes and pathological outcomes; however, significant research gaps exist, especially in clinical populations. (11)

Referencer

  1. Xie, Z., Chen, F., Li, W. A., Geng, X., Li, C., Meng, X., … Yu, F. (2017). A review of sleep disorders and melatonin. Neurological research, 39(6), 559–565. doi: https://doi.org/10.1080/01616412.2017.1315864
  2. Pin Arboledas G. (2019). El sueño del niño con trastornos del neurodesarrollo [The sleep in children with neurodevelopmental disorders]. Medicina, 79 Suppl 1, 44–50. 
  3. [No authors listed] Drugs and Lactation Database (LactMed). National Library of Medicine (US) 20062006– – Review. PMID 30000923
  4. Claustrat, B., & Leston, J. (2015). Melatonin: Physiological effects in humans. Neuro-Chirurgie, 61(2-3), 77–84. doi: https://doi.org/10.1016/j.neuchi.2015.03.002
  5. Bruni, O., Alonso-Alconada, D., Besag, F., Biran, V., Braam, W., Cortese, S., … Curatolo, P. (2014). Current role of melatonin in pediatric neurology: clinical recommendations. European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society, 19(2), 122–133. doi: https://doi.org/10.1016/j.ejpn.2014.12.007
  6. McDonagh, M. S., Holmes, R., & Hsu, F. (2019). Pharmacologic Treatments for Sleep Disorders in Children: A Systematic Review. Journal of child neurology, 34(5), 237–247. doi: https://doi.org/10.1177/0883073818821030
  7. Foley, H. M., & Steel, A. E. (2018). Adverse events associated with oral administration of melatonin: A critical systematic review of clinical evidence. Complementary therapies in medicine, 42, 65–81. doi: https://doi.org/10.1016/j.ctim.2018.11.003
  8. Coogan, A. N., & McGowan, N. M. (2017). A systematic review of circadian function, chronotype and chronotherapy in attention deficit hyperactivity disorder. Attention deficit and hyperactivity disorders, 9(3), 129–147. doi: https://doi.org/10.1007/s12402-016-0214-5
  9. Masi, G., Fantozzi, P., Villafranca, A., Tacchi, A., Ricci, F., Ruglioni, L., … Cortese, S. (2019). Effects of melatonin in children with attention-deficit/hyperactivity disorder with sleep disorders after methylphenidate treatment. Neuropsychiatric disease and treatment, 15, 663–667. doi: https://doi.org/10.2147/NDT.S193891
  10. Andersen, I. M., Kaczmarska, J., McGrew, S. G., & Malow, B. A. (2008). Melatonin for Insomnia in Children With Autism Spectrum Disorders. Journal of Child Neurology, 23(5), 482–485. doi: https://doi.org/10.1177/0883073807309783
  11. Barlow, K. M., Esser, M. J., Veidt, M., & Boyd, R. (2018). Melatonin as a Treatment after Traumatic Brain Injury: A Systematic Review and Meta-Analysis of the Pre-Clinical and Clinical Literature. Journal of neurotrauma, 36(4), 523–537. doi: https://doi.org/10.1089/neu.2018.5752