Pediatr Drugs DOI 10.1007/s40272-015-0125-5

REVIEW ARTICLE

Prophylaxis of Migraine in Children and Adolescents Joanne Kacperski

Ó Springer International Publishing Switzerland 2015

Abstract While it has been established that headaches in the pediatric age group are relatively common, the characterization of headache disorders and their treatment in this group has historically been limited. Due to the paucity of controlled studies on prophylaxis of the primary headache disorders in children, the diagnosis of migraine often rests on criteria similar to those used in adults. Data from adult studies are often extrapolated and applied to the pediatric patient. Although it appears that many prophylactic agents are safe, well tolerated and efficacious in children, currently only topiramate is FDA-approved for use in patients 12 years and over. As a result, despite often experiencing significant disability, many children who present to their physician with migraines do not receive preventive therapy. One-third of adolescents meet the criteria for warranting prophylactic therapy, yet few are offered a preventative medication. Moreover, controlled clinical trials investigating the use of both abortive and prophylactic medications in children have suffered from high placebo response rates. A diverse group of medications are used to prevent migraine attacks, including antidepressants, antiepileptics, antihistamines and antihypertensive agents, yet there still remains a serious lack of controlled studies on the pharmacological treatment of pediatric migraine.

Key Points Because migraines can commonly start in childhood, early recognition, establishment of a treatment plan and implementation of lifestyle changes can alter disease progression and ultimately improve the child’s quality of life. The goals of treatment should ultimately include reducing headache frequency, reducing the progression to chronic daily headache and lessening associated disability. Numerous agents have had limited data in this population and many agents lack efficacy. Although amitriptyline, topiramate, and valproic acid have the most data on their use for prophylaxis in children, there still remains a serious lack of controlled studies on the pharmacological treatment of pediatric migraine, and consequently, there is an urgent need for further studies in this population. Neutraceuticals may be an alternative option in treating migraine and may be offered to parents who are reluctant to start their child on a daily medication. The best evidence currently exists for coenzyme Q10 and riboflavin. Behavioral measures, including biofeedback and relaxation therapy, are the most widely accepted non-drug techniques for headache control and prevention and have been shown to reduce headache frequency and severity.

J. Kacperski (&) Division of Neurology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave-MLC 2015, Cincinnati, OH 45229-3039, USA e-mail: [email protected]

1 Introduction

J. Kacperski Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, OH, USA

Primary headache disorders are recognized as one of the most prevalent health problems worldwide. The prevalence

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of headaches during childhood have been investigated across pediatric age groups with varying estimates ranging from 3 % in school-age children to 20 % in adolescents [1– 3]. Epidemiological analyses have established the high incidence of headaches in children and adolescents, with migraine being the most disabling type [4]. Aydin et al. [5] reported that migraine was the most common cause of headache in a pediatric neurology outpatient clinic, comprising 57.1 % of all headaches presenting for an initial evaluation. In 1962, Bille [6] demonstrated that 25 % of children report a significant headache by the age of 5 and up to 75 % of children report a notable headache by the age of 15 years. Prior to puberty, the prevalence of migraine is slightly higher in boys when compared with girls [7]. The mean age of onset is 7 years for boys and 11 years for girls [8]. Data from the American Migraine Prevalence and Prevention (AMPP) study demonstrated that as children approach adolescence, however, the incidence and prevalence of migraine appear to increase more rapidly in girls when compared with their male counterparts [9]. Migraines can often become a chronic and disabling disorder and can have a significant effect on the child’s quality of life. It often contributes to school absenteeism and can affect peer and social interactions. Population studies have shown that over 130,000 school days are missed every 2 weeks and 3 million bedridden days occur per month as a result of migraine headaches in the US [10]. Powers et al. [11] determined that the negative impact of having migraines on a child’s overall quality of life is similar to that of pediatric cancer, heart disease and rheumatic disease. Because migraines can commonly start in childhood, early recognition, establishment of a treatment plan, and implementation of lifestyle changes can alter disease progression and ultimately improve the child’s quality of life [12]. Despite often experiencing significant disability, many children who present to their physician with migraines do not receive preventive therapy. One-third of adolescents meet the criteria for warranting prophylactic therapy, yet only 10–19 % are offered a preventative medication [13]. Moreover, controlled clinical trials investigating the use of both abortive and prophylactic medications in children have suffered from high placebo response rates. This may be secondary to the differences described between pediatric and adult migraines. For example, children tend to describe a shorter duration of headaches making the designing of randomized controlled trials in this age group more problematic and limiting. As a result, treatment practices can vary widely, even among headache specialists, owing to the absence of evidence-based guidelines from clinical trials. The aim of this review is thus to help clinicians better define which patients warrant prophylactic therapy, offer strategies and guidelines to not only choose an

appropriate preventive, but also aid the clinician in prescribing a medication with the aim of limiting the development of adverse effects and promoting compliance with therapy. In addition, although limited studies exist in the pediatric population, studies with compelling evidence on some of the most commonly prescribed prophylactic therapies are included. Prophylaxis should be limited to those children and adolescents whose headaches occur with sufficient frequency and/or severity to warrant a daily medication. The goals of treatment should ultimately include reducing headache frequency, reducing the progression to chronic daily headache and lessening associated disability. Most specialists require that a child experience a minimum of one headache per week or three to four headaches per month to justify initiating a daily medication. Children who report intensive and prolonged headaches (lasting [48 hours), even if infrequent, should also be offered preventive therapy. Preventive treatment should also be considered if acute treatments are ineffective, not well tolerated, contraindicated or overused. Both the clinician and family must establish a sense of functional disability before committing the child to a course of daily medication, as therapy should also aim at the improvement of overall quality of life. All patients warranting prevention should be provided with appropriate education on their diagnosis and treatment plan, thus enabling the child to manage their disease and enhance personal control of their headaches. Clinicians should discuss this long-term treatment plan so that families understand that the effort is often a long-term one and response will not occur rapidly. It should be emphasized that the onset of improvement is often delayed in the pediatric patient. Ideally, these medications should only be used for a finite period of time. A goal of three or fewer headaches per month is recommended for a sustained period of 4–6 months. The dose of the prophylactic medication should be titrated slowly to minimize side effects. Once an effective dose is achieved, relief must be sustained for 2–3 months before considering an alternative medication. Once these goals are obtained, a plan to slowly wean the child off the agent is also necessary. A diverse group of medications are used to prevent migraine attacks including antidepressants, antiepileptics, antihistamines, and antihypertensive agents (summarized in Table 1). The majority of these medications are extensively prescribed for other conditions, including depression, mood disorders, epilepsy and other pain disorders, thus making their side effect profiles well defined. When selecting a medicine, the clinician should take into account any co-morbid conditions that may be present. Clear instructions should be given to families regarding the medication’s mechanism of action, potential

Prophylaxis of Migraine Table 1 Commonly used medications for the prevention of childhood and adolescent migraine Agent

Dosing

Available formulations

Commonly encountered adverse effects

Amitriptyline

10–150 mg qhs (max 1 mg/kg/day)

Tablets—10, 25, 50, 75, 100, 125, 150 mg

Sedation, dizziness, constipation, decreased gastrointestinal motility, increased appetite, weight gain, urinary retention

Nortriptyline

10–75 mg qhs

Capsules—10, 25, 50, 75 mg Liquid susp—10 mg/5 mL

Drowsiness, dizziness, constipation, increased appetite, orthostatic hypotension, QT prolongation

1–10 mg/kg/day

Tablets—25, 50, 100, 200 mg

Typical dose 50 mg bid

Sprinkle caps—15, 25 mg

Paresthesia, somnolence, dizziness, anorexia, metabolic acidosis, cognitive/memory dysfunction, abdominal pain

Antidepressants

Antiepileptics Topiramate

Valproic acid

15–30 mg/kg/day

Tablets DR—125, 250, 500 mg Tablets ER—250, 500 mg Sprinkle caps—125 mg

Somnolence, nausea/vomiting, thrombocytopenia, tremor, alopecia, increased appetite, weight gain, emotional lability, lymphopenia, hyperammonemia, elevated pancreatic enzymes

Liquid susp—250 mg/5 mL Levetiracetam

500–1,500 mg bid

Tablets—250, 500, 750, 1,000 mg

Somnolence, fatigue, irritability, mood/behavioral changes

Zonisamide

100–600 mg/day

Tablets—25, 50, 100 mg

Somnolence, dizziness, anorexia, nausea, irritability

Gabapentin

300–1,200 mg tid

Tablets—100, 300, 400, 600, 800 mg

Dizziness, sedation, ataxia, fatigue, peripheral edema

Liquid susp—100 mg/mL

Liquid susp—50 mg/mL Antihistamines Cyproheptadine

0.25–1.5 mg/kg/day

Tablets—4 mg

Drowsiness, fatigue, increased appetite, weight gain, dizziness

Liquid susp—2 mg/5 mL Antihypertensives Propranolol

2–4 mg/kg/day

Verapamil

4–10 mg/kg/day tid

Tablets—10, 20, 40, 60, 80 mg Tablets ER—60, 80, 120, 160 mg

Fatigue, dizziness, constipation, hypotension, depression, exercise-induced asthma

Liquid susp—20, 40 mg/5 mL Tablets—40, 80, 120 mg

Constipation, dizziness, nausea, hypotension

Tablets ER—120, 180, 240 mg Flunarizinea

5–10 mg qhs

Tablets—10 mg

Sedation, weight gain

bid twice daily, DR delayed release, ER extended release, qhs every night at bedtime, tid three times daily a

Not available in the US

side effects, and the importance of remaining adherent to therapy. Clear titration instructions should also be provided. It is important to remind families that it may take time, often several weeks, for the preventive to become effective. Slow titration over a period of 4–12 weeks may be necessary to assure that the child tolerates the medication with minimal adverse effects. If a trend of improvement is seen, the dose may be adjusted for optimal control. Treatment should not be abandoned until it has been given an adequate trial of at least 6–8 weeks on the full dose unless there are intolerable side effects. When improvement is sustained and a satisfying response is achieved over a period of 4–6 months, then the child may be slowly weaned off of therapy.

2 Antidepressants Antidepressants have become the mainstay of migraine prevention in adults; however, few studies exist in children. They were first recognized as an effective migraine preventative therapy in the 1970s, with the tricyclic antidepressants being the most widely studied [14]. Amitriptyline is used to treat a number of different medical conditions, but major depressive disorder is its only FDA-approved indication. It remains one of the most widely used prophylactic medications both in adult and pediatric migraine. It is the only tricyclic antidepressant for which studies have provided consistent evidence for prophylaxis in the adult population. In adults, it has been

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suggested that the effective dose range may vary widely, from 10 to 150 mg. However, in children, most of the studies with amitriptyline have been open-label with no placebo-controlled trials, resulting in dosing that has remained unclear in this age group [15]. Despite this, it still remains one of the most widely used agents in children and adolescents. Starting doses are commonly 5–12.5 mg once daily [16]. Because of its side effects, most commonly somnolence, it must be titrated slowly over a period of 8–12 weeks, increasing by 0.25 mg/kg/day every 2 weeks to a goal dose of 1 mg/kg/day [17]. Patients should also be counseled about possible weight gain, orthostatic hypotension, tremor, agitation, and mood changes. Owing to its anticholinergic side effects, patients may also experience dry eyes, dry mouth, urinary retention, or reduced gastrointestinal motility. Nortriptyline, an active metabolite of amitriptyline, has been used to replace amitriptyline due to its less sedating side effects. Nortriptyline, however, does raise the concern for increased risk of arrhythmia, and regular electrocardiograms may need to be performed for surveillance [17]. Hershey et al. [17] surveyed the perceptions of 192 children with headache treated with amitriptyline for prevention with slow increments to a maximum dose of 1 mg/ kg. When the full dose was achieved, migraine attack frequency and severity were reduced by 80–89 %. Eightyfour percent of patients also reported ‘‘feeling better’’. In a retrospective chart review by Eidlitz-Markus et al. [15], the effectiveness of non-pharmacologic measures combined with low-dose amitriptyline or propranolol was assessed in 118 patients. Ninety-three children received propranolol (mean initial dose, 0.4 ± 0.17 mg/kg/day), and 25 received amitriptyline (mean initial dose, 0.26 ± 0.1 mg/kg/day). In both groups, headache frequency was reduced by [50 % per month in approximately 80 % of patients. They concluded that low-dose propranolol and low-dose amitriptyline, when combined with non-pharmacologic measures, are equally effective in reducing the frequency of migraine. However, significantly more tolerable side effects were experienced by those children receiving amitriptyline when compared with the propranolol group. In another retrospective review of the use of prophylactic agents for 73 children and adolescents (ages 3.2–18 years) within a child neurology practice found that amitriptyline produced a ‘‘positive response rate’’ of 89 %. This was defined as an overall decrease in headache frequency and intensity. Headache frequency was reduced from a mean baseline of 11 to 4.1 headaches per month. The most commonly reported side effect was mild sedation [13]. Currently, Hershey et al. are conducting the Childhood and Adolescent Migraine Prevention Study (CHAMP), which is a double-blinded, placebo-controlled, multicenter trial comparing the effectiveness of amitriptyline and

topiramate for the prevention of episodic and chronic migraine. The study will aim to recruit 675 pediatric patients diagnosed with migraine between the ages of 8 and 17 years over a 7-year period (to be completed by 2017). Patients will be randomized to amitriptyline, topiramate or placebo arms in a 2:2:1 ratio. The target dose of amitriptyline is 1 and 2 mg/kg for the topiramate group. The primary outcome will be a 50 % reduction in headache frequency. The fundamental goal of this study is to obtain level 1 evidence for the effectiveness of two of the most widely used preventatives for the treatment of migraine in the pediatric population, which could subsequently help guide clinicians in treatment, thereby improving disability and outcomes [18].

3 Antiepileptics Antiepileptics have been the most widely studied migraine preventive agents in both adults and children and include topiramate, valproic acid, levetiracetam, zonisamide, and gabapentin. Both topiramate and valproic acid are approved by the FDA for prevention in adult patients, and, in 2014, topiramate became the first drug approved for migraine prevention in children ages 12 and over. The rationale for their use is based on our current understanding of migraine pathophysiology which is thought to involve a migrating wave of regional cortical excitation followed by a prolonged period of neuronal depression. This pathway is postulated to be altered by antiepileptic medications [13]. Numerous retrospective studies have demonstrated a reduction in headache severity with antiepileptic drugs. Clearly, more prospective studies are needed in children to assess efficacy and tolerability for use as migraine prevention. Data from several studies suggest that topiramate is effective in the preventive treatment of pediatric migraine, leading to its recent FDA approval. Topiramate is considered a first-line option for migraine prevention in adults. The effective dose in the pediatric population is not known, but a dose of 2–4 mg/kg/day appears to be effective. These doses are much lower than those indicated for the treatment of epilepsy (5–9 mg/kg/day). It must be titrated slowly, typically by quarter steps over an 8- to 12-week period. The most commonly observed side effects include drowsiness, paresthesias, memory or language dysfunction, decreased appetite and anorexia, metabolic acidosis, hyperthermia, dizziness, and abdominal pain [12, 13]. Lewis et al. [19] conducted a randomized, doubleblinded trial confirming the superiority of topiramate at a dose of 100 mg/day over placebo. Adolescents aged 12–17 years with a 6-month history of migraine were randomly assigned to receive 16 weeks of daily treatment

Prophylaxis of Migraine

with topiramate 50, 100 mg/day or placebo. The primary efficacy measure was the percent reduction in monthly migraine episodes. Several secondary efficacy measures were also evaluated, including the reduction from baseline in the monthly migraine rate and 50 % responder rate, in addition to safety and tolerability. Topiramate at 100 mg/day, but not 50 mg/day, resulted in a statistically significant reduction in the monthly migraine episodes from baseline versus placebo (median: 72.2 vs 44.4 %) during the last 12 weeks of double-blind treatment. The responder rate favored topiramate at 100 mg/day (83 vs 45 % for placebo). Topiramate at a dose of 50 mg/day failed to show superiority when compared with placebo. The most commonly reported adverse effects included upper respiratory tract infection, paresthesias, and dizziness [19]. In a placebo-controlled trial including 162 children aged 6–15 years, Winner et al. [20] randomized patients to receive placebo or topiramate with a goal dose of 2 mg/kg/day. Topiramate was titrated over 8 weeks to 2–3 mg/kg per day, or maximum tolerated dose, whichever was less (maximum allowed dose was 200 mg/day). The target dose was then maintained for a total of 12 weeks. The primary efficacy variable was the change in mean number of migraine days per month during the doubleblind phase relative to the 4-week prospective baseline phase for each treatment group. Treatment with topiramate was associated with a mean reduction of 2.6 migraine days per month when compared with 2.0 in the placebo group (p = 0.061). Response to topiramate, defined as a 50 % reduction in headache frequency, was 55 % compared with 47 % in the placebo group. A significantly greater percentage of topiramate patients (32 %) experienced a C75 % reduction in mean monthly migraine days compared with placebo (14 %, p = 0.02). Discontinuation rates due to adverse events were low: 6.5 % for the topiramate group and 4.0 % for the placebo group. The mean average daily dose of topiramate during the maintenance period was 2.0 mg/kg per day. The most commonly reported adverse events in the topiramate group included upper respiratory tract infection, anorexia, weight decrease, gastroenteritis, paresthesia, and somnolence [20]. Winner et al. [21] also performed a post hoc subset analysis of the efficacy and safety data from 51 patients, ages 12–17 years, enrolled in three pivotal trials of topiramate for migraine prophylaxis. They reported that daily treatment with topiramate 50, 100, and 200 mg for 26 weeks reduced monthly migraine frequency from baseline by 46 % (p = 0.07), 63 % (p = 0.02), and 65 % (p = 0.04), respectively, compared with the placebo group (16 %). Topiramate 200 mg/day did not appear to offer greater efficacy than 100 mg/day. Topiramate was generally well tolerated; however, adverse events were more frequently reported in the 200 mg/day dose group [21].

In another study by Hershey et al. [22] the efficacy of topiramate was assessed in 97 children, 75 of whom were re-evaluated at a first follow-up visit (after 88.7 ± 35.7 days) and 41 at a second follow-up visit (after 203.1 ± 45.6 days). Only children reporting three or more headaches per month were included. Topiramate was administered at the dose of 1.4 ± 0.74 mg/kg/day. They reported that headache frequency decreased from 16.5 ± 10 headaches/month to 11.6 ± 10.2 headaches/month (p \ 0.001) at the first follow-up visit, with 43.1 % of the patients experiencing a 50 % or greater reduction in the number of headaches. Moreover, by the second follow-up visit, headache frequency had decreased to 9.4 ± 8.4, with 56.1 % of the patients experiencing a 50 % or greater reduction in the number of headaches. In addition, mean headache severity, duration and disability (measured by the PedMIDAS) were also reduced. Twenty-five percent of patients reported side effects including cognitive changes, weight loss, and paresthesias, which declined in subsequent visits. However, about 50 % of patients were on additional prophylactic medication, most often amitriptyline or divalproex [22]. Valproic acid is considered a first-line therapy for migraine prevention in adults and several open-label and retrospective studies have suggested that it may also be effective in the pediatric population. Doses of 15–20 mg/ kg/day appear to be effective, and like most other preventive therapies, it must be titrated over a period of 8–12 weeks to avoid adverse effects. Commonly described side effects include dizziness, drowsiness, alopecia, weight gain, thrombocytopenia, lymphopenia, hyperammonemia, and elevated pancreatic enzymes. Laboratory surveillance every 3–6 months is thus critical. It is also important to discuss the risk of teratogenicity and fertility-related side effects with female patients of child-bearing age prior to initiation of therapy [23]. In a retrospective study comparing the effectiveness of valproic acid with topiramate, Unalp et al. [24] reported that both treatments demonstrated effectiveness in preventing migraines in children. In those children treated with valproic acid, mean monthly headache frequency, headache intensity, headache duration, and PedMIDAS scores decreased from 20.1 ± 10.2 to 6.6 ± 8.6, from 7.1 ± 1 to 3.4 ± 2.1, from 7 ± 12 to 1.4 ± 2.5 h, and from 20.5 ± 16.1 to 5.5 ± 9.2, respectively (p \ 0.05) [24]. In another 12-month, open-label study involving adolescents (n = 112), patients were placed on the extended release form of divalproex in dosages ranging from 250–1000 mg per day. Patient diaries revealed a 75 % decrease in the number of headache days over a 4-week period between the first and the fourth months of the study. Overall, divalproex was well tolerated. The most commonly reported adverse events included weight gain

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(15 %), nausea (14 %), somnolence (12 %), upper respiratory infection (11 %) and hyperammonemia (8 %) [25]. In an earlier study (n = 10), patients aged 9–17 years who were diagnosed with migraine were placed on sodium valproate 500–1000 mg and therapy was continued for 12 weeks. Mean headache attacks per month were 6 ± 4.2 at baseline and were 0.8 ± 1.9 at the end of the treatment period (p = 0.002). The duration of the headaches was significantly decreased from a mean of 5.5 ± 3.9 h to 1.1 ± 2.5 h with treatment (p = 0.001). Side effects included dizziness, drowsiness, and increase in appetite. Headaches recurred in two patients after the cessation of valproate and therapy was subsequently restarted. In the remainder of the subjects, good headache control was reported at 6 months following cessation of medication [26]. To compare the efficacy and tolerability of sodium valproate against propranolol, children aged 5–15 years (n = 60) were entered into a prospective, double-blinded clinical trial. Patients were randomly assigned to receive propranolol up to 3 mg/kg/day or sodium valproate up to 30 mg/kg/day. They were followed for at least 6 months following initiation of therapy. Valproic acid was found to be as safe and as effective when compared with propranolol. However, when the reduction in baseline headache frequency was evaluated, 83 % of propranolol recipients exhibited improvement of [50 % headache reduction compared with 63 % of those who received valproic acid [27]. Levetiracetam, an adjunctive therapy in the treatment of partial onset seizures in adults and children aged 4 years and older, has also shown some efficacy in treating adult and pediatric headaches. With a relatively safe and desirable safety profile, it has also been considered a relatively reasonable therapeutic option. Adverse effects including irritability, aggressiveness, and mild memory issues are most often reported. In a small retrospective chart review (n = 19), Miller investigated the efficacy and safety of levetiracetam for headache prevention. Patients 17 years and younger were included (mean age 11.9 years). It was found to be well tolerated and mean headache frequency decreased from 6.3 headaches per month before treatment to 1.7 per month, representing a reduction compared with baseline (p \ 0.0001). Headaches were completely eliminated in 10 patients (52.6 %), and 7 patients (36.8 %) had less severe and less frequent headaches. Two patients (10.5 %) reported no change in headache frequency [28]. In another small open-label study including children ages 6–17 years placed on levetiracetam for migraine prophylaxis (20–40 mg/kg/day), Pakalnis et al. [29] found that 18 out of 20 children experienced [50 % reduction in monthly headache frequency (90 % response rate) with a significant decrease in PedMIDAS scores following treatment.

Zonisamide, a sulfonamide, is used in children with epilepsy and some reports in the literature suggest efficacy in adult migraine patients. Pakalnis and Kring studied its efficacy in pediatric migraine in a retrospective chart review that included eight refractory patients with migraine (aged 10–17 years). The dosage of zonisamide ranged from 4 to 11.8 mg/kg/day. Seven of the eight patients had a positive response to zonisamide with a more than 50 % reduction in headache frequency (87.5 % response rate). Zonisamide was also well tolerated, citing weight loss and behavioral changes in two patients [30]. Gabapentin has been used to treat various pain syndromes, including neuropathic pain, fibromyalgia, and postoperative pain and has been studied for migraine prophylaxis in adult patients, with conflicting results [31]. One retrospective study using gabapentin in children (n = 18) at doses of 15 mg/kg/day found that over 80 % of patients reported greater than 50 % reduction in headache frequency and severity. The most desirable feature of gabapentin may be the low incidence of side effects, with sedation occurring most often [32].

4 Antihistamines Cyproheptadine, an antihistamine with antiserotonergic properties, has often been prescribed for pediatric migraine since the 1980s; however, efficacy data is limited. Despite the lack of data, it is often prescribed in doses of 0.2–0.4 mg/kg/day and is widely considered a first-line option for children under the age of 6 years. It comes in both tablet and a liquid formulation for younger patients who may have difficulty swallowing pills. The most commonly reported side effects include sedation and increased appetite with weight gain [23]. There is insufficient evidence in the pediatric population to comment on its effectiveness. In reviewing the literature, data appears to be limited to one retrospective study and one open-label study in children \12 years, both of which reported that cyproheptadine was effective in reducing headache frequency [33]. Johnson et al. reported on the prescription patterns by drug type, age, and sex of the patients at a large academic pediatric hospital. They found that cyproheptadine was the most commonly prescribed preventive therapy to the youngest subset of their population, at 20.3 % of migraineurs aged 2–6 years [34].

5 Antihypertensives Beta blockers, particularly propranolol, have long been used for the prevention of migraine attacks in children.

Prophylaxis of Migraine

While often viewed as one of the first-line agents in children, they have failed to consistently demonstrate effectiveness in randomized, double-blind studies. Although one of the original studies demonstrated propranolol’s effectiveness, follow-up studies have been controversial and, in a recent practice parameter, it was found to have mixed responsiveness when used for childhood headache prevention. In this study, which was a double-blind, crossover trial in children ages 7–16 years (n = 28), propranolol was administered at a dose of 60–120 mg per day (0.5–1 mg/ kg/day divided three times daily). Among the patients treated with propranolol, 20 of 28 patients (71 %) had complete remission from headaches and another three patients (10 %) experienced a 66 % reduction in headache frequency. On the contrary, in the placebo group, only three children experienced complete remission and one patient experienced a 66 % improvement in headache frequency. Based on these results, the author concluded that propranolol was an effective choice for prophylaxis in children [35]. In a follow-up study, Forsythe et al. [36] demonstrated that there was no difference between treatment with propranolol and placebo with regards to frequency, severity or average duration of migraine attacks. Instead, there was some evidence that propranolol increased the average length of headaches [36]. Interestingly, propranolol is often used as a comparative agent in controlled trials. Suggested dosing ranges from 0.5 to 2 mg/ kg/day [35]. Hypotension, as well as exercise-induced asthma and depressive side effects, limits its usefulness in pediatrics [23, 37]. Calcium channel blockers have been extensively studied for migraine prevention in adults, but evidence is also lacking in the pediatric population with the exception of flunarizine. This non-selective calcium channel blocker with selective effects on the cerebrovascular system is not currently available in the US, but multiple studies have illustrated its effectiveness in migraine prevention [38]. Sorge et al. [39], in a double-blind, placebo-controlled, crossover study in 70 children ages 5–11 years, demonstrated that the baseline headache frequency was reduced in those treated with flunarizine compared with those receiving placebo. Adverse effects most commonly reported were daytime sedation and weight gain [39] (Table 1).

6 OnabotulinumtoxinA The prevalence of chronic migraines in children and adolescents, defined as C15 headache days/month for 3 consecutive months, is between 2 and 3 %. Many of these patients are intractable and have often failed two or more oral preventive medication options. OnabotulinumtoxinA was approved by the FDA for the use of chronic migraine

in adult migraineurs in 2010; however, there is limited experience in its use in pediatric patients. Bernhard et al. [40] injected ten patients aged 13–17 years with 150 units of OnabotulinumtoxinA in the 31 specific injection sites according to the approved scheme. Primary outcome was 50 % reduction in headache days per month. The responder rate was reported as seven of ten patients at 3 months after injection and the average number of headache days per month was reduced from 19.2 to a minimum of 10.1. Only slight local side effects were reported, including redness or temporary pain, in all ten patients [40]. In another retrospective case series to assess tolerability and efficacy of OnabotulinumtoxinA, ten patients aged 11–17 years were injected. Four patients reported subjective but clinically meaningful relief consisting of a decrease in headache intensity, and two patients reported a decrease in headache frequency. The four responders also reported meaningful improvements in quality of life [41]. Kabbouche et al. [42] also conducted a retrospective review of pediatric patients receiving OnabotulinumtoxinA for chronic migraine and reported that monthly headache frequency improved with statistical significance. Moreover, a 30-point improvement in the pediatric disability scoring between first injection and follow-up injection was also observed, with a change from severe disability to moderate disability on PedMIDAS [42].

7 Neutraceuticals Neutraceuticals may be an alternative option in treating migraine and may be offered to parents who are reluctant to start their child on a daily medication. For example, multiple studies support the concept that migraineurs are in a state of mitochondrial energy depletion and there is growing support for the mitochondrial theory of migraine which views migraine pathogenesis as a process linked to mitochondrial energy failure. Coenzyme Q10 is crucial in supporting mitochondrial energy stores given that it is an electron carrier in the mitochondrial electron transport chain. Hence, if migraine is even partly engendered by mitochondrial energy depletion, then the use of coenzyme Q10 in migraine prophylaxis may be justified [43]. Hershey et al. [44] reported a deficiency of coenzyme Q10 in many children and adolescents with frequent headaches. In an open-label observation study, supplementation was associated with a reduction in headache frequency [44]. In a double-blind, placebo-controlled, add-on study, Slater et al. randomized 120 children, ages 6–17 years, to receive placebo or CoQ10 at a dose of 100 mg once daily. Both the placebo and CoQ10 groups showed reduced migraine frequency (p \ 0.001), severity (p = 0.006), and duration (p = 0.016) over time. Patients given CoQ10 had a

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significantly greater improvement in frequency from subject-reported baseline starting within 4 weeks of initiation [45]. Riboflavin has also been shown to be a vital component of mitochondrial energy production. Multiple studies in adults have shown the effectiveness and tolerability of riboflavin in migraine prevention, but data on children are scarce. A retrospective study in 41 pediatric patients (ages 8–18 years; mean age 13 years) who received riboflavin 200 or 400 mg/day single oral dose for 3 and 4 months for prevention, demonstrated a reduction in attack frequency and intensity (p \ 0.01). However, this was not sustained after 6 months of treatment [46]. It has long been postulated that pediatric migraine patients are deficient in magnesium [47]. The AAN guidelines state that magnesium is probably effective for adult migraine prophylaxis on the basis of Level B evidence [48]. Evidence, however, remains limited in children. There is one published randomized controlled trial in which children were randomized to receive either magnesium oxide capsules containing 9 mg/kg of elemental magnesium per day divided three times daily or placebo. Children included were ages 3–17 years. They reported a statistically significant and sustained improvement in migraine frequency in the magnesium group but not in the placebo group. However, regression analyses comparing the two groups did not yield any statistically significant difference in terms of these downward trends. There was a significant difference between the two groups with regards to side effects: the magnesium group reported more soft stools and/or diarrhea compared with the placebo group (19 vs 7 %) [49].

8 Behavioral Measures Nonpharmacologic treatments are widely prescribed to pediatric patients and their families, but their effectiveness has rarely been evaluated. Lifestyle modifications are often discussed with patients, including maintenance of good sleep hygiene, a well balanced diet, sufficient daily hydration and regular exercise [50]. Good sleep hygiene is often defined as regular bedtimes and waking times with sufficient sleep time. Bruni et al. [51] investigated the role of sleep in headache patients and reported a reduction in mean duration and frequency of headaches in 70 children who were carefully instructed on appropriate sleep hygiene and were compared with 94 children who were not. Maintenance of a regular diet also appears to be important; however, regarding dietary restrictions, the American Headache Society only limits caffeine intake and does not restrict any type of food unless a very specific food trigger is identified [50, 52]. A balanced diet was found to be

beneficial in adolescent girls, who often skip meals out of concern over body weight, and subsequently develop headache [52]. Patients are also often counseled on the importance of keeping well hydrated as dehydration is commonly identified as a headache trigger. In addition to 1–2 l of fluid intake, a slight increase in dietary sodium is often recommended [50]. Biofeedback, progressive muscle relaxation and abdominal breathing are several behavioral medicine techniques shown to reduce headaches and improve quality of functioning. When employed regularly and combined with preventative medication and optimized acute therapy, quality of life can be significantly improved compared with medication alone. Biofeedback and progressive muscle relaxation are the most widely accepted non-drug techniques for headache control and prevention. Blume et al. [53] analyzed records from 132 children diagnosed with migraines, ages 8–18 years, who attended two or more biofeedback sessions. Median headache frequency dropped from 3.5 to 2 headache days/week between the first and last visits. The response rate was 58 % overall; 48 % for chronic headaches and 73 % for episodic headaches [53]. Powers et al. [54] looked at 20 children (mean age 11.6 years) consecutively referred for biofeedback and relaxation therapy who received standard multidisciplinary treatment and biofeedback based on headache presentation and developmental status. Children were taught age-appropriate skills in deep breathing, progressive muscle relaxation, and guided imagery. These children were encouraged to practice with an audio tape at least three times each week (for 2 weeks) and at headache onset. Thereafter, the children were instructed to perform relaxation regularly on their own. Headache severity decreased from a mean of 5.0 (0 to 10 scale; 10 = most pain) to 4.5. Average headache frequency decreased from 12.9 to 9.7 days/month, and duration also decreased from 6.9 to 5.2 h. In general, 85 % of parents reported that their child was functioning ‘‘better’’ at the end of the study [54].

9 Conclusion Pediatric headache remains a frequent health problem for children and their families, yet there remain many gaps in our knowledge with regards to its pathophysiology and treatment. Our understanding of primary pediatric headache disorders is improving with increased recognition of the characteristics and associated symptomology. This should further guide the individualized treatment approaches for improved outcome and reduction of progression into adulthood. The management of migraine headaches in children and adolescents demands an individualized therapeutic approach, taking into account the

Prophylaxis of Migraine

developmental stage of the child and the high rate of psychiatric and other comorbidities. Numerous agents have had limited data in this population and many agents lack efficacy. Although amitriptyline, topiramate, and valproic acid have the most data on their use for prophylaxis in children, there still remains a serious lack of controlled studies on the pharmacological treatment of pediatric migraine, and consequently, there is an urgent need for new and evidence-based approaches to this long-neglected field of research. Acknowledgments The author has no conflicts of interest to report. No funding was received for the preparation of this review.

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