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Journal of Pediatric Psychology logoLink to Journal of Pediatric Psychology
. 2021 Dec 3;47(4):376–387. doi: 10.1093/jpepsy/jsab123

Multimodal Assessment of Medication Adherence Among Youth With Migraine: An Ancillary Study of the CHAMP Trial

Brooke L Reidy 1,2,✉, Scott W Powers 1,2, Christopher S Coffey 3, Leigh A Chamberlin 1, Dixie J Ecklund 3, Elizabeth A Klingner 3, Jon W Yankey 3, Leslie L Korbee 4, Linda L Porter 5, James Peugh 1, Marielle A Kabbouche 2,6, Joanne Kacperski 2,6, Andrew D Hershey 2,6; for the CHAMP Investigators*
PMCID: PMC9216483  PMID: 34865085

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.

Keywords: adherence/self-management, adolescents, clinical trial, headache and migraine, school age children

Introduction

Across pediatric conditions, difficulties with medication adherence can exceed 50% in childhood (Rapoff, 2010), with even higher rates of adherence difficulties occurring in adolescence (Hommel et al., 2009; Logan et al., 2003). Difficulties with pediatric medication adherence have been linked to increased health care utilization (McGrady & Hommel, 2013), poorer patient health-related quality of life (Fredericks et al., 2008; Hommel et al., 2008), and poorer treatment outcomes (DiMatteo et al., 2002), making patient treatment adherence a significant public health target.

Unfortunately, little is known about medication adherence among youth with primary headache disorders. A systematic review by Ramsey et al. (2014) found only five studies on children and adolescents with headaches reported on participant adherence, with the majority of these studies relying on qualitative information about adherence obtained through retrospective verbal reports. In one of the only studies to systematically examine medication adherence in youth with headache, Kroon Van Diest et al. (2016) found medication adherence rates of 64–75% in a clinical sample of adolescents with migraine using objective electronic pill bottle monitoring and self-report measures via daily diary. Given that migraine is a common pediatric disease associated with high societal and economic burden, impaired school functioning, and poorer quality of life (Slater et al., 2018), additional assessment is needed to objectively examine medication adherence in this population under a variety of clinical contexts, identify sociodemographic factors associated with adherence, and elucidate the role of medication adherence in patient outcomes (Ramsey et al., 2014).

Clinical trials represent an important area of focus for ongoing investigation of adherence among youth with migraine, as treatment adherence may influence primary outcomes in efficacy studies. Investigating medication adherence in the context of a clinical trial is also advantageous, given the level of monitoring required in a controlled study. Although this monitoring could lead to inflated adherence rates in clinical trials, poor to moderate medication adherence rates have been documented in the context of randomized controlled trials for adults with chronic illness (Osterberg & Blaschke, 2005), suggesting that medication adherence remains a meaningful focus for pediatric clinical trials research.

This study took a multimodal approach to assess medication treatment adherence using data from the Childhood and Adolescent Migraine Prevention (CHAMP) trial (Powers et al., 2017), a multicenter, phase 3, NIH-funded, double-blind, randomized clinical trial that compared amitriptyline, topiramate, and placebo as treatment for youth with migraine (ClinicalTrials.gov ID: NCT01581281). This trial was stopped for study futility after an interim analysis revealed that placebo was just as effective as either preventive headache medication in reducing headache days and headache-related functional disability among study participants. Exploration of detectible drug levels at study endpoint revealed that the majority of youth were taking study medication at the end of the CHAMP trial and that adherence did not differ between the amitriptyline and topiramate groups. These findings suggested that adherence was not likely to have contributed to the null findings in the efficacy analyses (Powers et al., 2017). That said, a more nuanced investigation of multimodal adherence across the CHAMP trial period is needed, as this ancillary work could have implications for clinical practice and will inform future adherence assessment and promotion in clinical trials for youth with headache disorders.

This study used self-report diary measures, pill counts, and blood serum drug levels to examine medication adherence over the course of the trial and assessed the extent to which these study adherence measures were associated. Due to the ongoing monitoring that occurred over the course of the CHAMP trial, we expected average medication adherence rates to be consistent with or higher than rates previously reported (64–75%) among pediatric headache populations receiving standard clinical care that included a prescription preventive medication (Kroon Van Diest et al., 2016). In line with the pediatric adherence literature in other chronic illness populations, we anticipated that self-reported medication adherence would be higher than pill count and serum assay measures (Bender et al., 2000; Greenley et al., 2012; Hommel et al., 2009; Loiselle et al., 2016; Modi et al., 2006; Yang et al., 2018).

We also examined associations between sociodemographic variables (age, race, gender, and socioeconomic status) and CHAMP participant adherence. We then explored the extent to which medication adherence predicted pediatric headache treatment outcomes, including headache days and migraine-related disability. Because participants receiving placebo, amitriptyline, and topiramate did not differ in terms of clinical outcomes (Powers et al., 2017), we examined self-report, pill count, and blood serum adherence measures in the combined CHAMP sample.

Methods

Participants

Participants included 328 children and adolescents with migraine (8–17 years old) who participated and were included in primary efficacy analyses for the CHAMP study. Participants were recruited from 31 study sites located across the United States; sample size was chosen a priori to ensure adequate power to detect between group differences in headache day reduction of 50% or more, and was limited to participants who were enrolled in the study at the time of initial interim analyses that led to CHAMP study closure (see Powers et al., 2017 for more information). To be enrolled in the CHAMP trial, youth had to have (a) a diagnosis of migraine with or without aura, or chronic migraine without continuous headache, as defined by the International Classification of Headache Disorders [Headache Classification Committee of the International Headache Society (IHS), 2018]; (b) mild to severe headache-related functional impairment, as measured by the Pediatric Migraine Disability Assessment Scale (PedMIDAS; Hershey et al., 2001); and (c) a baseline headache frequency of ≥ 4 days, as measured via a 28-day prospective headache diary. Potential participants were deemed ineligible for the CHAMP study if they were (a) experiencing continuous migraine (or unrelenting headache for a 28-day period), (b) weighed an amount (<30 kg or >120 kg) that could have been problematic and/or potentially unsafe in terms of medication dosing, given the weight-based dosing schedule used for the trial, (c) were overusing their acute headache medications, (d) had previously failed an adequate (≥3 months) trial of amitriptyline or topiramate or had a known allergic reaction to either medication, (e) were taking preventive anti-migraine medication around the time of the CHAMP baseline period, (f) were taking disallowed medications or products (e.g., opioids, muscle relaxants or sedatives, selective serotonin reuptake inhibitors [SSRIs] or serotonin-norepinephrine reuptake inhibitors [SNRIs]),  (g) were pregnant or at risk of becoming pregnant (i.e., were sexually active and not using medically acceptable forms of contraception), or (h) had a history of medical conditions/findings that were contraindicated for the study (e.g., abnormal ECG at baseline, diagnosis of epilepsy or other neurological diseases besides migraine, history of kidney stones). If participants were unable to swallow pills after using behavioral techniques during the baseline period, they were not randomized in the CHAMP trial. More comprehensive information about the recruitment, retention, and baseline characteristics of this sample can be found in the published study protocol, the primary efficacy publication for the CHAMP trial, and/or a manuscript summarizing initial demographic and treatment-related characteristics of the CHAMP sample (Hershey et al., 2013; Powers et al., 2016, 2017).

Written consent and—if deemed developmentally appropriate—written assent were obtained from all families during the informed consent process. Specifically, developmentally tailored written explanations of the CHAMP study were provided for younger study participants; each site followed their own institutional guidance regarding at what age separate written assent was required. At the study coordinating site, youth ages 15 and younger were asked to read and sign a developmentally tailored assent document. Families received monetary compensation for each study visit that they completed. Study procedures were approved by the institutional review board guidelines of participating sites, an independent data and safety monitoring board appointed by the National Institute of Neurological Disorders and Stroke, and an investigational new drug application filed with the U.S. Food and Drug Administration.

Procedure

At their initial study visit, families completed a study demographics form and information about participant general concomitant medications, and were instructed on medication use during a subsequent screening phase/baseline period for the CHAMP trial. In particular, families were instructed to discontinue preventive medication at least 2 weeks prior to the start of the prospective baseline period if they were taking a medication prescribed clinically. Participants and a parent/guardian were also instructed on how to complete their daily headache diary (more information is provided when discussing study measures below).

If eligible following a 28-day baseline period, participants were randomized to one of the medication treatment arms or placebo in a 2:2:1 ratio and moved through the 24-week long active trial period, which consisted of an 8-week long titration period and a 16-week long maintenance period (see Figure  1). Study medication was provided through an investigational pharmacy, and participants and a parent/guardian were instructed on daily pill taking of study medication. This study focused on data collection during the active trial period, at which time participants took two pill capsules per day—once in the morning and once in the evening. Approximately every month, participants met with study staff for study medication pill counts and to obtain new bottles with additional study drug. At study visits midway through the trial (end of titration, trial month 3) and at the end of the active trial period, participants also completed several questionnaires and/or study procedures, including blood draws to assess for serum medication levels. During study visits, study staff were instructed—per study protocol—to discuss the importance of adherence with all participants in the context of drug accountability procedures and conducting pill counts. Additional counsel and problem-solving were provided informally by staff at their discretion if they identified participant adherence difficulties. Per protocol, intervisit phone calls were also conducted in the first half of the CHAMP trial to ensure subject safety during medication titration and to remind families of study diary completion and instructions for taking their study medication. Later intervisit calls were also made to reinforce diary completion and/or medication adherence for all study participants. CHAMP trial procedures were reported in accordance with the Consolidated Standards for Reporting Trials (CONSORT); a CONSORT checklist for the current ancillary paper is available as Supplementary Material.

Figure 1.

Figure 1.

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Schematic of CHAMP trial procedure. During the 8-week long titration period, dosage of study drug was increased every 2 weeks until desired or most tolerated dosing (target of 1 mg/kg daily for amitriptyline; 2 mg/kg daily for topiramate) was achieved. The duration of this titration phase was modified based on tolerability, and could extend to 10 weeks. Subsequently, participants were kept at a constant dose of study drug over the course the maintenance period, and then weaned off of medication for ∼2 weeks. A safety phone call was completed 4 weeks after participants were successfully weaned off of medication to terminate the study. The vast majority of participants were able to successfully continue with the trial on a maximum tolerable dose (∼5% of participants discontinued due to side effects; Powers et al., 2017).

Measures

Demographics

At their baseline study visit prior to randomization, participants and/or a parent/caregiver completed a demographic questionnaire that included information regarding participant birthdate (from which initial age was calculated), self-reported gender (item options were male or female), and race/ethnicity identification. Ethnic (i.e., Hispanic or Latino, Not Hispanic or Latino, Other, Unknown) and racial categories (i.e., Asian, American Indian or Alaska Native, Black or African-American, Native Hawaiian or Other Pacific Islander, White, and Unknown) used for participant or parent-proxy report were provided in accordance with the NIH common elements requirements repository and requirements from the study funding agency. Household income responses were reported using the following categories: (a) Under $20,000, (b) $20,000–$34,999; (c) $35,000–$49,999; (d) $50,000–$74,999; (e) $75,000–$99,999; (f) $100,000–149,999; and (g) $150,000 or more.

Medication Adherence

Self-reported medication adherence was assessed using participants’ daily headache diaries. Specifically, participants indicated whether or not (by circling “yes” or “no”) they had taken their morning and/or evening medication dose each day on their diaries. The paper and pencil diary used is part of the National Institute of Neurological Disorders and Stroke (NINDS) Common Data Elements for trials of people with headache disorders (https://www.commondataelements.ninds.nih.gov/). Morning and evening medication adherence endorsements were summed for each month of the active CHAMP trial, as well as for the duration of the entire trial period. Percent adherence ratings were then calculated by dividing these summed counts by the number of days in a given month, or the number of days that the participant was actively in the CHAMP trial, and then multiplying these values by 100. Rates for morning and evening medication adherence were calculated separately and then averaged.

Pill count measures of medication adherence were also obtained at monthly visits with study staff. Separate bottles of study medication (amitriptyline, topiramate, and placebo pill) were given at study visits for morning and evening pill taking; in the active trial period, the fill quantity of each pill bottle was 42 capsules each. Study coordinators counted the number of pills that were returned from a given bottle at a subsequent study visit, and noted any data management or adherence issues when they recorded pill count data. For the current analyses, pill count data were excluded if there were comments regarding a data entry of clerical error, if dates of bottle distribution were missing (precluding adherence calculations; see below), if there were a significant and/or nonspecific amount of potentially wasted pills noted, if a bottle was not returned, or if pills were not taken because of tolerability issues.

Pill count measures of adherence were computed for each pill bottle dispensed to families as: (the number of pills taken/the number of days taking pills from that bottle) × 100. The number of pills taken was established by calculating the difference between number of pills dispensed in a given bottle and the number of pills returned to study staff. Days taking pills were computed by summing the number of days between each study visit, inclusive of the day in which pills were dispensed. Date of randomization was not included in pill taking adherence calculations. If excess pills were taken from a bottle (i.e., if more pills were not returned than what would have been expected given the number of days between study visits, and subsequent adherence percentages were calculated as being over 100%), percentages were recoded to 100%. Percentages were averaged for each participant for the entire trial period and by trial month.

Biological assays for amitriptyline or topiramate were also collected at a study visit ∼12 weeks postrandomization (end of titration, trial month 3) and then again at the end of the active trial. Nonfasting blood samples were centrifuged; blood serum was frozen, and shipped from CHAMP sites to Cincinnati Children’s Hospital Medical Center for storage and processing. Samples were stored until both samples (if applicable) were collected and then analyzed by mass spectrometry for amitriptyline and topiramate levels. Lab staff were unblinded to treatment group to facilitate proper sample analysis (of note: these individuals did not have direct contact with participants or study staff that interacted with participants). Given that the pharmacokinetics of topiramate can vary widely with age and other factors (e.g., comedications, compromised renal function), and that there are not established dose-response relationships with either preventive medication, blood serum drug levels were categorized as zero and nonzero for the current analyses as an initial proximal measure of objective medication treatment adherence.

Headache Frequency

On their daily headache diaries, participants were asked to report (i.e., circle yes or no) whether a headache occurred on a given day, as well as any migraine symptoms that may have occurred on days in which headaches were endorsed. Headache day endorsements were summed for the baseline period, and for the active trial period. For comparisons with pill count and blood serum levels, total number of headache days was also computed for each month of the active trial period.

Headache-Related Functional Disability

In consultation with their parents, participants completed the PedMIDAS (Hershey et al., 2001), a 6-item scale that evaluates the impact of migraines on recent engagement (i.e., over the past 90 days) in school, home, play, and social activities. Items prompted participants to report the number of days in which they missed various activities due to headaches. Responses were confirmed as part of a clinical interview with study staff (Hershey et al., 2001) Participants completed the PedMIDAS on the day of randomization, as well as at the end of the active trial period. The current study focused on postintervention PedMIDAS summed scores. Scores on the PedMIDAS range from 0 to 240; scores of 0–10 indicate no headache-related functional disability, scores of 11–30 indicate mild disability, scores of 31–50 indicate moderate disability, and scores over 50 indicate severe disability (Hershey et al., 2004). For more information regarding CHAMP trial procedures and measures, please see the published CHAMP protocol (Hershey et al., 2013).

Data Analysis Plan

Descriptive statistics (means and standard deviations) were calculated across the CHAMP sample for our three measures of medication adherence, sociodemographic variables of interest (age, gender, race, and household income), and primary clinical outcome variables in the CHAMP trial. Correlation analyses were conducted to examine associations among self-report and pill count measures of medication adherence that captured adherence rates from the entire active trial period. We also visualized mean values of our assessments of self-reported and pill-count medication adherence with 95% confidence intervals (CIs) for each visit mean value; the presence of nonoverlapping CIs was used to determine whether our monthly adherence rates (a) differed significantly over time and (b) were significantly different from one another at a given month of the CHAMP active trial period.

Given that blood serum levels provide a proximal estimate of adherence for the ∼5 days prior to sample collection, we compared self-reported adherence averages from the week leading up to sample collection for youth who were determined to have a zero drug level midway through the trial (∼12 weeks postrandomization; trial month 3) and at the end of the trial. We also examined pill count adherence rates from bottles collected at the time of the third trial month blood draw and trial end point blood draw among participants with zero drug levels. A paired t-test was conducted to compare mean rates of nonzero blood serum levels collected in the middle and end of the active trial period.

As part of our exploratory analyses examining associations between sociodemographic factors and medication adherence, bivariate correlations were run to examine potential associations between age and our adherence measures. Independent t-tests were conducted to compare adherence rates between male and female participants, as well as between White and non-White participants [racial categories for individuals who did not identify as White were collapsed for analyses due to the relative frequency counts of participants that identified as being a member of specific racial groups (e.g., Asian, Black/African American, Native American or Alaskan Native)] and Hispanic or Latino participants versus not Hispanic or Latino participants. Analysis of variance was conducted to assess for socioeconomic differences in self-report and pill count, measures of adherence. Chi-square analyses were run and assess for socioeconomic differences in our serum drug level measures of adherence. Multiple regression analysis was conducted to test medication adherence as a predictor of posttreatment headache frequency and headache-related functional disability, accounting for pretreatment measures of headache clinical status. Maximum likelihood estimation was used to account for missing data in our regression analyses. Analyses were conducted in SPSS version 25.0 and MPlus Version 8.6; p values < .05 (two-tailed) constituted statistically significant findings for all analyses.

Results

As has been previously reported (Powers et al., 2017), the CHAMP sample was predominantly White (81.7%; sample was 14.9% Black or African American, 0.6% Asian, 0.9% American Indian or Alaska Native, and 1.8% not reported or unknown), Not Hispanic or Latino (86.9%; 8.2% of the sample endorsed being Hispanic or Latino, and 4.8% did not report on ethnicity or ethnicity was unknown) and female (68.9%). Mean age for the sample was 13.75 years (SD = 2.41). Sample household income spanned the full range of possible income levels, with a median income level of $75,000–$99,999.

Table  I shows adherence percentages for self-report, pill count, and blood serum level data; self-report and pill count medication adherence rates were consistently high (over 90%) across months of the active trial period and were significantly correlated with one another (r = .250, p < .001). Figure  2 plots means (with 95% CIs) of (a) self-reported adherence and (b) pill count adherence measures across months of the active CHAMP trial period. Comparisons of CIs between adherence measures indicated that self-report adherence rates were significantly higher than pill count adherence measures in the first 3 months of the active trial; as Figure  2 highlights, self-report measures did not differ from one another across months of the trial, whereas pill count adherence rates in the first month of the trial were significantly lower than those calculated for months 4 and 6 of the trial.

Table I.

Self-Report, Pill Count, and Serum Blood Level Measures of Medication Adherence

Adherence rates (percentages, standard deviation) by measure
Time point Self-report Pill count Nonzero blood levels
Trial average 94.76%, SD = 8.60 91.93 %, SD = 10.05 —
Trial month 1 94.50%, SD = 10.29 91.23 %, SD = 13.32 —
Trial month 2 95.98%, SD = 8.39 91.78 %, SD = 11.23 —
Trial month 3 95.82%, SD = 9.99 92.30 %, SD = 11.47 84.04 %, SD = 36.71
Trial month 4 95.73%, SD = 9.85 93.79 %, SD = 9.98 —
Trial month 5 95.28%, SD = 11.96 93.38 %, SD = 10.42 —
Trial month 6 94.58%, SD = 13.13 93.98 %, SD = 9.13 76.10 %, SD = 42.75
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Figure 2.

Figure 2.

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(a) Self-reported Adherence Percentages across CHAMP Trial Months, Shown with 95% confidence intervals. (b). Pill Count Adherence Percentages across CHAMP Trial Months, Shown with 95% confidence intervals. *denotes confidence interval nonoverlapping (indicating a significant difference) with other adherence measure from same month of CHAMP trial; + denotes confidence interval nonoverlapping with same adherence measure at a different month in trial period.

Rates of nonzero blood levels were lower than more subjective measures of adherence (percentages ranging from 76% to 84%), and were found to decline significantly over the course of the active trial period [t (198) = 3.23, p = .001]. Among youth with serum drug levels of zero, self-reported adherence rates in the week prior to participants’ mid-trial blood draw was 91.52% (SD = 25.43); likewise, pill count adherence rates from the bottles returned at the time of the mid-trial blood draw was 92.39% (SD = 14.23). It should be noted that although this could not be systematically assessed, several participants had comments in pill count data suggesting at least some missed doses in the days prior to participants’ mid-trial blood draw. Among youth with zero serum drug levels at the end of the CHAMP trial, self-reported adherence rates in the week prior to participants end of trial blood draw was 91.49% (SD = 24.90) and pill count adherence rates from the bottles returned at the time of this blood draw was 97.46% (SD = 5.61).

In terms of associations between sociodemographic variables and CHAMP adherence measures, participant age was positively associated with self-reported medication adherence (r = .123, p = .030), as well as pill-count measures of adherence during the active trial period (r = .143, p = .011). Participant age was not associated with rates of nonzero drug levels. Participant gender was not associated with any measures of adherence, and race/ethnic differences were found only for pill count adherence measures; in particular, non-White participants were found to have lower pill count adherence rates than White participants [t (55.80) = −2.22, p = .031], and Hispanic or Latino participants had lower pill count adherence rates than non-Hispanic participants [t (28.00) = −2.19, p = .037]. For household income, only trial endpoint serum drug levels showed differences [χ2(7) = 16.60, p = .020], such that youth in households with an income of <$20,000 had lower adherence rates than youth in families with larger household incomes.

Multiple regression results investigating participant adherence as a predictor of headache outcomes revealed that mid-trial blood drug levels predicted headache-related disability at trial end (b = 0.205, p = .011), as did baseline headache frequency (b = 0.583, p = .011). No adherence measures predicted headache frequency at the end of the CHAMP trial.

Discussion

This study is one of the first systematic multimodal investigations of adherence to daily preventive medication for youth with migraine in the context of a randomized clinical trial. Results indicated that participants from the Child and Adolescent Migraine Prevention (CHAMP) study generally sustained high levels of adherence across the active trial period, with rates ranging from ∼75% to over 95%. As predicted, self-report and pill count measures were higher than blood serum drug levels, as evidenced by proximal self-reported/pill count adherence rates of >90% among youth with zero blood serum drug levels at trial month 3 (approximately the midpoint of the CHAMP trial). In contrast to self-report and pill-count adherence measures, which were stable to increasing across months of the active CHAMP trial period, blood serum drug levels decreased from the midpoint of the trial to the end of the active trial period. These findings highlight that youth do tend to inflate their level of preventive headache medication adherence and align with other findings in the pediatric adherence literature. That said, even our more objective serum drug level data revealed relatively good rates of adherence, suggesting that children and adolescents with migraine can sustain medication adherence over an extended course of treatment (in this case, over a period of 6 months).

CHAMP study rates of medication adherence tended to be higher than those reported in a clinic-based investigation of pill-count and self-report adherence among youth with migraine (Kroon Van Diest et al., 2016), and highlight the strengths and rigor of participant monitoring that occurred in the context of the CHAMP trial. Participants in the CHAMP study received regular follow-up reminders (through intervisit phone calls or monthly visit counsel from study staff) regarding the importance of medication adherence, which was not the case over the 45-day assessment period in the clinic-based study by Kroon Van Diest et al. (2016). Regular adherence reminders may have influenced the current findings, and aligns with pilot research showing that ongoing follow-up with patients via progressive electronic reminders can improve daily preventive treatment adherence in adolescents with migraine (Ramsey et al., 2018). Our findings have implications for clinical practice and for the systematic evaluation of methods to promote medication adherence in clinical trials with pediatric populations. Future research should examine the relative utility of different types of adherence prompts and/or follow-up (e.g., informational handout, telephone call, evidence-based mobile health apps with electronic monitoring and other behavior change strategies [see Gamwell et al., 2021]) in maximizing treatment outcomes for youth receiving clinic-based treatment for migraine.

Another methodological strength of this study lies in the multimodal assessment of medication adherence that was enabled by the infrastructure and funding of a large multisite clinical trial. Robust assessment strategies that include objective and patient-reported adherence measures provide critical information that can serve as the foundation for efficacy studies investigating adherence promoting interventions among youth with migraine, and can also help to contextualize informal assessments of medication adherence conducted in clinical settings (Plevinsky et al., 2020). Because different measures were collected repeatedly, we were able to compare adherence measures at different time points across the CHAMP trial. Drug distribution was also tracked over the course of the CHAMP study, precluding the need for assessment measures such as pharmacy records.

This study was not explicitly designed to assess adherence, and our self-report measure of adherence was limited in terms of CHAMP study staff’s ability to ensure that participant’s daily diary was, in fact, completed prospectively. Similarly, pill count measures were completed retrospectively (in that pill counts took place in the context of monthly study visits) and used a simple count of returned pills to calculate rates of adherence. This measure could not systematically incorporate comments from study staff regarding missing pills and could not be used to determine if all pills taken from study pill bottles had been ingested (vs. spilled, thrown away). Although we excluded data in rare cases where significant amounts of wasted pills were described by study staff, future studies focused on medication treatment adherence among youth with migraine may benefit from incorporation of more objective, in vivo capture of medication usage [e.g., electronic monitoring using Medication Event Monitoring Systems (MEMS) TrackCaps]. However, the issue of systematically identifying causes for wasted pills is also a limitation of MEMS tracking devices. Adding technological monitoring to a large, multicenter trial can also increase costs to what are already multimillion dollar endeavors.

Some limitations should also be considered with regard to our serum drug level measures of adherence. Despite being a more objective, biologic measure, our serum drug level measures could not (due to the pharmokinetics of study medications) provide information related to ongoing or long-term medication adherence. Our blood serum drug levels could also not be reliably used to characterize relative levels of adherence beyond zero versus nonzero adherence. Use of such measures is recommended in future clinical trials of migraine treatments, particularly if dose–response relationships could be established for children and adolescents; however, when taking into account cost and regulatory needs to store and process blood samples, the use of this measure is limited in terms of its practical utility in clinical research. Best practices for including robust adherence assessments in clinical research are needed. A sampling approach where multimodal adherence measures are collected at discrete, randomly selected periods of time throughout a study’s data collection period may serve as a feasible and cost-effective alternative approach to ongoing adherence assessment.

Although objective adherence measures are considered more ideal, incorporation of validated patient-reported adherence measures is important for generalizability to clinic or community-based research, as these measures are low cost, easy to administer, and can be developed to assess disease-specific aspects of treatment (Plevinsky et al., 2020). There are some general adherence measures for use with pediatric populations that demonstrate adequate to good psychometric properties (Plevinsky et al., 2020). Future studies are needed to validate patient-reported adherence measures for use with headache patients specifically, and to investigate associations with other adherence measures that are readily used among youth with migraine.

Previous research has found differences in adherence rates among youth who took a preventive headache medication once versus twice daily (Kroon Van Diest et al., 2016); given that all participants took pills twice a day regardless of their treatment condition, the current adherence rates reported for the CHAMP study are particularly impressive. That said, generalizability of the current findings to clinical practice is limited by the fact that the CHAMP study did not assess acute medication treatment adherence. Gold standard headache treatment for youth with migraine includes acute and potentially preventive medication prescriptions, adherence to behavioral recommendations for healthy lifestyle habits (e.g., sleep, daily fluid intake, etc.), and often engagement in behavioral therapies to promote pain coping. Investigations of adherence to biopsychosocial intervention for headache disorders that includes a systematic assessment of acute and preventive headache medication treatment adherence, use of behavioral coping strategies, and some exploration of other treatment-related factors (e.g., complexity of overall patient treatment regimen, comorbid conditions, etc.) would be important avenues for future research.

A comprehensive and statistically rigorous investigation of sociodemographic factors and treatment adherence was beyond the scope of this article; however, this study represents an important initial exploration of the role of factors like age, race/ethnicity, and socioeconomic status in youth preventive headache medication treatment adherence. The nature of our findings linking age and some adherence measures (self-report, pill count) was surprising, as adolescents typically have greater adherence difficulties than younger children (Danziger-Isakov et al., 2016; Eaton et al., 2018; Gray et al., 2018; Killian et al., 2018; Loiselle et al., 2016). However, interpretation and contextualization of these findings is limited by the fact that factors such as parental monitoring were not systematically assessed. Future studies should investigate the role of parenting styles, beliefs, and/or parenting stress in youth headache medication adherence (Armstrong et al., 2014; Loiselle et al., 2015; Saletsky et al., 2014).

Our findings linking race/ethnicity and socioeconomic status with preventive medication adherence were also inconsistent across measures, and generally align with the pattern of mixed findings seen in other pediatric populations (Carbone et al., 2013; Danziger‐Isakov et al., 2016; Gray et al., 2018; Killian et al., 2018; Modi et al., 2011; Wadhwani et al., 2020). Although the current multisite study drew participants from geographic regions across the United States and included a relatively socioecomomically diverse sample, current findings are limited by the relative lack of variability in adherence among our study adherence variables, and some of the demographic homogeneity (e.g., related to gender, race/ethnicity) of the CHAMP study sample.

More research is needed to investigate sociodemographic factors associated with adherence in a variety of clinical settings. The Pediatric Self-Management Model, a conceptual model that has been used to integrate the adherence literature in other patient populations and proposes that health-management behaviors are influenced by factors that occur across individual, family, community, and health care system levels (Gray et al., 2018; Modi et al., 2012), could be a particularly relevant framework for examining the role of multifaceted sociodemographic factors in adherence for youth with migraine. Future descriptive and/or adherence promotion work that selects from diverse community samples may deepen understanding of the role of sociodemographic factors on headache treatment adherence.

Finally, in line with many clinical trials focused on medication treatments, exclusion criteria (e.g., no use of SSRIs or SNRIs) for the CHAMP study likely limited the involvement of youth with severe mental health diagnoses. Safety considerations related to drug–drug interactions and/or possible confounding effects of concomitant medications often drive decisions about exclusion criteria in trials focused on headache disorders. Although understandable, these criteria can affect generalizability of the findings into clinical practice. Given the associations between headache and mental health disorders (e.g., anxiety, depression; see Slater et al., 2012), as well as links between psychological symptoms and medication adherence among youth with other chronic health conditions (Hamilton et al., 2018; Pai & Ostendorf, 2011), future research should explore the role of mental health symptoms on medication adherence among youth with headaches and/or migraine.

This study enhances our understanding of medication adherence in pediatric clinical trials and offers suggestions for how to enhance assessment of adherence in future medication trials for youth with migraine. This work also addresses gaps in the literature that can be built upon in clinic or community-based research that more directly investigate sociodemographic, psychological, and family factors in medication adherence among youth with migraine, and examine strategies for promoting headache medication adherence in the context of clinical care. Our findings indicate that participants in the CHAMP trial demonstrated good overall adherence; this adds increased confidence to the findings that resulted from this clinical trial and its ancillary studies (Powers et al., 2021; Reidy et al., 2021).

Supplementary Data

Supplementary data can be found at: https://academic.oup.com/jpepsy.

Supplementary Material

jsab123_Supplementary_Data
Click here for additional data file. (219KB, doc)

Acknowledgments

S. W. Powers, C. S. Coffey, and A. D. Hershey contributed equally to the CHAMP Study and its associated ancillary studies.

Funding

This work was supported by the National Institute of Neurological Disorders and Stroke (NINDS) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH; grant numbers U01NS076788 and U01NS077108), as well as through an NIH-funded T32 fellowship (grant number T32DK063929) in Child Behavior and Nutrition at Cincinnati Children’s Hospital Medical Center. Role of the Funder/Sponsor: As part of the U01 cooperative agreement with NINDS and NICHD, Dr L. L. Porter served as a scientific program officer for the CHAMP Study and was involved as a team member in the execution of the trial and the interpretation of efficacy study results.

Conflicts of interest: Dr. Hershey reports serving as a consultant for the following corporations: Alder/Lundbeck, Allergan, Avanir, Biohaven, Curelator, Electrocore, Impax, Lilly, Migraine Research Foundation, Teva, Theranica, Supernus, and Upsher-Smith, and receives research support from Curelator, Impax, and Teva. All payments for Dr. Hershey’s work are made directly to Cincinnati Children’s Hospital Medical Center. Dr. Kabbouche serves as a consultant for IMPEl. Dr. Kacperski has received research funding for participation in ongoing studies sponsored by Amgen, Teva, Impax, Currax and Curelator. All consulting and research funds for this work are paid directly to Cincinnati Children’s Hospital Medical Center. This work does not impact the current findings. Dr. Kacperski declares that there is no other potential conflict of interest for this study.

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Associated Data

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Supplementary Materials

jsab123_Supplementary_Data
Click here for additional data file. (219KB, doc)

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