Anticonvulsant Use for Prophylaxis of the Pediatric Migraine
Article Outline
Teri Woo, PhD(c), MS, RN, CPNP
University of Portland School of Nursing
Kaiser Permanente
Portland, Oregon
Elizabeth Farrington, PharmD, FCCP, BCPS
University of North Carolina
School of Pharmacy and
North Carolina Children’s Hospital
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Migraines are common in the pediatric population. Approximately 3% of children aged 3 to 7 years experience migraines. Prevalence increases to 4% to 11% in children 7 to 11 years of age, and it increases to 8% to 23% in children older than 11 years (Lewis et al., 2004). Boys tend to have an earlier onset of migraines than do girls (7.2 versus 10.9 years, respectively).
Many children with migraines require prophylactic therapy. Nonpharmacologic therapies such as abiding by appropriate sleep patterns, diet, and exercise may be helpful in preventing headaches. If the patient can identify triggers, such as particular foods or caffeine, avoidance is recommended, if possible. Although no clinical studies are available in the pediatric population, children may benefit from nonpharmacologic therapies.
Pharmacotherapy prophylaxis may be utilized to reduce the frequency, duration, or severity of migraines and improve the patient’s quality of life (Lewis et al., 2004). Reducing disability and increasing function are important goals of therapy. Prophylactic therapy may be considered when patients have frequent migraines, recurrent episodes that cause impairment despite acute relief, or uncommon migraine conditions such as basilar or hemiplegic migraines (Silberstein, 2000). Patients who are unable to tolerate, overuse, or have contraindications for acute therapies should also be considered for prophylactic therapy (Silberstein). Patient preference in addition to financial issues may warrant therapy as well (Silberstein). Further considerations in children are that the family may be directly or indirectly affected by the child’s migraines. Parents may have to leave work to pick up a child with a migraine from school. Parental and child social functioning also may be impaired if the child has frequent migraines.
Several mediations have been touted to prevent migraines in children. However, few actually have clinical trials demonstrating efficacy in this population (Eiland, Jenkins, & Durham, 2007). Amitriptyline and cyproheptadine have been found to be efficacious, but additional studies are warranted. Conflicting data have been reported for propranolol. Recently, more anticonvulsants are being studied for migraine prophylaxis. Valproic acid is an older anticonvulsant that has several trials in children for migraine prophylaxis, yet most of the data are from small populations and adverse effects such as weight gain, somnolence, and alopecia may limit its use (Eiland et al.; Caruso et al 2000, Serdaroglu et al 2002, Freitag et al 2002, Pakalnis et al 2001).
Newer anticonvulsants such as zonisamide and levetiracetam are becoming more popular for migraine use. One anticonvulsant, topiramate, received a Food and Drug Administration indication for migraine prophylaxis in the adult population in 2004. Few clinical studies exist regarding anticonvulsant use for migraine prophylaxis, and currently no anticonvulsants are approved for this indication in children. Gabapentin, topiramate, levetiracetam, and zonisamide use in children are detailed in this review.
Gabapentin
A retrospective review of gabapentin has been described in one abstract presentation (Belman, Milazo, Savatic, & Gabis, 2001). Fifteen children, ages 6 to 17 years, experienced greater than a 50% reduction in migraine frequency and duration. Three children stopped the medication because of adverse effects (dizziness and sleep disturbance) or lack of efficacy. Because this is the only published information regarding gabapentin in children, other studies are needed prior to recommending for migraine prophylaxis.
Topiramate
Topiramate is the anticonvulsant for which the most data have been compiled in children. Although not Food & Drug Administration indicated, several trials have evaluated its use in the pediatric population. First, it was studied in an open-label trial of 97 children (mean age approximately 13 years) who presented to a headache clinic and experienced more than three headaches per month (Hershey, Powers, Vockell, LeCates, & Kabbouche, 2002). Children initially were started on topiramate monotherapy or used it as an adjunct agent (58%). The majority of children had migraines or migraines with aura, as defined by the International Headache Society. Prior to therapy the average headache frequency was 16.5 (±10) episodes per month. The mean duration was 8 (±9) hours, and severity was 6 (±1.9) on a 10-point scale. At the first follow-up, 80.6% of patients (n = 75) reported an overall improvement in their migraines. Topiramate doses ranged from 12.5 to 200 mg/day, with an average of 84 (±38.6) mg. Only 12.5% of patients reported no change in their migraines. Patients continued to report overall improvement in migraines at the second (n = 41) and third (n = 17) visit. Specifically, headache frequency decreased to 11.6 (±10.2) at the first visit, 9.4 (±8.4) at the second visit, and 8.7 (±10.8) at the third visit, all statistically significant compared with baseline. The headache duration decreased to 5.7 (±9.8) hours at the first visit. Although not statistically significant, it may be clinically significant for some patients. The second and third visits were statistically significant at 3.7 (±6.2) and 1.9 (±2.2) hours, respectively. Severity decreased to approximately 5 out of 10 for all subsequent visits.
A strength of this trial is that it included evaluations of school days missed and the Pediatric Migraine Disability Assessment (PedMIDAS). School days missed decreased from 2.7 (±7.4) to 1.2 (±2.3), P < .05. The PedMIDAS is a scale that assesses school absences and performance as well as disabilities at home or in the social environment. The PedMIDAS score was reduced by 50% in 48.6% of children at the first visit. At the second visit, 62.5% of children reached this response. Both of these results were statistically significant compared with baseline scores.
Cognitive effects were the most common adverse effect seen with topiramate (12.5% at the first visit); however, only three patients discontinued the medication because of this effect. Paresthesias were seen at the first visit (2.8%), but 7.3% experienced it at the second visit. Patients were asked to drink orange juice to help with this adverse effect. At the first visit, 5.6% of patients had weight loss or appetite changes, but only 2.4% reported these effects at the second visit. However, the weight loss was greater (-2.7 kg ± 5.2, P < .001) at the second visit.
Overall, this study found topiramate to be effective for decreasing migraine frequency, duration, and severity in children, as well as reducing the school days missed and improving quality of life in the child. Limitations included the open label nonblinded design, with a possible placebo effect in the children.
Winner and colleagues (2005) conducted a multicenter, parallel-group, double-blind trial comparing topiramate with placebo in 162 children, aged 6 to 15 years. Patients were randomized in a 2:1 fashion, topiramate to placebo. Patients had to experience 3 to 10 migraine days (with or without aura) for 3 months prior to enrollment and the same during the 4-week prospective baseline phase. Patients for whom two or more migraine prophylaxis therapies had failed or who used other prophylaxis therapy within 14 days of enrollment were excluded from this study. Parents kept headache diaries during the baseline phase and treatment phases. The study consisted of an 8-week titration phase (25 mg/day initially and increased to 200 mg/day maximum) and a 12-week maintenance phase. The average daily dose during the maintenance period was 2 mg/kg/day. The baseline number of migraine days was 5.4 ± 1.8 per month.
In the intention to treat group (n = 157)—patients who had at least one dose of study medication and one post-baseline efficacy measurement—topiramate reduced the mean migraine days per month by 2.6 and placebo reduced it by 2 (P = .61). The per-protocol group (n = 126) showed significance with topiramate versus placebo in reducing the mean headache days by 2.8 and 2.2, respectively (P = .033). However, when examining only the last 28 days of therapy, topiramate reduced mean migraines day by 3.1 versus 2.4 with placebo in the intention to treat group (P = .023).
A total of 54.6% of patients taking topiramate and 46.9% of patients taking a placebo experienced a ≥ 50% reduction of mean migraine days per month. No difference was found between groups. However, 32.4% of patients in the topiramate group experienced ≥75% reduction in migraine days, whereas only 14.3% of patients taking a placebo had the same effect (P = .02).
Common adverse effects included upper respiratory tract infections, anorexia, weight loss (-0.7 kg ± 3.9 change), gastroenteritis, paresthesia, and somnolence. Although the primary endpoint of the study was not significant, outcomes favored topiramate for reducing mean migraine days per month in children.
A 24-patient case series also found topiramate to be beneficial for migraine prophylaxis in children (aged 6-14 years) for whom other prophylaxis medications had failed (Campistol, Campos, Casas, & Herranz, 2005). This open-label evaluation provided topiramate after a 1-month wash-out to patients. Topiramate was titrated up to 200 mg daily or 6 mg/kg/day. The mean monthly migraine episodes decreased from 3.6 at baseline to 2.9 at 2 month (P < .0001) and 2.7 at 4 months (P = .001). Severity decreased while the subjects took topiramate; in addition, 90% of children experienced a shorter migraine than previously. Phonophobia, photophobia, and nausea all produced a statistically significant decrease at months 2 and 4 while the subjects took topiramate. No patients experienced worse headaches while taking topiramate.
Common adverse effects included impaired concentration, emotional instability, paresthesia, anorexia, asthenia, and weight loss. A -1.7 kg ± 0.6 kg changes in weight was seen over the 4-month period, but this finding was not statistically significant.
These three initial studies show positive results for topiramate use in children for migraines. Three other trials evaluated topiramate in older adolescents and adults and found beneficial results as well (Brandes et al 2004, Silberstein et al 2004, Shaygannedjad et al 2006). Topiramate may be considered in pediatric patients who require migraine prophylaxis. Adverse effects, such as impaired concentration and paresthesias, may limit topiramate use in some children.
Levetiracetam
Levetiracetam has been evaluated in three small studies for migraine prophylaxis. Nineteen children (aged 3-17 years) were included in one retrospective review (Miller, 2004). Eleven of these children previously had used other prophylaxis medications. Mean headache frequency decreased from 6.3 to 1.7 per month (P < .0001). Ten patients became headache free. Seven others experienced improvement with levetiracetam; however, two patients found no benefit. Secondary symptoms such as nausea and vomiting completely disappeared in seven patients. Doses ranged from 125 to 750 mg twice daily, and mean duration of therapy was 4.1 months. Three patients experienced adverse effects with therapy. One patient had asthenia, somnolence, and dizziness, and another became irritable, hyperactive, and hostile. The third patient had irritability and moodiness. Only two of these patients discontinued therapy because of adverse effects.
One open-label monotherapy trial included 30 patients (aged 6-19 years) who had at least two migraines per week (Vaisleib, Neft, & Schor, 2005). After 10 weeks, 19 patients completed the study. Six of these patients had a greater than 50% decrease in migraine frequency and severity. Eight patients had a greater than 75% decrease in both, and three patients were headache free. Only two patients experienced worse headaches while taking levetiracetam. The PedMIDAS score decreased by more than 75% in 15 patients. One patient experienced violent behavior and delusions and thus withdrew from the trial. Ten others withdrew because of noncompliance, lack of efficacy, or seizure disorder.
A smaller study retrospectively evaluated 15 patients (aged 11-19.5 years) for whom levetiracetam was prescribed for chronic headaches (DeSouza, Shahid, & Waren). The majority of the patients (73%) experienced migraines. During a 6-week period, mean headache frequency decreased from 16.8 to 1.5. Ten patients responded with significant improvement, and two patients became headache free. Doses were initiated at 250 mg twice daily and titrated. The final average dose was 660 mg/day, with a range of 500 to 1500 mg/day. One patient, however, did not find benefit from levetiracetam, and one patient experienced more headaches on therapy. Four patients experienced fatigue, dizziness, and mood swings.
These three small trials show initial benefit with levetiracetam for migraine prophylaxis in children; however, several patients experienced adverse effects or withdrew from the study because of noncompliance. Larger studies with stronger designs are needed to fully evaluate the benefit of levetiracetam in this population.
Zonisamide
One small retrospective review evaluated 12 patients (aged 10-17 years) for whom zonisamide was prescribed and who had migraines over a 1-year period (Pakalnis & Kring, 2006). Four of the patients had chronic tension migraines. At least two prior medications for migraine prophylaxis had failed for all patients, and they had from two to 30 headache days per month. Eight patients experienced more than a 50% reduction in headache frequency with zonisamide therapy. Seven of these patients had episodic migraines. Patients with chronic daily headaches did not benefit from taking zonisamide. The duration of follow-up was 3 to 18 months, and the average daily dose of those who responded was 5.8 mg/kg/day. One patient discontinued the medication because of weight loss, and another discontinued it because of behavioral changes. This small evaluation warrants further investigation of zonisamide for migraine prophylaxis in children.
Newer anticonvulsant medications have been evaluated in small trials or retrospective reviews for use in children with migraines. However, none of these agents has been approved for migraine prophylaxis in the pediatric population, and dosing regimens have not been solidified. Of these medications, topiramate has the most data and shows efficacy, but additional trials are needed. Adverse effects should be monitored as well. Larger pediatric trials are required prior to widespread use of levetiracetam. Zonisamide and gabapentin only have one past evaluation each; therefore, additional studies are warranted before recommending these agents for migraine prophylaxis in children.
References
- . Gabapentin for migraine prophylaxis in children. [Abstract] Annals of Neurology. 2001;50:S109
- Topiramate for migraine prevention. Journal of the American Medical Association. 2004;291:965–973
- . Topiramate in the prophylactic treatment of migraine in children. Journal of Child Neurology. 2005;20:251–253
- . The efficacy of divalproex sodium in the prophylactic treatment of children with migraine. Headache. 2000;40:672–676
- . The use of levetiracetam in the prophylactic treatment of migraine headaches in adolescents. [Abstract] Headache. 2005;45:819–820
- . Pediatric migraine: Pharmacological agents for prophylaxis. Annals of Pharmacotherapy. 2007;41:1181–1190
- . A randomized trial of divalproex sodium extended-release tablets in migraine prophylaxis. Neurology. 2002;58:1652–1659
- . Effectiveness of topiramate in the prevention of childhood headaches. Headache. 2002;42:810–818
- Practice parameter: Pharmacological treatment of migraine headache in children and adolescents (Report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society). Neurology. 2004;63:2215–2224
- . Efficacy and safety of levetiracetam in pediatric migraine. Headache. 2004;44:238–243
- . Pediatric migraine prophylaxis with divalproex. Journal of Child Neurology. 2001;16:731–734
- . Zonisamide prophylaxis in refractory pediatric headache. Headache. 2006;46:804–807
- Sodium valproate prophylaxis in childhood migraine. Headache. 2002;42:819–822
- . Comparison of the effect of topiramate and sodium valproate in migraine prevention: A randomized blinded crossover study. Headache. 2006;46:642–648
- . Practice parameter: Evidence-based guidelines for migraine headache (an evidence-based review) (Report of the Quality Standards Subcommittee of the American Academy of Neurology). Neurology. 2000;55:754–762
- . Topiramate in migraine prevention. Archives of Neurology. 2004;61:490–495
- . Role of levetiracetam in prophylaxis of migraine headaches in childhood. [Abstract] Neurology. 2005;64:A343
- . Topiramate for migraine prevention in children: A randomized, double-blind, placebo-controlled trial. Headache. 2005;45:1304–1312
PII: S0891-5245(07)00304-5
doi:10.1016/j.pedhc.2007.08.006
© 2007 National Association of Pediatric Nurse Practitioners. Published by Elsevier Inc. All rights reserved.
