Preventive treatment of migraine in children

INTRODUCTION — Migraine is a common acute and recurrent headache syndrome in children. It is characterized by severe periodic episodes of headache often accompanied by nausea, vomiting, photophobia, and phonophobia and is relieved with sleep. In children, it may last from 2 to 72 hours (sometimes shorter), is often bilateral, and often occurs without aura.

The preventive treatment of migraine in children is reviewed here. Other aspects of pediatric migraine are discussed separately. (See "Types of migraine and related syndromes in children" and "Pathophysiology, clinical features, and diagnosis of migraine in children" and "Acute treatment of migraine in children".)

APPROACH TO THERAPY — The management of migraine consists of general lifestyle measures, acute treatment, and preventive treatment. An individual patient may need all three approaches. Unfortunately, there are limited data from randomized controlled trials regarding prevention of migraine in children and adolescents [1-5].

Indications for preventive therapy — Indications for preventive therapy of episodic migraine include the following:

●Frequent or long-lasting migraine headaches

●Migraine attacks that cause significant disability or diminished quality of life

●Contraindication to, failure of, or adverse effects of acute therapies

●Medication overuse headache

●Menstrual migraine

While there are no strict definitions for the precise frequency or duration of migraine headaches that would prompt preventive therapy, any child with relatively frequent, prolonged, or disabling headaches that are poorly responsive to acute treatments is a candidate for preventive therapy. Examples of patients who may benefit include children who have migraine attacks that cause them to miss school or other activities, have frequent attacks (eg, more than about once a week), or have severe attacks that cause them to seek emergency care.

Choosing therapy

●Lifestyle measures – All children and adolescents with migraine should receive patient education and counseling about lifestyle measures that can be helpful for preventing attacks. These include good sleep hygiene, regular exercise, routine meal schedules, adequate fluid intake, and management of migraine triggers, as discussed below. Lifestyle measures may be the most important aspect of migraine management. (See 'Lifestyle measures' below.)

●Additional treatment options – Besides lifestyle measures, preventive options for migraine include pharmacologic treatment, neurostimulation, and behavioral therapy. The choice among these options depends upon multiple factors, including the clinical setting, patient values and preferences, comorbid conditions, and the adverse effect profile, availability, cost, insurance coverage, and clinician familiarity for specific treatments. Reasonable initial choices for select children include the following:

•For young children who cannot swallow tablets, cyproheptadine can be given as an oral syrup. (See 'Cyproheptadine' below.)

•For children and their families or caregivers who prefer treatment with supplements rather than prescription medications, nutraceuticals including riboflavin (vitamin B2), melatonin, or magnesium are reasonable options. The efficacy of nutraceuticals for pediatric migraine is unproven, but they are typically quite safe and well tolerated. While nutraceuticals are not equivalent to placebo, there is evidence from a randomized controlled trial (CHAMP) that placebo treatment is as effective but better tolerated than pharmacologic treatment with amitriptyline or topiramate for pediatric migraine prevention [6]. This finding has prompted some experts to suggest that first-line treatments for pediatric migraine prevention should have an adverse effect profile comparable to that of placebo [7]. (See 'Nutraceuticals' below.)

•For children of any age, many pediatric headache specialists will offer amitriptyline, topiramate, or propranolol. However, there are few high-quality pediatric data to guide us as to the most efficacious or safest choice of pharmacologic therapy in children. (See 'Amitriptyline' below and 'Topiramate' below and 'Propranolol' below.)

•Cognitive-behavioral therapy (CBT) combined with preventive medication (amitriptyline) is appropriate initial therapy for children with migraine that is causing significant disability or diminished quality of life. Barriers to this therapy, including limited availability and inadequate insurance coverage, make it difficult to obtain for many patients. (See 'Cognitive-behavioral therapy' below.)

•Botulinum toxin therapy, injectable calcitonin gene-related peptide (CGRP) antagonists, and portable neurostimulation devices are alternatives for the acute and preventive treatment of migraine when oral medications fail or result in significant adverse effects. (See 'Botulinum toxin' below and 'CGRP antagonists' below and 'Neurostimulation' below.)

The presence of comorbid disorders may influence the choice of migraine therapy, though they are not the main factor in the decision. As examples, amitriptyline may be used to treat migraine for children with depression (see 'Amitriptyline' below), topiramate may be used for children with obesity or epilepsy (see 'Topiramate' below), and valproate may be used for males with comorbid epilepsy. (See 'Valproate' below.)

●Need for sustained commitment – The child and caregivers should understand the rationale, dosing, duration, and side effects of a particular treatment. Preventive migraine therapy requires a sustained commitment on the part of the child and family or caregivers to achieve benefit. Partly due to these reasons, parents or caregivers of younger children frequently prefer symptomatic treatment to administering daily preventive medication. (See "Acute treatment of migraine in children".)

Follow-up and monitoring — Once preventive treatment is started, patients should be followed to guide titration of drug therapy, assess for treatment response, and identify any adverse effects of therapy.

●Headache tracking – Clinicians should encourage headache occurrences to be tracked with the use of a diary, which can help to identify possible triggering factors, clarify features of the attacks, and evaluate the effectiveness of treatment [8]. A headache diary suitable for children is available for downloading from Boston Children's Hospital. For older teens and adults, smart phone apps such as Migraine Buddy can be used to track migraine attacks, migraine triggers, and sleep.

●Titration – Most preventive medications are started at a low dose and titrated up gradually over three to four weeks until therapeutic benefit develops, the maximum dose is reached, or significant side effects intervene.

●Laboratory studies – The need for laboratory testing during follow-up varies according to the specific preventive therapy, as discussed for the individual agents in the sections below. (See 'Pharmacologic treatment' below.)

Although there is no consensus, many headache experts monitor serum levels of selected migraine drugs (most commonly valproate, topiramate, and amitriptyline) for adherence and toxicity. For patients treated with a beta blocker (eg, propranolol), heart rate and orthostatic blood pressure should be monitored during treatment. For patients treated with a tricyclic (eg, amitriptyline), an electrocardiogram should be obtained at baseline and when higher doses are used, particularly if there is a family history suspicious for a prolonged QT syndrome. For patients treated with valproate, it is reasonable to obtain a complete blood count, liver function testing, and amylase level at least twice yearly.

●Duration of treatment – The chosen medication should be given an adequate trial in terms of dose and duration; treatment for six to eight weeks at the target dose may be required before full benefit is reached. Children who are intolerant of the initial drug or have an unsatisfactory response despite an adequate trial can be switched to a different agent.

The optimum duration of effective preventive therapy is uncertain. Our approach is to continue to treat for 6 to 12 months if headaches are well controlled. We then taper the drug over the course of several weeks.

Treatment failure — For patients who fail to improve despite an adequate trial of preventive medication, we suggest switching to a migraine prevention medication from a different class or switching to neurostimulation or CBT if available. However, there is little evidence to guide therapy for children or adolescents when initial preventive therapy is ineffective or poorly tolerated.

Select populations

Chronic migraine — Chronic migraine is defined as 15 or more headache days per month for at least three months, at least eight of which have migrainous features [9]. The management of chronic migraine should focus on preventive therapy and avoidance of acute headache medication overuse. As with migraine in general, preventive interventions may include pharmacotherapy, behavioral therapy, physical therapy, and lifestyle modification. Management often requires the simultaneous use of these different therapeutic modalities.

●For adolescents with chronic migraine, we recommend the combination of CBT (where available) and preventive migraine medication, such as amitriptyline, as a good starting approach [7]. (See 'Cognitive-behavioral therapy' below.)

●When CBT is not available, we suggest a trial with one of the first-line prophylactic migraine medications. First-line prophylactic agents are propranolol, amitriptyline, and topiramate; valproic acid and its derivatives are first line for males but not for females of childbearing potential. The choice among migraine prophylactic agents depends upon individual patient values, preferences, and comorbid conditions.

Although efficacy is unproven in adolescents, botulinum toxin injections with onabotulinumtoxinA are an option for adolescents who have chronic migraine and who have not had success with at least three classes of migraine preventive medications (antiseizure, antidepressant, and antihypertensive). (See 'Botulinum toxin' below.)

Estrogen-associated (menstrual) migraine — Many female patients have migraine associated with their menstrual period. Menstrual migraine (also called menstrually associated migraine or catamenial migraine) is defined as migraine headache that occurs in close temporal relationship to the onset of menstruation. (See "Estrogen-associated migraine headache, including menstrual migraine".)

Short-term preventive therapy during the perimenstrual period may be useful for those who have menstrual migraine that occurs on a predictable schedule. This treatment strategy is called "mini-prophylaxis" and usually consists of preventive medication started one or two days prior to the expected onset of headache and continued for the expected duration of the headache.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often used for mini-prophylaxis. Naproxen sodium 550 mg twice daily during the perimenstrual period is one commonly used regimen. Other options for the preventive treatment of menstrual migraine, including hormonal strategies using estrogen-based therapy and nonhormonal strategies using long-acting triptans, are reviewed in detail separately. (See "Estrogen-associated migraine headache, including menstrual migraine", section on 'Treatment progression'.)

LIFESTYLE MEASURES — Lifestyle measures may be the most important aspect of migraine management.

Education — Educating the child and family or caregiver about migraine headache is an important aspect of care. Clinicians should provide literature describing migraine in children (see 'Information for patients' below). More information is available online at Headache Relief Guide, a website created by pediatric headache specialists [10].

Sleep hygiene — Healthy sleep practices are important for children (table 1) and adolescents (table 2). Getting sufficient sleep along with keeping relatively constant bedtime and wake-up times on weekdays and weekends are particularly important [7]. Sleep disturbances, such as insomnia, snoring, or frequent awakenings, may worsen headache frequency. Identification of sleep problems in children is discussed in detail separately. (See "Assessment of sleep disorders in children".)

Regular exercise — Regular exercise is not proven to have a benefit for migraine in children, but several studies and a small randomized trial in adults suggest that regular aerobic exercise may reduce migraine frequency [11-13].

Hydration — In small trials of adult patients with migraine, increased daily water intake was associated with reduced headache severity [14] and improved migraine-specific quality-of-life measures [15].

Routine meal schedules — There is evidence that fasting or skipping meals is a migraine trigger and should be avoided [16-18].

Managing migraine triggers — Precipitating factors for migraine (eg, stress, sleep disturbances, skipping meals, weather changes) should be identified when possible. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Precipitating and exacerbating factors'.)

Migraines occur more often during the school year, and a school history should be explored in the child with frequent migraines [19].

Caffeine withdrawal is a known migraine precipitant. Management options for adolescents include total caffeine avoidance or regular, modest, age-appropriate use [7].

Premonitory symptoms of migraine include fatigue, irritability, mood changes, neck stiffness, and food cravings [7]. These can be mistaken for migraine triggers. (See "Pathophysiology, clinical features, and diagnosis of migraine in children", section on 'Premonitory phase'.)

PHARMACOLOGIC TREATMENT — Data are limited on the effectiveness of preventive migraine drugs in children [1,2,20,21]. Possibly useful oral agents include cyproheptadine, nutraceuticals (eg, riboflavin), propranolol, amitriptyline, topiramate, cinnarizine, and flunarizine; injectable agents include calcitonin gene-related peptide (CGRP) antagonists and botulinum toxin.

In addition to these medications, preventive therapy options include cognitive-behavioral therapy (CBT) (see 'Cognitive-behavioral therapy' below) and neurostimulation (see 'Neurostimulation' below). The choice of therapy should be individualized according to the clinical situation, patient values and preferences, comorbid conditions, and adverse effect profile, cost, and insurance coverage as discussed above. (See 'Indications for preventive therapy' above and 'Choosing therapy' above.)

A 2020 meta-analysis of preventive migraine treatments in children suggested short-term benefit for propranolol and topiramate but failed to show long-term benefit for any intervention [22]. The evidence base for specific drugs is reviewed in the sections below.

Cyproheptadine — Cyproheptadine is an antihistamine and serotonin antagonist with anticholinergic and calcium channel-blocking properties that is used for migraine prevention [2,23,24].

Data for cyproheptadine are limited to a few small retrospective studies. One was a study of 126 children and adolescents who received various preventive treatments for migraine [23]. A positive response, defined as an overall decrease in headache frequency and intensity plus acceptability of the agent, occurred with cyproheptadine in 25 of 30 (83 percent) children. Headache frequency decreased with cyproheptadine (2 to 8 mg daily) from 8.4 to 3.7 headaches per month. In an earlier retrospective review of 12 children with abdominal migraine treated with preventive cyproheptadine, pain ceased in four, became milder and less frequent in six, and had no effect in two [24].

Cyproheptadine (2 to 8 mg daily given at bedtime) is given as an oral syrup or tablet for migraine prevention.

Appetite stimulation with weight gain is a common adverse effect and tends to limit use of cyproheptadine in older children. Somnolence occurs but is less common when the dose is slowly increased and medication is administered only at night. Clinical experience suggests that a single dose at bedtime helps to avoid daytime sleepiness and appears to be as effective as two or three daytime doses. Anticholinergic toxicity is rare and has been reported in a single child receiving therapeutic doses of the drug [25].

Nutraceuticals — Nutraceuticals sometimes used for pediatric migraine prevention include riboflavin, melatonin, coenzyme Q10, butterbur, ginkgolide B, magnesium, and polyunsaturated fats. Supporting data are limited and generally low quality [7,26,27].

Riboflavin — Although riboflavin (vitamin B2) is among the most studied supplements used for the prevention of pediatric migraine, the evidence is inconclusive [2,26,28-32]. Nevertheless, some experts prefer to use riboflavin as initial preventive therapy because it is well tolerated. We prefer it to other nutraceuticals for those who want therapy with nutritional supplements rather than conventional drugs.

For migraine prevention, riboflavin is dosed at 25 to 400 mg daily. A standard adult dose is 200 mg twice daily. Riboflavin can cause bright yellow or yellow-orange discoloration of urine and occasional gastrointestinal upset if taken on an empty stomach.

Melatonin — Melatonin is used as preferred initial therapy for pediatric migraine by some experts [7], although data in children and adolescents are scant [33]. The evidence from short-term, placebo-controlled trials in adults is conflicting; one found that melatonin (3 mg once at night) was beneficial for migraine prevention with a side effect profile that was similar to placebo [34], while another found no benefit [35]. (See "Preventive treatment of episodic migraine in adults".)

Melatonin is typically well tolerated, particularly at low doses (≤0.5 mg daily), and some studies suggest no adverse effects with melatonin 3 mg daily [33]. High serum concentrations of melatonin may cause daytime sleepiness, impaired mental and physical performance, temperature suppression, and elevated prolactin levels. (See "Pharmacotherapy for insomnia in adults", section on 'Melatonin'.)

Beta blockers

Propranolol — Propranolol is a commonly used preventive treatment for children with migraine, primarily based upon evidence of its effectiveness for adults. (See "Preventive treatment of episodic migraine in adults", section on 'Beta blockers'.)

However, few placebo-controlled trials have evaluated propranolol for migraine prevention in children, dosing schedules have not been studied systematically, and the available evidence is conflicting [1,4,20]. In one double-blind crossover trial of 39 children, the frequency, severity, and duration of headaches were similar with propranolol and placebo [36]. In another report, self-hypnosis was superior to propranolol (3 mg/kg per day) [37].

In contrast, an earlier double-blind crossover trial in 32 children (ages 7 to 16 years) found that propranolol provided effective prevention [38]. Based upon evidence from this trial, a 2019 guideline from the American Academy of Neurology (AAN) and the American Headache Society (AHS) concluded that propranolol was possibly more effective than placebo for achieving at least a >50 percent reduction in headache frequency (risk ratio [RR] 5.20, 95% CI 1.6-17.0) [4].

Propranolol also may be effective for prevention of abdominal migraine (see "Types of migraine and related syndromes in children", section on 'Abdominal migraine'). In a retrospective review of 24 affected children treated with propranolol, pain ceased in 18, became milder and less frequent in 2, and had no effect in 4 [24].

Propranolol is started at 1 mg/kg per day in three divided doses and can be titrated up as needed to a maximum daily dose of 3 mg/kg. Heart rate and orthostatic blood pressure should be monitored after increasing the dose. The heart rate should be >60 beats per minute after one minute of exercise. This drug often is discontinued by children who participate in strenuous physical activities. A long-acting form of propranolol is available for once-a-day dosing.

Beta blockers can cause increased bronchial obstruction and airway reactivity and resistance to the effects of beta receptor agonists; therefore, they should be used with great caution in children with asthma. In addition, they should be used cautiously in patients with a history of diabetes or depression. Additional adverse effects of beta blockers include hypotension, bradycardia, emotional disturbances, and nightmares. (See "Treatment of hypertension in asthma and COPD", section on 'Beta blockers' and "Major side effects of beta blockers".)

Atenolol — Atenolol can be an economical alternative to propranolol for once-daily dosing. Evidence of efficacy for migraine prevention is based upon studies in adults; data in children are limited. (See "Preventive treatment of episodic migraine in adults", section on 'Beta blockers'.)

Atenolol is started at 0.3 mg/kg per day, given once daily, and can be titrated up as needed to a maximum dose of 1 mg/kg per day. As with other beta blockers, heart rate and orthostatic blood pressure should be monitored after increasing the dose. The heart rate should be >60 beats per minute after one minute of exercise. Atenolol, a beta-1 selective blocker, is safer than nonselective beta blockers (eg, propranolol) but should still be used with caution in children with asthma. It should be used cautiously as well in patients with a history of diabetes or depression. (See "Treatment of hypertension in asthma and COPD", section on 'Beta blockers' and "Major side effects of beta blockers".)

Tricyclic medications

Amitriptyline — Tricyclic antidepressants are used commonly for migraine prevention. Studies of these drugs are limited in children [4,6], and treatment is supported mainly by data in adults. (See "Preventive treatment of episodic migraine in adults", section on 'Antidepressants'.)

●Dosing – Clinical experience suggests that a single dose of amitriptyline (0.25 to 0.5 mg/kg per day) given at night often is effective [39]. The dose is advanced slowly as needed if headaches persist. The daily dose rarely should exceed 100 mg or 2 mg/kg per day. However, the optimal dose of amitriptyline for migraine prevention in children has not been established, and recommended doses vary. In one retrospective report, 192 children with more than three headaches per month were treated with amitriptyline in a dose of 1 mg/kg per day [21]. Of these, 84 percent reported improvement. Treatment was associated with reduced headache frequency (17 to 9 per month), severity (6.8 to 5.1 on a 10-point pain scale), and duration (11.5 to 6.3 hours).

●Adverse effects – Amitriptyline may cause anticholinergic effects and will often increase heart rate. It is potentially sedating and best administered at bedtime. Other side effects include fatigue, dry mouth, dizziness, and altered mood [6]. Electrocardiographic changes such as prolongation of the QT interval may occur with amitriptyline.

●Monitoring – For patients treated with amitriptyline, an electrocardiogram should be obtained at baseline and when higher doses are used, particularly if there is a family history suspicious for a prolonged QT syndrome. It is reasonable to monitor heart rate, blood pressure, mental status, and weight and for worsening depression, suicidality, and associated behaviors (especially at the beginning of therapy or when doses are increased or decreased).

Therapeutic serum levels of tricyclic medications have not been established for migraine. However, some experts check serum levels when medication adherence or toxicity are concerns and when higher doses are used. For treatment of depression, a reasonable therapeutic range of amitriptyline plus nortriptyline (its active metabolite) is 100 to 250 ng/mL (360 to 900 nmol/L). For amitriptyline and/or nortriptyline, a level >500 ng/mL (>1800 nmol/L) is considered toxic.

Amitriptyline has been preferred by some experts as a first-line choice for migraine prevention in children because of once-daily dosing [2]. However, amitriptyline was no better than placebo or topiramate for headache prevention in the 24-week CHAMP randomized controlled trial of children and adolescents (8 to 17 years of age) with episodic or chronic migraine [6]. The primary outcome was the proportion of patients with a reduction of ≥50 percent in the number of headache days, comparing the last 28 days of the trial with the 28-day baseline period. The trial was stopped early due to futility at an interim analysis after enrolling only 361 of the planned 675 subjects; final data were available for only 264 subjects. By intention-to-treat analysis, the proportion of patients who achieved a relative reduction of ≥50 percent in the number of headache days was similar for the amitriptyline, topiramate, and placebo groups (52, 55, and 61 percent, respectively), and the differences between groups were not statistically significant. Adverse events were more common in the amitriptyline and topiramate groups. The results are in agreement with other data showing that a high placebo response rate seems to be characteristic of pediatric migraine [40,41].

Other tricyclics

●Nortriptyline – Nortriptyline is a tricyclic antidepressant and a less sedating alternative to amitriptyline [2]. The dose range is 0.25 to 1 mg/kg once daily at bedtime. The drug is started at the lower end of the dosing range and can be titrated up. No randomized controlled trial data are available for this agent in treatment of childhood and adolescent migraine. An electrocardiogram should be obtained at baseline, and patients taking nortriptyline should be monitored for hypotension, weight changes, and mood disorders. For nortriptyline, the therapeutic serum range is 50 to 150 ng/mL (190 to 570 nmol/L).

●Trazodone – An alternative agent is trazodone, a triazolopyridine antidepressant. In a trial of 35 children ages 7 to 18 years, both the trazodone and placebo groups had significant reduction in migraine frequency and duration during the first crossover phase, and the trazodone group had "significant further improvement" in migraine frequency and duration compared with placebo during the second crossover phase [42]. No side effects were observed in either group. With trazadone, liver enzymes should be monitored. For trazadone, a reasonable therapeutic serum range is 0.5 to 2.5 mcg/mL (1 to 6 micromoles/L). A level >2.5 mcg/mL (>6 micromoles/L) is potentially toxic, while >4 mcg/mL (>10 micromoles/L) is considered toxic.

Antiseizure medications

Topiramate — There is conflicting evidence from randomized controlled trials regarding the efficacy of topiramate for migraine prevention in children and adolescents. Based upon evidence from four trials [6,43-45], the 2019 AAN/AHS guideline concluded that topiramate was probably more effective than placebo for reducing the frequency of migraine or headache days (standardized mean difference [SMD] 0.39, 95% CI 0.13-0.66) [4]. Topiramate is the only migraine pharmacologic preventive approved by the US Food and Drug Administration (FDA) for use in children ages 12 to 17 years. However, topiramate appeared no more effective than placebo for achieving a 50 percent reduction in headache frequency (RR 1.33, 95% CI 0.93-1.89). Note that one of the included trials (the CHAMP trial) in the meta-analysis found that topiramate was no better than placebo or amitriptyline for headache prevention [6], as discussed above (see 'Amitriptyline' above).

●Dosing – The dose of topiramate often used for migraine is between 1 and 2 mg/kg per day. For children age 12 years and older, the initial dose is 25 mg once daily at night for one week; the dose can be increased to effect at weekly intervals in 25 mg/day increments as tolerated to a total daily dose of 100 mg. The half-life of the immediate-release form of topiramate is 21 hours, so either single-daily dosing or twice-daily dosing may be appropriate.

●Adverse effects – Potential side effects of topiramate include paresthesia, cognitive slowing, closed-angle glaucoma, decreased sweating, weight loss, and kidney stones [2].

There was a higher incidence of anorexia, upper respiratory tract infections, weight loss, gastroenteritis, paresthesia, and somnolence with topiramate than with placebo in clinical trials [6,43-45]. Topiramate may also cause cognitive impairment and concentration difficulty. It should be used with great caution in adolescents suspected of anorexia [46]. Topiramate should not be used for migraine prevention during preconception and pregnancy in females of childbearing age because of the associated risks of teratogenicity (eg, oral clefts) and low birth weight. (See "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Topiramate'.)

●Monitoring – Suggested monitoring for patients on topiramate includes baseline and periodic serum electrolytes and bicarbonate levels. Clinicians should also monitor for symptoms or signs of metabolic acidosis, chronic acidosis (eg, nephrolithiasis, rickets, reduced growth rate), decreased sweating, anorexia, secondary angle closure glaucoma, and suicidality. Serum ammonia concentration should be checked in patients with vomiting or mental status changes.

Topiramate is an antiseizure medication that can cause weight loss as a side effect; it may therefore be useful when treating children with migraine who have comorbid epilepsy or obesity.

Valproate — In adults, valproate is more effective than placebo for reducing the frequency of migraine attacks (see "Preventive treatment of episodic migraine in adults", section on 'Anticonvulsants'). The mechanism of action of valproate is not fully understood but may relate to enhanced gamma-aminobutyric acid (GABA) neurotransmission.

Data for efficacy of valproate in children are limited. In a randomized controlled trial identified in the 2019 AAN/AHS guideline [4], 300 adolescents (ages 12 to 17 years) were randomly assigned to treatment with extended-release divalproex sodium (250 mg, 500 mg, or 1000 mg once daily) or placebo [47]. At 12 weeks, there was no significant difference between any of the active treatment groups and placebo for reducing the migraine headache rate. In another trial involving 158 children over 12 weeks, 66 percent of children receiving valproate at 15 mg/kg/day divided in two doses achieved more than 50 percent reduction in headache frequency. One patient discontinued the medication owing to sedation [48].

●Dosing – Valproate is started in a dose of 10 to 15 mg/kg per day in two divided doses. The dose can be increased in increments to a maximum dose of 30 mg/kg per day.

●Adverse effects – Adverse events associated with valproate use in children included upper respiratory tract infection, nausea, weight gain, and gastrointestinal upset [47]. Other side effects in children may include somnolence, dizziness, tremor, transient hair loss, elevated serum liver enzyme and ammonia levels, and polycystic ovary syndrome. Thrombocytopenia may occur at higher doses [49]. Valproate should be used cautiously in children younger than two years of age because of potential hepatotoxicity.

Valproate has teratogenic effects and is associated with neural tube, cardiac, skeletal, and other defects, as well as a characteristic pattern of dysmorphic facial features. Therefore, its use is not recommended in females of childbearing potential. (See "Risks associated with epilepsy during pregnancy and the postpartum period", section on 'Valproate'.)

●Monitoring – Patients treated with valproate should have monitoring for liver enzymes and bilirubin at baseline and at frequent intervals, especially during the first six months of therapy, along with a complete blood count with platelets at baseline and periodically during therapy. Additional testing should include periodic serum amylase and vitamin D levels. Prothrombin time (PT)/partial thromboplastin time (PTT) should be checked prior to surgery. Serum ammonia should be checked if there are mental status changes.

Patients should also be monitored for signs and symptoms of weight gain, suicidality, motor and cognitive function, and persistent vomiting.

Valproate serum levels should be checked within the first six months of therapy; thereafter, some experts suggest checking serum levels annually. A therapeutic serum concentration of valproate for migraine therapy has not been established. A reasonable therapeutic range is thought to be 50 to 100 mg/dL.

Others — Other antiseizure medications are sometimes used for migraine prevention in children, although there are no high-quality data [50]. Retrospective studies tend to overestimate the effectiveness of medications and should be interpreted with caution.

●Gabapentin – In a retrospective study, gabapentin was associated with a >50 percent decrease in headache frequency and duration in 15 of 18 children (83 percent) 6 to 17 years of age [51]. This may be a potential option in patients with comorbid restless legs syndrome.

●Levetiracetam – A controlled trial randomly assigned 68 children (ages 4 to 17 years) with pediatric migraine to treatment with levetiracetam (20 to 40 mg/kg per day) or placebo [52]. During the last four weeks of the 12-week trial, the number of patients with a ≥50 percent reduction in headache frequency from baseline was greater for the levetiracetam group compared with the placebo group (68 versus 30 percent). Adverse events involving irritability, sedation, and mild tics were reported by eight patients in the levetiracetam group and none in the placebo group. Limitations to this trial include small size and short duration of follow-up.

Calcium channel blockers

Cinnarizine — Cinnarizine is an antihistamine and L-type calcium channel blocker that appears to be effective for migraine prevention in children. In a placebo-controlled trial, 68 children ages 5 to 17 years with episodic migraine and four or more headaches per month were randomly assigned to treatment with cinnarizine or placebo [53]. The cinnarizine dose, administered at 9:00 pm, was 1.5 mg/kg per day for children weighing <30 kg and 50 mg per day for children weighing>30 kg. After 12 weeks, the proportion of children with a >50 percent reduction in headache frequency was greater in the cinnarizine group compared with the placebo group (60 versus 31 percent). In the 2019 AAN/AHS guideline analysis of this trial, children assigned to cinnarizine were more likely to have a reduction in headache frequency (SMD 0.83, 95% CI 0.31-1.35), headache severity (SMD 0.97, 95% CI 0.45-1.50), and a ≥50 percent decrease in headache frequency (RR 1.92, 95% CI 1.09-3.48) compared with those assigned to placebo [4]. In another trial, cinnarizine was administered 37.5 mg/day for children ages 6 to 11 years and 50 mg/day for children ages 12 to 17 years. At 12 weeks, 71 percent of patients taking cinnarizine reported a more than 50 percent headache reduction [48].

Cinnarizine was well tolerated and there were no serious adverse effects, though a few patients taking cinnarizine developed mild drowsiness and one experienced weight gain requiring a dose reduction [53].

Cinnarizine is not available in the United States.

Flunarizine — The calcium channel blocker flunarizine may be effective for treating pediatric migraine, but there are few randomized trials. In the largest placebo-controlled trial, with 63 children, treatment with flunarizine 5 mg/day reduced headache frequency and average headache duration compared with placebo [54]. However, based mainly upon data from this trial, the 2019 AAN/AHS guideline concluded that there was insufficient evidence to determine whether flunarizine is better than placebo for decreasing migraine attacks in children [4]. A 2013 meta-analysis evaluated the same trial [54], along with an earlier small trial [55], and found that the degree of improvement with flunarizine compared with placebo just missed statistical significance (difference in headaches per month -2.27, 95% CI -4.65 to 0.11) [1]. In contrast, a 2019 systemic review and meta-analysis that included adult and pediatric studies found that flunarizine was modestly effective for reducing headache frequency compared with placebo and seemed to be effective in children [56]. A retrospective study of children with Sturge-Weber syndrome reported that flunarizine treatment was associated with headache improvement [57].

Weight gain and sedation are the most frequent adverse effects of flunarizine [54].

Flunarizine is not available in the United States.

Verapamil — Some authors advocate the use of more widely available calcium channel blockers such as verapamil based on its use in adults, although data supporting its use in children with migraine are scant [58]. Verapamil may be considered as a first-line agent in a hemiplegic migraine, a sub-form of migraine with aura with a pediatric mean age of onset (11 to 17 years). (See "Hemiplegic migraine", section on 'First-line options'.)

Case reports have supported the use of verapamil in children with hemiplegic migraine typically at doses of 40 to 120 mg three times daily [59-61]. The optimal dose has not been established. Starting at 40 mg twice daily and increasing as necessary and tolerated on a weekly basis up to 360 mg total daily dose (divided three times daily) may help limit adverse effects such as hypotension, bradycardia, and constipation.

CGRP antagonists — Calcitonin gene-related peptide (CGRP) is found in unmyelinated sensory nerve fibers and is associated with the transmission of painful stimuli. In adults, monoclonal antibodies to CGRP or its receptor have been shown to be efficacious for migraine prevention. (See "Preventive treatment of episodic migraine in adults", section on 'CGRP antagonists'.)

The CGRP antagonists are not approved for patients under the age of 18 [62]. They are typically given as a once-per-month self-injection. Yearly costs are over USD $7000, and, even if prescribed off-label, insurance companies in the United States have been reluctant to support it, although that may change with time.

Botulinum toxin — There is evidence from randomized controlled trials that botulinum toxin injections with onabotulinumtoxinA decrease the number of headache days in adult patients with chronic migraine [63], as reviewed separately (see "Chronic migraine", section on 'Botulinum toxin'). However, the benefit in children is unclear.

A systematic review of seven studies involving 110 children showed modest reductions in headache frequency, duration, and intensity among responders [64]. However, the quality of the evidence was low and the results of the lone randomized trial included showed no benefit over placebo [65]. In this trial, 125 adolescents ages 12 to 17 years were randomly assigned to treatment with intramuscular injection of onabotulinumtoxinA using a standard adult dose of 155 units, a lower dose of 74 units, or a normal saline placebo. The mean change from baseline in headache days per 28-day period was similar across all groups (155 units, -6.3 days; 74 units, -6.4 days; placebo, -6.8 days). There was no significant difference in percentage of patients with a ≥50 percent reduction in frequency of headache days across groups.

OnabotulinumtoxinA is administered every three months by intramuscular injection. The most common adverse effects seen in treated groups compared with placebo were neck pain (9 versus 0 percent) and musculoskeletal pain (5 versus 0 percent) [65]. Yearly costs are USD $14,000 or more.

NEUROSTIMULATION — Results from small randomized trials in adults support several methods of neurostimulation for migraine prevention.

Transcutaneous nerve stimulation — In a randomized controlled trial of 67 adults with migraine, use of a device delivering supraorbital transcutaneous trigeminal nerve stimulation decreased the number of monthly headache days (6.9 to 4.9), whereas sham stimulation did not (6.5 versus 6.2) [66]. There were no adverse events in either group. (See "Preventive treatment of episodic migraine in adults", section on 'Neuromodulation'.)

The supraorbital transcutaneous nerve stimulator is worn on the forehead for approximately 20 minutes per day. The device used in this trial is approved for marketing in the United States, Canada, Europe, and several additional countries. It was originally approved for migraine prevention and later for acute treatment. The device costs approximately USD $500.

Transcranial magnetic stimulation — A portable, single-pulse, transcranial magnetic stimulator (TMS) device generates a 0.9 Tesla magnetic field in a brief pulse over the occipital area. A small trial found that TMS was better than sham stimulation for the acute treatment of migraine with aura [67]; open-label studies suggested efficacy for migraine prevention in adults [68] and tolerability in adolescent migraine prevention as well [69]. (See "Acute treatment of migraine in adults", section on 'Transcranial magnetic stimulation' and "Preventive treatment of episodic migraine in adults", section on 'Neuromodulation'.)

A single-pulse TMS device received approval in the United States by the US Food and Drug Administration (FDA) for the acute treatment and prevention of migraine in adolescents (age ≥12 years) and adults. The device is rented directly from the company for USD $750 per three months.

BEHAVIORAL THERAPY

Goals of therapy — The main goal of behavioral medicine techniques, including cognitive-behavioral therapy (CBT) and biofeedback training, is to reduce headache symptoms. Additional goals of CBT in children can include maintaining function despite pain, staying in school, improving sleep, and coping with comorbid anxiety or depression.

Types of interventions

Cognitive-behavioral therapy — CBT often includes education, relaxation exercises, coping skills training, and stress management; cognitive therapy focuses on helping the patient identify and correct distorted, maladaptive beliefs. Behavioral therapy uses thought exercises or real experiences to facilitate symptom reduction and improved functioning. (See "Overview of psychotherapies", section on 'Cognitive and behavioral therapies'.)

A controlled trial randomly assigned 135 children and adolescents (ages 10 to 17 years) with chronic migraine (ie, headache present on ≥15 days/month) to treatment with either CBT or headache education; both groups also received amitriptyline (1 mg/kg per day) [70]. CBT consisted of a coping skills protocol for pediatric pain, including biofeedback with thermal and electromyographic monitoring of the response to relaxation. At 20 weeks, a greater proportion of subjects in the CBT plus amitriptyline group compared with those in the education plus amitriptyline group achieved a ≥50 percent reduction in headache days (66 versus 36 percent, odds ratio [OR] 3.5, 95% CI 1.7-7.2; absolute risk difference [ARD] 30 percent). In addition, more patients in the CBT plus amitriptyline group had a headache disability score in the mild to none range (75 versus 56 percent; OR 2.4, 95% CI 1.1-5.1; ARD 19 percent).

Biofeedback — Other biofeedback techniques for migraine treatment have limited evidence of efficacy [5]; these include peripheral skin temperature monitoring, blood volume pulse biofeedback, and electromyography.

A 2016 meta-analysis of biofeedback as prophylaxis in pediatric migraine identified five randomized, unblinded trials with 137 subjects and found that patients assigned to biofeedback techniques showed improvement in migraine frequency, attack duration, and headache intensity [71]. However, the quality of the few included trials was low.

As an example, one of the trials included in the meta-analysis randomly assigned 43 children with migraine to stress management training using either progressive relaxation or cephalic vasomotor feedback for six weeks or to treatment with metoprolol for 10 weeks [72]. Reduction in the headache index (a measure of frequency and intensity of headache episodes) was greatest with relaxation and stress management training, intermediate with cephalic vasomotor feedback and stress management training, and least with metoprolol. Clinical improvement persisted through follow-up at eight months. However, outcome data were incomplete, as 16 children were lost to follow-up [71].

Limitations — Although behavioral techniques appear to be effective, several issues limit their widespread use. These include restricted availability (particularly for young children) with few providers trained in these methods appropriate to headache prevention, high cost that may not be covered by health insurance, and the failure of children to practice these techniques consistently [7,73]. There are no high-quality randomized trials evaluating CBT without medication for pediatric migraine.

UNPROVEN INTERVENTIONS — There are a number of unproven preventive treatments for migraine, a list which includes cannabis, LSD, daith piercing, hyperbaric oxygen treatment, turmeric, and others.

Another unproven therapy, surgical removal of muscle or nerve tissue from headache "trigger sites," has been studied in adults and is discussed separately. (See "Preventive treatment of episodic migraine in adults", section on 'Other interventions not recommended'.)

PROGNOSIS — Children with migraine have a relatively good prognosis [74-79]. Long-term follow-up studies suggest that many patients improve with time, although others continue to have headaches or relapse after a headache-free period [80]. As examples, one study reported 81 patients with migraine (onset at 6 to 54 years of age) who were followed for 10 to 20 years [75]. The frequency of headaches decreased considerably in 54 percent of cases and increased in 25 percent. Headaches became less or more severe in 36 and 6 percent, respectively, and resolved completely in 11 percent. Another longitudinal study followed 73 children who had severe migraine with onset at approximately six years of age [74,76]. Although 23 percent were headache-free before the age of 25 years, more than one-half reported migraines at ages 30 and 50 years. Relapses were more frequent in females than males.

Early age at onset may portend a less favorable prognosis. In a 10-year follow-up study of 181 children with migraine, onset occurred before 6 years or at 6 to 10 years of age in 24 and 57 percent, respectively [77]. The clinical course was favorable in 88 percent of patients; the remainder received preventive treatment. In this series, in contrast with others, an unfavorable course was associated with earlier onset of migraine.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Migraine and other primary headache disorders".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Migraines in children (The Basics)" and "Patient education: Headaches in children (The Basics)")

●Beyond the Basics topic (see "Patient education: Headache in children (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Indications for preventive therapy – Preventive migraine treatment is indicated when headaches are frequent, prolonged, or disabling. In addition, preventive therapy is used when patients fail to respond to or are intolerant of acute (symptomatic) treatments. (See 'Indications for preventive therapy' above.)

●Lifestyle measures – All children and adolescents with migraine headache should receive patient education and counseling about lifestyle measures that may be helpful for controlling migraine. These include good sleep hygiene (table 1 and table 2), regular exercise, routine meal schedules, adequate fluid intake, and management of migraine triggers. (See 'Choosing therapy' above and 'Lifestyle measures' above.)

●Preventive therapies for children with episodic migraine – Preventive options for episodic migraine include pharmacologic treatment, neurostimulation, and behavioral therapy. Reasonable initial choices for select children include the following:

•Cyproheptadine syrup for young children who cannot swallow tablets (see 'Cyproheptadine' above)

•Nutraceuticals (eg, riboflavin) for those who prefer treatment with supplements rather than prescription medications (see 'Nutraceuticals' above)

•Pharmacologic treatment with amitriptyline, topiramate, propranolol, cinnarizine, or flunarizine (where available) for older children and adolescents (see 'Tricyclic medications' above and 'Antiseizure medications' above and 'Beta blockers' above and 'Calcium channel blockers' above)

•Cognitive-behavioral therapy (CBT) (where available) combined with amitriptyline for children with migraine that is causing significant disability or diminished quality of life (see 'Cognitive-behavioral therapy' above)

•Portable neurostimulation devices for adolescents (age ≥12 years) who prefer to avoid prescription medications (see 'Neurostimulation' above)

The choice among these options depends upon multiple factors, including the clinical setting, patient values and preferences, comorbid conditions, and the adverse effect profile, availability, cost, and insurance coverage for specific treatments. (See 'Choosing therapy' above.)

●Preventive measures for children with chronic migraine – For adolescents with chronic migraine (≥15 headache days per month for at least three months, at least eight of which have migrainous features), we recommend the combination of CBT (where available) and amitriptyline rather than preventive migraine medication alone (Grade 1B). When CBT is not available, it is reasonable to treat with one of the first-line preventive migraine medications (eg, propranolol, amitriptyline, and topiramate). (See 'Chronic migraine' above.)

●Prognosis – Children with migraine have a relatively good prognosis. Many patients improve with time, although others continue to have headaches or relapse after a headache-free period. (See 'Prognosis' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Robert Cruse, DO, who contributed to earlier versions of this topic review.