Review Article | Published:

Paediatric migraine: evidence-based management and future directions

Nature Reviews Neurologyvolume 14pages515527 (2018) | Download Citation


Migraine is prevalent in children and adolescents and constitutes an important cause of disability in this population. Early, effective treatment of paediatric migraine is likely to result in improved outcomes. Findings from the past few years suggest that a biopsychosocial approach that uses interdisciplinary multimodal care is most effective for treatment of migraine in the paediatric population. Key elements of this management include effective and timely acute pharmacological interventions (such as NSAIDs and/or triptans), education of patients regarding self-management techniques, and psychological interventions such as biofeedback, relaxation and cognitive–behavioural therapy. The efficacy of current pharmacological or nutraceutical interventions for migraine prevention in children and adolescents is unclear, although reported placebo response patterns suggest that the effect of pill-taking behaviour is positive. As such, clinicians can consider adding a preventive intervention that involves a daily pill-taking behaviour to evidence-based non-pharmacological first-line preventive interventions (such as cognitive–behavioural therapy). More rigorous research is needed to delineate the role of pharmacological and nutraceutical interventions, the mechanisms of the clinically relevant placebo response, and interventions that enhance this response for migraine prevention in this population. Given the prevalence of migraine, cost-effective and efficacious strategies are needed for the large-scale delivery of interdisciplinary multimodal paediatric migraine care.

Key points

  • Paediatric migraine is very common, affecting ~8% of children and adolescents, and causes a substantial amount of disability in this population.

  • Establishment of a diagnosis and treatment of migraine early in the disease course can prevent disease progression.

  • The goals of paediatric migraine treatment are to reduce migraine-associated disability, improve pain-coping strategies, improve health-related quality of life and reduce the risk of migraine chronification.

  • Evidence-based paediatric migraine treatment involves consistently effective, appropriately dosed acute interventions and interdisciplinary multimodal preventive care, including self-management, lifestyle interventions and tailored psychological, pharmacological and/or complementary and alternative interventions.

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  1. 1.

    Stewart, W. F., Wood, C., Reed, M. L., Roy, J. & Lipton, R. B. Cumulative lifetime migraine incidence in women and men. Cephalalgia 28, 1170–1178 (2008).

  2. 2.

    Victor, T. W., Hu, X., Campbell, J. C., Buse, D. C. & Lipton, R. B. Migraine prevalence by age and sex in the United States: a life-span study. Cephalalgia 30, 1065–1072 (2010).

  3. 3.

    Bille, B. A. 40-year follow-up of school children with migraine. Cephalagia 17, 488–491 (1997).

  4. 4.

    Galinski, M. et al. Early diagnosis of migraine necessary in children: 10-year follow-up. Pediatr. Neurol. 53, 319–323 (2015).

  5. 5.

    Guidetti, V. & Galli, F. Evolution of headache in childhood and adolescence: an 8-year follow-up. Cephalalgia 18, 449–454 (1998).

  6. 6.

    Virtanen, R. et al. Changing headache from preschool age to puberty. A controlled study. Cephalalgia 27, 294–303 (2007).

  7. 7.

    Monastero, R., Camarda, C., Pipia, C. & Camarda, R. Prognosis of migraine headaches in adolescents: a 10-year follow-up study. Neurology 67, 1353–1357 (2006).

  8. 8.

    Dooley, J. M., Augustine, H. F., Brna, P. M. & Digby, A. M. The prognosis of pediatric headaches — a 30-year follow-up study. Pediatr. Neurol. 51, 85–87 (2014).

  9. 9.

    Charles, J. A. et al. Favorable outcome of early treatment of new onset child and adolescent migraine-implications for disease modification. J. Headache Pain 10, 227–233 (2009).

  10. 10.

    Kabbouche, M. A. et al. Outcome of a multidisciplinary approach to pediatric migraine at 1, 2, and 5 years. Headache 45, 1298–1303 (2005).

  11. 11.

    Powers, S. W. et al. Trial of amitriptyline, topiramate, and placebo for pediatric migraine. N. Engl. J. Med. 376, 115–124 (2017).

  12. 12.

    Kacperski, J. & Bazarsky, A. New developments in the prophylactic drug treatment of pediatric migraine: what is new in 2017 and where does it leave us? Curr. Pain Headache Rep. 21, 38 (2017).

  13. 13.

    Jackson, J. L. Pediatric migraine headache — still searching for effective treatments. N. Engl. J. Med. 376, 169–170 (2017).

  14. 14.

    Colloca, L. Treatment of pediatric migraine. N. Engl. J. Med. 376, 1386–1387 (2017).

  15. 15.

    Mauro, R. Treatment of pediatric migraine. N. Engl. J. Med. 376, 1386–1387 (2017).

  16. 16.

    Powers, S., Coffey, C. & Hershey, A. Treatment of pediatric migraine. N. Engl. J. Med. 376, 1386–1387 (2017).

  17. 17.

    Abu-Arafeh, I., Razak, S., Sivaraman, B. & Graham, C. Prevalence of headache and migraine in children and adolescents: a systematic review of population-based studies. Dev. Med. Child Neurol. 52, 1088–1097 (2010).

  18. 18.

    Doja, A. et al. Canadian Paediatric Neurology Workforce Survey and Consensus Statement. Can. J. Neurol. Sci. 43, 402–409 (2016).

  19. 19.

    Curless, R. G. Diagnostic problems in three pediatric neurology practice plans. Pediatr. Neurol. 19, 272–274 (1998).

  20. 20.

    Hsiao, H. J. et al. Headache in the pediatric emergency service: a medical center experience. Pediatr. Neonatol 55, 208–212 (2014).

  21. 21.

    Conicella, E. et al. The child with headache in a pediatric emergency department. Headache 48, 1005–1011 (2008).

  22. 22.

    Burton, L. J., Quinn, B., Pratt-Cheney, J. L. & Pourani, M. Headache etiology in a pediatric emergency department. Pediatr. Emerg. Care 13, 1–4 (1997).

  23. 23.

    Kan, L., Nagelberg, J. & Maytal, J. Headaches in a pediatric emergency department: etiology, imaging, and treatment. Headache 40, 25–29 (2000).

  24. 24.

    Lucado, J., Paez, K. & Elixhauser, A. Headaches in US hospitals and emergency departments, 2008: statistical brief #111 (Agency for Healthcare Research and Quality, 2011).

  25. 25.

    Lipton, R. B. & Bigal, M. E. Migraine: epidemiology, impact, and risk factors for progression. Headache 45, S3–S13 (2005).

  26. 26.

    Merikangas, K. R. Contributions of epidemiology to our understanding of migraine. Headache 53, 230–246 (2013).

  27. 27.

    Vos, T. et al. Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 1990-2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 380, 2163–2196 (2012).

  28. 28.

    Feigin, V. L. et al. Global, regional, and national burden of neurological disorders during 1990–2015: a systematic analysis for the Global Burden of Disease Study 2015. Lancet Neurol. 16, 877–897 (2017).

  29. 29.

    Powers, S. W., Patton, S. R., Hommel, K. A. & Hershey, A. D. Quality of life in childhood migraines: clinical impact and comparison to other chronic illnesses. Pediatrics 112, e1–e5 (2003).

  30. 30.

    Orr, S. L., Christie, S. N., Akiki, S. & McMillan, H. J. Disability, quality of life, and pain coping in pediatric migraine: an observational study. J. Child Neurol. 32, 717–724 (2017).

  31. 31.

    Hershey, A. D., Powers, S. W., Lecates, S., Kabbouche, M. A. & Maynard, M. K. PedMIDAS — development of a questionnaire to assess disability of migraines in children. Neurology 57, 2034–2039 (2001).

  32. 32.

    Hershey, A. et al. Development of a patient-based grading scale for PedMIDAS. Cephalalgia 24, 844–849 (2004).

  33. 33.

    Kröner-Herwig, B., Heinrich, M. & Vath, N. The assessment of disability in children and adolescents with headache: adopting PedMIDAS in an epidemiological study. Eur. J. Pain 14, 951–958 (2010).

  34. 34.

    Arruda, M. & Bigal, M. E. Migraine and migraine subtypes in preadolescent children: association with school performance. Neurology 79, 1881–1888 (2012).

  35. 35.

    Rocha-Filho, P. A. & Santos, P. V. Headaches, quality of life, and academic performance in schoolchildren and adolescents. Headache 54, 1194–1202 (2014).

  36. 36.

    Amouroux, R. & Rousseau-Salvador, C. [Anxiety and depression in children and adolescents with migraine: a review of the literature]. Encephale 34, 504–510 (2008).

  37. 37.

    Bruijn, J., Locher, H., Passchier, J., Dijkstra, N. & Arts, W.-F. Psychopathology in children and adolescents with migraine in clinical studies: a systematic review. Pediatrics 126, 323–332 (2010).

  38. 38.

    Balottin, U., Fusar Poli, P., Termine, C., Molteni, S. & Galli, F. Psychopathological symptoms in child and adolescent migraine and tension-type headache: a meta-analysis. Cephalalgia 33, 112–122 (2013).

  39. 39.

    Pinquart, M., Shen, Y. & Sych, P. Depressive symptoms in children and adolescents with chronic physical illness: an updated meta-analysis. J. Pediatr. Psychol. 36, 375–384 (2011).

  40. 40.

    Kemper, K. J., Heyer, G., Pakalnis, A. & Binkley, P. F. What factors contribute to headache-related disability in teens? Pediatr. Neurol. 56, 48–54 (2016).

  41. 41.

    Öztop, D. et al. Assessment of psychopathology and quality of life in children and adolescents with migraine. J. Child Neurol. 31, 837–842 (2016).

  42. 42.

    Vannatta, K. et al. Friendships and social interactions of school-aged children with migraine. Cephalalgia 28, 734–743 (2008).

  43. 43.

    Orr, S. L., Potter, B. K., Ma, J. & Colman, I. Migraine and mental health in a population-based sample of adolescents. Can. J. Neurol. Sci. 44, 44–50 (2017).

  44. 44.

    Gelfand, A. Psychiatric comorbidity and paediatric migraine. Curr. Opin. Neurol. 28, 261–264 (2015).

  45. 45.

    Qubty, W. & Gelfand, A. A. Psychological and behavioral issues in the management of migraine in children and adolescents. Curr. Pain Headache Rep. 20, 1–7 (2016).

  46. 46.

    Blaauw, B. A. et al. The relationship of anxiety, depression and behavioral problems with recurrent headache in late adolescence — a Young-HUNT follow-up study. J. Headache Pain 16, 1–7 (2015).

  47. 47.

    Pine, D. S., Cohen, P. & Brook, J. The association between major depression and headache: results of a longitudinal epidemiologic study in youth. J. Child Adolesc. Psychopharmacol. 6, 153–164 (1996).

  48. 48.

    Hernandez-Latorre, M. & Roig, M. Natural history of migraine in childhood. Cephalalgia 20, 573–579 (2000).

  49. 49.

    Brna, P., Dooley, J., Gordon, K. & Dewan, T. The prognosis of childhood headache: a 20-year follow-up. Arch. Pediatr. Adolesc. Med. 159, 1157–1160 (2005).

  50. 50.

    Kienbacher, C. et al. Clinical features, classification and prognosis of migraine and tension-type headache in children and adolescents: a long-term follow-up study. Cephalalgia 26, 820–830 (2006).

  51. 51.

    Headache Classification Committee of the International Headache Society. The International Classification of Headache Disorders, 3rd edition. Cephalalgia 38, 1–211 (2018).

  52. 52.

    Ashina, S., Olesen, J. & Lipton, R. B. How well does the ICHD 3 (beta) help in real-life migraine diagnosis and management? Curr. Pain Headache Rep. 20, 1–6 (2016).

  53. 53.

    Jensen, R. et al. A basic diagnostic headache diary (BDHD) is well accepted and useful in the diagnosis of headache. a multicentre European and Latin American study. Cephalalgia 31, 1549–1560 (2011).

  54. 54.

    Russell, M. et al. Presentation of a new instrument: the diagnostic headache diary. Cephalalgia 12, 369–374 (1992).

  55. 55.

    Kelley, S. A., Hartman, A. L. & Kossoff, E. H. Comorbidity of migraine in children presenting with epilepsy to a tertiary care center. Neurology 79, 468–473 (2012).

  56. 56.

    Toldo, I. et al. Comorbidity between headache and epilepsy in a pediatric headache center. J. Headache Pain 11, 235–240 (2010).

  57. 57.

    Wirrell, E. C. & Hamiwka, L. D. Do children with benign rolandic epilepsy have a higher prevalence of migraine than those with other partial epilepsies or nonepilepsy controls? Epilepsia 47, 1674–1681 (2006).

  58. 58.

    Stevenson, S. B. Epilepsy and migraine headache: is there a connection? J. Pediatr. Heal. Care 20, 167–171 (2006).

  59. 59.

    Yamane, L. E., Montenegro, M. A. & Guerreiro, M. M. Comorbidity headache and epilepsy in childhood. Neuropediatrics 35, 99–102 (2004).

  60. 60.

    Lateef, T. M., Cui, L., Nelson, K. B., Nakamura, E. F. & Merikangas, K. R. Physical comorbidity of migraine and other headaches in US adolescents. J. Pediatr. 161, 1–13 (2012).

  61. 61.

    Farello, G., Ferrara, P., Antenucci, A., Basti, C. & Verrotti, A. The link between obesity and migraine in childhood: a systematic review. Ital. J. Pediatr. 43, 1–7 (2017).

  62. 62.

    Shreberk-Hassidim, R. et al. Atopic dermatitis in israeli adolescents from 1998 to 2013: trends in time and association with migraine. Pediatr. Dermatol. 34, 247–252 (2017).

  63. 63.

    Eidlitz-Markus, T., Zolden, S., Haimi-Cohen, Y. & Zeharia, A. Comparison of comorbidities of migraine and tension headache in a pediatric headache clinic. Cephalalgia 37, 1135–1144 (2017).

  64. 64.

    Aupiais, C. et al. Association between migraine and atopic diseases in childhood: a potential protective role of anti-allergic drugs. Headache 57, 612–624 (2017).

  65. 65.

    Ozge, A. et al. Atopic disorders are more common in childhood migraine and correlated headache phenotype. Pediatr. Int. 56, 868–872 (2014).

  66. 66.

    Lateef, T. M. et al. Headache in a national sample of american children: prevalence and comorbidity. J. Child Neurol. 24, 536–543 (2009).

  67. 67.

    Angriman, M., Cortese, S. & Bruni, O. Somatic and neuropsychiatric comorbidities in pediatric restless legs syndrome: a systematic review of the literature. Sleep Med. Rev. 34, 34–45 (2017).

  68. 68.

    Valrie, C. R., Bromberg, M. H., Palermo, T. & Schanberg, L. E. A systematic review of sleep in pediatric pain populations. J. Dev. Behav. Pediatr. 34, 120–128 (2013).

  69. 69.

    Arruda, M. A., Arruda, R., Guidetti, V. & Bigal, M. E. ADHD Is comorbid to migraine in childhood: a population-based study. J. Atten. Disord. (2017).

  70. 70.

    Jameson, N. D. et al. Medical comorbidity of attention-deficit/hyperactivity disorder in US adolescents. J. Child Neurol. 31, 1282–1289 (2016).

  71. 71.

    Wagner, J. L., Wilson, D. A., Smith, G., Malek, A. & Selassie, A. W. Neurodevelopmental and mental health comorbidities in children and adolescents with epilepsy and migraine: a response to identified research gaps. Dev. Med. Child Neurol. 57, 45–52 (2015).

  72. 72.

    Machnes-Maayan, D. et al. Screening for psychiatric comorbidity in children with recurrent headache or recurrent abdominal pain. Pediatr. Neurol. 50, 49–56 (2014).

  73. 73.

    Pavone, P. et al. Primary headaches in children: clinical findings on the association with other conditions. Int. J. Immunopathol. Pharmacol. 25, 1083–1091 (2012).

  74. 74.

    Rousseau-Salvador, C. et al. Anxiety, depression and school absenteeism in youth with chronic or episodic headache. Pain Res. Manag. 19, 235–240 (2014).

  75. 75.

    Ghosh, D. et al. Headache in children with Tourette syndrome. J. Pediatr. 161, 303–307.e6 (2012).

  76. 76.

    Kwak, C., Vuong, K. & Jankovic, J. MIgraine headache in patients with tourette syndrome. Arch. Neurol. 60, 1595–1598 (2003).

  77. 77.

    Wang, S.-J., Fuh, J.-L., Juang, K.-D. & Lu, S.-R. Migraine and suicidal ideation in adolescents aged 13 to 15 years. Neurology 73, 1713–1714 (2009).

  78. 78.

    Powers, S. W. et al. Cognitive behavioral therapy plus amitriptyline for chronic migraine in children and adolescents: a randomized clinical trial. JAMA 310, 2622–2630 (2013).

  79. 79.

    Stewart, W. F. et al. Longitudinal change in migraine headache-days and indirect cost consequences. J. Occup. Env. Med. 53, 478–487 (2011).

  80. 80.

    Stewart, W. F. et al. Employment and work impact of chronic migraine and episodic migraine. J. Occup. Env. Med. 52, 8–14 (2010).

  81. 81.

    Burton, W. N., Landy, S. H., Downs, K. E. & Runken, M. C. The impact of migraine and the effect of migraine treatment on workplace productivity in the United States and suggestions for future research. Mayo Clin. Proc. 84, 436–445 (2009).

  82. 82.

    Eccleston, C. et al. Psychological therapies for the management of chronic and recurrent pain in children and adolescents (review). Cochrane Database Syst. Rev. 5, 1–79 (2014).

  83. 83.

    Leroux, E. et al. A nursing intervention increases quality of life and self-efficacy in migraine: a 1-year prospective controlled trial. Headache (2017).

  84. 84.

    Probyn, K. et al. Prognostic factors for chronic headache: a systematic review. Neurology 89, 291–301 (2017).

  85. 85.

    Hershey, A. D. et al. Obesity in the pediatric headache population: a multicenter study. Headache 49, 170–177 (2009).

  86. 86.

    Lu, S.-R. et al. Incidence and risk factors of chronic daily headache in young adolescents: a school cohort study. Pediatrics 132, e9–e16 (2013).

  87. 87.

    Scher, A. I., Stewart, W. F., Ricci, J. A. & Lipton, R. B. Factors associated with the onset and remission of chronic daily headache in a population-based study. Pain 106, 81–89 (2003).

  88. 88.

    Bigal, M. E., Liberman, J. N. & Lipton, R. B. Obesity and migraine: a population study. Neurology 66, 545–550 (2006).

  89. 89.

    Bigal, M. E. et al. Body Mass Index and Episodic Headaches. Arch. Intern. Med. 167, 1964–1970 (2007).

  90. 90.

    Bigal, M. & Lipton, R. Obesity is a risk factor for transformed migraine but not chronic tension-type headache. Neurology 67, 252–257 (2006).

  91. 91.

    Wang, S. J., Fuh, J. L., Lu, S. R. & Juang, K. D. Outcomes and predictors of chronic daily headache in adolescents: a 2-year longitudinal study. Neurology 68, 591–596 (2007).

  92. 92.

    Louter, M. A. et al. Cutaneous allodynia as a predictor of migraine chronification. Brain 136, 3489–3496 (2013).

  93. 93.

    Ashina, S. et al. Depression and risk of transformation of episodic to chronic migraine. J. Headache Pain 13, 615–624 (2012).

  94. 94.

    Bigal, M. E. et al. Acute migraine medications and evolution from episodic to chronic migraine: a longitudinal population-based study. Headache 48, 1157–1168 (2008).

  95. 95.

    Lipton, R. B. et al. Ineffective acute treatment of episodic migraine is associated with new-onset chronic migraine. Neurology 84, 688–695 (2015).

  96. 96.

    Katsarava, Z. et al. Incidence and predictors for chronicity of headache in patients with episodic migraine. Neurology 62, 788–790 (2004).

  97. 97.

    Zwart, J. A. et al. Analgesic use: A predictor of chronic pain and medication overuse headache. Neurology 61, 160–164 (2003).

  98. 98.

    Scher, A. I., Lipton, R. B., Stewart, W. F. & Bigal, M. Patterns of medication use by chronic and episodic headache sufferers in the general population: Results from the frequent headache epidemiology study. Cephalalgia 30, 321–328 (2010).

  99. 99.

    Scher, A. I., Rizzoli, P. B. & Loder, E. W. Medication overuse headache: An entrenched idea in need of scrutiny. Neurology 89, 1296–1304 (2017).

  100. 100.

    Hershey, A. D., Burdine, D., Kabbouche, M. A. & Powers, S. W. Genomic expression patterns in medication overuse headaches. Cephalalgia 31, 161–171 (2011).

  101. 101.

    Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edn (beta version). Cephalalgia 33, 629–808 (2013).

  102. 102.

    Foley, K. A. et al. Treating early versus treating mild: timing of migraine prescription medications among patients with diagnosed migraine. Headache 45, 538–545 (2005).

  103. 103.

    Ferrari, A., Stefani, M., Sternieri, S., Bertolotti, M. & Sternieri, E. Analgesic drug taking: beliefs and behavior among headache patients. Headache 37, 88–94 (1997).

  104. 104.

    Lantéri-Minet, M., Mick, G. & Allaf, B. Early dosing and efficacy of triptans in acute migraine treatment: the TEMPO study. Cephalalgia 32, 226–235 (2012).

  105. 105.

    Cady, R. K. et al. Allodynia-associated symptoms, pain intensity and time to treatment: Predicting treatment response in acute migraine intervention. Headache 49, 350–363 (2009).

  106. 106.

    Goadsby, P. J. et al. Early versus non-early intervention in acute migraine — ‘Act when Mild (AwM)’. a double-blind, placebo-controlled trial of almotriptan. Cephalalgia 28, 383–391 (2008).

  107. 107.

    Cady, R. K. et al. Treatment of mild headache in disabled migraine sufferers: results of the spectrum study. Headache 40, 792–797 (2000).

  108. 108.

    Halpern, M. T. et al. Costs and outcomes of early versus delayed migraine treatment with sumatriptan. Headache 42, 984–999 (2002).

  109. 109.

    Hershey, A., Powers, S., Winner, P. & Kabbouche, M. Pediatric Headaches in Clinical Practice. (John Wiley & Sons, Ltd, 2009).

  110. 110.

    Hamalainen, M. L., Hoppu, K., Valkeila, E. & Santavuori, P. Ibuprofen or acetaminophen for the acute treatment of migraine in children: a double-blind, randomized, placebo-controlled, crossover study. Neurology 48, 103–107 (1997).

  111. 111.

    Lewis, D. W. et al. Children’s ibuprofen suspension for the acute treatment of pediatric migraine. Headache 42, 780–786 (2002).

  112. 112.

    Evers, S. et al. Treatment of childhood migraine attacks with oral zolmitriptan and ibuprofen. Neurology 67, 497–499 (2006).

  113. 113.

    Hodkinson, D. J. et al. Cerebral analgesic response to nonsteroidal anti-inflammatory drug ibuprofen. Pain 156, 1301–1310 (2015).

  114. 114.

    Richer, L. et al. Drugs for the acute treatment of migraine in children and adolescents. Cochrane Database Syst. Rev. 1, 1–154 (2016).

  115. 115.

    Derosier, F. J. et al. The efficacy and safety of a combination product containing sumatriptan and naproxen sodium for the acute treatment of migraine in adolescents. Ann. Neurol. 70 (S15), S166 (2011).

  116. 116.

    McDonald, S. A. et al. Long-term evaluation of sumatriptan and naproxen sodium for the acute treatment of migraine in adolescents. Headache 51, 1374–1387 (2011).

  117. 117.

    Winner, P., Linder, S. & Hershey, A. D. Consistency of response to sumatriptan/naproxen sodium in a randomized placebo-controlled, cross-over study for the acute treatment of migraine in adolescence. Headache 55, 519–528 (2015).

  118. 118.

    Goadsby, P. J. et al. Pathophysiology of migraine: a disorder of sensory processing. Physiol. Rev. 97, 553–622 (2017).

  119. 119.

    Ho, T. W. et al. Efficacy and tolerability of rizatriptan in pediatric migraineurs: results from a randomized, double-blind, placebo-controlled trial using a novel adaptive enrichment design. Cephalalgia 32, 750–765 (2012).

  120. 120.

    Hamalainen, M., Jones, M., Loftus, J. & Saiers, J. Sumatriptan nasal spray for migraine — a review of studies in patients aged 17 years and younger. Int. J. Clin. Pr. 56, 704–709 (2002).

  121. 121.

    Ueberall, M. & Wenzel, D. Intranasal sumatriptan for the acute treatment of migraine in children. Neurology 52, 1507–1510 (1999).

  122. 122.

    Ahonen, K., Hämäläinen, M. L., Rantala, H. & Hoppu, K. Nasal sumatriptan is effective in treatment of migraine attacks in children: A randomized trial. Neurology 62, 883–887 (2004).

  123. 123.

    Callenbach, P. M. C. et al. Sumatriptan nasal spray in the acute treatment of migraine in adolescents and children. Eur. J. Paediatr. Neurol. 11, 325–330 (2007).

  124. 124.

    Fujita, M., Sato, K., Nishioka, H. & Sakai, F. Oral sumatriptan for migraine in children and adolescents: a randomized, multicenter, placebo-controlled, parallel group study. Cephalalgia 34, 365–375 (2013).

  125. 125.

    Hämäläinen, M. L., Hoppu, K. & Santavuori, P. Sumatriptan for migraine attacks in children: a randomized placebo-controlled study. Do children with migraine respond to oral sumatriptan differently from adults? Neurology 48, 1100–1103 (1997).

  126. 126.

    Rothner, A. & Asgharnejad, M. Tolerability of sumatriptan tablets in the acute treatment of migraine in adolescent patients: a review of data from clinical trials. Eur. J. Neurol. 6, 106 (1999).

  127. 127.

    Winner, P. et al. A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents. Pediatrics 106, 989–997 (2000).

  128. 128.

    Winner, P., Rothner, A. D., Wooten, J. D., Webster, C. & Ames, M. Sumatriptan nasal spray in adolescent migraineurs: a randomized, double-blind, placebo-controlled, acute study. Headache 46, 212–222 (2006).

  129. 129.

    Winner, P., Prensky, A., Linder, S. & DeBussey, S. Adolescent migraine: efficacy and safety of sumatriptan tablets. J. Neurol. Sci. 150, S172 (1997).

  130. 130.

    Ahonen, K., Hämäläinen, M. L., Eerola, M. & Hoppu, K. A randomized trial of rizatriptan in migraine attacks in children. Neurology 67, 1135–1140 (2006).

  131. 131.

    Winner, P. et al. Rizatriptan 5 mg for the acute treatment of migraine in adolescents: a randomized, double-blind, placebo-controlled study. Headache 42, 49–55 (2002).

  132. 132.

    Visser, W. H. et al. Rizatriptan 5 mg for the acute treatment of migraine in adolescents: results from a double-blind, single-attack study and two open-label, multiple-attack studies. Headache 44, 891–899 (2004).

  133. 133.

    Winner, P. et al. Eletriptan for the acute treatment of migraine in adolescents: results of a double-blind, placebo-controlled trial. Headache 47, 511–518 (2007).

  134. 134.

    Linder, S. L. et al. Efficacy and tolerability of almotriptan in adolescents — a randomized, double-blind, placebo-controlled trial. Headache 48, 1326–1336 (2008).

  135. 135.

    Rothner, A., Edwards, K., Kerr, L., DeBussey, S. & Asgharnejad, M. Efficacy and safety of naratriptan tablets in adolescent migraine. J. Neurol. Sci. 150, S106 (1997).

  136. 136.

    Lewis, D. W., Winner, P., Hershey, A. D. & Wasiewski, W. W. Efficacy of zolmitriptan nasal spray in adolescent migraine. Pediatrics 120, 390–396 (2007).

  137. 137.

    Rothner, A. D., Wasiewski, W., Winner, P., Lewis, D. & Stankowski, J. Zolmitriptan oral tablet in migraine treatment: high placebo responses in adolescents. Headache 46, 101–109 (2006).

  138. 138.

    Winner, P. et al. Efficacy and tolerability of zolmitriptan nasal spray for the treatment of acute migraine in adolescents: results of a randomized, double-blind, multi-center, parallel-group study (TEENZ). Headache 56, 1107–1119 (2016).

  139. 139.

    Smith, T. R. et al. Sumatriptan and naproxen sodium for the acute treatment of migraine. Headache 45, 983–991 (2005).

  140. 140.

    Brandes, J. L. et al. Sumatriptan-naproxen for acute treatment of migraine. JAMA 297, 1443–1454 (2007).

  141. 141.

    Blumenfeld, A., Gennings, C. & Cady, R. Pharmacological synergy: the next frontier on therapeutic advancement for migraine. Headache 52, 636–647 (2012).

  142. 142.

    Solotareff, L., Cuvellier, J.-C., Duhamel, A., Vallée, L. & Nguyen The Tich, S. Trigger factors in childhood migraine: a prospective clinic-based study from north of france. J. Child Neurol. 32, 754–758 (2017).

  143. 143.

    Neut, D., Fily, A., Cuvellier, J. C. & Vallee, L. The prevalence of triggers in paediatric migraine: a questionnaire study in 102 children and adolescents. J. Headache Pain 13, 61–65 (2012).

  144. 144.

    Hoffmann, J. & Recober, A. Migraine and triggers: post hoc ergo propter hoc? Curr. Pain Headache Rep. 17, 1–11 (2013).

  145. 145.

    Peris, F., Donoghue, S., Torres, F., Mian, A. & Wöber, C. Towards improved migraine management: determining potential trigger factors in individual patients. Cephalalgia 37, 452–463 (2017).

  146. 146.

    Robberstad, L. et al. An unfavorable lifestyle and recurrent headaches among adolescents: the HUNT study. Neurology 75, 712–717 (2010).

  147. 147.

    Milde-Busch, A. et al. Associations of diet and lifestyle with headache in high-school students: results from a cross-sectional study. Headache 50, 1104–1114 (2010).

  148. 148.

    Bektas, O. et al. Relationship of childhood headaches with preferences in leisure time activities, depression, anxiety and eating habits: a population-based, cross-sectional study. Cephalalgia 35, 527–537 (2014).

  149. 149.

    Woldeamanuel, Y. W. & Cowan, R. P. The impact of regular lifestyle behavior in migraine: a prevalence case–referent study. J. Neurol. 263, 669–676 (2016).

  150. 150.

    Spigt, M., Weerkamp, N., Troost, J., van Schayck, C. P. & Knottnerus, J. A. A randomized trial on the effects of regular water intake in patients with recurrent headaches. Fam. Pract. 29, 370–375 (2012).

  151. 151.

    Verrotti, A. et al. Impact of a weight loss program on migraine in obese adolescents. Eur. J. Neurol. 20, 394–397 (2013).

  152. 152.

    Varkey, E., Cider, A., Carlsson, J. & Linde, M. Exercise as migraine prophylaxis: a randomized study using relaxation and topiramate as controls. Cephalalgia 31, 1428–1438 (2011).

  153. 153.

    Santiago, M. D. et al. Amitriptyline and aerobic exercise or amitriptyline alone in the treatment of chronic migraine: a randomized comparative study. Arq. Neuropsiquiatr. 72, 851–855 (2014).

  154. 154.

    Ødegård, S. S. et al. The long-term effect of insomnia on primary headaches: a prospective population-based cohort study (HUNT-2 and HUNT-3). Headache 51, 570–580 (2011).

  155. 155.

    Heyer, G. L., Rose, S. C., Merison, K., Perkins, S. Q. & Lee, J. E. M. Specific headache factors predict sleep disturbances among youth with migraine. Pediatr. Neurol. 51, 489–493 (2014).

  156. 156.

    Miller, V. A., Palermo, T. M., Powers, S. W., Scher, M. S. & Hershey, A. D. Migraine headaches and sleep disturbances in children. Headache 43, 362–368 (2003).

  157. 157.

    Bruni, O., Galli, F. & Guidetti, V. Sleep hygiene and migraine in children and adolescents. Cephalalgia 19, 57–59 (1999).

  158. 158.

    Markey, P. M. et al. Adherence to biobehavioral recommendations in pediatric migraine as measured by electronic monitoring — the adherence in migraine (AIM) study. Headache 56, 1137–1146 (2016).

  159. 159.

    AAP Section on Integrative Medicine. Mind-body therapies in children and youth. Pediatrics 138, e20161896 (2016).

  160. 160.

    Agoston, A. M. & Sieberg, C. B. Nonpharmacologic treatment of pain. Semin. Pediatr. Neurol. 23, 220–223 (2016).

  161. 161.

    Harris, P., Loveman, E., Clegg, A., Easton, S. & Berry, N. Systematic review of cognitive behavioural therapy for the management of headaches and migraines in adults. Br. J. Pain 9, 213–224 (2015).

  162. 162.

    Ng, Q. X., Venkatanarayanan, N. & Kumar, L. A systematic review and meta-analysis of the efficacy of cognitive behavioral therapy for the management of pediatric migraine. Headache 57, 349–362 (2017).

  163. 163.

    Kroon Van Diest, A. M. et al. Treatment adherence in child and adolescent chronic migraine patients. Clin. J. Pain 33, 892–898 (2017).

  164. 164.

    Stubberud, A., Varkey, E., McCrory, D. C., Pedersen, S. A. & Linde, M. Biofeedback as prophylaxis for pediatric migraine: a meta-analysis. Pediatrics 138, 1–13 (2016).

  165. 165.

    Ernst, M., O’Brien, H. & Powers, S. Cognitive-behavioral therapy: how medical providers can increase patient and family openness and access to evidence-based multimodal therapy for pediatric migraine. Headache 55, 1382–1396 (2015).

  166. 166.

    Fisher, E., Law, E., Palermo, T. M. & Eccleston, C. Psychological therapies (remotely delivered) for the management of chronic and recurrent pain in children and adolescents. Cochrane Database Syst. Rev. 23, 1–48 (2015).

  167. 167.

    Interagency Pain Research Coordinating Committee. National pain strategy. National Institutes of Health (2016).

  168. 168.

    Interagency Pain Research Coordinating Committee. Federal pain research strategy. National Institutes of Health (2017).

  169. 169.

    Lai, L. L., Koh, L., Ho, J. A.-C., Ting, A. & Obi, A. Off-label prescribing for children with migraines in US ambulatory care settings. J. Manag. Care Spec. Pharm. 23, 382–387 (2017).

  170. 170.

    El-Chammas, K. et al. A comparative effectiveness meta-analysis of drugs for the prophylaxis of pediatric migraine headache. JAMA Pediatr. 167, 250–258 (2013).

  171. 171.

    Shamliyan, T., Kane, R., Ramakrishnan, R. & Taylor, F. Migraine in children: preventive pharmacologic treatments. Rockv. Agency Healthc. Res. Qual. 28, 1225–1237 (2013).

  172. 172.

    Le, K., Yu, D., Wang, J., Ali, A. I. & Guo, Y. Is topiramate effective for migraine prevention in patients less than 18 years of age? A meta-analysis of randomized controlled trials. J. Headache Pain 18, 69 (2017).

  173. 173.

    Evers, S., Marziniak, M., Frese, A. & Gralow, I. Placebo efficacy in childhood and adolescence migraine: An analysis of double-blind and placebo-controlled studies. Cephalalgia 29, 436–444 (2009).

  174. 174.

    Faria, V., Linnman, C., Lebel, A. & Borsook, D. Harnessing the placebo effect in pediatric migraine clinic. J. Pediatr. 165, 659–665 (2014).

  175. 175.

    Holroyd, K. A. et al. Effect of preventive (beta blocker) treatment, behavioural migraine management, or their combination on outcomes of optimised acute treatment in frequent migraine: randomised controlled trial. BMJ 341, c4871 (2010).

  176. 176.

    Holroyd, K. et al. Enhancing the effectiveness of relaxation-thermal biofeedback training with propranolol hydrochloride. J. Consult. Clin. Psychol. 63, 327–330 (1995).

  177. 177.

    Cormier, S., Lavigne, G. L., Choiniere, M. & Rainville, P. Expectations predict chronic pain treatment outcomes. Pain 157, 329–338 (2016).

  178. 178.

    Linde, K. et al. The impact of patient expectations on outcomes in four randomized controlled trials of acupuncture in patients with chronic pain. Pain 128, 264–271 (2007).

  179. 179.

    Pollo, A. et al. Response expectancies in placebo analgesia and their clinical relevance. Pain 93, 77–84 (2001).

  180. 180.

    Witt, C. M., Martins, F., Willich, S. N. & Schützler, L. Can I help you? Physicians’ expectations as predictor for treatment outcome. Eur. J. Pain 16, 1455–1466 (2012).

  181. 181.

    Galer, B. S., Schwartz, L. & Turner, J.a. Do patient and physician expectations predict response to pain-relieving procedures? Clin. J. Pain 13, 348–351 (1997).

  182. 182.

    Gracely, R. H., Dubner, R., Deeter, W. R. & Wolskee, P. J. Clinicians’ expectations influence placebo analgesia. Lancet 325, 43 (1985).

  183. 183.

    Kalra, E. K. Nutraceutical-definition and introduction. AAPS PharmSci 5, E25 (2003).

  184. 184.

    Dalla Libera, D., Colombo, B., Pavan, G. & Comi, G. Complementary and alternative medicine (CAM) use in an Italian cohort of pediatric headache patients: the tip of the iceberg. Neurol. Sci. 35, 145–148 (2014).

  185. 185.

    Bethell, C., Kemper, K. J., Gombojav, N. & Koch, T. K. Complementary and conventional medicine use among youth with recurrent headaches. Pediatrics 132, e1173–e1183 (2013).

  186. 186.

    Orr, S. L. & Venkateswaran, S. Nutraceuticals in the prophylaxis of pediatric migraine: evidence-based review and recommendations. Cephalalgia 34, 568–583 (2014).

  187. 187.

    Orr, S. L. Diet and nutraceutical interventions for headache management: a review of the evidence. Cephalalgia 0, 1–22 (2015).

  188. 188.

    Tepper, S. J. Nutraceutical and other modalities for the treatment of headache. Continuum (NY) 21, 1018–1031 (2015).

  189. 189.

    Pringsheim, T. et al. Canadian Headache Society guideline for migraine prophylaxis. Can. J. Neurol. Sci. 39, 1–62 (2012).

  190. 190.

    Holland, S. et al. Evidence-based guideline update: NSAIDs and other complementary treatments for episodic migraine prevention in adults: report of the Quality Standards Subcommittee of the American Academy of Neurology and the American Headache Society. Neurology 78, 1346–1353 (2012).

  191. 191.

    Prieto, J. M. Update on the efficacy and safety of Petadolex®, a butterbur extract for migraine prophylaxis. Bot. Targets Ther. 4, 1–9 (2014).

  192. 192.

    Snyder, F. J., Dundas, M. L., Kirkpatrick, C. & Neill, K. S. Use and safety perceptions regarding herbal supplements: a study of older persons in southeast Idaho. J. Nutr. Elder. 28, 81–95 (2009).

  193. 193.

    Wrobel Goldberg, S. & Silberstein, S. D. Targeting CGRP: a new era for migraine treatment. CNS Drugs 29, 443–452 (2015).

  194. 194.

    Deen, M. et al. Blocking CGRP in migraine patients — a review of pros and cons. J. Headache Pain 18, 96 (2017).

  195. 195.

    Pellesi, L., Guerzoni, S. & Pini, L. A. Spotlight on anti-CGRP monoclonal antibodies in migraine: the clinical evidence to date. Clin. Pharmacol. Drug Dev. 6, 534–547 (2017).

  196. 196.

    Tso, A. R. & Goadsby, P. J. Anti-CGRP monoclonal antibodies: the next era of migraine prevention? Curr. Treat. Opt. Neurol. 19, 27 (2017).

  197. 197.

    Goadsby, P. J. et al. A Controlled trial of erenumab for episodic migraine. N. Engl. J. Med. 377, 2123–2132 (2017).

  198. 198.

    Silberstein, S. D. et al. Fremanezumab for the preventive treatment of chronic migraine. N. Engl. J. Med. 377, 2113–2122 (2017).

  199. 199.

    Skljarevski, V. et al. Effect of different doses of galcanezumab versus placebo for episodic migraine prevention: a randomized controlled. JAMA Neurol. 75, 187–193 (2017).

  200. 200.

    Kroner, J. W. et al. Cognitive behavioral therapy plus amitriptyline for children and adolescents with chronic migraine reduces headache days to ≤4 Per month. Headache 56, 711–716 (2016).

  201. 201.

    Kroner, J. W. et al. Trajectory of improvement in children and adolescents with chronic migraine: results from the cognitive-behavioral therapy and amitriptyline trial. J. Pain 18, 637–644 (2017).

  202. 202.

    O’Brien, H. L. & Cohen, J. M. Young adults with headaches: The transition from adolescents to adults. Headache 55, 1404–1409 (2015).

  203. 203.

    Brown, L. W. et al. The neurologist’s role in supporting transition to adult health care: A consensus statement. Neurology 87, 835–840 (2016).

  204. 204.

    Orr, S. L. et al. The non-inferiority margins in migraine research (NIMM) survey. Headache 57, 729–736 (2017).

  205. 205.

    Wellek, S. & Blettner, M. On the proper use of the crossover design in clinical trials. Dtsch. Arztebl Int. 109, 276–281 (2012).

  206. 206.

    Almirall, D., Nahum-Shani, I., Sherwood, N. E. & Murphy, S. A. Introduction to SMART designs for the development of adaptive interventions: with application to weight loss research. Transl Beh Med. 4, 260–274 (2014).

  207. 207.

    Lei, H., Nahum-Shani, I., Lynch, K., Oslin, D. & Murphy, S. A. A ‘SMART’ Design for Building Individualized Treatment Sequences. Annu. Rev. Clin. Psychol. 8, 21–48 (2012).

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Nature Reviews Neurology thanks A. Verotti, P. Parisi and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    • Serena L. Orr
    • , Marielle A. Kabbouche
    • , Hope L. O’Brien
    • , Joanne Kacperski
    •  & Andrew D. Hershey
  2. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    • Marielle A. Kabbouche
    • , Hope L. O’Brien
    • , Joanne Kacperski
    • , Scott W. Powers
    •  & Andrew D. Hershey
  3. Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    • Scott W. Powers


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S.L.O. wrote the article. S.L.O., S.W.P. and A.D.H. researched data for the article. All authors contributed substantially to discussion of content and review of the manuscript before submission.

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The authors declare no competing interests.

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Correspondence to Serena L. Orr.

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