Hope L. O’Brien

Cognitive Behavioral Therapy Plus Amitriptyline for Chronic Migraine in Children and Adolescents A Randomized Clinical Trial

IMPORTANCE Early, safe, effective, and durable evidence-based interventions for children and adolescents with chronic migraine do not exist. OBJECTIVE To determine the benefits of cognitive behavioral therapy (CBT) when combined with amitriptyline vs headache education plus amitriptyline. DESIGN, SETTING, AND PARTICIPANTS A randomized clinical trial of 135 youth (79% female) aged 10 to 17 years diagnosed with chronic migraine (≥15 days with headache/month) and a Pediatric Migraine Disability Assessment Score (PedMIDAS) greater than 20 points were assigned to the CBT plus amitriptyline group (n = 64) or the headache education plus amitriptyline group (n = 71). The study was conducted in the Headache Center at Cincinnati Childrens Hospital between October 2006 and September 2012; 129 completed 20-week follow-up and 124 completed 12-month follow-up. INTERVENTIONS Ten CBT vs 10 headache education sessions involving equivalent time and therapist attention. Each group received 1 mg/kg/d of amitriptyline and a 20-week end point visit. In addition, follow-up visits were conducted at 3, 6, 9, and 12 months. MAIN OUTCOMES AND MEASURES The primary end point was days with headache and the secondary end point was PedMIDAS (disability score range: 0-240 points; 0-10 for little to none, 11-30 for mild, 31-50 for moderate, >50 for severe); both end points were determined at 20 weeks. Durability was examined over the 12-month follow-up period. Clinical significance was measured by a 50% or greater reduction in days with headache and a disability score in the mild to none range (<20 points). RESULTS At baseline, there were a mean (SD) of 21 (5) days with headache per 28 days and the mean (SD) PedMIDAS was 68 (32) points. At the 20-week end point, days with headache were reduced by 11.5 for the CBT plus amitriptyline group vs 6.8 for the headache education plus amitriptyline group (difference, 4.7 [95% CI, 1.7-7.7] days; P = .002). The PedMIDAS decreased by 52.7 points for the CBT group vs 38.6 points for the headache education group (difference, 14.1 [95% CI, 3.3-24.9] points; P = .01). In the CBT group, 66% had a 50% or greater reduction in headache days vs 36% in the headache education group (odds ratio, 3.5 [95% CI, 1.7-7.2]; P < .001). At 12-month follow-up, 86% of the CBT group had a 50% or greater reduction in headache days vs 69% of the headache education group; 88% of the CBT group had a PedMIDAS of less than 20 points vs 76% of the headache education group. Measured treatment credibility and integrity was high for both groups. CONCLUSIONS AND RELEVANCE Among young persons with chronic migraine, the use of CBT plus amitriptyline resulted in greater reductions in days with headache and migraine-related disability compared with use of headache education plus amitriptyline. These findings support the efficacy of CBT in the treatment of chronic migraine in children and adolescents. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00389038.

Treatment of pediatric migraine.

Opinion statementThe diagnosis of migraine in the pediatric population is increasing as providers are becoming more familiar with recognizing the condition. Over-the-counter and migraine-specific treatment, once considered off-label, have proven to be effective, especially if given at the early onset of head pain. Mild to severe cases of migraine should be treated with nonsteroidal anti-inflammatory drugs (NSAIDs), with triptans used alone or in combination in moderate to severe headaches unresponsive to over-the-counter therapy. Rescue medication including dihydroergotamine (DHE), a potent vasoconstrictor should be used for intractable migraines and is preferred in the hospital setting. Anti-emetics that have anti-dopaminergic properties can be helpful in patients with associated symptoms of nausea and vomiting along with headache, especially when used in combination therapy. Preventative treatment should be initiated early in patients with frequent headaches to improve headache outcomes and quality of life. Patients and families should be educated on non-pharmacologic management, such as lifestyle modification and avoidance of triggers, that can prevent progression and worsening of migraine.

Psychiatric comorbidity in pediatric chronic daily headache

Objectives: The objectives of this study were to assess comorbid psychiatric diagnoses in youth with chronic daily headache (CDH) and to examine relationships between psychiatric status and CDH symptom severity, as well as headache-related disability. Methods: Standardized psychiatric interviews (Kiddie Schedule for Affective Disorders and Schizophrenia, KSADS) were conducted with 169 youth ages 10–17 diagnosed with CDH. Participants provided prospective reports of headache frequency with a daily headache diary and completed measures of symptom severity, headache-related disability (PedMIDAS) and quality of life (PedsQL). Results: Results showed that 29.6% of CDH patients met criteria for at least one current psychiatric diagnosis, and 34.9% met criteria for at least one lifetime psychiatric diagnosis. No significant relationship between psychiatric status and headache frequency, duration, or severity was found. However, children with at least one lifetime psychiatric diagnosis had greater functional disability and poorer quality of life than those without a psychiatric diagnosis. Discussion: Contrary to research in adults with chronic headaches, most youth with CDH did not appear to be at an elevated risk for comorbid psychiatric diagnosis. However, patients with a comorbid psychiatric diagnosis were found to have higher levels of headache-related disability and poorer quality of life. Implications for treatment are discussed.

OnabotulinumtoxinA in pediatric chronic daily headache.

Chronic migraine occurs in about 3% of pediatric headaches. Many would be intractable to more than two preventive medications. OnabotulinumtoxinA has been approved by the US Food and Drug Administration for the use of chronic migraine in adults in 2010. Data on effectiveness and tolerability in the pediatric population are very limited. The study described in this article is a retrospective review of available data of all patients who received OnabotulinumtoxinA for chronic migraine in a large pediatric headache center from 2004 to 2010. Botox is recommended to any pediatric patient coming to the multidisciplinary clinic for chronic headache if they fail two or more preventive medications. This study showed a major change in the frequency of the headache with a statistical difference in the improvement of headache days per month. There was a 30-point drop in the pediatric disability scoring between first injection and follow-up injection with a change from severe disability to moderate disability.

Vitamins and paediatric migraine: Riboflavin as a preventative medication

Migraine is a common condition among adults and has become increasingly more recognised as a common condition among children and adolescents. When headaches are frequent or disabling, preventative treatments are indicated. Few studies have addressed the effectiveness of preventative treatments in children and adolescents in a controlled manner. Due to a concern of potential adverse risks, parents are often reluctant to start prophylactic medications and inquire about the use of alternative treatments including vitamin supplementation. Vitamins, in general, are viewed as more ‘natural’ and may be involved in the biological pathways underlying migraine. The use of nutraceutical treatment for migraine is a favourable option because they are essentially well tolerated with minimal side effects. Several nutraceuticals have been studied in the literature with some showing positive results in adult patients with migraine (1); however, studies in children and adolescents are scarce with none showing favourable outcomes. As children and adolescents are increasingly diagnosed with migraine, the need for prophylactic or preventative treatment is warranted. Therefore, it is important that headache clinicians and researchers treating paediatric migraine explore therapies that are safe, effective and affordable. Riboflavin, or vitamin B2, is a co-factor used in mitochondrial function and has been shown to be effective in children with mitochondrial disorders with mild side effects (2). In order to achieve this, high doses were required to overcome the mitochondrial impairment. In the pathogenesis of migraine, riboflavin is believed to be a major co-factor in oxidative metabolism as it acts as a precursor to flavin compounds involved in electron transport and generation of energy in the mitochondria (3,4). Thus, in theory, low riboflavin levels may be associated with mitochondrial dysfunction linked to migraine. Several studies have shown efficacy and tolerability of riboflavin in migraine prevention in adults (5,6); however. MacLennan et al. (7) were the first to study the efficacy of high-dose riboflavin (at least 200mg/day) in migraine prevention in children. The results did not show any difference in those who received treatment with riboflavin compared to placebo – although the placebo rate was high. A subsequent, open-label, retrospective study examining high-dose riboflavin in children and adolescents with migraine who failed pharmacological preventative therapy suggested that riboflavin may be effective in migraine, with a more favourable response in boys (8). This sample population was notable for more individuals with severe migraine. A randomised, placebocontrolled study of a combination of high-dose riboflavin, magnesium and feverfew using low-dose riboflavin (25mg), found no difference between high-dose and low-dose riboflavin with equivalent responses (9). The study by Bruijn et al. (10) presented the results of a randomised, double-blind, placebo-controlled, crossover designed trial that addressed the effectiveness of a medium dose of riboflavin (50mg/day) in the prevention of childhood migraine. Subjects were 6–13 years old that met ICHD II criteria for migraine with or without aura and a frequency of at least two headache attacks per month recruited from two hospitals. The study showed no difference in migraine frequency, severity or duration between riboflavin and placebo in each phase. However, there was a reduction in frequency of the tension-type headaches in these children. The reason for this ineffectiveness in contrast to the positive results in adults is likely multifactorial. First, the dose of riboflavin used may not be sufficient to alter mitochondrial metabolism or be clinically relevant. The pharmacokinetics of riboflavin suggested that the maximal amount of riboflavin the human body can absorb from a single dose is 27mg with saturation of absorption reached at doses 30–50mg decreasing the absorption at higher doses (11,12). Furthermore, the half-life of riboflavin is between 1–2 h. This observation of limited absorption with a short half-life suggests that riboflavin therapy may require multiple daily dosing to attain a positive effect. This may explain why the single

Treatment of acute migraine in the pediatric population.

Opinion statementThe recognition of the diagnosis of migraine in the pediatric population is increasing. Early and aggressive treatment of migraine in children and adolescents with the use of over-the-counter medications has proven effective. In addition, the off-label use of many migraine-specific medications is often accepted in the absence of sufficient evidence-based trials. Mild to severe cases of migraine should be treated with NSAIDs, with triptans used for moderate to severe headaches that are unresponsive to over-the-counter therapy. Rescue medication including dihydroergotamine (DHE) should be used for intractable migraines, preferably in the hospital setting. In patients with associated symptoms of nausea and vomiting, antiemetics with antidopaminergic properties can be helpful through their action on central migraine generation. Furthermore, patients and families should be educated about nonpharmacologic aspects of management such as preventing episodic migraine through lifestyle modification and avoidance of triggers.

Aberrant Neuromagnetic Activation in the Motor Cortex in Children with Acute Migraine: A Magnetoencephalography Study

Migraine attacks have been shown to interfere with normal function in the brain such as motor or sensory function. However, to date, there has been no clinical neurophysiology study focusing on the motor function in children with migraine during headache attacks. To investigate the motor function in children with migraine, twenty-six children with acute migraine, meeting International Classification of Headache Disorders criteria and age- and gender-matched healthy children were studied using a 275-channel magnetoencephalography system. A finger-tapping paradigm was designed to elicit neuromagnetic activation in the motor cortex. Children with migraine showed significantly prolonged latency of movement-evoked magnetic fields (MEF) during finger movement compared with the controls. The correlation coefficient of MEF latency and age in children with migraine was significantly different from that in healthy controls. The spectral power of high gamma (65–150 Hz) oscillations during finger movement in the primary motor cortex is also significantly higher in children with migraine than in controls. The alteration of responding latency and aberrant high gamma oscillations suggest that the developmental trajectory of motor function in children with migraine is impaired during migraine attacks and/or developmentally delayed. This finding indicates that childhood migraine may affect the development of brain function and result in long-term problems.

Treatment Adherence in Child and Adolescent Chronic Migraine Patients: Results from the Cognitive Behavioral Therapy and Amitriptyline Trial.

Objectives: To examine treatment adherence among children and adolescents with chronic migraine who volunteered to be in a clinical trial using 3 measures: treatment session attendance, therapy homework completion, and preventive medication use by daily diary. Materials and Methods: Analyses are secondary from a trial of 135 youth aged 10 to 17 years diagnosed with chronic migraine and with a Pediatric Migraine Disability Score over 20. Participants were randomly assigned to cognitive-behavioral therapy plus amitriptyline (CBT+A, N=64) or headache education plus amitriptyline (HE+A, N=71). Therapists recorded session attendance. Completion of homework/practice between sessions was reported to therapists by patients. Patients reported preventive medication adherence using a daily headache diary. Results: Mean session attendance adherence out of 10 treatment sessions was 95% for CBT+A and 99% for HE+A. CBT+A participants reported completing a mean of 90% of home practice of CBT skills between the 10 sessions. Participants reported taking amitriptyline daily at a mean level of 90% when missing diaries were excluded and 79% when missing diaries were considered as missed doses of medication. Discussion: Our findings demonstrate that youth with chronic migraine who agree to be a part of a clinical trial do quite well at attending therapy sessions, and report that they are adherent to completing home/practice between sessions and taking medication. These results lend further support to consideration of CBT+A as a first-line treatment for youth with chronic migraine and suggest that measurement of adherence when this treatment is provided in practice will be important.

The optimal management of headaches in children and adolescents

The recognition of the diagnosis of migraine in children is increasing. Early and aggressive treatment of migraine in this population with the use of over-the-counter medications has proven effective. The off-label use of many migraine-specific medications is often accepted in the absence of sufficient evidenced-based trials. Mild to severe cases of migraine should be treated with nonsteroidal anti-inflammatory drugs, with triptans used in moderate to severe headaches unresponsive to over-the-counter therapy. Rescue medication including dihydroergotamine [DHE] should be used for status migrainosus, preferably in the hospital setting. Antiemetics that have antidopaminergic properties can be helpful in patients with associated symptoms of nausea and vomiting through their action on central migraine generation. Furthermore, patients and families should be educated on nonpharmacologic management such as lifestyle modification and avoidance of triggers that can prevent episodic migraine.

Comorbid Psychological Conditions in Pediatric Headache

Children and adolescents with chronic daily headaches (CDH) often have comorbid psychological conditions, though their prevalence is unclear. Pediatric patients with CDH may have higher rates of disorders such as anxiety and depression. However, some researchers have found that scores on depression and anxiety screening measures for pediatric patients with migraine are within reference range. Barriers to identify patients with psychiatric disorders have included limited validated screening tools and lack of available mental health resources. Several validated screening tools have recently been used in studies of pediatric patients with CDH. Once identified, treatment of comorbid psychological conditions may lead to improved functioning and headache outcomes.