Mind and Body Approaches to Pain Reduction in Youth With Migraine
Mind and Body Approaches to Pain Reduction in Youth With Migraine
The overarching objective of this protocol is to identify and understand the neural and pain
 processing mechanisms by which youth with migraine improve in response to preventive
 treatment. The study design of this mechanistic investigation includes functional magnetic
 resonance imaging (fMRI), daily headache diaries, assessment of conditioned pain modulation
 via quantitative sensory testing, and validated psychometric assessments before and after the
 delivery of one of five treatments over an 8 week period [cognitive behavioral therapy (CBT),
 biofeedback-assisted relaxation training (BART) and cognitive reappraisal (CR) training,
 amitriptyline, and placebo]. We are examining both distinct and common pathways that may help
 explain the response to various preventive treatments, as well as potential predictors of
 outcome.
Pediatric migraine is a prevalent disorder that results in significant pain and disability
 for children and adolescents. Despite the prevalence and cost, commonly used pharmacologic
 treatments to treat pediatric migraine have limited evidence of efficacy over placebo in
 preventing migraine in youth. In our prior research, published in NEJM (Trial of
 Amitriptyline, Topiramate, and Placebo for Pediatric Migraine. N Engl J Med.
 2017;376(2):115-124),we have shown in a large, national, multicenter trial that the most
 widely used conventional preventive medications, amitriptyline (AMI) and topiramate, are no
 more effective than placebo. Psychological therapies for pediatric headache (in particular,
 cognitive behavioral therapy [CBT]) result in better outcomes than control conditions by
 effectively reducing headache days and disability in children and adolescents with migraine.
 Our own work indicates that youth receiving combined CBT plus amitriptyline (AMI, the most
 widely used migraine prophylactic in youth) had greater reductions in headache days and
 disability than a group receiving education control plus AMI. Specifically, we found that CBT
 combined with AMI improved outcomes for about 2 out of 3 pediatric chronic migraineurs (ages
 10-17). Reduction in headache days by ≥ 50% was seen within the first 8 weeks of this 5-month
 trial (Powers SW, Kashikar-Zuck SM, Allen JR, et al. Cognitive behavioral therapy plus
 amitriptyline for chronic migraine in children and adolescents: a randomized clinical trial.
 JAMA. 2013;310(24):2622-2630).

 Despite this evidence of efficacy, the mechanisms supporting CBT for migraine remain poorly
 understood. This lack of mechanistic understanding leaves patients, providers, and payers
 reluctant to promote CBT as a primary treatment modality. Moreover, opportunities to optimize
 and individualize CBT remain unrealized because of limited basic understanding by which
 different components of CBT exert their effects. Little remains known about the specific
 brain mechanisms by which CBT reduces pain. Therefore, it is critical that we understand how
 and why CBT may improve headache outcomes in contrast to pill-taking treatments, specifically
 placebo. Brain imaging and quantitative sensory testing are novel tools to investigate
 possible mechanisms of CBT, placebo, and medication. In addition understanding the components
 of CBT and how they may work at the brain and pain processing levels is important. As such,
 two broad components of CBT represent clear targets for investigation: relaxation and
 cognitive reappraisal.

 Evolving consensus in the pain community and at a national level suggests that examining
 biological mechanisms of how mind and body approaches lead to benefits for patients will
 advance care, improve outcomes, and legitimize non-pharmacological treatment for pediatric
 chronic pain. As such, this mechanistic/basic science study seeks to identify the neural
 mechanisms by which youth with migraine improve in response to preventive treatment.
 Pediatric medical and behavioral clinicians can use mechanistic insights from this study to
 provide patients and families with a stronger rationale for treatment, thereby decreasing
 stigma and increasing confidence in and commitment to the care plan.
Inclusion Criteria:

 -  Diagnosis: Migraine with or without aura or chronic migraine that meets the
 International Classification of Headache Disorders, 3rd Edition (beta) (ICHD-3b)
 criteria

 -  Frequency: Headache frequency based upon prospective headache diary of 28 days must be
 ≥ 8 and ≤ 28

 -  PedMIDAS: PedMIDAS Disability Score > 10, indicating at least mild disruption in daily
 activities and < 140, indicating extreme disability that may require more
 comprehensive, multi-component therapy

 -  English speaking: able to complete interviews and questionnaires in English

 Exclusion Criteria:

 -  Continuous migraine defined as an unrelenting headache for a 28 day period

 -  Weight less than 30 kg or greater than 120 kg, or weight/size incompatible with
 magnetic resonance imaging (MRI) scanner

 -  Must agree not to take non-specific acute medication, such as nonsteroidal
 anti-inflammatory drugs (NSAIDS) (e.g., ibuprofen), more than 3 times per week, or
 migraine specific acute medications, such as triptans, more than 6 times per month

 -  No current prophylactic anti-migraine medication within a period equivalent to < 5
 half-lives of that medication before entering the screening phase, and agree to not
 begin a migraine prevention medication during the study period

 -  Current use of the following medications/products: opioids, antipsychotics,
 antimanics, barbiturates, benzodiazepines, muscle relaxants, sedatives, tramadol,
 nutraceuticals

 -  Known history of allergic reaction or anaphylaxis to amitriptyline

 -  Abnormal findings on electrocardiogram (ECG) at baseline, particularly lengthening of
 the QT interval ≥ 450 msec

 -  Orthodontic braces, metallic or electronic implants, or other metal objects in the
 body which obscure or interfere with the MRI, or pose a risk from heating, movement,
 or malfunction in the MRI environment

 -  Claustrophobia

 -  Youth who are pregnant, or those who are sexually active and not using a medically
 accepted form of contraception (barrier or hormonal methods)

 -  Diagnosis of epilepsy or other neurological diseases

 -  Inability to learn how to swallow pills using behavioral techniques (if indicated)

 -  Present psychiatric disease as defined by the Diagnostic and Statistical Manual (DSM)
 IV (e.g. psychosis, bipolar disorder, major depression, generalized anxiety disorder),
 alcohol or drug dependence, or documented developmental delays or impairments (e.g.,
 autism, cerebral palsy, attention deficit hyperactivity disorder (ADHD), or mental
 retardation) that, in the opinion of the investigator, would interfere with adherence
 to study requirements or safe participation in the study