Indications for preventive treatment

The 2019 practice guideline for pharmacologic treatment for pediatric migraine prevention by the American Academy of Neurology (AAN) and the American Headache Society (AHS) recommend discussing the potential role of preventive treatment in children and adolescents who have frequent migraine, migraine-related disability, or both; and those with medication overuse. There was no specified minimum headache frequency at which to have this conversation, however, pediatric clinical trials for migraine prevention have generally included patients with 4 headache days per month or more. In adults, headache frequency of more than 6 days per month is a risk factor for headache chronicity. Migraine-related disability can be assessed using the Pediatric Migraine Disability Assessment (Ped-MIDAS) and a score of > 30 indicates moderate to severe disability.

Cognizant of some similarities in the challenges of migraine treatment in children and adult, other points to guide clinicians when considering preventive treatment adapted from the US, Canadian, and European adult migraine guidelines are: failure of or contraindication to acute therapies, patient preference, and presence of uncommon and potentially frightening migraine conditions such as hemiplegic migraine.

Goals of preventive therapy

When starting a preventive therapy, the main goal is to reduce headache frequency. Consequently, this can reduce disability and improve function. Another clinically observed benefit of preventive therapy is potentially making acute therapy more effective.

When starting a preventive treatment, emphasis must be made on setting realistic goals of treatment and to inform patients that there is currently no cure for migraine. While it is reasonable in many cases to set the goal to reduction of headache frequency by 50%; and to reduce disability, it is also important to involve patients and parents in what they would consider to be a meaningful treatment outcome. Their participation in clinical decision making will improve adherence to and success of treatment. It is also important to counsel patients and families that it generally take 6–8 weeks in this age group to know whether a migraine preventive treatment will work.

Antiepileptic medications

The two most commonly used and studied antiepileptic medications for pediatric migraine are topiramate and divalproex sodium.

Topiramate is the only FDA approved medication for migraine prevention for youths 12 years and older. There were 4 class I studies in topiramate in the pediatric setting. All of these studies showed that there is reduction in the mean number of headache days at the end of treatment for those in the Topiramate group. Two of these studies showed that Topiramate was not superior to placebo in reducing migraine days and migraine related disability by 50%. In the clinical trials, the dose used was 1–3 mg/kg/day with typical target dose of 100 mg/day and a maximum allowed dose of 200 mg/day. Common adverse events were paresthesia, anorexia, weight loss, fatigue, upper respiratory tract infection, and memory impairment. Serious side effects such as renal stones and suicidal ideation are rare. Topiramate is also known cause increased risk of development of cleft lip and cleft palate in infants born to women on this medication during pregnancy; putting Topiramate in category D for teratogenic risk. At a higher dose (above 200 mg/day), it also lowers efficacy of estrogen containing contraceptives.

Divalproex sodium (combination of valproic acid and sodium valproate) is the other anti-epileptic drug that has FDA approval and level A evidence for migraine prevention in adults. A retrospective study comparing valproic acid with Topiramate showed that both medications are effective in reducing headache frequency, intensity, duration, and disability. A small open label trial of sodium valproate in 15 pediatric patients showed similar results. A prospective double-blind clinical trial comparing efficacy and tolerability of propranolol and sodium valproate also supported that both medications are effective in reducing headache frequency, severity, and duration. The typical dose is 15–30 mg/kg/day and overall is well tolerated. Side effects include nausea, weight gain, dizziness, somnolence. Treatment using this medication needs close monitoring due its risk of hyperammonemia, pancreatitis, liver failure, thrombocytopenia, and other blood dyscrasias. Avoid using this in children younger than 5 years due to its hepatotoxic risk. It is also well known for its teratogenic effects particularly for neural tube defects, so must be used with caution in adolescent females.

Other anti-epileptic drugs that are currently used in clinical practice, although with very limited evidence, are gabapentin, levetiracetam, and zonisamide. Gabapentin is commonly used for neuropathic pain, fibromyalgia, and other pain syndromes in adults hence it is compelling to be used in migraine as well. However, a clinical trial for migraine in adults showed no significant difference between active treatment and placebo. One retrospective study in children showed a > 50% decrease in headache frequency and duration in 15 of 18 children aged 6–17 years. The effective dose used in this study is 15 mg/kg/day. Common side effects are dizziness, sedation, fatigue, weight gain, and peripheral edema. One disadvantage of using this drug is its three times a day dosing.

An open-label study of 63 adult patients showed that Zonisamide is effective and well tolerated for migraine prevention in patient’s refractory to topiramate. A small pediatric retrospective study ( N = 12) also showed that Zonisamide with dosing of 4–10 mg/kg/day was effective with more than 50% reduction of headache frequency. Side effects are similar to Topiramate although to a lesser degree.

Levetiracetam is a widely used anti-epileptic drug for generalized and focal seizures and its use in pediatric migraine is based on several small studies. A recent randomized controlled trial ( N = 31 in Levetiracetam group and 30 in placebo group) showed both groups to have reduction in migraine frequency and intensity; with 68% of patients in the levetiracetam group having greater than 50% reduction of migraines compared to placebo. A retrospective study on the efficacy and safety of levetiracetam in 19 pediatric patients also demonstrated that headache frequency decreased by 1.7 days per month from baseline. It also showed that it was well tolerated. A small open label study similarly showed that 18 out of 20 patients had significant reduction in headache frequency and disability. The typical dose in these trials was 125–750 mg BID. Levetiracetam is well tolerated however it is notorious for causing irritability, aggressive behavior, and mood change. This can be unfavorable for migraineurs who can have anxiety and depression as co-morbid conditions.

Antidepressants

Amitriptyline, a tricyclic anti-depressant, has a level B evidence for migraine prevention in adults. It is widely used for both pediatrics and adults not only for migraine but also for other pain syndromes. In pediatrics, the CHAMP study is the only randomized controlled trial on Amitriptyline. Its results showed that Amitriptyline reduced the number of headache days per month; headache frequency by 50% and headache disability, however, was not more effective than placebo. The effective dose in adults is variable from 10 to 150 mg daily; and in the pediatric trial, a dose of 1 mg/kg/day was utilized. Clinical experience also suggests that even a low dose 0.25 mg/kg/day may be adequate to control migraines. Common side effects are sedation (hence it is recommended to be given as a night time dose), dizziness, dry mouth, and weight gain. At higher doses, it can cause cardiac arrhythmia with prolonged QTc. Due to its potential cardiac effects, some clinicians obtain EKG prior to starting this medication.

Antihypertensives

Beta blockers, particularly propranolol, metoprolol, and timolol, received level A evidence in the adult guidelines for migraine prevention. In children and adolescents, propranolol has long been used as migraine prevention and there have been no newer clinical trials on this medication. There were two double blind cross-over design studies on propranolol. Forsythe et al. performed the study on patients aged 9–15 years using a dose of propranolol 40 mg BID. It did not show any difference in reducing headache frequency, duration, or associated symptoms between propranolol and placebo. In the study in 1974, 28 children with migraine aged 7–16 years were randomized to propranolol treatment group or placebo. Propranolol dose was 20 mg TID for patients weighing less than 35 kg and 40 mg TID for those weighing above 35 kg. This study showed 71% of patients treated with propranolol had complete remission from headaches and another 10% had reduction of attacks to less than one third. In the second phase of the study, similar efficacy was observed. Based on the magnitude of effect of this study, the 2019 pediatric guideline upgraded its level of evidence and concluded that children treated with propranolol are possibly more likely to have 50% reduction of headaches compared to those on placebo. Recommended dosing for propranolol is 1 mg to 3 mg/kg/day. Side effects are sedation, hypotension, bradycardia, and weight gain. Due to its effect on heart rate and blood pressure, and bronchospasm, caution must be used especially when prescribing to young athletes and those with asthma. Similar caution must be taken when prescribing to those with depression as this may worsen depressive symptoms. Propranolol, on the other hand, may benefit those with anxiety without depression and those with essential tremors.

Three calcium channel blockers, flunarizine, cinnarizine, and nimodipine, have been reviewed in the 2019 pediatric migraine prevention guidelines. Both flunarizine and cinnarizine are not available in the United Stated. The effectiveness of flunarizine for migraine prevention was based on one double blind placebo controlled cross-over design study in children with migraine aged 5–11 years of age. They were randomized to flunarizine group (dose of 5 mg/day) or placebo group. Result showed that headaches were reduced significantly in the flunarizine treated group than placebo. Side effects reported were daytime sedation and weight gain. Cinnarizine, an anti-histamine and calcium channel blocker, has shown its efficacy in one double blind placebo-controlled parallel group study. There was reduction in headache frequency, achieved more than 50% reduction in month headaches and reduction in headache severity in the cinnarizine group compared to placebo. The dose used in this study was 1.5 mg/kg/day for those weighing less than 30 kg; and 50 mg/day for weights > 30 kg). Drowsiness and weight gain were reported side effects. One randomized controlled trial with crossover design was done on Nimodipine for migraine prevention in children. Headache frequency was reduced from a mean of ~ 2.7 attacks/month to ~ 1.9 vs. no change for placebo. Abdominal discomfort was reported as a side effect.

Antihistamine

Cyproheptadine is a 5-HT2 antagonist with calcium channel blocking properties is widely used for migraine prevention especially in younger children. While there are no randomized clinical trials, clinical experience demonstrates its effectiveness in controlling migraine as well as recurrent abdominal pain. It is also the most commonly prescribed preventive medication among the youngest children with migraine. Its availability in liquid and tablet formulations and tolerability in children makes Cyproheptadine a commonly prescribed preventive medication and preferred treatment option by parents of children with migraine. Typical dose is 0.25–1.5 mg/kg/day and based on clinical experience, rarely exceeds 12 mg/day. Common side effects are sedation, increased appetite, and weight gain. Due to its sedating effect, most clinicians recommend single dosing at bedtime.