A multicenter, randomized, double-blind, placebo-controlled, crossover trial to evaluate the efficacy and safety of zolmitriptan nasal spray for the acute treatment of migraine in patients aged 6 to 11 years, with an open-label extension.

OBJECTIVE: To evaluate the efficacy and safety of zolmitriptan nasal spray (ZNS) in the acute treatment of migraine headache in patients aged 6 to 11 years. BACKGROUND: Triptans have demonstrated efficacy in adults, but pediatric studies of these agents have largely failed and there are few triptan options for these patients. Because lack of response to 1 triptan does not necessarily preclude response to an alternate triptan, additional triptan options for pediatric patients are desirable. METHODS: This Phase 3, randomized, double-blind, placebo-controlled, multicenter crossover trial with an open-label extension enrolled patients aged 6 to 11 years with a diagnosis of migraine for ≥6 months and ≥16 headache-free days/month (N = 373). After a run-in period to eliminate placebo responders, 186 patients were randomized within their body weight stratum to ZNS followed by matching placebo, or placebo followed by matching ZNS. Patients <50 kg who were randomly allocated to ZNS were randomized to 5:1 to ZNS 2.5 or 1.0 mg; those ≥50 kg were randomized 5:1 to ZNS 5.0 or 2.5 mg. Patients had 6 weeks to treat 1 moderate to severe migraine headache and then crossed over to the alternate arm, during which they had 6 weeks to treat a second migraine attack. Patients could participate in a subsequent 6-month outpatient open-label extension. The primary efficacy endpoint was pain-free status at 2 h in patients treated with the high dose from each stratum. RESULTS: The trial was terminated early due to slow enrollment. Three hundred patients (mean age, 9 years) entered the placebo run-in period and 186 entered the double-blind period. Pain-free status at 2 h postdose was achieved by 45/133 (33.8%) and 30/128 (23.4%) of patients who received high-dose ZNS and placebo, respectively (p = 0.0777; odds ratio [OR] 1.51; 95% confidence interval [CI] 0.96, 2.38). Several secondary endpoints achieved statistical significance. There were few treatment-related adverse events and none led to discontinuation. ZNS retained efficacy and demonstrated a consistent safety profile throughout the 6-month open-label extension. CONCLUSION: The effect of high-dose ZNS on the primary endpoint of pain-free status at 2 h did not achieve statistical significance. ZNS was safe and well tolerated in this pediatric population.

Efficacy of IV Valproic Acid and Oral Valproic Acid Tapers for the Treatment of Pediatric Headaches in the Emergency Department.

Background and Objectives: Pediatric headaches, including migraine, are a common reason for emergency department (ED) presentation. IV valproic acid (VPA) followed by oral VPA tapers are often used to abort pediatric headache and reduce recurrence, though limited data exist regarding this approach. This study evaluated the effectiveness of IV VPA and oral VPA tapers for the treatment of acute pediatric headaches in the ED in preventing return encounters. Methods: This is a retrospective cohort study of patients aged 5-21 years presenting to a tertiary-care pediatric ED from 2010 to 2016 who received IV VPA for headache or migraine. Primary outcomes were ED disposition, percent pain reduction (initial vs 2-hour patient-reported pain score [10-point scale]), and return for acute headache treatment within 1 month. Results: A total of 486 ED encounters were included with a median patient age of 15 years; most of them were females (76%, 369/486). Of available pain scores within 2 hours of IV VPA administration, 41% (173/425) had ≥50% pain reduction. Fifty-two percent (254/486) were discharged without additional treatment, 14% (69/486) were discharged after additional treatment, and 33% (163/486) were admitted to the hospital. Initial pain score, number of preceding home treatments, and number of preceding ED treatments were not associated with ED disposition. Oral VPA tapers were prescribed in 39% (94/253) of encounters when the patient was discharged after IV VPA. Oral VPA tapers produced a transient decrease in recurrence at 72 hours, which was no longer present at 1 week nor 1 month. There was no difference in the time to recurrence or total number of return visits within 1 month. Discussion: IV VPA was efficacious in treating pediatric headaches evaluated in the ED, with nearly two-thirds of patients discharged home after administration. Oral VPA tapers did not reduce total headache recurrence nor time to recurrence. Given the limited benefit of oral VPA tapers, this practice should be re-examined. Classification of Evidence: This study provides Class IV evidence that for children with headache seen in the ED, IV VPA reduces head pain and Class III evidence that following this with an oral VPA taper is of no benefit.

Headache and Sleep Disturbances in the Pediatric Population.

The relationship between sleep disturbances and headaches in the pediatric population is bidirectional. Common underlying molecular mechanisms of sleep and headaches have been speculated to explain the clinical connection. We will summarize various sleep disturbances and their known relationships to headache, focusing on the pediatric population. Careful recognition and assessment of sleep disturbances in patients with headache is critical and may help guide treatment. First line therapies for sleep disturbances consist of behavioral approaches, though surgical and pharmacologic strategies are utilized in particular circumstances.

Pharmacologic treatment of migraine.

Nonsteroidal anti-inflammatory drugs are the mainstay of migraine treatment for children and adolescents by most primary care physicians. Not all patients respond to these readily available agents. Triptans have been studied in children and adolescents, and there is reasonable evidence to support the use of these agents in these populations. Other agents, such as combination preparations and ergot compounds, are also used in clinical practice, although there has been little scientific study. Prophylactic agents have been less well studied in those under 18 years of age. Agents such as antidepressants, anticonvulsants, and antihypertensives are commonly used in clinical practice. Safety issues are fairly well understood because of historical use and use for other conditions. Efficacy and optimal dosing have yet to be established for the treatment of migraine in children and adolescents in double-blind, randomized, placebo-controlled trials.