Pediatric Annals

CME Article 

Treatment of Pediatric and Adolescent Migraine

Andrew D. Hershey, MD, PhD, FAHS; Marielle A. Kabbouche, MD; Scott W. Powers, PhD, FAHS

Abstract

When headaches become disabling by interfering with a patient’s and family’s life because of severity, associated symptoms, frequency, duration, or unresponsiveness to treatment, a multidisciplinary approach is needed to improve the outcome. The treatment approach needs to be integrated with the history, comorbid conditions, lifestyle, and diagnosis of the patient. The approach needs to include acute treatment, both outpatient and inpatient when needed; preventive treatment when the headaches are frequent; and biobehavioral treatment to affect the lifestyle and adherence patterns. All three of these components should be addressed at the initial evaluation and re-addressed as the headaches evolve with developmental growth.

Abstract

When headaches become disabling by interfering with a patient’s and family’s life because of severity, associated symptoms, frequency, duration, or unresponsiveness to treatment, a multidisciplinary approach is needed to improve the outcome. The treatment approach needs to be integrated with the history, comorbid conditions, lifestyle, and diagnosis of the patient. The approach needs to include acute treatment, both outpatient and inpatient when needed; preventive treatment when the headaches are frequent; and biobehavioral treatment to affect the lifestyle and adherence patterns. All three of these components should be addressed at the initial evaluation and re-addressed as the headaches evolve with developmental growth.

Andrew D. Hershey, MD, PhD, FAHS, is with Department of Pediatrics, University of Cincinnati, College of Medicine and Division of Neurology, Cincinnati Children’s Hospital Medical Center. Marielle A. Kabbouche, MD, is with Department of Pediatrics, University of Cincinnati, College of Medicine, and Division of Neurology, Cincinnati Children’s Hospital Medical Center. Scott W. Powers, PhD, FAHS, is with Department of Pediatrics, University of Cincinnati, College of Medicine, and Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center.

Dr. Hershey and Dr. Powers have disclosed no relevant financial relationships.. Dr. Kabbouche has disclosed the following relevant financial relationships: Allergan: Consultant.

Address correspondence to: Andrew D. Hershey, MD, PhD, Director, Headache Center, Division of Neurology, MLC #2015, 3333 Burnet Ave., Cincinnati, OH 45229-3039; or fax 513-535-1888.

When headaches become disabling by interfering with a patient’s and family’s life because of severity, associated symptoms, frequency, duration, or unresponsiveness to treatment, a multidisciplinary approach is needed to improve the outcome. The treatment approach needs to be integrated with the history, comorbid conditions, lifestyle, and diagnosis of the patient. The approach needs to include acute treatment, both outpatient and inpatient when needed; preventive treatment when the headaches are frequent; and biobehavioral treatment to affect the lifestyle and adherence patterns. All three of these components should be addressed at the initial evaluation and re-addressed as the headaches evolve with developmental growth.

Acute Treatment of Migraine in Children and Adolescents

Once the diagnosis of primary headache and migraine has been established, the decision on treating individual attacks should be made. The choice of therapy should be individualized with the goal of fast relief, no recurrence, no side effects, and return to normal activity.

The U.S. Headache Consortium1 identified the following goals for successful treatment of acute migraine:

  • Treat attacks rapidly and consistently, and without recurrence;
  • Restore the patient’s ability to function;
  • Minimize the use of back-up and rescue medications;
  • Optimize self-care and reduce subsequent use of resources;
  • Cost-effective for overall management; and
  • Have minimal or no side effects.

This article focuses on outpatient management of acute headache in children and adolescents.

There is a lack of scientific resources reviewing available therapies for acute use in this age group. Double-blind, placebo-controlled studies are very limited, but multiple options are clinically available and effective in clinical setting. Some of the treatments reviewed in this chapter are not approved by the Food and Drug Administration (FDA) for use in children, but off-label use can be tailored toward the individual child (see Table 1, page 418).

Options for Acute Treatment of Pediatric Migraine

Table 1. Options for Acute Treatment of Pediatric Migraine

NSAIDs (Nonsteroidal Anti-Inflammatory Drugs)

Ibuprofen has been shown to be effective and safe for acute treatment of headaches in children. Multiple, double-blinded, placebo-controlled studies have been carried out.2–4 One study compared ibuprofen, acetaminophen, and placebo. Ibuprofen and acetaminophen were more effective than placebo in pain relief. Ibuprofen had a 53% response (headache improvement), compared with 51% with acetaminophen. The difference was not statistically significant. Considering at headache relief, ibuprofen was more effective then acetaminophen (60% compared with 39%) at 2 hours.

It is recommended to use acute therapy at onset of the headache. Ibuprofen at a dose of 10 mg/kg/dose can be initiated at onset of the aura, if present, even before headache starts. Initial dose may be repeated once in 3 to 4 hours for the same headache, if needed. The use of analgesics should not exceed treatment of three headaches per week to prevent transformation into an analgesic overuse headache.

5-HT1 Receptor Agonists: The Triptans

Most of the available triptans with the exception of almotriptan, are not FDA approved for use in children and adolescents. The lack of approval is mostly because of the difficulty in designing an appropriate study that can analyze the high placebo response in children and still show efficacy. Almotriptan was just recently approved for use in primary headache in children and adolescents due to a good tolerability and safety profile.

Multiple class I studies have demonstrated efficacy and safety of sumatriptan nasal spray in adolescents.5–7 Results revealed an 85% response at 2 hours, with improvement of nausea and phonophobia. Fifty-one percent headache relief at 2 hours was also seen in children 8 to 17 years, compared with a 31% placebo response.

The available triptans in the United States are:

  • Sumatriptan: Nasal spray, tablet, subcutaneous, combination tablet: sumatriptan/naproxen
  • Zolmitriptan: Nasal spray, tablet and melt
  • Rizatriptan: tablet and melt form
  • Almotriptan: tablet
  • Naratriptan: tablet
  • Frovatriptan: tablet

All triptans are very close in their safety profile. They should be avoided or very carefully prescribed in the presence of underlying coronary artery disease, uncontrolled hypertension, and basilar-type or hemiplegic migraine. Chest tightness, asthenia, jaw tightness, and other minor side effects have been described and are self-limited. Children usually tolerate the triptans well.

The triptans can be used in a stratified protocol as a rescue medication, if patients fail NSAIDs, or as initial therapy alone or in combination with an NSAIDs at the onset of the headache. Triptans cannot be used at the onset of the aura where their vasoconstrictive effect is not beneficial. Their use is limited to four to six headaches per month. All triptans also have a prompt onset of action as well as short half life, except for frovatriptan and naratriptan, the latter having a slower onset as well as longer half life. The triptan should not be combined with any ergot medications (eg, dihydroergotamine). A 24-hour window should be considered between use of these two classes of medicines.

All abortive migraine medications have the potential risk of analgesic rebound, now classified as analgesic overuse headache. Children with migraine are at higher risk for this complication. Migraine abortive therapies should be limited to a maximum of three headaches per week.

When the acute headache is not relieved by the outpatient regimen and lasts more than 72 hours, more aggressive therapies should be initiated for this specific attack. Multiple protocols are available, but again, the literature lacks good scientific double-blinded, placebo-controlled studies. The following are some of the available treatment for acute treatments of an intractable attack.

• Antidopaminergic Drugs

Prochlorperazine and metoclopramide are two antiemetics that have shown efficacy in acute migraine treatment in the emergency room setting. Prochlorperazine has been shown to be effective in aborting an acute migraine attack when given intravenously in the Emergency Department, with 75% improvement of headache and 50% with headache freedom in 1 hour. The effectiveness at 2 hours was 95% for headache improvement and 60% for headache freedom.8 When compared with metochlopramide and placebo in a class I study, the response to prochlorperazine was 82% compared with 42% to metochlopramide and 29% for placebo.9,10

These medications can be used in combination with fluid hydration as well as an intravenous NSAIDs, such as ketorolac. They are usually well tolerated. Extrapyramidal symptoms are more frequent in this age group but can be treated with 25 to 50 mg of diphenhydramine if present.

• NSAIDs: Ketorolac

Ketorolac is often used in the emergency department as monotherapy or in combination with other therapies for acute management of migraine attack.10–12 The response to ketorolac in monotherapy is 55% improvement of headache pain. When used in combination with prochlorperazine the response increased to 93%.

• Other

Other acute therapies for intractable acute headache are clinically used, including sodium valproate.13,14 The mechanism by which it works in aborting attacks is not well understood. It is used as an intravenous bolus 15 to 20 mg/kg rapid infusion over 5 to 10 minutes. It is well tolerated and is used for patients who failed the above treatments or cannot tolerate them.

Inpatient Treatment

Six to seven percent of migraine patients will not improve in the emergency department and will need to be admitted to an inpatient bed for more aggressive therapies, especially if their headache is still disabling. Dihydroergotamine (DHE) is the treatment with the most literature available for inpatient treatment. DHE is used as a vasoconstrictive acute therapy repetitively every 8 hours until headache relief or a maximum of 15 mg is reached. DHE has been shown to be 97% effective in headache improvement and 77% in headache relief in a small retrospective study.15

Double-blind, controlled studies (Class 1) for acute treatment of pediatric headache are not widely available. This should not translate into a lack of clinical therapies available to use for children and adolescents with headache and migraine. Appropriate and aggressive treatment of these headaches at an early age may prevent further evolution to chronic intractable disabling headache in adulthood.

Preventive Treatment of Migraine in Children and Adolescents

Often, headaches in children and adolescents become more frequent (more than once a week) or disabling (PedMIDAS score above 30 — Grade III or IV) and require intervention (see Table 2). When headaches start to interfere with a child’s life, preventive treatment should be considered. This should not only help lessen the effect to the child and family, but may also reduce the risk of disease progression. No medications are currently approved by the Food and Drug Administration (FDA) for the prevention of pediatric migraine; however, in Europe, flunarizine has been approved.

PedMIDAS Grading Scale

Table 2. PedMIDAS Grading Scale

The goal of preventive treatment is to reduce the headache frequency (to less than 1 to 2 per month), with decreased disability (PedMIDAS < 10) for a sustained period of time (4 to 6 months). To do this, the full involvement of the child and parent are required. When there are comorbid conditions, the preventive medication should be adjusted to benefit the treatment of both conditions or, at least, not to exacerbate the other condition. Guidelines have been developed to address the medications and evidence for their effectiveness with much more work required.16

Pharmaceutical and neutriceutical agents have been studied for pediatric migraine prevention (see Table 3, page 420). These compounds include antidepressant medications, such as amitriptyline,17 antihypertensive medications, such as propranolol,18–20 antihistamine/antiserotonergic medications, such as cyproheptadine,21 and antiepileptic medications, such as valproic acid22 and topiramate,23 while nutriceuticals are only beginning to be studied in children.

Options for Preventive Agents for Pediatric Migraine

Table 3. Options for Preventive Agents for Pediatric Migraine

Antidepressant Medications

The tricyclic antidepressants were first used for headache prevention in the 1970s, with amitriptyline being the best studied.24 As early as 1982, it began to be used in children.25 Frequently, however, the dose was not standardized. One open-label study suggested that the most effective dose was 1 mg/kg.26

Antihypertensive Medications

Beta-blockers and calcium channel blockers have been used for migraine prevention in children. The only approved medication for the prevention of migraine in children (in Europe) is the calcium channel blocker flunarizine, with several older studies identifying its effectiveness.27–29 In a double-blind, placebo-controlled crossover study, the baseline headache frequency was reduced in the flunarizine-treated patients, compared with placebo.29

Beta-blockers have long been used for prevention of childhood headaches, with propranolol being the most commonly used.18,20 The studies have varied in their findings; in the practice parameter that reviewed preventive migraine medication in children and adolescents, propranolol was found to have mixed effectiveness.16 The induction of exercise-induced asthma and depressive effects are the biggest limitations in using these medications in children.

Antiserotonergic Medications

Cyproheptadine, an antihistamine with antiserotonergic effects that also may have some calcium antagonistic properties, has long been used for the prevention of childhood headaches. Dosage studies have not been performed, but it appears to be effective in a dosage range of 0.2 to 0.4 mg/kg/day. In addition, it appears to be comparable with amitriptyline and propranolol.21

Antiepileptic Medications

Recently, the antiepileptic medications have been the most studied medications for migraine prophylaxis in adults and children. This has included randomized, placebo-controlled studies of topiramate and divalproex sodium, as well as several open-labeled studies.

A pilot, double-blind, randomized, placebo-controlled study of topiramate in 162 children (6 to 15 years) found a reduction of 2.6 migraine days per month for topiramate, compared with 2.0 for placebo (P = 0.061) with significantly more children treated with topiramate having a > 75% reduction in headache frequency compared with placebo (32% vs. 14%, P = 0.02).23 A double-blind, placebo-controlled study of 44 children who were more representative of children with migraine seen in headache clinics found a reduction from 16.14 ± 9.35 days per month to 4.27 ± 1.95 days per month in children receiving up to 100 mg per day of topiramate in divided doses compared with placebo response of 13.38 ± 7.78 to 7.48 ± 5.94 days per month, with a corresponding improvement in PedMIDAS score and school absences.31 The 100-mg dose divided into two equal doses in a randomized, double-blind, placebo-controlled study of 103 adolescents (12 to 17 years) was similarly found to be more effective than placebo (median headache frequency reduction in the last 12 weeks of treatment of 72.2% versus 44.4%).32

Divalproate has also been shown to be well tolerated, with significant reduction in headache frequency in open-label study.33,34

A study comparing 28 patients treated with topiramate and 20 patients treated with valproic acid, found both medications to be effective in decreasing in frequency, severity, duration, and PedMIDAS score at a similar rate.35

Nutriceuticals

Nutriceuticals may also be effective in preventing pediatric headaches. CoEnzyme Q10 appears to be deficient in a significant number of children and adolescents with frequent headaches, while supplementation was associated with improvement in headache frequency in this open-label clinic observation study.36 Other possible agents include butterbur — with 77% of children having a 50% or greater reduction in headache frequency in an open-label study37 — riboflavin, and magnesium.

From these limited, controlled studies in pediatrics and adolescents, it appears that agents used in adults are also effective in children. Key decisions to start prophylactic agents need to be guided by the frequency and effect as measured by disability and quality of life. In addition, defined endpoints for measuring the effectiveness of the response and the duration of the treatment need to be addressed. Many of these issues in pediatric migraine remain understudied, including these duration factors and comparative analysis of the various pharmacological and neutriceutical compounds.

Biobehavioral Treatment of Migraine in Children and Adolescents

Pediatric headache care is biobe-havioral care.38–41 Every aspect of migraine evaluation and management has a biobehavioral component, including establishing rapport with patients and families experiencing a notable pain condition, conducting developmentally-sound assessments, providing understandable and adherence-promoting intervention plans, and applying empirically-supported biobehavioral treatments as central features of an individually tailored care plan.42,43 As such, this brief summary of biobehavioral treatment and the reviews of the pharmacological acute and preventive treatments presented in this report are meant to be integrated into a comprehensive approach to care. This interdisciplinary-informed approach is critical for maximizing the success of therapy for migraines in children and adolescents (as well as adults).44

Often, children and adolescents with migraine upon presentation for treatment have been experiencing pain for awhile and may have encountered situations in which they doubted that their pain was understood by adults and/or truly believed. This creates a clear need for effective clinical skills when first evaluating a patient (and family) for migraine. That first encounter can set the stage for what will be optimal care, or it can render a well-conceived intervention plan less effective than it could otherwise be. It is important to obtain the information needed to make a diagnosis and develop a management plan while also accomplishing the goals of establishing strong rapport. It is important to listening directly to the young patient, expressing a sincere belief in their pain experience, and expressing confidence that, together, you and they will find a plan that works to decrease the frequency of their headaches and increases their overall quality of life. It is also a time to engage in a contract with the child or adolescent that to effectively help them with their migraines, you will need them to be active in doing the things that will be important to make measurable progress in headache frequency and quality of life. Clarity and understanding of the plan and your respective roles in ensuring success is a key outcome of the evaluation and management planning process, and a key hallmark of biobehavioral care.39,40,45

Assessment of children and adolescents for migraine needs to involve interview, patient-report, and family-report approaches that are tailored to the pediatric age group.42,43 Features of migraines that research has shown to be relevant in youth need to be understood by medical care givers when evaluating, diagnosing, and treating pediatric migraine.46 Headache diary and pain assessment tools that have been validated in pediatrics should be used, as should disability and quality of life measures.44,45 Such instruments include the PedMIDAS and PedsQL.38–41,47 Although much is still untested in childhood migraines (and is a priority for clinical and translational research), downsizing from what is known about adults is not adequate.45 Pediatric-specific data and assessment tools have been developed, and it is critical for optimal care (and assessment of the outcomes of treatment) for these instruments to be used.45,48

The behaviors involved in optimal use of pharmacological therapies need to be emphasized and clearly presented to children, adolescents, and families. The differences in how to take abortive and preventive medications effectively need to be understood by patients. To optimize these adherence-promoting goals and obtain the best possible results from the therapies, an approach that incorporates known biobehavioral principles is needed. Developing an agreement that clearly defines the tasks, roles and responsibilities, and measurement of progress is important. Remembering that adherence is about collaborating on how to do the actions that will lead to better health outcomes, in contrast to a unidirectional instruction or prescription, is another hallmark of biobehavioral care.38–41

Psychological and biobehavioral therapies work to reduce pain and headache frequency for children and adolescents with migraine.49,50 Relative to trials that have investigated pharmacological therapies, more research has been conducted on psychological treatments. Systematic reviews clearly show the value and effectiveness of these approaches, but also call for more clinical trials. Evaluation of the combined effects of integrated drug and non-drug treatments are clearly needed.38,42 Biofeedback and cognitive-behavioral therapies specifically designed for children and adolescents should now be part of standard care, and ways to translate these efficacious therapies into care need to be a focus of research and dissemination efforts.38,49,50 In addition, health behaviors that can be instrumental and helpful to children and adolescents with migraine (adequate liquid intake, eating regularly, regular sleep, exercise) are part of biobehavioral care.38–41

Clinical care can be enhanced by taking a biobehavioral approach. Further advancements in care for children and adolescents with migraine will occur as the result of more clinical and translational research; specifically, investigations that test integrated therapies informed from a biobehavioral science and practice base.38

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Options for Acute Treatment of Pediatric Migraine

DrugTrade NameDosing Forms
Acetaminophen # (10–15 mg/kg/dose)Tylenol80, 160, 325 mg tablets160 mg/tsp syrup
Ibuprofen # (7.5–10 mg/kg/dose)Advil100 mg chewable tabs100 mg/tsp syrup200,400,600,800 mg tabs
Naproxen sodium (2.5–5 mg/kg)Aleve220 (OTC), 250, 375, 500 mg
5-HT agonist (‘Triptans’)
Almotriptan *#Axert12.5 mg
FrovatriptanFrova2.5 mg&
Rizatriptan #Maxalt5, 10 mg tabs5, 10 mg disintegrating tablet
Sumatriptan #Imitrex25 mg, 50 mg, 100 mg tabs6 mg subcutaneous injection5 mg, 20 mg nasal spray#
Sumatriptan/naproxen combination #Treximet85 mg sumatriptan/500 mg naproxen
Zolmitriptan #Zomig2.5 mg, 5 mg2.5 mg, 5 mg disintegrating tablet5 mg nasal spray#

PedMIDAS Grading Scale

PedMIDAS Score RangeDisability Grade
0 to 10Little to none
11 to 30Mild
31 to 50Moderate
> 50Severe

Options for Preventive Agents for Pediatric Migraine

DrugDoseAvailable Form
Antihistamines
Cyproheptadine0.25–1.5 mg/kgtab 4 mgSyrup 2 mg/tsp
Anticonvulsants
Topiramate1–10 mg/kg/day (usual 50 mg bid)Sprinkles 15, 25 mgTablets 25, 100 mg
Disodium valproate20–40 mg/kg/daySyrup 250 mg/tspSprinkles 125 mgER tabs 250,500
Antidepressants
Amitriptyline10–50 mg qhsTabs 10, 25,50 mg
Nortriptyline10–75 mg qhsTabs 10, 25, 50, 75 mg
Non-steroidal Anti-inflammatory Agents
Naproxen sodium250–500 bidTab 220, 250, 375, 500 mg
Calcium Channel Blockers
Verapamil4–10 mg/kg/day tidTab 40, 80, 120 mgSR tab 120, 180, 240 mg
Flunarizine5–10 mg po at bedtime10 mg tablets*
Beta-blockers#
Propranolol2–4 mg/kg/day10, 20, 40, 60, 80 mgLA cap 60,80,120,160 mg

CME Educational Objectives

  1. Discuss the spectrum of therapeutic options for pediatric migraine.

  2. Evaluate the appropriate use of and options for acute treatment of migraine in children.

  3. Assess the need for daily prophylactic agents based upon the level of disability produced by migraine.

Authors

Andrew D. Hershey, MD, PhD, FAHS, is with Department of Pediatrics, University of Cincinnati, College of Medicine and Division of Neurology, Cincinnati Children’s Hospital Medical Center. Marielle A. Kabbouche, MD, is with Department of Pediatrics, University of Cincinnati, College of Medicine, and Division of Neurology, Cincinnati Children’s Hospital Medical Center. Scott W. Powers, PhD, FAHS, is with Department of Pediatrics, University of Cincinnati, College of Medicine, and Division of Behavioral Medicine and Clinical Psychology, Cincinnati Children’s Hospital Medical Center.

Dr. Hershey and Dr. Powers have disclosed no relevant financial relationships.. Dr. Kabbouche has disclosed the following relevant financial relationships: Allergan: Consultant.

Address correspondence to: Andrew D. Hershey, MD, PhD, Director, Headache Center, Division of Neurology, MLC #2015, 3333 Burnet Ave., Cincinnati, OH 45229-3039; or fax 513-535-1888.

10.3928/00904481-20100623-06

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