Which medication, if any, to use to prevent the headache of pediatric migraine has not been established.
We conducted a randomized, double-blind, placebo-controlled trial of amitriptyline (1 mg per ...kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo in children and adolescents 8 to 17 years of age with migraine. Patients were randomly assigned in a 2:2:1 ratio to receive one of the medications or placebo. The primary outcome was a relative reduction of 50% or more in the number of headache days in the comparison of the 28-day baseline period with the last 28 days of a 24-week trial. Secondary outcomes were headache-related disability, headache days, number of trial completers, and serious adverse events that emerged during treatment.
A total of 361 patients underwent randomization, and 328 were included in the primary efficacy analysis (132 in the amitriptyline group, 130 in the topiramate group, and 66 in the placebo group). The trial was concluded early for futility after a planned interim analysis. There were no significant between-group differences in the primary outcome, which occurred in 52% of the patients in the amitriptyline group, 55% of those in the topiramate group, and 61% of those in the placebo group (amitriptyline vs. placebo, P=0.26; topiramate vs. placebo, P=0.48; amitriptyline vs. topiramate, P=0.49). There were also no significant between-group differences in headache-related disability, headache days, or the percentage of patients who completed the 24-week treatment period. Patients who received amitriptyline or topiramate had higher rates of several adverse events than those receiving placebo, including fatigue (30% vs. 14%) and dry mouth (25% vs. 12%) in the amitriptyline group and paresthesia (31% vs. 8%) and weight loss (8% vs. 0%) in the topiramate group. Three patients in the amitriptyline group had serious adverse events of altered mood, and one patient in the topiramate group had a suicide attempt.
There were no significant differences in reduction in headache frequency or headache-related disability in childhood and adolescent migraine with amitriptyline, topiramate, or placebo over a period of 24 weeks. The active drugs were associated with higher rates of adverse events. (Funded by the National Institutes of Health; CHAMP ClinicalTrials.gov number, NCT01581281 ).
Chronic pain, one of the most common reasons adults seek medical care (1), has been linked to restrictions in mobility and daily activities (2,3), dependence on opioids (4), anxiety and depression ...(2), and poor perceived health or reduced quality of life (2,3). Population-based estimates of chronic pain among U.S. adults range from 11% to 40% (5), with considerable population subgroup variation. As a result, the 2016 National Pain Strategy called for more precise prevalence estimates of chronic pain and high-impact chronic pain (i.e., chronic pain that frequently limits life or work activities) to reliably establish the prevalence of chronic pain and aid in the development and implementation of population-wide pain interventions (5). National estimates of high-impact chronic pain can help differentiate persons with limitations in major life domains, including work, social, recreational, and self-care activities from those who maintain normal life activities despite chronic pain, providing a better understanding of the population in need of pain services. To estimate the prevalence of chronic pain and high-impact chronic pain in the United States, CDC analyzed 2016 National Health Interview Survey (NHIS) data. An estimated 20.4% (50.0 million) of U.S. adults had chronic pain and 8.0% of U.S. adults (19.6 million) had high-impact chronic pain, with higher prevalences of both chronic pain and high-impact chronic pain reported among women, older adults, previously but not currently employed adults, adults living in poverty, adults with public health insurance, and rural residents. These findings could be used to target pain management interventions.
The National Institutes of Health and its independent advisors recognize the need to develop a strong pain research workforce and provide opportunities, particularly for clinicians, to pursue ...research careers. A survey was conducted to better understand the challenges facing the clinical pain research community. Respondents reported that time and funding to pursue research were the most critical factors either enabling or holding them back from a research career. Respondents who received some kind of formal research training or mentorship were more likely than those who did not to have federal research funding and to be at more advanced stages of their careers. The findings point to a need for all stakeholders in the pain research community to help formalize research training and provide funding or protected time to support the ambitions of aspiring researchers.
A consensus meeting was convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide recommendations for interpreting clinical importance of ...treatment outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments. A group of 40 participants from universities, governmental agencies, a patient self-help organization, and the pharmaceutical industry considered methodologic issues and research results relevant to determining the clinical importance of changes in the specific outcome measures previously recommended by IMMPACT for 4 core chronic pain outcome domains: (1) Pain intensity, assessed by a 0 to 10 numerical rating scale; (2) physical functioning, assessed by the Multidimensional Pain Inventory and Brief Pain Inventory interference scales; (3) emotional functioning, assessed by the Beck Depression Inventory and Profile of Mood States; and (4) participant ratings of overall improvement, assessed by the Patient Global Impression of Change scale. It is recommended that 2 or more different methods be used to evaluate the clinical importance of improvement or worsening for chronic pain clinical trial outcome measures. Provisional benchmarks for identifying clinically important changes in specific outcome measures that can be used for outcome studies of treatments for chronic pain are proposed.
Systematically collecting and reporting the recommended information needed to evaluate the clinical importance of treatment outcomes of chronic pain clinical trials will allow additional validation of proposed benchmarks and provide more meaningful comparisons of chronic pain treatments.
There has been an increase in the number of chronic pain clinical trials in which the treatments being evaluated did not differ significantly from placebo in the primary efficacy analyses despite ...previous research suggesting that efficacy could be expected. These findings could reflect a true lack of efficacy or methodological and other aspects of these trials that compromise the demonstration of efficacy. There is substantial variability among chronic pain clinical trials with respect to important research design considerations, and identifying and addressing any methodological weaknesses would enhance the likelihood of demonstrating the analgesic effects of new interventions. An IMMPACT consensus meeting was therefore convened to identify the critical research design considerations for confirmatory chronic pain trials and to make recommendations for their conduct. We present recommendations for the major components of confirmatory chronic pain clinical trials, including participant selection, trial phases and duration, treatment groups and dosing regimens, and types of trials. Increased attention to and research on the methodological aspects of confirmatory chronic pain clinical trials has the potential to enhance their assay sensitivity and ultimately provide more meaningful evaluations of treatments for chronic pain.
Objective
Identify preventive medication treatment response trajectories among youth participating in the Childhood and Adolescent Migraine Prevention study.
Methods
Data were evaluated from 328 ...youth (ages 8–17). Childhood and Adolescent Migraine Prevention study participants completed headache diaries during a 28-day baseline period and a 168-day active treatment period during which youth took amitriptyline, topiramate, or placebo. Daily headache occurrence trajectories were established across baseline and active treatment periods using longitudinal hierarchical linear modeling. We tested potential treatment group differences. We also compared final models to trajectory findings from a clinical trial of cognitive behavioral therapy plus amitriptyline for youth with chronic migraine to test for reproducibility.
Results
Daily headache occurrence showed stability across baseline. Active treatment models revealed decreases in headache frequency that were most notable early in the trial period. Baseline and active treatment models did not differ by treatment group and replicated trajectory cognitive behavioral therapy plus amitriptyline trial findings.
Conclusions
Replicating headache frequency trajectories across clinical trials provides strong evidence that youth can improve quickly. Given no effect for medication, we need to better understand what drives this clinically meaningful improvement. Results also suggest an expected trajectory of treatment response for use in designing and determining endpoints for future clinical trials.
Trial Registration. ClinicalTrials.gov Identifier: NCT01581281
To examine group differences in self-reported migraine days among youth who completed the Childhood and Adolescent Migraine Prevention (CHAMP) trial prior to its closure and explore the relationship ...between self-reported and "nosology-derived" (i.e., International Classification of Headache Disorders, 3rd edition ICHD-3) migraine days.
The CHAMP trial compared amitriptyline and topiramate to placebo for migraine prevention in youth and proposed to analyze change in migraine days as a secondary outcome. There is considerable variability in the field regarding what constitutes a "migraine day," how this is determined and reported in trials, and how consistent these measures are with diagnostic nosology.
CHAMP trial completers (N = 175) were randomized to receive amitriptyline (n = 77), topiramate (n = 63), or placebo (n = 35). Participants maintained daily headache diaries where they reported each day with headache and if they considered that headache to be a migraine. For each headache day, participants completed a symptom record and reported about symptoms such as pain location(s) and presence of nausea/vomiting or photophobia and phonophobia. We examined group differences in self-reported migraine days at trial completion (summed from trial weeks 20-24) compared to baseline. We also used an algorithm to determine whether participants' symptom reports met ICHD-3 criteria for migraine without aura, and examined the association between self-reported and "nosology-derived" migraine days.
Results showed no significant differences between groups in self-reported migraine days over the course of the trial. Self-reported and "nosology-derived" migraine days during the baseline and treatment phases were strongly associated (r's = 0.73 and 0.83, respectively; p's < 0.001).
Regardless of treatment, CHAMP trial completers showed clinically important reductions in self-reported migraine days over the course of the trial (about 3.8 days less). The strong association between self-reported and "nosology-derived" migraine days suggests youth with migraine can recognize a day with migraine and reliably report their headache features and symptoms. Greater rigor and transparency in the calculation and reporting of migraine days in trials is needed.
Abstract
Objective
Examine preventive medication adherence among youth with migraine.
Methods
Adherence (self-report, pill count, and blood serum drug levels) was assessed as an ancillary study that ...utilized data from 328 CHAMP Study participants (ages 8–17). CHAMP was a multisite trial of preventive medications. Participants completed a prospective headache diary during a six-month active treatment period during which youth took amitriptyline, topiramate, or placebo pill twice daily. Self-reported medication adherence was collected via daily diary. At monthly study visits, pill count measures were captured. At trial month 3 (trial midpoint) and 6 (end of active trial), blood serum drug levels were obtained. Self-report and pill count adherence percentages were calculated for the active trial period, at each monthly study visit, and in the days prior to participants’ mid-trial blood draw. Percentages of nonzero drug levels were calculated to assess blood serum drug level data. Adherence measures were compared and assessed in context of several sociodemographic factors. Multiple regression analyses investigated medication adherence as a predictor of headache outcomes.
Results
Self-report and pill count adherence rates were high (over 90%) and sustained over the course of the trial period. Serum drug level adherence rates were somewhat lower and decreased significantly (from 84% to 76%) across the trial period t (198) = 3.23, p = .001. Adherence measures did not predict headache days at trial end; trial midpoint serum drug levels predicted headache-related disability.
Conclusions
Youth with migraine can demonstrate and sustain relatively high levels of medication adherence over the course of a clinical trial.
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