Calcitonin Gene-Related Peptide Inhibitors in the Treatment of Migraine in the Pediatric and Adolescent Populations: A Review.

There are limited well-studied treatments for migraine in the pediatric population. Calcitonin gene-related peptide (CGRP) inhibitors are an established safe and effective treatment in adults, and use may be appropriate for pediatric patients in certain clinical situations. We describe migraine pathophysiology as it relates to CGRP, provide an overview of available medications, and discuss clinical usage in this population.

Premonitory Symptoms in Episodic and Chronic Migraine From a Pediatric Headache Clinic.

OBJECTIVE: We evaluated the frequency of six commonly reported adult migraine premonitory symptoms in children and adolescents with episodic and chronic migraine and elicited psychological or behavioral comorbidities that may be associated with these symptoms. BACKGROUND: Premonitory symptoms are commonly reported in the adult migraine population; however, little information is available for the pediatric population. METHODS: Data were collected on new patients being evaluated in our multidisciplinary pediatric headache clinic over a six-month time interval. The data collected from patients diagnosed with migraine were then reviewed for the following premonitory symptoms: yawning, neck stiffness, fatigue, increased urination, mood changes, and food cravings. History was obtained regarding the frequency of headaches and other associated behavioral or psychological problems. RESULTS: A total of 176 patients were enrolled over a six-month interval, ranging in age from four to 18 years (mean age 12 years); 64% were female, and 42% (74 of 176) of the subjects had at least one premonitory symptom. Patients with migraine with aura were noted to have a significantly higher association with premonitory symptoms (59%, 30 of 51) (P < 0.05). Anxiety disorder was also significantly associated with premonitory symptoms (55%, 11 of 20) (P < 0.05). Fatigue and mood changes were the most commonly reported premonitory symptoms. CONCLUSIONS: Premonitory symptoms occurred frequently in our population of pediatric patients with migraine. Fatigue and mood changes were the most frequent symptoms. There were no significant differences in premonitory symptoms by gender or age group (less than 12 years versus greater than 12 years). Anxiety and migraine with aura were correlated with an increased likelihood of premonitory symptoms.

ACR Appropriateness Criteria® Headache-Child.

Headaches in children are not uncommon and have various causes. Proper neuroimaging of these children is very specific to the headache type. Care must be taken to choose and perform the most appropriate initial imaging examination in order to maximize the ability to properly determine the cause with minimum risk to the child. This evidence-based report discusses the different headache types in children and provides appropriate guidelines for imaging these children. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Management of Pediatric Migraine: Current Therapies.

Migraine is one of the most common neurologic conditions in pediatrics. It can be a significant stressor, causing absences from school and interruption of parents' work and family schedules. The mainstay of treatment remains educating patients about healthy lifestyle practices and the influences of sleep, stressors, and hydration on triggering migraine attacks. Psychological therapies such as biofeedback or cognitive-behavioral therapy may be beneficial in some patients, especially those with prominent psychological comorbidities. New advances in the pathophysiology of migraine and additional pediatric approval of abortive therapy with triptans have led to significant advances in the management of migraine in children. Some challenges to preventive therapy were recently noted with the negative results obtained in the Childhood and Adolescent Migraine Prevention Study, which compared prescription drugs to placebo. Inherent differences between adult and pediatric headaches, with shorter duration of pediatric migraine and prominent placebo effect, present recurring challenges for clinicians. [Pediatr Ann. 2018;47(2):e55-e60.].

Migraine and Hormones.

This article discusses the role that hormones play in adolescent girls and young women with headaches, which are very common in adolescent girls, in particular, migraine. In many cases, migraine onset may occur shortly around the time of menarche, prevalence of recurrent migraine in this population approaches 15%, and typically the symptoms continue through adulthood. Hormonal changes associated with puberty and the menstrual cycle may significantly influence migraine in young women. This article reviews the following topics: management of menstrually related headaches, changes in ovarian hormones and their relationship to migraine, and oral contraceptives and pregnancy effects on migraine.

What Factors Contribute to Headache-Related Disability in Teens?

BACKGROUND: Our aim was to describe the relationship between risk factors, such as stress, depression, and anxiety, and potentially protective factors against pediatric headache-related disability, such as mindfulness, resilience, and self-compassion, and to determine teens' interest in mind-body skills training to help reduce headache-related disability. METHODS: This was a cross-sectional survey among adolescents seen in an academic neurology clinic reporting four or more headaches monthly using standardized instruments to determine the relationship between putative risk and protective factors as well as physiologic markers of inflammation and vagal tone and headache-related disability. RESULTS: Among the 29 participants, 31% were male, the average age was 14.8 years, average headache frequency was 11.6 per month, and the most commonly reported trigger was stress (86%). The only risk or protective factor significantly associated with headache-related disability was depression (r = 0.52, P = 0.004). Depression was negatively correlated with mindfulness, resilience, and self-compassion (P < 0.01 each) and positively correlated with stress, sleep disturbance, and anxiety (P < 0.01 each). Biomarkers of vagal tone and inflammation were correlated with each other but not with headache-related disability or depression. There was strong interest in learning skills like slow, deep breathing practices supported by a smart phone application to reduce stress and the negative impact of headaches on daily life. DISCUSSION: Among teens with frequent migraine headaches, depression is the strongest risk factor for headache-related disability. Stress is viewed as a headache trigger, and teens reported wanting to learn simple stress management strategies supported by a smart phone application to help reduce headache-related disability.

A randomized trial of telephone-based motivational interviewing for adolescent chronic headache with medication overuse.

INTRODUCTION: Nearly 2% of youths suffer from chronic migraine or chronic tension-type headache (CTTH). A contributing factor in approximately 20%-50% of these youths is medication overuse, which involves taking analgesics three or more times per week for three months. The objective of this study was to test motivational interviewing (MI) as an approach to promote adherence to recommendations regarding not only analgesic overuse but also other aspects of treatment plans. METHODS: A randomized controlled trial was conducted comparing the experimental condition (standard of care clinic-based treatment with supplemental MI phone calls; N = 24) to a control condition (standard of care clinic-based treatment without these supplemental MI phone calls; N = 23). Four months after enrollment, a research assistant who was blinded to study condition telephoned adolescents inquiring about headache frequency, headache severity, and disability. RESULTS: Headache frequency was lower in the experimental condition versus control condition for those with relatively lower initial levels of headache frequency. In contrast, we did not find greater improvement in headache severity and disability for the experimental condition relative to the control condition. DISCUSSION: Our findings provided some preliminary, albeit limited, support for MI as an approach to improve outcomes for adolescent medication-overuse headache (MOH).

Chronic daily headache, medication overuse, and obesity in children and adolescents.

Obesity and headaches are common in children and adults. Adult studies suggest obesity is a risk factor for chronic daily headache and increased migraine frequency and severity. Pediatric studies have suggested a relationship between obesity, increasing headache frequency, and disability. The authors retrospectively evaluated 925 children from their Pediatric Headache Clinic between July 2004 and July 2008, assessing headache frequency, medication overuse, and body mass index compared to population-based norms. The pediatric headache group as a whole had a greater percentage of overweight than the general population. This was also true with the subgroup of patients with chronic tension-type headache, although the numbers were small. Data did not show increased incidence of overweight in children with medication overuse or chronic migraine. This contrasts with adult data, which have suggested a closer link between chronic migraine and obesity and have not supported a link with chronic tension-type headache.

Headaches and hormones.

It is clear that hormones play an important role in modulating and exacerbating headaches. From an epidemiologic standpoint, we know that before puberty, incidence of new headache is similar for boys and girls. By age 18, however, most new cases of migraine occur in young women. The role of sex hormones in headache is described in the context of pubertal development. Obesity and Pseudotumor also impact headache through hormonal influences. Menstrual migraine will often present in the teenage years. Oral contraceptives may worsen or ameliorate headache. This article will introduce these concepts and help the reader become familiar with the role of hormones in headache.

Long-term, open-label safety study of oral almotriptan 12.5 mg for the acute treatment of migraine in adolescents.

OBJECTIVES: This study evaluated the long-term safety of oral almotriptan 12.5 mg for the treatment of multiple migraine episodes in adolescents over a 12-month period. Efficacy outcomes were assessed as a secondary objective. METHODS: Adolescent migraineurs aged 12-17 years were enrolled in this 12-month, open-label study (Study ID CR002827). Patients were instructed to record their assessments on paper headache records whenever they experienced a migraine headache that they treated with study medication. Safety was assessed descriptively and assessments included adverse event (AE) recording, change in laboratory values, vital signs, and electrocardiogram parameters. Efficacy outcomes were assessed descriptively and outcomes included rates for 2- and 24-hour pain relief and sustained pain relief, 2- and 24-hour pain-free and sustained pain-free, and presence of migraine-associated symptoms of photophobia, phonophobia, nausea and vomiting. RESULTS: Overall, 67.1% of patients reported >or=1 AE over the course of the trial, 7.6% had an AE judged by the study investigator to be related to treatment with almotriptan, 2.4% discontinued because of an AE, and 1.9% reported serious AEs. The most commonly reported treatment-related AEs (occurring in >or=1% of patients) were nausea (1.4%) and somnolence (1.4%). Pain relief responses for treated migraines of moderate or severe intensity at baseline were 61.7% and 68.6%, at 2 and 24 hours, respectively; the sustained pain relief rate was 55.5%. Pain-free responses were reported for 40.5% of all treated migraines at 2 hours and 65.9% of treated migraines at 24 hours; the sustained pain-free rate was 38.4%. The proportion of migraines that achieved the pain relief, sustained pain relief, pain-free and sustained pain-free endpoints were similar in the 12- to 14-year and 15- to 17-year age groups. Treating with almotriptan 12.5 mg when headache pain was mild was associated with higher rates of pain relief and pain-free at 2 and 24 hours, and sustained pain relief and sustained pain-free, compared with treatment initiated when pain was severe. CONCLUSIONS: Almotriptan 12.5 mg was well tolerated in this adolescent population over a 12-month period. No unexpected safety or tolerability concerns were revealed over the course of this study. The results are consistent with almotriptan 12.5 mg being effective for the acute treatment of pain and symptoms associated with migraine in both younger and older adolescents.

Sociodemographic differences in diagnosis and treatment of pediatric headache.

The authors investigated the sociodemographic differences in receiving a headache diagnosis for pediatric health care visits using 2 nationally representative databases--the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey. For those visits involving a headache diagnosis, the authors explored 2 possible disparities in care--being diagnosed by a neurologist and being prescribed an evidence-based medication. A headache diagnosis was less common during visits for private insurance patients versus Medicaid patients. In addition, while a headache diagnosis was equally likely for visits by Caucasian American children versus African American children and children of other races, visits for the latter 2 groups were less likely to involve a headache diagnosis from a neurologist. Finally, only 37% of the headache visits involved a prescription of an evidence-based medication. The authors conclude that some sociodemographic disparities exist in pediatric headache care across the United States.

Serotonin effects on sleep and emotional disorders in adolescent migraine.

OBJECTIVE: To determine frequency of emotional disorders and sleep disturbances in adolescent migraineurs with episodic and chronic headaches. To determine the relationship of whole blood serotonin, caffeine consumption, and frequency of sleep and mood disorders. BACKGROUND: The neurotransmitter serotonin has been implicated to play a role in the initiation and maintenance of sleep and in modulating mood. A putative role in migraine pathophysiology is also known. METHODS: Adolescents from 13 to 17 years of age were identified from our headache clinic with episodic or chronic migraine (according to International Classification of Headache Disorders-Second Edition criteria) and healthy controls enrolled. Psychological rating scales were completed, including Adolescent Symptom Inventory (4th Edition) and Child Depression Inventory. Sleep questionnaires (Pediatric Sleep Questionnaire and Child Sleep Habit Questionnaire) were completed by the teenager's parents/guardian. Whole blood serotonin levels were drawn and analyzed and caffeine consumption obtained by history. RESULTS: A total of 18 controls (8 girls) and 15 patients each with episodic migraines (9 girls) and chronic migraine (10 girls) were studied. Patients with headache had significantly more sleep problems than controls. Patients with chronic migraines had increased daytime sleepiness and dysthymia compared with teenagers with episodic migraines. Serotonin levels were not significantly different, and no association was noted between serotonin levels and sleep abnormalities or emotional rating scales. Increased caffeine intake was related to sleep and depressive complaints. CONCLUSIONS: Sleep and emotional disorders were common in adolescents with migraine. Sleep disorders and dysthymia were more prevalent with increased headache frequency. No correlation was noted with whole blood serotonin levels.

Safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches: results of an open-label extension trial in adolescents.

OBJECTIVE: To evaluate the long-term safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches in adolescents. BACKGROUND: Divalproex sodium has been approved for migraine prophylaxis in adults. A previous double-blind, placebo-controlled study of the efficacy and safety of divalproex sodium extended-release for prevention of migraine in adolescents was followed by the present long-term extension trial, which was designed to collect additional safety and tolerability data. METHODS: This was a 12-month, Phase 3, open-label extension of a 3-month, double-blind, placebo-controlled, multicenter study of adolescents aged 12 to 17 years with migraine headaches who had either completed the previous study or had discontinued because of lack of efficacy. Subjects from the previous trial who had experienced serious adverse events possibly or probably related to study drug were excluded. Divalproex sodium extended-release 500 mg daily was administered for 15 days then increased to 1000 mg. Study visits were conducted at days 1 and 15 and months 1, 2, 3, 6, 9, and 12. Safety assessments included adverse event collection, laboratory testing, physical and neurological examinations, vital signs, and electrocardiograms, as well as reproductive endocrine analyses for postmenarchal female subjects. Efficacy was evaluated by sequential 4-week migraine headache rates calculated from subjects' headache diaries. RESULTS: A total of 112 subjects enrolled in the trial. The most common adverse events were weight gain (15%), nausea (14%), somnolence (12%), upper respiratory tract infection (11%), increased ammonia (8%), and sinusitis (8%). Five (4%) subjects experienced serious adverse events, and 15 (13%) subjects prematurely discontinued because of an adverse event. Increased ammonia levels were noted in some individuals, and the mean ammonia level for all subjects increased 19.2 microm from baseline. No other clinically significant changes were observed in laboratory values, vital signs, or electrocardiograms. Improvement in mean and median 4-week migraine headache rates occurred by the fourth month and lasted for the duration of the trial. CONCLUSIONS: In this long-term open-label extension study, the safety profile of divalproex sodium extended-release in adolescents with migraine was consistent with that observed in the preceding 3-month, double-blind trial and in previous adult studies. Overall, divalproex sodium extended-release was well-tolerated in adolescents aged 12 to 17 years.

Current therapies in childhood and adolescent migraine.

This review summarizes recent guidelines for diagnosis of migraine in children and adolescents and inherent issues regarding their headaches that influence evaluation of therapies. With the shorter duration of pediatric migraine attacks and the prominent placebo responder rate, design of randomized clinical trials becomes more problematic than in the adult population. Regarding abortive therapies, several agents have appreciable efficacy in randomized controlled trials. Ibuprofen, acetaminophen, and sumatriptan nasal spray are probably beneficial and safe to use in pediatric migraine. For the minority of children who should be candidates for prophylactic therapy, there is a limited amount of information available for clinicians to make judicious treatment decisions.

Levetiracetam prophylaxis in pediatric migraine--an open-label study.

BACKGROUND: Migraine is common in the pediatric population. Levetiracetam, an anti-epileptic drug, has shown some efficacy in small prospective adult headache studies. METHODS: We prospectively evaluated levetiracetam in an open-label study in 20 pediatric migraine patients to assess tolerability and efficacy. RESULTS: Eighteen of 20 patients had significant reduction in headache frequency. PedMIDAS showed significant decrease in disability scores, side effects were minimal (mild behavioral changes). CONCLUSION: Levetiracetam had some efficacy in reducing migraine frequency and disability. Further larger studies are warranted, possibly utilizing a placebo-controlled design.

Emotional problems and prevalence of medication overuse in pediatric chronic daily headache.

Chronic daily headaches are an increasingly recognized neurologic issue in children. Frequent headaches can be a source of significant disability and family discord with work/school absenteeism. Medication overuse and emotional disorder would significantly impact treatment and progression. This study examined the frequency of emotional and behavioral problems in children and adolescents with chronic daily headache compared with age-related healthy controls. Prevalence of medication overuse in this chronic daily headache group was evaluated. Otherwise healthy children and adolescents with chronic daily headache (according to International Classification of Headache Disorders-II criteria) were enrolled from the Headache Clinic. Healthy controls were prospectively enrolled from physician offices. Multiple psychological rating scales, headache diaries, presence of medication overuse, and disability surveys (Pediatric Migraine Disability Assessment Survey) were completed. A total of 57 healthy controls and 70 patients were studied. The sample consisted largely of females, many of whom (60%) had medication overuse before medical treatment. Headache patients had significantly more symptoms of anxiety, depression, and somatization compared with controls. Patients with chronic daily headache were at higher risk for emotional disorders, and medication overuse was a significant occurrence, suggesting a need for multisystem treatment approach.

Zonisamide prophylaxis in refractory pediatric headache.

INTRODUCTION: Currently, no medications are approved for pediatric headache prophylaxis in the United States. Zonisamide is an antiepileptic drug with preliminary studies suggesting some efficacy in the adult headache population. METHODS: A retrospective chart review was conducted on refractory headache patients in our multidisciplinary Headache Clinic who were treated with zonisamide, an antiepileptic drug, for headache prophylaxis. Records were reviewed for pertinent data including patient history, diagnosis, prior treatment regimens, and zonisamide response, along with headache frequency. RESULTS: Twelve patients were identified (8 girls); mean age was 13.5 years. Eight of the 12 patients had a positive response to zonisamide with greater than 50% reduction in headaches from pretreatment values. CONCLUSION: Zonisamide had some efficacy in headache reduction. It was well tolerated with only minor side effects. Further prospective studies with zonisamide are warranted in refractory pediatric headache patients.