The role of melatonin in pediatric headaches


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The role of melatonin in pediatric headaches

  1. 1. Evidence Based Medicine Series: The role of melatonin in pediatric headaches Sarah Lallaman 3 rd Year Pediatric Resident
  2. 2. Patient Presentation <ul><li>16 year old female with complicated past medical history presents for evaluation of long standing headaches </li></ul><ul><ul><li>Her past medical history is not pertinent to the headaches and all seems to be stable or improved </li></ul></ul><ul><ul><li>Reports daily headaches – tension like in nature, non-disabling, 3-5/10 </li></ul></ul><ul><ul><li>Occurring over the last year </li></ul></ul>
  3. 3. Patient Presentation <ul><li>Has tried intermittent use of acetaminophen and NSAIDS with improvement, but frequent use is a concern </li></ul><ul><li>Intensity and frequency not increasing </li></ul><ul><li>No new symptoms associated with the headache </li></ul><ul><li>ROS: + only for difficulty initiating and maintaining sleep </li></ul>
  4. 4. Patient management <ul><li>Patient interested in starting medication trial </li></ul><ul><li>Patient was started on amitriptyline 10mg qhs </li></ul><ul><ul><li>Intention to treat headaches and assist with sleep </li></ul></ul><ul><li>Scheduled for a 3 month follow-up and encouraged to keep a headache diary </li></ul>
  5. 5. Patient Follow-up <ul><li>3 month follow-up </li></ul><ul><ul><li>Good patient compliance with amitriptyline – no side-effects, no missed doses </li></ul></ul><ul><ul><li>Mom also started patient on melatonin OTC </li></ul></ul><ul><ul><li>Headaches are nearly resolved – 4 in the last 3 months (3 in the first month after appt) </li></ul></ul><ul><ul><li>Mom wants to know if it the melatonin could have helped as well? </li></ul></ul>
  6. 6. Background Information: The pineal gland <ul><li>Melatonin is the main secretory product of the pineal gland </li></ul><ul><li>Pineal gland is located behind the third ventricle in the center of the brain </li></ul>
  7. 7. Background Information: Melatonin <ul><li>Melatonin is synthesized from the amino acid tryptophan through an intermediate of serotonin </li></ul><ul><li>Considered both a hormone and a vitamin. Both produced naturally and can be ingested in diet as well </li></ul><ul><li>Current indications include: sleeping disorders, circadian rhythm disorders, insomnia, Alzheimer's disease and as an adjuvant therapy in cancer treatment </li></ul>
  8. 8. Background Information: Melatonin <ul><li>Building evidence that dysregulation of endogenous melatonin synthesis may be associated with processes including depression, fibromyalgia, chronic fatigue and headaches, particularly migraines </li></ul><ul><li>First investigated in migraines in 1989 and has since been studied in the role of migraine, cluster and hypnic headaches with positive results </li></ul>
  9. 9. Properties of melatonin <ul><li>Anti-inflammatory effect </li></ul><ul><li>Free radical scavenger </li></ul><ul><li>Inhibition of dopamine release </li></ul><ul><li>Similar to structure of indomethacin </li></ul><ul><li>GABA potentiation </li></ul><ul><li>Opioid analgesia </li></ul><ul><li>Serotonin modulation </li></ul>
  10. 10. Clinical Question: <ul><li>Does Melatonin have a role in treating chronic headaches in the pediatric population? </li></ul><ul><ul><li>P: Pediatric population with chronic headaches (migraine or otherwise) </li></ul></ul><ul><ul><li>I: Melatonin </li></ul></ul><ul><ul><li>C: Continued care with routine headache therapy </li></ul></ul><ul><ul><li>O: Improvement in baseline intensity, frequency or duration of headaches </li></ul></ul>
  11. 11. Literature Search: Pub Med <ul><li>Key Word: Headache (MeSH = Headache) </li></ul><ul><ul><li>51315 results </li></ul></ul><ul><li>Key Word: Melatonin (MeSH = melatonin) </li></ul><ul><ul><li>15788 results </li></ul></ul><ul><li>Combined Headache and Melatonin </li></ul><ul><ul><li>98 results </li></ul></ul><ul><li>Limits of clinical trials, meta-analysis, RCT and children 0-18 years of age (MeSH = Infant, child, adolescent) and English language </li></ul><ul><ul><li>4 results – 1 applicable study </li></ul></ul>
  12. 12. Other literature searches <ul><li>Dynamed – no results for melatonin with headaches </li></ul><ul><li>Related searches on PubMed (melatonin in children etc.) </li></ul><ul><li>Reverse search from references </li></ul><ul><li>Online sources including eMedicine, UpToDate </li></ul>
  13. 13. Selected Article <ul><li>“ Melatonin to prevent migraine or tension-type headache in children” </li></ul><ul><ul><li>Miano, S. et al. Melatonin to prevent migraine or tension-type headache in children. Neurological Science, 2008 (29) 285 – 287. </li></ul></ul><ul><ul><li>Directly applied to population I wanted to address </li></ul></ul><ul><ul><li>Used melatonin as I would use in my population </li></ul></ul><ul><ul><li>Addressed headaches in children </li></ul></ul><ul><ul><li>The only article available to do so </li></ul></ul><ul><li>Drawbacks from the start </li></ul><ul><ul><li>Small study </li></ul></ul><ul><ul><li>Not randomized, blinded or control based study </li></ul></ul>
  14. 14. Reviewing the article: The Patients <ul><li>Outpatients from the Paediatric Headache Centre of the S. Andrea Hospital, Rome </li></ul><ul><li>22 consecutive patients over a 4 month acquisition period in 2006 </li></ul><ul><ul><li>Demographics: Caucasian, middle socioeconomic status, all from same urban area </li></ul></ul><ul><ul><li>Age range 6-16 years of age: mean age 12.2 years </li></ul></ul><ul><ul><li>10 boys and 12 girls </li></ul></ul>
  15. 15. Reviewing the article: The Headaches <ul><li>Headache Types </li></ul><ul><ul><li>13 had recurrent migraine without aura </li></ul></ul><ul><ul><li>1 with recurrent migraine with aura </li></ul></ul><ul><ul><li>8 with chronic tension-type headache </li></ul></ul><ul><li>Duration of headaches was 40.05 +/- 30.2 months in the whole sample </li></ul><ul><li>Diagnosed according to the International Headache Society diagnostic criteria </li></ul>
  16. 16. Reviewing the article: Exclusions for the study <ul><li>Patients were excluded from the study if: </li></ul><ul><ul><li>Received preventive therapy for headaches in the previous 3 months </li></ul></ul><ul><ul><li>Had any sleep problems or sleep/wake rhythm disorders </li></ul></ul><ul><ul><li>None of the patients were obese, had serious physical, neurological or psychiatric disorders </li></ul></ul><ul><ul><li>All causes for secondary headaches were excluded as necessary </li></ul></ul>
  17. 17. Reviewing the article: The study design <ul><li>Open label, non-blinded clinical trial </li></ul><ul><li>Study lasted 4 months </li></ul><ul><ul><li>1 month for baseline with no therapy </li></ul></ul><ul><ul><li>3 subsequent months with therapy (3mg pure melatonin PO qhs) </li></ul></ul><ul><ul><li>Parents filled out a structured daily headache diary </li></ul></ul><ul><ul><li>3 follow-up appointments </li></ul></ul><ul><ul><li>Primary end-point of the study was a >50% reduction in headache symptoms </li></ul></ul>
  18. 18. Reviewing the article: The data <ul><li>22 enrolled, 21 patients completed study </li></ul><ul><ul><li>1 migraine without aura stopped therapy due to excessive daytime sleepiness </li></ul></ul><ul><li>The number of children who had “severe attacks” improved from 17 at baseline to 6 at the end of the 3 month trial </li></ul><ul><li>14 of the 21 report that attacks had decreased by more than 50% compared to their baseline </li></ul>
  19. 19. Reviewing the article: The data Mean (SD) P<0.001 9.7 (14.5) 9.9 (14.4) 10.4 (14.3) 13.5 (15.9) Duration of attacks (h) P<0.001 5.7 (6.7) 6.9 (7.1) 8.7 (7.5) 12.3 (8.9) Frequency of attacks / month Friedman test 3 month follow-up 2 month follow-up 1 month follow-up Baseline
  20. 20. Reviewing the article: The nitty-gritty about the stats <ul><li>Friedman test: non-parametric test used to detect differences in treatments across multiple test attempts; based on ranks </li></ul><ul><li>Friedman P values were based on the whole 3 month treatment period and not specific to any 1 time point in the 3 months </li></ul>
  21. 21. Reviewing the article: The weaknesses of the stats <ul><li>Used mean (SD) and perhaps should have used the median due to skewed data </li></ul><ul><li>Could have added strength to the study if they had included confidence intervals </li></ul><ul><li>No follow-up with pair-wise comparisons </li></ul>
  22. 22. Reviewing the article: Is this evidence valid? <ul><li>Type of study: open label, non-randomized, non-blinded clinical trial – Not gold standard </li></ul><ul><li>Population: correctly addresses children </li></ul><ul><li>Representative sample of patients assembled at a common point in symptoms? – No </li></ul><ul><li>Patient follow-up sufficiently long and complete? – Yes </li></ul><ul><li>Assignment of patients randomized? – No </li></ul><ul><li>All patients accounted for in the end? - Yes </li></ul>
  23. 23. Reviewing the article: The weaknesses <ul><li>Clearly not a randomized controlled trial </li></ul><ul><li>Non-blinded </li></ul><ul><li>Small and not demographically diverse population </li></ul><ul><li>No control group </li></ul>
  24. 24. Reviewing the article: Is this information important? <ul><li>Although the study is small and not the gold standard randomized, controlled blinded study, it definitely suggests that this may be a beneficial option for children </li></ul><ul><li>2/3 of the subjects in the study reported reaching the desired endpoint of a >50% reduction of symptoms at the end of therapy </li></ul>
  25. 25. Application of the evidence: Risks for the therapy <ul><li>Melatonin has a low side effect profile but can include: </li></ul><ul><ul><li>Daytime sleepiness </li></ul></ul><ul><ul><li>Dizziness </li></ul></ul><ul><ul><li>Headaches </li></ul></ul><ul><ul><li>Abdominal discomfort </li></ul></ul><ul><ul><li>Confusion </li></ul></ul><ul><ul><li>Sleepwalking </li></ul></ul><ul><ul><li>Nightmares </li></ul></ul><ul><li>Melatonin may interact with various medications, including: </li></ul><ul><ul><li>anticoagulants </li></ul></ul><ul><ul><li>Immunosuppressant </li></ul></ul><ul><ul><li>Diabetes medications </li></ul></ul><ul><ul><li>Birth control pills </li></ul></ul><ul><li>Possible complications of using melatonin long-term is not known </li></ul><ul><li>OTC supplement not subject to quality assurance and may be variable in the ingredients, concentrations and quality of the product </li></ul>
  26. 26. Applying the evidence: Availability, cost and ease <ul><li>Melatonin is available over the counter and all pharmacies, nutritional stores and various other locations </li></ul><ul><li>Cheap! ~$7-15 per bottle that could last up to 4 months </li></ul><ul><li>Easily taken if you can swallow pills </li></ul><ul><li>Best taken before bed to mimic the natural release of melatonin </li></ul>
  27. 27. How this applies to my patient <ul><li>There is a good chance that the melatonin she started taking did improve her baseline headache symptoms </li></ul><ul><li>Concomitant use of amitriptyline did obscure the individualized effect of either medication </li></ul><ul><li>Patient also benefited by much improved sleep symptoms (initiation and maintenance) </li></ul>
  28. 28. Knowing what I know now... <ul><li>I would recommend this as a potential therapy for my patients with chronic headaches </li></ul><ul><ul><li>Relatively safe </li></ul></ul><ul><ul><li>Cheap </li></ul></ul><ul><ul><li>“not a medicine” </li></ul></ul><ul><li>Caution with long term use </li></ul><ul><li>Discourage use with any side effects </li></ul>
  29. 29. Where to go from here? <ul><li>Collective evidence in both adults and children at this stage is growing and is all suggestive of the benefits of melatonin </li></ul><ul><li>Justifies the need for a RCT and research into the long term use of the medication </li></ul><ul><li>Funding may be an issue for future studies </li></ul><ul><li>Room for improvement in the analysis of the available data </li></ul>
  30. 30. References <ul><li>Miano, S. et al. Melatonin to prevent migraine or tension-type headache in children. Neurological Science, 2008 (29) 285 – 287. </li></ul><ul><li>Peres, M. Melatonin, the pineal gland and their implications for headache disorders. Cephalalgia, 2005 (25) 403 – 411. </li></ul><ul><li>Peres et. al. Melatonin, 3 mg, is effective for migraine prevention. Neurology, 2004 (63) 757. </li></ul><ul><li>Wasiewski, W. Preventive Therapy in Pediatric Migraine. Journal of Child Neurology, 2001 (16) 71 – 78. </li></ul>
  31. 31. Acknowledgements <ul><li>Dr Greg Petroski, Statistician </li></ul><ul><li>Dr Timothy Fete, Preceptor </li></ul><ul><li>Caryn Scoville, Librarian </li></ul>