OTTAWA—Managing treatment of children and adolescents with migraines requires a tailored regimen of pharmacologic and behavioral measures that take into account headache pattern, pain tolerance, and lifestyle, according to Donald W. Lewis, MD. Multiple pharmacologic options are available, and Dr. Lewis, Professor of Pediatrics and Neurology at the Eastern Virginia Medical School and Children’s Hospital of the King’s Daughters in Norfolk, Virginia, reviewed a number of them at the 33rd National Meeting of the Child Neurology Society.

ACUTE TREATMENT OPTIONS

Although the pharmacologic management of pediatric migraine has been well studied, controlled data are limited. To date, intermittent analgesics have been the mainstay of all treatment of migraine in children. Ibuprofen, acetaminophen, and sumatriptan nasal spray have been the most rigorously studied agents for the acute treatment of pediatric migraine, and all have demonstrated safety and efficacy in controlled trials.

In one study involving ibuprofen, Dr. Lewis and colleagues treated 84 children with an over-the-counter dose of 7.5 mg/kg. About 76% of patients responded positively at two hours; placebo response was 53%. “There are good data to support the use of ibuprofen in migraine,” commented Dr. Lewis. There was a notable gender difference, however, with all of the positive responders being males; the nonresponders were virtually all females.

Three triptans have been studied in children with migraines. The largest such study, conducted by Winner et al with sumatriptan nasal spray, included 510 patients. At two hours, 66% of subjects experienced a decrease in headache severity with a 5-mg dose, and 63% had a reduction with a 20-mg dose. Placebo response was about 53%. In another trial with sumatriptan nasal spray, Ahonen et al found that 64% of patients responded positively at two hours; placebo response was 39%.

In other research, rizatriptan was given to children in a double-blind placebo-controlled trial using 5- and 10-mg doses. At two hours, 66% of respondents had pain relief, compared with 56% of the placebo group. In an open-label trial with zolmitriptan, pain relief was found in 88% of patients, while 66% became pain-free.

“The problem with these studies all along has been the placebo responder rate,” asserted Dr. Lewis. “The placebo responder rate approaches the mid-50s to 60% in most of these studies. So, obviously something needs to be done to figure out some way of attacking this problem, or none of the triptans will ever be approved in our lifetime for children. New study designs need to be developed. A lot of things are being investigated. Is it study design? Is it the patient population? Is it the centers that are doing the studies? The bottom line here as far as the acute treatment is that three agents have been found to be effective or probably useful”: sumatriptan nasal spray, ibuprofen, and acetaminophen. “While the data and practice parameters say that sumatriptan nasal spray is the only triptan shown to be efficacious in adolescents, the FDA did not approve it, based on its recalculation of that data.”

PROPHYLACTIC AGENTS

The goal with preventive agents is to decrease the frequency, severity, and duration of headaches, increase response to acute treatment agents, and improve a patient’s function and quality of life, according to Dr. Lewis. “Unfortunately, as with the acute data, there are very little control data” regarding prophylactics in children and adolescents. Cyproheptadine has been studied in one retrospective analysis of 30 patients, ages 3 to 12, who were given a dose of 2 to 4 mg/day. Patients experienced a reduction in headaches from 8.4 to 3.75 per month; 83% of participants found the medicine acceptable or effective in reducing headache frequency. Side effects were weight gain and sedation—“not unexpectedly,” said Dr. Lewis.

Propranolol has had mixed results in treating migraine in children and has been “gradually falling off the radar screen,” commented Dr. Lewis. Of three controlled trials that have been conducted, two have shown results that were no better than placebo. One study found no difference between propranolol and hypnosis in reducing headache severity. However, one trial showed that 20 of 28 patients had complete remission of headache with propranolol, while only three of 28 on placebo had complete remission.

Clonidine has been studied in two double-blind, crossover, parallel trials, neither of which showed efficacy versus placebo. Amitriptyline has been analyzed in two retrospective and open-label trials, and results were roughly the same in both. Hershey et al found that the drug was effective in 84% of patients at a dose of 1 mg/ kg per day. Dr. Lewis and colleagues’ retrospective study found 89% effectiveness with amitriptyline, using a 5- to 25-mg range of dosing.

Two studies of note have been conducted with valproic acid. Caruso et al examined 42 patients, ages 7 to 16, using a moderate to high dose of 15 to 45 mg/kg/day. After four months of treatment, the researchers found that 79% of patients had a 50% headache reduction, 14% had a 75% reduction, and 9.5% became headache-free. Serdaroglu and colleagues, using isolated doses of valproic acid of 500 to 1,000 mg/day, showed that headache severity decreased from 6.8 to .7 on a 10-point scale, headache frequency declined from six to .8 per month, and headache duration was reduced from almost 5.5 to 1.1 hours.

Hershey et al did a trial with topiramate in 41 patients ages 3 to 18 who were given a dose of 1.4 mg/kg/day and found that patients’ headache frequency decreased from 16.5 to 11.6 per month. “This included a lot of patients with chronic daily headache,” Dr. Lewis said. “They decreased in severity, duration, and disability.” Toxicities were weight loss, cognitive changes, and sensory symptoms.

Miller, in a study of 19 patients (average age, 12) taking levetiracetam, using low doses of 125 to 750 mg bid, found that patients’ frequency of headaches decreased from 6.3 to 1.7 headaches per month, and elimination of headaches occurred in 52% of patients. Toxicities were observed in three patients, including somnolence, dizziness, and irritability.

Nimodipine, a calcium channel blocker, has been studied in one trial, with nonsignificant results. Flunarizine, another calcium channel blocker, has had far better success in multiple trials. “Now this is where the irony occurs,” said Dr. Lewis. “The drug that has been most rigorously studied and has been shown to be efficacious is the one not available in the United States. It is available in Canada.” Results from two double-blind, placebo-controlled, crossover trials, in which patients took a dose of 5 mg/ day of flunarizine, resulted in a significant decrease in frequency and severity of headaches. Toxicities were drowsiness and weight gain. “Based on this information, the American Academy of Neurology’s practice parameter, published in December 2004, states that the only drug that’s probably effective with the best level of data is flunarizine,” said Dr. Lewis. “Insufficient evidence exists for the others we’ve been talking about.”

ADVICE FOR CLINICIANS

Dr. Lewis emphasized that clinicians should keep the following rule in mind when it comes to treating children and adolescents with migraine, a sentence that was added to the latest practice parameters: “Failure of an agent for acute or preventive therapy to demonstrate efficacy to a statistically significant degree does not imply that these medications have no role in the pediatric population, and their use must be based upon good clinical judgment.

“I think [this] is really important to take home,” said Dr. Lewis.

NR

—Colby Stong

Suggested Reading
Ahonen K, Hamalainen ML, Rantala H, Hoppu K. Nasal sumatriptan is effective in treatment of migraine attacks in children: a randomized trial. Neurology. 2004;62:883-887.
Caruso JM, Brown WD, Exil G, Gascon GG. The efficacy of divalproex sodium in the prophylactic treatment of children with migraine. Headache. 2000;40:672-676.
Lewis DW, Diamond S, Scott D, Jones V. Prophylactic treatment of pediatric migraine. Headache. 2004;44:230-237.
Hershey AD, Powers SW, Bentti AL, Degrauw TJ. Effectiveness of amitriptyline in the prophylactic management of childhood headaches. Headache. 2000;40:539-549.
Hershey AD, Powers SW, Vockell AL, et al. Effectiveness of topiramate in the prevention of childhood headaches. Headache. 2002;42:810-818.
Lewis DW, Kellstein D, Dahl G, et al. Children’s ibuprofen suspension for the acute treatment of pediatric migraine. Headache. 2002;42:780-786.
Miller GS. Efficacy and safety of levetiracetam in pediatric migraine. Headache. 2004;44:238-243.
Serdaroglu G, Erhan E, Tekgul H, et al. Sodium valproate prophylaxis in childhood migraine. Headache. 2002;42:819-822.
Winner P, Rothner AD, Saper J, et al. A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents. Pediatrics. 2000;106:989-997.

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