Headache is a common presenting complaint to the general pediatrician. The estimated overall prevalence of any headache in children is 58%, with the prevalence of migraine being 8%.1 Shorter duration of migraine headache, bilateral rather than unilateral location, prominence of gastrointestinal symptoms, and difficulty articulating symptoms such as photophobia are more common in pediatric patients with migraine compared to adult migraine sufferers.2 Pediatric migraines pose a high burden to society, but significant relief in children is possible with appropriate intervention. We present an updated review on the current outpatient management strategies for pediatric migraine headaches as well as therapies in the pipeline.
The goal of migraine therapy in the pediatric population is quick resolution of the headache with minimal side effects, allowing the child to return to his or her normal activity level. Abortive over-the-counter medications are the first-line medications in the treatment of pediatric migraine headaches. Ibuprofen and, to a lesser degree, acetaminophen, has been found effective for acute migraine treatment in children and adolescents.3,4 In one double-blind, placebo-controlled, crossover study (n = 88), both ibuprofen (10 mg/kg) and acetaminophen (15 mg/kg) showed significant efficacy compared to placebo and a good safety profile, but ibuprofen had a better response at 2 hours and a longer duration of action.4 Acetaminophen can be used as a second-line treatment for those with hypersensitivity or a contraindication to nonsteroidal anti-inflammatory drugs.
Four of the seven triptan medications approved by the US Food and Drug Administration (FDA) for treatment of migraines in adults now have an indication in the pediatric population.5 Drugs that end in “triptan,” such as sumatriptan or rizatriptan, are often collectively referred to as triptans. These serotonin 5-hydroxytryptamine receptor 1B/D (5-HT1B/D) agonists are primarily used in moderate to severe headaches or after the failure of over-the-counter analgesics. Rizatriptan is approved for use in children as young as age 6 years.6 Almotriptan and a combination of sumatriptan and naproxen are oral formulations, and zolmitriptan is a nasal spray approved3 specifically for use in adolescents (Table 1).
Triptans for Acute Treatment of Pediatric Migraine
All of the approved medications have studies showing good tolerability and safety profile with some efficacy in the pediatric population, as presented in the recent systematic review of acute treatment therapies in pediatrics.3,6 Although not currently approved for pediatric use, sumatriptan nasal spray also has studies showing good efficacy and tolerability.3,7 In general, nasal spray formulations may be more effective in shorter-duration pediatric headaches due to faster onset of action, with bad taste as the main side effect. The early administration of any abortive medication is crucial for successful analgesia. Due to their vasoconstrictor properties, contraindications to use of triptans include basilar or hemiplegic migraine, Raynaud's disease, poorly controlled hypertension, and ischemic heart disease.
Patients should be counseled on prevention of medication overuse headache (MOH) and the need to discontinue all abortive analgesics for 4 weeks if MOH occurs. The use of any abortive analgesic, regardless of indication for use, should be limited to three treatments per week. One treatment can include ibuprofen or acetaminophen repeated in 4 to 6 hours or a triptan repeated in 2 hours as necessary after the initial dose.8
Children who suffer frequent or severe migraine attacks may require daily preventive therapy. This should include a multimodal treatment approach involving optimizing lifestyle factors, use of nonpharmacological or pharmacological agents, or a combination of these therapies.
Although no published guidelines exist for when to start migraine preventive therapy in children, recommendations for adults in the American Migraine Prevalence and Prevention Study included initiation in patients with ≥6 headache days per month or 3 to 4 headache days per month with at least a mild or moderate impairment.9 Offering preventive therapy for children would be appropriate at ≥4 headache days per month, failure or poor tolerance of abortive therapies, or a significant disability from less frequent headaches.8–10 It is important to inform families that a response may often take several weeks. Patients should be re-evaluated in approximately 8 weeks with a conversation about therapy adherence and lifestyle factors before considering any changes to that preventive therapy. Doses should be titrated slowly to minimize adverse effects.10 After a patient has achieved effective migraine control on a therapy, the timing of the medication wean is often guided by clinician experience and patient preference.
Migraine preventive medications include antiepileptic agents, antidepressants, antihypertensives, antihistamines, and nutraceuticals. In clinical pediatric practice, a variety of these agents are used based on adult data, clinician experience, or drug safety and efficacy in limited clinical pediatric trials without clear consensus (Table 2).9,10 A pediatric migraine meta-analysis from 2013 concluded that placebo was effective, topiramate had limited efficacy, and use of other commonly used drugs, such as divalproex sodium and propranolol, had limited support in the included studies.11
Preventive Therapy in Pediatric Migraine
Nutraceuticals include herbal therapies or vitamin supplementation. There has long been interest in such treatments among patients, parents, and clinicians. Magnesium oxide is one such widely used oral therapy. A pediatric double-blind, placebo-controlled study showed good efficacy in reducing migraine attacks with magnesium oxide (9 mg/kg per day) with side effects limited to diarrhea.12 One large, open-label, pediatric study showed some improvement in headache disability scores with coenzyme Q10 (CoQ10) supplementation for those with a CoQ10 deficiency.13 An open-label trial of butterbur root (Petasitus hybridus) showed ≥50% reduction in headache in 77% of pediatric patients.14 Butterbur is a known carcinogen and, therefore, unknown long-term effects and concern for hepatotoxicity for unpurified forms of the formulation create reservations about its use in the pediatric population. Riboflavin and feverfew also had some success in the adult migraine population.15 Nutraceuticals are readily available over-the-counter and usually relatively inexpensive. Uncertainty about dosing, purity of formulations on the market, efficacy, and safety are all areas requiring additional research.
Topiramate is the only FDA-approved migraine-preventive therapy for adolescents. It has been studied in the pediatric population in several open-label and placebo-controlled randomized trials with some indication of effect and a tolerable side-effect profile.16,17 A larger double-blind, placebo-controlled study in children age 6 to 15 years, showed equivocal results; there was a nonstatistically significant trend toward headache reduction.17 A subsequent smaller randomized, double-blind, placebo-controlled trial of adolescents age 12 to 17 years showed topiramate to be statistically more effective in headache reduction compared to placebo at doses of 100 mg/day but not at doses of 50 mg/day.18 A different study of neuropsychological profiles in children taking topiramate showed psychomotor slowing may be a potential adverse effect but learning and memory tend to remain unchanged.19
The recent Childhood and Adolescent Migraine Prevention (CHAMP) trial20 attempted to address the deficit of pediatric migraine studies by using a 24-week, large, multicenter, randomized, double-blind, placebo-controlled study comparing the effectiveness of two commonly used drugs—amitriptyline and topiramate, as well as placebo. Patients on active medication treatment were titrated to 1 mg/kg per day of amitriptyline and 2 mg/kg per day of topiramate. Level 1 evidence showed that more than one-half of children with migraines improved but there was no difference in efficacy between topiramate, amitriptyline, and placebo, although greater side effects were seen with active drug treatment. There was no significant difference in the efficacy between the prescription drugs and placebo (52% for amitriptyline group vs 55% for topiramate group vs 61% for placebo).20
Important considerations exist when comparing the results of the CHAMP trial versus the positive topiramate study by Lewis et al.18 Lewis et al.18 only included adolescents, whereas both adolescents and younger children were included in CHAMP, and younger children are potentially more susceptible to placebo effect. CHAMP studied patients with both episodic and chronic migraine whereas the study by Lewis et al.18 focused only on episodic migraine.20 The superior efficacy seen in the study by Lewis et al.18 bears the question of whether a treatment effect may still be present in adolescents despite the negative CHAMP study results, which included the younger age group.
Other antiepileptic agents have been used for pediatric migraine. Divalproex sodium is one widely used drug approved in adults but its effectiveness is equivocal in children.21 Some open-label and retrospective studies11,22 suggested efficacy. Conversely, in a randomized, multicenter, placebo-controlled study (n = 300), divalproex sodium extended-release did not differ from placebo as a preventive agent for pediatric migraine headaches, although the drug was generally well tolerated in adolescents.23 It should be titrated slowly to avoid side effects. Screening laboratory studies are necessary due to the risk of hepatotoxicity. Divalproex sodium remains a reasonable treatment option in boys but teratogenicity limits its use in adolescent girls, who make up the majority of adolescent migraine patients. Levetiracetam and zonisamide are two newer antiepileptic agents that have shown effectiveness in reducing headache intensity, frequency, or disability with good tolerability in small, open-label or retrospective pediatric studies.24,25
Amitriptyline, a tricyclic antidepressant used as a first-line therapy in adults, has relied heavily on adult studies with only some pediatric data.26 Cardiac abnormalities such as Q-T interval prolongation would be a contraindication. Comorbid depression would require close consideration given the black-box warning for increased suicidality in the pediatric population with use of antidepressants for the treatment of depression.
Beta-blockers, including propranolol and timolol, are approved in adults, but there are equivocal results in pediatric migraine.21 An open-label, smaller, and older study suggested efficacy,27 but follow-up pediatric studies have been less effective, and a recent meta-analysis did not find evidence supporting propranolol use as a migraine preventive agent in children.11 Hypotension, exercise intolerance, exacerbation of asthma, and depression are the side effects that limit its usefulness in children.
Cyproheptadine (0.2–0.4 mg/kg per day) is widely used in younger children because of its availability in liquid formulation, although data on efficacy is uncertain. Increased appetite and sedation are the most common side effects, so potential weight gain limits its utility in adolescence.8
Botulinum toxin intramuscular injection was approved for chronic migraine in adults and represents a potential treatment option for adolescents.8 Because it is an expensive therapy, cost remains a barrier.
The question arises as to what clinical therapies should be offered to pediatric migraine patients and how to proceed further with clinical research. The CHAMP study's high placebo response rate has been an issue in previous pediatric studies.20 Whereas the adult placebo response rate in migraine studies has been approximately 35%, previous studies in the pediatric migraine population have shown placebo rates up to 50% to 60% in both abortive and preventive therapies.6,11 Although the high placebo rate poses a challenge for the design of new protocols, it also carries therapeutic potential in clinical practice.
New Horizons in Pediatric Migraine
Recent developments in the understanding of the pathophysiology of migraine have led researchers to the neuropeptide calcitonin gene-related peptide (CGRP). CGRP is postulated to be released from trigeminal ganglion cells and mediate release of inflammatory substances, inducing neurogenic inflammation and vasodilation of blood vessels, which play an important role in genesis of migraine.28 Treatment of migraine with triptans is associated with normalizing of CGRP levels in serum.29 Botulinum toxin A, which has efficacy in reducing migraine attacks in chronic migraine sufferers, may inhibit release of CGRP from trigeminal sensory neurons.30 The recent development of monoclonal antibodies to CGRP may be a promising new therapy in migraine prophylaxis. Clinical trials for prevention of migraine using these large proteins in adults are underway.31 It has been found to be generally well tolerated and efficacious in preliminary studies in adults.32,33 It is hoped that studies in the pediatric population will be forthcoming in the near future.
Education about lifestyle factors is an important part of any headache management plan. Research has shown that psychological approaches, including cognitive-behavioral therapy and biofeedback, can be highly beneficial and remain effective for at least 1 year.34 Healthy lifestyle habits for migraine prevention include adequate hydration, proper sleep hygiene, eliminating caffeine, a healthy balanced diet, regular exercise, and keeping a headache diary to identify migraine triggers.
A randomized clinical trial of pediatric migraine patients evaluated the efficacy of cognitive-based therapy and amitriptyline (CBT+A) versus headache education and amitriptyline (HE+A). Results showed a statistically significant improvement in the CBT+A group as compared to the HE+A group in headache reduction (66% vs 36%) and Pediatric Migraine Disability Assessment scores.35 This trend was sustained at the 12-month follow-up. Notably, the authors commented that they do not know the effectiveness of CBT alone against medication as there was an ethical and recruitment concern at the time about using CBT alone in chronic migraine patients.35
A 2016 Cochrane review on adults with episodic migraine suggested acupuncture was effective compared to sham treatments and was at least as effective as preventive medications.36 Osteopathic manipulative therapy may represent another option based on some efficacy in adult headache patients,37 but larger and more rigorous research studies are needed.
Pediatric migraine remains a significant burden on children and families, but a comprehensive approach can provide relief to many patients. Ibuprofen is a safe and effective abortive therapy in children, and triptans now provide a needed acute therapy for moderate to severe headaches. A large evidence gap exists in pediatric preventive treatment options. Topiramate has become the first FDA-approved preventive migraine medication in the adolescent subpopulation;16,17 however, the well-designed CHAMP pediatric trial20 provided a negative result on the use of amitriptyline and topiramate versus placebo. Strong consideration should also be given to the potential therapeutic benefit of using psychological therapy as first-line or adjunctive therapy in pediatric migraine. Thus, the decision of which preventive strategy to use is still often guided by medication side-effect profile, best clinical judgment, and patient and parent preference for therapy.
- 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. 2010;52(12):1088–1097. doi:. doi:10.1111/j.1469-8749.2010.03793.x [CrossRef]
- Headache Classification Committee of the International Headache Society (IHS). The International Classification of Headache Disorders, 3rd edition (beta version). Cephalalgia. 2013;33(9):629–808. doi:. doi:10.1177/0333102413485658 [CrossRef]
- Patniyot IR, Gelfand AA. Acute treatment therapies for pediatric migraine: a qualitative systematic review. Headache. 2016;56(1):49–70. doi:. doi:10.1111/head.12746 [CrossRef]
- Hamalainen ML, 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. 1997;48(1):103–107. doi:10.1212/WNL.48.1.103 [CrossRef]
- Richer L, Billinghurst L, Lindsell MA, et al. Drugs for the acute treatment of migraine in children and adolescents. Cochrane Database Syst Rev. 2016;4:CD005220. doi:10.1002/14651858.CD005220.pub2 [CrossRef].
- Ho TW, Pearlman E, Lewis D, 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. 2012;32(10):750–765. doi:. doi:10.1177/0333102412451358 [CrossRef]
- Winner P, Rothner AD, Saper J, et al. A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents. Pediatrics. 2000;106(5):989–997. doi:10.1542/peds.106.5.989 [CrossRef]
- Kacperski J, Kabbouche MA, O'Brien HL, Weberding JL. The optimal management of headaches in children and adolescents. Ther Adv Neurol Disorder. 2016;9(1):53–68. doi:. doi:10.1177/1756285615616586 [CrossRef]
- Lipton RB, Bigal ME, Diamond M, et al. Migraine prevalence, disease burden, and the need for preventive therapy. Neurology. 2007;68(5):343–349. doi:. doi:10.1212/01.wnl.0000252808.97649.21 [CrossRef]
- Pakalnis A. Current therapies in childhood and adolescent migraine. J Child Neurol. 2007;22(11):1288–1292. doi:. doi:10.1177/0883073807307971 [CrossRef]
- El-Chammas K, Keyes J, Thompson N, Vijayakumar J, Becher D, Jackson JL. Pharmacologic treatment of pediatric headaches: a meta-analysis. JAMA Pediatr. 2013;167(3):250–258. doi:. doi:10.1001/jamapediatrics.2013.508 [CrossRef]
- Wang F, Van Den Eeden SK, Ackerson LM, Salk SE, Reince RH, Elin RJ. Oral magnesium oxide prophylaxis of frequent migrainous headache in children: a randomized, double-blind, placebo-controlled trial. Headache. 2003;43(6):601–610. doi:10.1046/j.1526-4610.2003.03102.x [CrossRef]
- Hershey AD, Powers SW, Vockell AL, et al. Coenzyme Q10 deficiency and response to supplementation in pediatric and adolescent migraine. Headache. 2007;47(1):73–80. doi:. doi:10.1111/j.1526-4610.2007.00652.x [CrossRef]
- Pothmann R, Danesch U. Migraine prevention in children and adolescents: results of an open study with a special butterbur root extract. Headache. 2005;45(3):196–203. doi:. doi:10.1111/j.1526-4610.2005.05044.x [CrossRef]
- Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: a randomized trial. Headache. 2004;44(9):885–901. doi:. doi:10.1111/j.1526-4610.2004.04170.x [CrossRef]
- Hershey AD, Powers SW, Vockell AL, et al. Effectiveness of topiramate in the prevention of childhood headaches. Headache. 2002;42:810–818. doi:10.1046/j.1526-4610.2002.02185.x [CrossRef]
- Winner P, Pearlman EM, Linder SL, Jordan DM, Fisher AC, Hulihan J. Topiramate for migraine prevention in children: a randomized, double-blind, placebo-controlled trial. Headache. 2005;45(10):1304–1312. doi:10.1111/j.1526-4610.2005.00262.x [CrossRef]
- Lewis D, Winner P, Saper J, et al. Randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of topiramate for migraine prevention in pediatric subjects 12 to 17 years of age. Pediatrics. 2009;123(3):924–934. doi:. doi:10.1542/peds.2008-0642 [CrossRef]
- Pandina GJ, Ness S, Polverejan E, et al. Cognitive effects of topiramate in migraine patients aged 12 through 17 years. Pediatr Neurol. 2010;42(3):187–195. doi:. doi:10.1016/j.pediatrneurol.2009.10.001 [CrossRef]
- Powers SW, Coffey CS, Chamberlin LA, et al. Trial of amitriptyline, topiramate, and placebo for pediatric migraine. N Engl J Med. 2017;376(2):115–124. doi:. doi:10.1056/NEJMoa1610384 [CrossRef]
- Ashrafi MR, Shabanian R, Zamani GR, Mahfelati F. Sodium valproate versus propranolol in paediatric migraine prophylaxis. Eur J Paediatr Neurol. 2005:9:333–338. doi:. doi:10.1016/j.ejpn.2005.05.004 [CrossRef]
- Pakalnis A, Greenberg G, Drake ME Jr, Paolicchi J. Pediatric migraine prophylaxis with divalproex. J Child Neurol. 2001;16:731–734. doi:. doi:10.1177/088307380101601005 [CrossRef]
- Apostol G, Cady RK, Laforet GA, et al. Divalproex extended-release in adolescent migraine prophylaxis: results of a randomized, double-blind, placebo-controlled study. Headache. 2008;48(7):1012–1025. doi:10.1111/j.1526-4610.2008.01081.x [CrossRef]
- Pakalnis A, Kring D, Meier L. Levetiracetam prophylaxis in pediatric migraine—an open-label study. Headache. 2007;47(3):427–430. doi:. doi:10.1111/j.1526-4610.2007.00728.x [CrossRef]
- Pakalnis A, Kring D. Zonisamide prophylaxis in refractory pediatric headache. Headache. 2006;46(5):804–807. doi:. doi:10.1111/j.1526-4610.2006.00455.x [CrossRef]
- Hershey AD, Powers SW, Bentti AL, Degrauw TJ. Effectiveness of amitriptyline in the prophylactic management of childhood headaches. Headache. 2000;40(7):539–549. doi:10.1046/j.1526-4610.2000.00085.x [CrossRef]
- Olness K, Macdonald JT, Uden DL. Comparison of self hypnosis and propranolol in the treatment of juvenile classic migraine. Pediatrics. 1987;79(4):593–597.
- Hay DL, Walker CS. CGRP and its receptors. Headache. 2017;57(4):625–636. doi:. doi:10.1111/head.13064 [CrossRef]
- Goadsby PJ, Edvinsson L. The trigeminovascular system and migraine: studies characterizing cerebrovascular and neuropeptide changes seen in humans and cats. Ann Neurol. 1993;33(1):48–56. doi:10.1002/ana.410330109 [CrossRef]
- Durham PL, Cady R, Cady R. Regulation of calcitonin gene-related peptide secretion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache. 2004;44(1):35–42; discussion 42–43. doi:. doi:10.1111/j.1526-4610.2004.04007.x [CrossRef]
- Tso AR, Goadsby PJ. Anti-CGRP monoclonal antibodies: the next era of migraine prevention?Curr Treat Options Neurol. 2017;19(8):27. doi:. doi:10.1007/s11940-017-0463-4 [CrossRef]
- Goadsby PJ, Reuter U, Hallstrom Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017:377(22):2123–2132. doi:. doi:10.1056/NEJMoa1705848 [CrossRef]
- Skljarevski V, Oakes TM, Zhang Q, et al. Effect of different doses of galcanezumab vs placebo for episodic migraine prevention: a randomized clinical trial. JAMA Neurol. 2017Dec. 18 [Epub ahead of print]. doi:10.1001/jamaneurol.2017.3859 [CrossRef].
- Trautmann E, Lackschewitz H, Kroner-Herwig B. Psychological treatment of recurrent headache in children and adolescents—a meta-analysis. Cephalalgia. 2006;26(12):1411–1426. doi:. doi:10.1111/j.1468-2982.2006.01226.x [CrossRef]
- Powers SW, Kashikar-Zuck SM, Allen JR, et al. Cognitive behavioral therapy plus amitriptyline for chronic migraine in children and adolescents: a randomized clinical trial. JAMA. 2013;310(24):2622–2630. doi:. doi:10.1001/jama.2013.282533 [CrossRef]
- Linde K, Allais G, Brinkhaus B, et al. Acupuncture for the prevention of episodic migraine. Cochrane Database Syst Rev. 2016(6):Cd001218. doi:10.1002/14651858.CD001218.pub3 [CrossRef].
- Nelson CF, Bronfort G, Evans R, et al. The efficacyof spinal manipulation, amitriptyline, and the combination of both therapies for the prohylaxis of migraine headache. J Manipulative Physiol Ther. 1998:21(8):511–519.
Triptans for Acute Treatment of Pediatric Migraine
||6.25 mg; 25 mg
||20 mg; 40 mg
||5 mg (20–39 kg); 10 mg (>40 kg)
||2.5 mg; 5mg
||25 mg; 50 mg; 100 mg
5 mg; 20 mg
0.06 mg/kg; 4 mg; 6 mg
| Sumatriptan and naproxen sodium concentration
||10/65 mg; 85/500 mg
Preventive Therapy in Pediatric Migraine
| Divalproex sodium
||Weight gain, hepatotoxicity, teratogenicity
||1–2 mg/kg/day; alternative dosing is 100 mg/day
||Paresthesias, weight loss, kidney stones
||Behavioral changes, irritability
||Behavioral changes, sedation
||Fatigue, depression, exercise intolerance, asthma exacerbation
|Calcium channel blocker
||Sedation, weight gain
||1 mg/kg/day divided twice daily
||Sedation, weight gain, cardiac effects (Q-T prolongation)
||Sedation, dry mouth, visual blurriness
||Sedation, weight gain
| Magnesium oxide
||9 mg/kg/day; alternative dosing is 400 mg/day
| Coenzyme Q10
||1–3 mg/kg/day; alternative dosing is 100 mg/day
||Gastrointestinal, anorexia, rash