Evidence Based Medicine Series:Evidence Based Medicine Series:

The role of melatonin in pediatric The role of melatonin in pediatric

headachesheadaches

Sarah LallamanSarah Lallaman33rdrd Year Pediatric Resident Year Pediatric Resident

Patient PresentationPatient Presentation

16 year old female with complicated 16 year old female with complicated past medical history presents for past medical history presents for evaluation of long standing headachesevaluation of long standing headaches Her past medical history is not pertinent Her past medical history is not pertinent

to the headaches and all seems to be to the headaches and all seems to be stable or improvedstable or improved

Reports daily headaches – tension like in Reports daily headaches – tension like in nature, non-disabling, 3-5/10nature, non-disabling, 3-5/10

Occurring over the last yearOccurring over the last year

Patient PresentationPatient Presentation

Has tried intermittent use of Has tried intermittent use of acetaminophen and NSAIDS with acetaminophen and NSAIDS with improvement, but frequent use is a improvement, but frequent use is a concernconcern

Intensity and frequency not increasingIntensity and frequency not increasing No new symptoms associated with the No new symptoms associated with the

headacheheadache ROS: + only for difficulty initiating and ROS: + only for difficulty initiating and

maintaining sleepmaintaining sleep

Patient managementPatient management

Patient interested in starting medication Patient interested in starting medication trialtrial

Patient was started on amitriptyline 10mg Patient was started on amitriptyline 10mg qhsqhs Intention to treat headaches and assist with Intention to treat headaches and assist with

sleepsleep

Scheduled for a 3 month follow-up and Scheduled for a 3 month follow-up and encouraged to keep a headache diaryencouraged to keep a headache diary

Patient Follow-upPatient Follow-up

3 month follow-up3 month follow-up Good patient compliance with amitriptyline Good patient compliance with amitriptyline

– no side-effects, no missed doses– no side-effects, no missed doses Mom also started patient on melatonin Mom also started patient on melatonin

OTC OTC Headaches are nearly resolved – 4 in the Headaches are nearly resolved – 4 in the

last 3 months (3 in the first month after last 3 months (3 in the first month after appt)appt)

Mom wants to know if it the melatonin Mom wants to know if it the melatonin could have helped as well?could have helped as well?

Background Information:Background Information:The pineal glandThe pineal gland

Melatonin is the Melatonin is the main secretory main secretory product of the product of the pineal glandpineal gland

Pineal gland is Pineal gland is located behind located behind the third the third ventricle in the ventricle in the center of the center of the brainbrain

Background Information:Background Information:MelatoninMelatonin Melatonin is synthesized from the amino Melatonin is synthesized from the amino

acid tryptophan through an intermediate acid tryptophan through an intermediate of serotoninof serotonin

Considered both a hormone and a Considered both a hormone and a vitamin. Both produced naturally and vitamin. Both produced naturally and can be ingested in diet as wellcan be ingested in diet as well

Current indications include: sleeping Current indications include: sleeping disorders, circadian rhythm disorders, disorders, circadian rhythm disorders, insomnia, Alzheimer's disease and as an insomnia, Alzheimer's disease and as an adjuvant therapy in cancer treatmentadjuvant therapy in cancer treatment

Background Information:Background Information:MelatoninMelatonin Building evidence that dysregulation Building evidence that dysregulation

of endogenous melatonin synthesis of endogenous melatonin synthesis may be associated with processes may be associated with processes including depression, fibromyalgia, including depression, fibromyalgia, chronic fatigue and headaches, chronic fatigue and headaches, particularly migrainesparticularly migraines

First investigated in migraines in 1989 First investigated in migraines in 1989 and has since been studied in the role and has since been studied in the role of migraine, cluster and hypnic of migraine, cluster and hypnic headaches with positive resultsheadaches with positive results

Properties of melatoninProperties of melatonin

Anti-inflammatory effectAnti-inflammatory effect Free radical scavengerFree radical scavenger Inhibition of dopamine releaseInhibition of dopamine release Similar to structure of indomethacinSimilar to structure of indomethacin GABA potentiationGABA potentiation Opioid analgesiaOpioid analgesia Serotonin modulationSerotonin modulation

Clinical Question:Clinical Question:

Does Melatonin have a role in treating Does Melatonin have a role in treating chronic headaches in the pediatric chronic headaches in the pediatric population?population? P:P: Pediatric population with chronic Pediatric population with chronic

headaches (migraine or otherwise)headaches (migraine or otherwise) I: I: MelatoninMelatonin C: C: Continued care with routine headache Continued care with routine headache

therapytherapy O:O: Improvement in baseline intensity, Improvement in baseline intensity,

frequency or duration of headachesfrequency or duration of headaches

Literature Search: Pub Literature Search: Pub MedMed Key Word: Headache (MeSH = Headache)Key Word: Headache (MeSH = Headache)

51315 results51315 results Key Word: Melatonin (MeSH = melatonin)Key Word: Melatonin (MeSH = melatonin)

15788 results15788 results Combined Headache and MelatoninCombined Headache and Melatonin

98 results98 results Limits of clinical trials, meta-analysis, Limits of clinical trials, meta-analysis,

RCT and children 0-18 years of age RCT and children 0-18 years of age (MeSH = Infant, child, adolescent) and (MeSH = Infant, child, adolescent) and English languageEnglish language 4 results – 1 applicable study4 results – 1 applicable study

Other literature searchesOther literature searches

Dynamed – no results for melatonin Dynamed – no results for melatonin with headacheswith headaches

Related searches on PubMed Related searches on PubMed (melatonin in children etc.)(melatonin in children etc.)

Reverse search from referencesReverse search from references Online sources including eMedicine, Online sources including eMedicine,

UpToDateUpToDate

Selected ArticleSelected Article ““Melatonin to prevent migraine or tension-Melatonin to prevent migraine or tension-

type headache in children”type headache in children” Miano, S. et al. Melatonin to prevent migraine Miano, S. et al. Melatonin to prevent migraine

or tension-type headache in children. or tension-type headache in children. Neurological Science, 2008 (29) 285 – 287. Neurological Science, 2008 (29) 285 – 287.

Directly applied to population I wanted to Directly applied to population I wanted to addressaddress

Used melatonin as I would use in my populationUsed melatonin as I would use in my population Addressed headaches in childrenAddressed headaches in children The only article available to do soThe only article available to do so

Drawbacks from the startDrawbacks from the start Small studySmall study Not randomized, blinded or control based studyNot randomized, blinded or control based study

Reviewing the article: Reviewing the article: The PatientsThe Patients Outpatients from the Paediatric Outpatients from the Paediatric

Headache Centre of the S. Andrea Headache Centre of the S. Andrea Hospital, RomeHospital, Rome

22 consecutive patients over a 4 month 22 consecutive patients over a 4 month acquisition period in 2006acquisition period in 2006 Demographics: Caucasian, middle Demographics: Caucasian, middle

socioeconomic status, all from same urban socioeconomic status, all from same urban areaarea

Age range 6-16 years of age: mean age 12.2 Age range 6-16 years of age: mean age 12.2 yearsyears

10 boys and 12 girls10 boys and 12 girls

Reviewing the article: Reviewing the article: The HeadachesThe Headaches Headache TypesHeadache Types

13 had recurrent migraine without aura13 had recurrent migraine without aura 1 with recurrent migraine with aura1 with recurrent migraine with aura 8 with chronic tension-type headache8 with chronic tension-type headache

Duration of headaches was 40.05 +/- Duration of headaches was 40.05 +/- 30.2 months in the whole sample30.2 months in the whole sample

Diagnosed according to the Diagnosed according to the International Headache Society International Headache Society diagnostic criteriadiagnostic criteria

Reviewing the article:Reviewing the article:Exclusions for the studyExclusions for the study Patients were excluded from the study if:Patients were excluded from the study if:

Received preventive therapy for headaches in Received preventive therapy for headaches in the previous 3 monthsthe previous 3 months

Had any sleep problems or sleep/wake Had any sleep problems or sleep/wake rhythm disordersrhythm disorders

None of the patients were obese, had serious None of the patients were obese, had serious physical, neurological or psychiatric physical, neurological or psychiatric disordersdisorders

All causes for secondary headaches were All causes for secondary headaches were excluded as necessaryexcluded as necessary

Reviewing the article:Reviewing the article:The study designThe study design Open label, non-blinded clinical trialOpen label, non-blinded clinical trial Study lasted 4 monthsStudy lasted 4 months

1 month for baseline with no therapy1 month for baseline with no therapy 3 subsequent months with therapy (3mg 3 subsequent months with therapy (3mg

pure melatonin PO qhs)pure melatonin PO qhs) Parents filled out a structured daily Parents filled out a structured daily

headache diaryheadache diary 3 follow-up appointments3 follow-up appointments Primary end-point of the study was a Primary end-point of the study was a

>50% reduction in headache symptoms>50% reduction in headache symptoms

Reviewing the article:Reviewing the article:The dataThe data 22 enrolled, 21 patients completed study22 enrolled, 21 patients completed study

1 migraine without aura stopped therapy 1 migraine without aura stopped therapy due to excessive daytime sleepinessdue to excessive daytime sleepiness

The number of children who had “severe The number of children who had “severe attacks” improved from 17 at baseline to attacks” improved from 17 at baseline to 6 at the end of the 3 month trial6 at the end of the 3 month trial

14 of the 21 report that attacks had 14 of the 21 report that attacks had decreased by more than 50% compared decreased by more than 50% compared to their baselineto their baseline

Reviewing the article:Reviewing the article:The dataThe data

BaselineBaseline 1 month 1 month follow-upfollow-up

2 month 2 month follow-upfollow-up

3 month 3 month follow-upfollow-up

Friedman Friedman testtest

Frequency of Frequency of attacks / attacks /

monthmonth

12.3 12.3 (8.9)(8.9)

8.7 8.7 (7.5)(7.5)

6.9 6.9 (7.1)(7.1)

5.75.7

(6.7)(6.7)P<0.0P<0.0

0101

Duration of Duration of attacks (h)attacks (h)

13.5 13.5 (15.9)(15.9)

10.4 10.4 (14.3)(14.3)

9.9 9.9 (14.4)(14.4)

9.7 9.7 (14.5)(14.5)

P<0.0P<0.00101

Mean (SD)

Reviewing the article:Reviewing the article:The nitty-gritty about the The nitty-gritty about the statsstats Friedman test: non-Friedman test: non-

parametric test used parametric test used to detect differences to detect differences in treatments across in treatments across multiple test multiple test attempts; based on attempts; based on ranksranks

Friedman P values Friedman P values were based on the were based on the whole 3 month whole 3 month treatment period and treatment period and not specific to any 1 not specific to any 1 time point in the 3 time point in the 3 months months

Reviewing the article: Reviewing the article: The weaknesses of the statsThe weaknesses of the stats

Used mean (SD) and Used mean (SD) and perhaps should have perhaps should have used the median used the median due to skewed datadue to skewed data

Could have added Could have added strength to the strength to the study if they had study if they had included confidence included confidence intervalsintervals

No follow-up with No follow-up with pair-wise pair-wise comparisonscomparisons

Reviewing the article:Reviewing the article:Is this evidence valid?Is this evidence valid? Type of study: open label, non-randomized, Type of study: open label, non-randomized,

non-blinded clinical trial – Not gold non-blinded clinical trial – Not gold standardstandard

Population: correctly addresses childrenPopulation: correctly addresses children Representative sample of patients Representative sample of patients

assembled at a common point in symptoms? assembled at a common point in symptoms? – No– No

Patient follow-up sufficiently long and Patient follow-up sufficiently long and complete? – Yescomplete? – Yes

Assignment of patients randomized? – NoAssignment of patients randomized? – No All patients accounted for in the end? - YesAll patients accounted for in the end? - Yes

Reviewing the article:Reviewing the article:The weaknessesThe weaknesses Clearly not a randomized controlled Clearly not a randomized controlled

trialtrial Non-blindedNon-blinded Small and not demographically Small and not demographically

diverse populationdiverse population No control groupNo control group

Reviewing the article:Reviewing the article:Is this information Is this information important?important? Although the study is small and not Although the study is small and not

the gold standard randomized, the gold standard randomized, controlled blinded study, it definitely controlled blinded study, it definitely suggests that this may be a suggests that this may be a beneficial option for childrenbeneficial option for children

2/3 of the subjects in the study 2/3 of the subjects in the study reported reaching the desired reported reaching the desired endpoint of a >50% reduction of endpoint of a >50% reduction of symptoms at the end of therapysymptoms at the end of therapy

Application of the evidence:Application of the evidence:Risks for the therapyRisks for the therapy Melatonin has a low side effect profile but can include:Melatonin has a low side effect profile but can include:

Daytime sleepiness Daytime sleepiness Dizziness Dizziness Headaches Headaches Abdominal discomfort Abdominal discomfort Confusion Confusion Sleepwalking Sleepwalking NightmaresNightmares

Melatonin may interact with various medications, Melatonin may interact with various medications, including: including: anticoagulantsanticoagulants Immunosuppressant Immunosuppressant Diabetes medications Diabetes medications Birth control pillsBirth control pills

Possible complications of using melatonin long-term is Possible complications of using melatonin long-term is not knownnot known

OTC supplement not subject to quality assurance and OTC supplement not subject to quality assurance and may be variable in the ingredients, concentrations and may be variable in the ingredients, concentrations and quality of the productquality of the product

Applying the evidence:Applying the evidence:Availability, cost and easeAvailability, cost and ease Melatonin is available over the Melatonin is available over the

counter and all pharmacies, counter and all pharmacies, nutritional stores and various other nutritional stores and various other locationslocations

Cheap! ~$7-15 per bottle that could Cheap! ~$7-15 per bottle that could last up to 4 monthslast up to 4 months

Easily taken if you can swallow pillsEasily taken if you can swallow pills Best taken before bed to mimic the Best taken before bed to mimic the

natural release of melatoninnatural release of melatonin

How this applies to my How this applies to my patientpatient There is a good chance that the There is a good chance that the

melatonin she started taking did improve melatonin she started taking did improve her baseline headache symptomsher baseline headache symptoms

Concomitant use of amitriptyline did Concomitant use of amitriptyline did obscure the individualized effect of obscure the individualized effect of either medicationeither medication

Patient also benefited by much improved Patient also benefited by much improved sleep symptoms (initiation and sleep symptoms (initiation and maintenance)maintenance)

Knowing what I know Knowing what I know now...now... I would recommend this as a I would recommend this as a

potential therapy for my patients potential therapy for my patients with chronic headacheswith chronic headaches Relatively safeRelatively safe CheapCheap ““not a medicine”not a medicine”

Caution with long term useCaution with long term use Discourage use with any side effectsDiscourage use with any side effects

Where to go from here?Where to go from here?

Collective evidence in both adults and Collective evidence in both adults and children at this stage is growing and is all children at this stage is growing and is all suggestive of the benefits of melatoninsuggestive of the benefits of melatonin

Justifies the need for a RCT and research Justifies the need for a RCT and research into the long term use of the medicationinto the long term use of the medication

Funding may be an issue for future Funding may be an issue for future studiesstudies

Room for improvement in the analysis of Room for improvement in the analysis of the available datathe available data

ReferencesReferences Miano, S. et al. Melatonin to prevent Miano, S. et al. Melatonin to prevent

migraine or tension-type headache in migraine or tension-type headache in children. Neurological Science, 2008 (29) children. Neurological Science, 2008 (29) 285 – 287. 285 – 287.

Peres, M. Melatonin, the pineal gland and Peres, M. Melatonin, the pineal gland and their implications for headache disorders. their implications for headache disorders. Cephalalgia, 2005 (25) 403 – 411.Cephalalgia, 2005 (25) 403 – 411.

Peres et. al. Melatonin, 3 mg, is effective Peres et. al. Melatonin, 3 mg, is effective for migraine prevention. Neurology, 2004 for migraine prevention. Neurology, 2004 (63) 757.(63) 757.

Wasiewski, W. Preventive Therapy in Wasiewski, W. Preventive Therapy in Pediatric Migraine. Journal of Child Pediatric Migraine. Journal of Child Neurology, 2001 (16) 71 – 78. Neurology, 2001 (16) 71 – 78.

AcknowledgementsAcknowledgements

Dr Greg Petroski, StatisticianDr Greg Petroski, Statistician

Dr Timothy Fete, PreceptorDr Timothy Fete, Preceptor

Caryn Scoville, LibrarianCaryn Scoville, Librarian