Abstract
The diagnosis of migraine headache in childhood rests on criteria similar to those used in migraine in adults. It is important, however, to appreciate several fundamental differences. These differences include the duration of attack, which is often far shorter than in an adult, and the location of the attack, which may be bilateral in many children.
The treatment of children and adolescents with migraines includes treatment modalities for acute attacks, preventive medications when the attacks are frequent, and biobehavioral modes of therapy to address long-term management of the disorder. The controlled clinical trials of medications in pediatric migraine have suffered from high placebo response rates that may be related to the sites conducting the study (ie, headache specialist vs clinical research organizations). The medications have proved to be safe in the pediatric age group.
Treatment modalities for acute migraine include over-the-counter nonsteroidal anti-inflammatory drugs (NSAIDs), as well as the oral triptans such as sumatriptan succinate, rizatriptan benzoate, and zolmitriptan and the nasal spray formulations of sumatriptan and zolmitriptan. Subcutaneous sumatriptan and parenteral dihydroergotamine have also been used limitedly.
Preventive treatment for patients with frequent or disabling migraines (or both) includes the antidepressants amitriptyline hydrochloride and nortriptyline hydrochloride, the anticonvulsants divalproex sodium and topiramate, and the antihistaminic agent cyprohepatine hydrochloride. Biobehavioral approaches aimed at addressing the fundamental lifestyle issues and nonpharmacologic approaches to management are fundamental to long-term success.
Headache, and more particularly migraine, is a frequent health problem in children and adolescents.
1 Estimates are that headaches occur in up to 75% of adolescents and 25% of younger children.
2 The greatest impact on a child and parent is from migraine, which occurs in up to 10.6% of children between the ages of 5 and 15 years,
3 and 28% in children aged 15 to 19 years.
4 This prevalence ranks headache and migraine in the top five health problems of childhood.
Despite its prevalence, migraine remains commonly undiagnosed or misdiagnosed, just as in adults in whom migraine is often attributed to sinus disease.
5 This misdiagnosis has been demonstrated in adults to result in a significant impact on treatment, disability, and quality of life. Similarly in children, frequent headaches can cause a significant impact on disability,
6,7 as well as quality of life,
8,9 prompting the need for early recognition and treatment.
The long-term outcome of childhood headaches and evolution into adult headaches remains largely unknown. It has been suggested that for adults migraine may represent a progressive disorder.
10 In children, however, the progressive nature is unclear and further studies into longitudinal outcome and phenotypic changes in childhood headaches have yet to be identified.
The 5-hydroxytryptamine 1 (5-HT1) agonists (triptans) have revolutionized the treatment of adults with moderate to severe migraines. Seven triptans are currently available for use in the United States. Currently, there are no triptans approved by the US Food and Drug Administration (FDA) for the use in pediatric migraine. They continue to be used in this age group, though additional studies need to be done in this age group to validate their effectiveness.
Triptans are now available as injections (sumatriptan), nasal sprays (sumatriptan and zolmitriptan), tablets (sumatriptan, zolmitriptan, rizatriptan, almotriptan malate, eletriptan hydrobromide, naratriptan hydrochloride, and frovatriptan succinate), and dissolving tablets (zolmitriptan and rizatriptan). The wide variety of medications and formulations allows for flexibility in treatment plans.
Several of these formulations have been evaluated in children. One of the initial studies evaluated subcutaneous sumatriptan succinate at a dose of 0.06 mg/kg. It had an overall effectiveness of 72% at 30 minutes and 78% at 2 hours, with a low recurrence rate of 6%.
22 Children, however, often reject the idea of needles or injections during headache attacks, and the use of the subcutaneous form of sumatriptan has been limited in children.
As in adults, children prefer the oral route of administration of medications, and several oral triptans have been studied in children.
23 Sumatriptan succinate has been studied in a double-blind, placebo-controlled study with 25-mg, 50-mg, and 100-mg tablets.
24 Overall, the active treatment showed that 74% had pain relief at 4 hours. The study's primary endpoint, however, was at 2 hours, and statistical significance was not reached because of a high placebo response rate.
Headache recurrence rates are lower in children than adults and average between 18% and 28% for sumatriptan. Serious adverse events are rare in children. Use of a 50-mg dose of sumatriptan succinate compared with placebo had a slightly increased risk of side effect for sensations such as warmth and tightness, burning pain, numbness, and strange feelings. Such side effects occurred in 1% to 4% of children at this dose and increased slightly at 100-mg doses.
Sumatriptan succinate nasal spray at 5-mg, 10-mg, and 20-mg doses has been studied in a randomized, double-blind, placebo-controlled trial in adolescents aged 12 to 17 years, for a single attack.
25 The 2-hour pain-free response showed the 20-mg dose was statistically significant with a 46% response rate compared with 25% for placebo. The 20-mg dose of sumatriptan succinate also produced significant reduction in the migraine-associated symptom of photophobia by 2 hours and yielded a reduced headache pain recurrence rate compared with placebo overall. There was no difference, however, in the need for rescue medication use in the active and placebo groups.
A more recent nasal sumatriptan succinate study using 5-mg, 20-mg, and placebo dosing in a 1:1 ratio with 738 adolescents did demonstrate that at 30 minutes, a 20-mg dose had a greater headache relief (42% vs 33%,
P = .026).
26 At 1 hour, this increased to 61% for active medicine versus 52% for placebo (not significant). By 2 hours, response was increased to 68% for sumatriptan versus placebo (
P = .025).
26 Also, the increased pain-free response was sustained. The most common side effect was taste disturbance for the sumatriptan-treated group. In summary, these studies demonstrate that the 20-mg sumatriptan succinate nasal spray provided rapid, well-tolerated treatment across the adolescent population. The results were similar to those in studies of sumatriptan nasal spray in adults.
Rizatriptan benzoate 5-mg tablets have also been evaluated in the 12-to-17-year age group in a double-blind, placebo-controlled, parallel-group, single-attack study.
27 Of 149 adolescents using rizatriptan compared with 147 using placebo, the response rate at 2 hours for the rizatriptan-treated group was 66% compared with 57% for placebo. The pain-free rate at 2 hours was 32% for the rizatriptan-treated group compared with 28% in the group receiving placebo. No serious adverse effects were noted. The most common adverse effects reported were fatigue, dizziness, somnolence, dry mouth, and nausea. In summary, Rizatriptan benzoate, 5 mg, was well tolerated, though because of the high placebo rate, statistical significance was not achieved.
Using both the 2.5-mg and the 5-mg dose, another study examined oral zolmitriptan in adolescents aged 12 to 17 years.
28 The response rates were 88% and 70%, respectively, with the treatment being well tolerated. Currently, other studies are ongoing looking at nasal spray zolmitriptan and some of the newer triptans, as well as uses of triptans in even younger populations.
Several treatment models for acute migraine have been applied to adults.
29 Ideally, it would be possible to translate these to the pediatric population. One is as rescue therapy or “stepwise treatment within an attack,” whereby the child starts with an NSAID at an appropriate dose of 10 mg of ibuprofen per kilogram of body weight at the onset of headaches. If the child recognizes that this therapy is not effective, then a triptan is used as rescue therapy.
The alternative method is the “stratified care model.” This model has been shown to be superior for management of adult headache. It requires the patient to recognize the headache severity at the onset. For either a mild or moderate headache, the patient takes the NSAID, whereas for severe headaches, the patient takes the triptan. In this way, the patient stratifies headaches and the subsequent treatment. This second method, however, often is not successful in children, as they have difficulty recognizing the headache severity at its onset.
Amitriptyline is the most widely used tricyclic antidepressant (TCA) for headache prevention. Amitriptyline has been used for many decades for its antidepressive properties and was first recognized in the 1970s as an effective migraine therapy.
36-38 Most of the studies using amitriptyline in children have been open-label studies; no placebo-controlled studies have been done.
In a crossover study comparing amitriptyline with propranolol and cyproheptadine, Levinstein
39 found amitriptyline to be effective in 50% to 60% of the children. In an open-label study, Hershey et al
40 demonstrated that amitriptyline hydrochloride at a dose of 1 mg/kg/d resulted in a perceived improvement in more than 80% of the children, with a subsequently decreased headache frequency and impact on the children.
40 Because of side effects such as somnolence, amitriptyline must be slowly titrated to this dose over 8 to 10 weeks, increasing the dose by 0.25 mg/kg/d every 2 weeks.
The side effects of amitriptyline include dry mouth, dry eyes, lightheadedness, constipation, sleepiness, and unmasking of an underlying cardiac arrhythmia. In general, however, most children tend to tolerate this TCA well without notable side effects. Nortriptyline hydrochloride has often been used in place of amitriptyline to reduce concern about the sleepiness side effect; however, it does increase the concern of arrhythmia. Therefore, regular monitoring with electrocardiograms may be required if nortriptyline is chosen.
Serotonin selective reuptake inhibitors (SSRIs) have been studied in the treatment of adults for headaches, but they have not been studied in children. They are not as effective, however, as the TCAs, most likely because of nonselective effects of the TCAs, compared with the SSRIs, suggesting that a more global decrease in neurotransmitter reuptake inhibition is needed to manage the hypersensitivity of childhood headache disorders.
Headaches in children and adolescents can be a frequently disabling disorder with a significant impact on the quality of life of both children and parents. Proper diagnosis and recognition are essential for management of these disorders. Migraine tends to be the most frequent disorder seen in primary care offices and tertiary referrals.
Treatment and management require a three-leveled approach, including medication management of acute episodes, often requiring a primary and secondary medication; prophylactic treatment for frequent or disabling headaches; and biobehavioral management for lifelong effectiveness. Evaluation requires full pediatric, neurologic, and comprehensive headache examinations, with consideration of ancillary testing if secondary headaches are suspected.
Dr Hershey currently receives grants or contracts or honoraria from MedPointe, Inc; Ortho-McNeil Pharmaceutical, Inc; Johnson & Johnson; Pfizer Inc; GlaxoSmithKline; and Merck & Co, Inc. Dr Winner is a consultant, speaker, and researcher with GlaxoSmithKline; Ortho-McNeil Pharmaceutical, Inc; AstraZeneca; Pfizer Inc; Merck & Co, Inc; and Allergan; and he is a research advisor to Capnia.
This continuing medical education publication supported by an unrestricted educational grant from Merck & Co, Inc
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