Randomized trial of sumatriptan and naproxen sodium combination in adolescent migraine.

BACKGROUND: Treatment of adolescent migraine remains a significant unmet medical need. We compared the efficacy and safety of 3 doses of sumatriptan and naproxen sodium (suma/nap) combination tablets to placebo in the acute treatment of adolescent migraine. METHODS: This randomized, parallel group study in 12 to 17 year olds required 2 to 8 migraines per month (typically lasting >3 hours untreated) for ≥ 6 months. Subjects entered a 12-week run-in phase, treating 1 moderate-to-severe migraine (attack 1) with single-blind placebo. Subjects reporting headache pain 2 hours after dosing were randomly assigned into a 12-week double-blind phase, treating 1 moderate-to-severe migraine (attack 2) with placebo (n = 145), suma/nap 10/60 mg (n = 96), 30/180 mg (n = 97), or 85/500 mg (n = 152). The primary end point was the percentage of subjects pain-free at 2 hours. RESULTS: The attack 2 adjusted (age; baseline pain severity) 2-hour pain-free rates were higher with suma/nap 10/60 mg (29%; adjusted P = .003), 30/180 mg (27%; adjusted P = .003), and 85/500 mg (24%; adjusted P = .003) versus placebo (10%). Posthoc primary end-point analyses did not demonstrate differences among the 3 doses or an age-by-treatment interaction. Statistically significant differences were found for 85/500 mg versus placebo for sustained pain-free 2 to 24 hours (23% vs 9%; adjusted P = .008), 2-hour photophobia-free (59% vs 41%; adjusted P = .008), and 2-hour phonophobia-free (60% vs 42%; adjusted P = .008). Analyses of other pain, associated symptoms, rescue medication use, and health outcome end points supported higher efficacy for active doses versus placebo. All active doses were well tolerated. CONCLUSIONS: All doses of suma/nap were well tolerated, providing similarly effective acute treatment of adolescent migraine pain and associated symptoms, as compared with placebo.

Long-term evaluation of sumatriptan and naproxen sodium for the acute treatment of migraine in adolescents.

OBJECTIVES: To evaluate the long-term safety, tolerability, effectiveness, impact on quality of life, and medication satisfaction of sumatriptan/naproxen sodium in the acute treatment of migraine headache in adolescents. METHODS: This 12-month, multicenter, open-label, safety study was conducted in adolescents (aged 12-17 years) with an average of 2-8 migraines/month typically lasting >2 hours untreated for >6 months prior to initiation. Subjects were instructed to treat migraines as early as possible and were allowed to rescue 2 hours post dose with a single dose of a naproxen-containing product, over-the-counter pain reliever, or anti-emetics. Subjects were advised not to take a second tablet of sumatriptan/naproxen sodium without at least a 24-hour headache-free period. Safety evaluations included adverse events, laboratory tests, and vital signs and electrocardiogram evaluation. Other evaluations included freedom from pain, quality of life, and medication satisfaction. RESULTS: Of the 656 subjects enrolled, 622 (95%) treated at least 1 migraine with sumatriptan/naproxen sodium, of which 435 (70%) and 363 (58%) completed 6 and 12 months of the study, respectively. Overall, there were 12,927 exposures to sumatriptan/naproxen sodium: on average 2.5 tablets were taken per month per subject. The most common treatment-related adverse events were nausea (7%), dizziness (3%), muscle tightness (3%), and chest discomfort (3%). There were no deaths; 4 subjects had 5 serious adverse events (suicide attempt, hemolytic anemia and syncope, suicidal ideation, spontaneous abortion) unrelated to sumatriptan/naproxen sodium and resolved without sequelae. Seven percent of subjects discontinued participation in the study because of an adverse event; 5% of subjects discontinued due to lack of efficacy. Overall, 42% of the migraine attacks were pain-free within 2 hours of treatment with sumatriptan/naproxen sodium, subjects reported improvements from baseline in 2 of 3 quality of life domains over time, and were generally satisfied with the efficacy and overall treatment at the end of the study. CONCLUSION: In adolescent migraineurs, after up to 12 months and over 12,000 exposures to sumatriptan/naproxen sodium, there were no new or clinically significant findings in the safety parameters, including the frequency and nature of adverse events, as compared to the individual components or to the adverse event profile in adults. In addition, sumatriptan/naproxen sodium provided freedom from pain over time, improvements in quality of life and medication satisfaction.

Favorable outcome of early treatment of new onset child and adolescent migraine-implications for disease modification.

There is evidence that the prevalence of migraine in children and adolescents may be increasing. Current theories of migraine pathophysiology in adults suggest activation of central cortical and brainstem pathways in conjunction with the peripheral trigeminovascular system, which ultimately results in release of neuropeptides, facilitation of central pain pathways, neurogenic inflammation surrounding peripheral vessels, and vasodilatation. Although several risk factors for frequent episodic, chronic, and refractory migraine have been identified, the causes of migraine progression are not known. Migraine pathophysiology has not been fully evaluated in children. In this review, we will first discuss the evidence that early therapeutic interventions in the child or adolescent new onset migraineur, may halt or limit progression and disability. We will then review the evidence suggesting that many adults with chronic or refractory migraine developed their migraine as children or adolescents and may not have been treated adequately with migraine-specific therapy. Finally, we will show that early, appropriate and optimal treatment of migraine during childhood and adolescence may result in disease modification and prevent progression of this disease.

Obesity in the pediatric headache population: a multicenter study.

OBJECTIVE: To examine the prevalence of obesity, the relationship between weight compared with headache frequency and disability, and effect of weight change on headache outcomes within a pediatric headache population. BACKGROUND: Headache and obesity are both common conditions in children and adults. Research in adults has suggested a relationship between the 2 conditions. This relationship has not yet been explored within a pediatric population. The effect of obesity and weight change on headache outcomes may have important implications for clinical care. METHOD: Data on height, weight, age, and gender, as well as headache frequency and disability, were collected on 913 consecutive patients at 7 pediatric headache centers, the body mass index (BMI) calculated and the BMI percentile determined. The same data were collected on patients seen at 3- (n = 213) and 6-month (n = 174) follow-up for comparative analysis. RESULTS: The prevalence of overweight patients at initial visit did not significantly differ from the general pediatric population. BMI percentile was significantly correlated with headache frequency and disability at initial visit, although the correlations were relatively small. For children who were obese or at risk for overweight as initial visit, change in BMI was significantly positively correlated with change in headache frequency at 3- and 6-month follow-up. CONCLUSIONS: Obesity is associated with headache frequency and disability in the pediatric headache population. For children who are overweight, weight loss can contribute to a reduction in headaches over time. Clinicians should consider child weight status in providing care for pediatric headache.

North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition consensus statement on the diagnosis and management of cyclic vomiting syndrome.

Cyclic vomiting syndrome (CVS) is a disorder noted for its unique intensity of vomiting, repeated emergency department visits and hospitalizations, and reduced quality of life. It is often misdiagnosed due to the unappreciated pattern of recurrence and lack of confirmatory testing. Because no accepted approach to management has been established, the task force was charged to develop a report on diagnosis and treatment of CVS based upon a review of the medical literature and expert opinion. The key issues addressed were the diagnostic criteria, the appropriate evaluation, the prophylactic therapy, and the therapy of acute attacks. The recommended diagnostic approach is to avoid "shotgun" testing and instead to use a strategy of targeted testing that varies with the presence of 4 red flags: abdominal signs (eg, bilious vomiting, tenderness), triggering events (eg, fasting, high protein meal), abnormal neurological examination (eg, altered mental status, papilledema), and progressive worsening or a changing pattern of vomiting episodes. Therapeutic recommendations include lifestyle changes, prophylactic therapy (eg, cyproheptadine in children 5 years or younger and amitriptyline for those older than 5), and acute therapy (eg, 5-hydroxytryptamine receptor agonists, termed triptans herein, as abortive therapy, and 10% dextrose and ondansetron for those requiring intravenous hydration). This document represents the official recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition for the diagnosis and treatment of CVS in children and adolescents.

Efficacy and tolerability of almotriptan in adolescents: a randomized, double-blind, placebo-controlled trial.

OBJECTIVES: To assess the efficacy and safety of almotriptan 6.25 mg, 12.5 mg, and 25 mg vs placebo for acute migraine treatment in adolescents. PATIENTS AND METHODS: In this double-blind, placebo-controlled, parallel-group, multicenter trial, 866 patients aged 12 to 17 years with a >1 year history of migraine (per International Headache Society criteria) were randomized to treat one migraine headache with almotriptan 6.25 mg, 12.5 mg, 25 mg, or placebo. The primary efficacy endpoint was headache pain relief 2 hours after dosing, adjusted for baseline severity, with absence of nausea, photophobia, and phonophobia 2 hours after dosing as coprimary endpoints. RESULTS: The 2-hour pain-relief rate was significantly higher with almotriptan 25 mg compared with placebo (66.7% vs 55.3%; P = .022). The incidence of nausea, photophobia, and phonophobia at 2 hours (adjusted for baseline pain intensity) for the almotriptan 25 mg and placebo groups was not significantly different. The 2-hour pain-relief rates (unadjusted) were significantly higher with almotriptan 6.25 mg (71.8%), 12.5 mg (72.9%), and 25 mg (66.7%) than with placebo (55.3%; P = .001, P < .001, and P = .028, respectively). Rates for sustained pain relief also were significantly greater with almotriptan 6.25 mg (67.2%), 12.5 mg (66.9%), and 25 mg (64.5%) than with placebo group (52.4%), P < .01 for the 6.25- and 12.5-mg doses and P < .05 for the 25-mg dose. Age group subanalysis demonstrated significantly greater 2-hour pain-relief rates with all 3 doses of almotriptan compared with placebo for patients aged 15 to 17 years, a significantly lower incidence of photophobia and phonophobia at 2 hours with almotriptan 12.5 mg compared with placebo for patients aged 15 to 17 years, and a significantly lower incidence of photophobia with almotriptan 12.5 mg compared with placebo for those aged 12 to 14 years. Almotriptan treatment was well tolerated, with the most common adverse events (>2%) of nausea, dizziness, and somnolence. CONCLUSIONS: Oral almotriptan was efficacious for relieving migraine headache pain in adolescents, with the 12.5-mg dose associated with the most favorable efficacy profile with respect to relieving headache pain and associated symptoms of migraine (photophobia and phonophobia). Almotriptan treatment was well tolerated in this adolescent population.

Atomoxetine treatment of ADHD in children with comorbid Tourette syndrome.

OBJECTIVE: This study examines changes in severity of tics and ADHD during atomoxetine treatment in ADHD patients with Tourette syndrome (TS). METHOD: Subjects (7-17 years old) with ADHD (Diagnostic and Statistical Manual of Mental Disorders, DSM-IV) and TS were randomly assigned to double-blind treatment with placebo (n = 56) or atomoxetine (0.5-1.5 mg/kg/day, n = 61) for approximately 18 weeks. RESULTS: Atomoxetine subjects showed significantly greater improvement on ADHD symptom measures. Treatment was also associated with significantly greater reduction of tic severity on two of three measures. Significant increases were seen in mean pulse rate and rates of treatment-emergent nausea, decreased appetite, and decreased body weight. No other clinically relevant treatment differences were observed in any other vital sign, adverse event, laboratory parameter, or electrocardiographic measure. CONCLUSION: Atomoxetine is efficacious for treatment of ADHD and its use appears well tolerated in ADHD patients with comorbid TS.

Post-traumatic headache.

Post-traumatic headaches as well as post-traumatic syndrome can occur in patients after mild, moderate, or severe traumatic brain injury. Most of the patients' symptoms clear within the first 3 to 6 months; however, there are no precise criteria for predicting the clinical outcome. The diagnostic criteria for post-traumatic headaches were defined by the International Headache Society in 2004 and are helpful for classification. Evaluation must be done on an individual basis, and patients who do not clear their symptoms may need neuroimaging. The headaches fall into the category of chronic tension-type headache as well as headaches compatible with migraine and are treated in a similar fashion. There is a small group of people who do not respond and have long-term problems. These patients may benefit from a combination of pharmacologic, nonpharmacologic, and neuropsychiatric treatment. Long-term studies are needed to help clarify the history of these patients.

Eletriptan for the acute treatment of migraine in adolescents: results of a double-blind, placebo-controlled trial.

BACKGROUND: Eletriptan is a potent 5-HT(1B/1D) agonist with proven efficacy in the acute treatment of migraine in adults. OBJECTIVE: To evaluate the efficacy and tolerability of eletriptan 40 mg versus placebo in adolescent patients (aged 12-17). METHODS: A multicenter, double-blind, parallel-group, placebo-controlled trial was conducted comparing 40 mg of oral eletriptan with placebo for the treatment of migraine in adolescent patients. The primary efficacy endpoint was 2-hour headache response, and a number of secondary endpoints were also evaluated. An exploratory analysis evaluated which clinical and demographic characteristics might be correlated with high placebo response. RESULTS: Of 274 patients who treated a migraine attack, 267 were evaluated for efficacy (n = 138 eletriptan; n = 129 placebo) at 2 hours post-dose. There was no significant difference in 2-hour headache response for eletriptan 40 mg versus placebo (57% vs 57%), and no significant improvements were observed for any of the outcomes at 1 or 2 hours post-dose. By contrast, there was a significant advantage for eletriptan 40 mg in reducing headache recurrence within 24 hours post-dose (11% vs 25%, P= .028), and post hoc analyses showed statistically significant differences for sustained headache response rates (52% vs 39%; P= .04) and sustained pain-free response rates (22% vs 10%; P= .013). The strongest clinical predictor of placebo response was triptan-naïve status (i.e., no previous use of any triptan). Eletriptan 40 mg was well tolerated in this population, and the profile of adverse events was similar to that observed in Phase III trials in adult patients. CONCLUSIONS: The high placebo response rates reported here for 1- and 2-hour outcomes are in accordance with other studies of triptans in adolescent patients. The evaluation of treatment effect in adolescent migraine might benefit from use of more stringent outcome measures, such as headache recurrence, sustained headache response, and sustained pain-free response at 24 hours post-dose.

Use of the ICHD-II criteria in the diagnosis of pediatric migraine.

OBJECTIVE: To evaluate the sensitivity of the new International Classification of Headache Disorders-2nd edition (ICHD-II) criteria in the diagnosis of childhood migraine and to propose specific criteria for the diagnosis of childhood migraine. BACKGROUND: In 2004, ICHD-II was adopted by the International Headache Society. The prior version had been criticized for its lack of sensitivity in diagnosing childhood headaches. ICHD-II is felt to be an improvement as it provides for some differences between pediatric and adult migraine diagnosis in its footnotes, however, has yet to be validated. Clinically, it is the impression of many pediatric headache specialists that children's migraines are of shorter duration, tend to be bilateral rather than unilateral, and that children more often report either photophobia or phonophobia, rather than both. METHODS: The characteristics of headache in 260 patients, ages 18 and under, clinically diagnosed with migraine at two large pediatric headache centers were compiled using standard intake questionnaires. Inter-rater reliability in clinical diagnosis was determined by consensus of the clinical diagnosis. These data were analyzed applying the International Classification of Headache Disorders-1st edition (ICHD-I) and ICHD-II criteria for migraine to determine sensitivity of migraine diagnosis in comparison with clinical impression. Each headache characteristic in ICHD-II was analyzed individually to determine its effect on sensitivity of diagnosis. RESULTS: 183/260 patients (70.4%) met ICHD-I criteria. 161/260 patients (61.9%) met the ICHD-II criteria with a 4- to 72-hour range. When the footnoted allowance of ICHD-II for short duration (2 hours) was utilized, 187/260 patients (71.9%) met criteria, while this improved to 192/260 patients (73.9%) with 1-hour duration. If duration was excluded, 210/260 patients (80.8%) met criteria. The most common reasons for patients not meeting the standard criteria were the requirement of unilateral location, headache duration and number of associated symptoms. Based on these observations, modified criteria were empirically derived and the sensitivity increased to 84.4%. Data were reanalyzed using the criteria of focal head pain, either bilateral or unilateral, shortened duration, and modified associated symptoms, which resulted in an improved sensitivity in migraine diagnosis of 84.4%. CONCLUSIONS: Modification of ICHD-II criteria to include bilateral headache, headache duration of 1 to 72 hours, and nausea and/or vomiting plus two of five other associated symptoms (photophobia, phonophobia, difficulty thinking, lightheadedness, or fatigue), in addition to the usual description of moderate to severe pain of a throbbing or pulsating nature worsening or limiting physical activity, improved sensitivity of migraine diagnosis to 84.4%.

Do children and adolescents have chronic daily headaches? Yes!

Chronic daily headaches in children and adolescents appear to have been increasing throughout the past few decades. The diagnosis, classification, treatment, and long-term prognosis continue to be poorly understood. Recent epidemiologic studies and updated classifications have been done in this area, but further work is needed to help these children.

Management of migraine in children and adolescents in the emergency department and inpatient setting.

Migraine is a chronic disorder that can be debilitating, especially when the attacks are severe and frequent. Children and adolescents are significantly affected. The prevalence of migraine in this age group is higher than predicted due to more recognition of the disease in this population throughout the past century. Severe chronic migraine can cause failure in academic work and may lead to depression. Multiple medications are used to break an acute attack. Most approaches are based on outpatient treatments and include the use of over-the-counter medications and triptans and narcotics. This manuscript reviews most of the available therapies for acute treatment of primary headache that did not respond to outpatient management.

Understanding the comprehensive pediatric headache examination.

Understanding and learning how to perform a comprehensive headache examination is an important part of any pediatric practice. Developing these skills allows clinicians to better take care of their patients and, when necessary, obtain a more extensive consultation.

Acute treatment of pediatric headache in the emergency department and inpatient settings.

Migraine headache can be debilitating. If initiated early, aggressive management may prevent severe disability and failure at school. It must be noted that treatments available for use for acute migraine headache in children and adolescents are off-label. Their use is widespread, but double-blind, placebo-controlled studies are still unavailable for this age group.