Buse, Dawn C.

Abstract Objective To assess the utility of the novel patient‐identified (PI) most bothersome symptom (MBS) measure from PROMISE‐2, a phase 3 trial of eptinezumab for the preventive treatment of chronic migraine. Background Relief of bothersome migraine symptoms can influence satisfaction with treatment and therapeutic persistence. Understanding the impact of preventive treatment on a PI‐MBS could improve clinical decision‐making. Methods In PROMISE‐2, patients with chronic migraine received eptinezumab 100, 300 mg, or placebo administered intravenously every 12 weeks for up to 2 doses ( n = 1072). PI‐MBS was an exploratory outcome requiring each patient to self‐report their MBS in response to an open‐ended question. At baseline and week 12, patients rated overall improvement in PI‐MBS. The relationships among PI‐MBS at week 12 and change in monthly migraine days (MMDs) from baseline to month 3 (weeks 9–12), Patient Global Impression of Change at week 12, and changes from baseline to week 12 in the 6‐item Headache Impact Test total, EuroQol 5‐dimensions 5‐levels visual analog scale, and 36‐item Short‐Form Health Survey component scores were assessed. Results Treatment groups had similar baseline characteristics and reported a total of 23 unique PI‐MBS, most commonly light sensitivity (200/1072, 18.7%), nausea/vomiting (162/1072, 15.1%), and pain with activity (147/1072, 13.7%). Improvements in PI‐MBS at week 12 correlated with changes in MMDs ( ρ = −0.49; p < 0.0001) and other patient‐reported outcomes. Controlling for changes in MMDs, PI‐MBS improvement predicted other patient‐reported outcomes in expected directions. The magnitude of the standardized mean differences between placebo and active treatment for PI‐MBS were 0.31 ( p < 0.0001 vs. placebo) and 0.54 ( p < 0.0001 vs. placebo) for eptinezumab 100 and 300 mg, respectively. Conclusions Improvement in PI‐MBS at week 12 was associated with improvement in other patient‐reported outcome measures, and PI‐MBS may be an important patient‐centered measure of treatment benefits in patients with chronic migraine.

Background Ictal cutaneous allodynia, common in chronic migraine, is associated with reduced responses to acute treatment with triptans. Allodynia’s impact on the efficacy of newer preventive treatments such as erenumab is unknown. Methods Post-hoc subgroup analysis of a double-blind, randomized, placebo-controlled 12-week study of erenumab in chronic migraine, contrasting those with no allodynia with those with moderate-severe allodynia assessed with the Allodynia Symptom Checklist-12, was undertaken. Results Of 648 randomized individuals with baseline Allodynia Symptom Checklist-12 scores, 386 (59.6%) had no allodynia and 153 (23.6%) had moderate-to-severe allodynia. Mean (standard deviation) baseline monthly migraine days were 17.6 (4.8) and 18.9 (4.3), respectively. Compared to placebo, the erenumab group had greater reductions in monthly migraine days and monthly acute migraine-specific medication days in both no allodynia and allodynia subgroups. Mean (95% confidence interval) treatment differences in change from baseline for monthly migraine days at week 12 were −2.5 (−3.7, −1.4) in the no allodynia subgroup and −3.3 (−5.3, −1.3) in the moderate-severe allodynia subgroup. Change in acute migraine-specific medication days were −3.3 (−4.3, −2.3) and −2.5 (−4.3, −0.8), respectively. Conclusions Erenumab’s efficacy in reducing monthly migraine days and acute migraine-specific medication days in chronic migraine was not impacted by the presence of moderate-severe ictal allodynia. Trial registration: ClinicalTrials.gov NCT02066415

Abstract Background/Objective To review the acute migraine clinical trial literature and provide a summary of the endpoints and outcomes used in such trials. Method A systematic literature review, following a prespecified (but unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses, was conducted to understand endpoints and outcomes used in acute migraine clinical trials. Predefined terms were searched in PubMed to locate clinical trials assessing acute migraine treatments. Final database search was conducted on October 28, 2019. Identified publications were reviewed against established inclusion and exclusion criteria to determine eligibility. Data related to general trial design characteristics, sample characteristics, and outcomes and endpoints reported in each publication were extracted from eligible publications. Descriptive summaries of design features, sample characteristics, and the endpoints and outcomes employed across publications were constructed. Outcomes are presented within four broad categories: (a) pain‐related outcomes (pain relief, pain freedom, etc.), (b) associated symptoms (nausea, photophobia, etc.), (c) disability/impairment/impact, (d) patient‐reported outcome measures (PROMs, general health and migraine/headache‐specific). Endpoint types were categorized within three broad categories: (a) change from baseline, (b) fixed timepoint, and (c) responder definitions (e.g., 50% reduction). This review focuses on a subset of recent (1998 or later) randomized and blinded publications evaluating drugs or medical devices. Results Of 1567 publications found through the initial search and reference section reviews, 705 met criteria and were included for data extraction. Inter‐rater agreement kappas for the descriptive variables extracted had an average kappa estimate of 0.86. The more recent, randomized and blinded pharmaceutical and medical device article subset includes 451 publications (451/705, 63.9%). The outcomes and endpoints varied substantially across trials, ranging from pain relief or freedom, freedom from or relief of migraine‐associated symptoms, use of acute or rescue medication, and various other PROMs, including measures of satisfaction and quality of life. Within the recent randomized and blinded article subset, most articles examined ≥1 pain‐related outcome (430/451, 95.3%). Of the publications that examined pain, outcomes most often used were pain relief (310/430, 72.1%), pain freedom (279/430, 64.9%), and headache recurrence (202/43,051, 47.0%) or rescue medication use (278/430, 64.9%). Associated symptoms such as nausea, photophobia, and phonophobia were more frequently measured (299/451, 66.3%) compared to most bothersome associated symptom (16/451, 3.5%), as it is a new addition to regulatory guidance. Over one‐third of eligible publications examined disability/impairment (186/451, 41.2%) or ≥1 PROM (159/451, 35.3%). The definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of “responders” to treatment based on wide variety of “responder definitions”) also differed substantially across publications. Conclusion Acute migraine clinical trials exhibit a large amount of variability in outcomes and endpoints used, in addition to the variability in how outcomes and endpoints were used from trial‐to‐trial. There were some common elements across trials that align with guidance from the International Headache Society, the Food and Drug Administration and other regulatory agencies (e.g., assessing pain and associated symptoms, 2‐hour post‐treatment). Other aspects of acute migraine clinical trial design did not follow guidance. For example, multi‐item PROMs intended to measure constructs (e.g., scales) are rarely used, the use of pain‐related outcomes is inconsistent, some associated symptom assessments are idiosyncratic, and the timing of the assessment of primary endpoints is variable. The development of a core set of outcomes and endpoints for acute migraine clinical trials that are patient‐centered and statistically robust could improve the conduct of individual trials, facilitate cross‐trial comparisons, and better support informed treatment decisions by healthcare professionals and patients.

Abstract Background Over the last six decades (earliest included publication from 1959), clinical trials of migraine preventive treatments have led to the regulatory approval of many medications and devices. Despite similar clinical goals, the outcomes and endpoints used in these trials are broad and not well standardized. Objective To describe results from a systematic literature review focused on outcomes and endpoints used in preventive migraine clinical trials. Method A systematic literature review, following a pre‐specified (unregistered) protocol developed to adhere to recommendations of the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses, was conducted to characterize the endpoints and outcomes used in preventive migraine clinical trials. Predetermined terms were searched in PubMed on October 28, 2019. Data related to trial design, subject characteristics, outcomes, and endpoints reported in each publication were extracted. Descriptive summaries of these features were tabulated for the recent subset of publications, published during or after 1988, that were randomized, blinded, and focused on pharmacological or device therapies for the preventive treatment of migraine. Results The initial literature search identified 1506 publications, of which 757 publications were eligible for data extraction. Of specific clinical interest were the recent subset of 268 articles (268/757, 35.4%) fulfilling the targeted criteria. Results showed that the outcomes used to define endpoints varied substantially across publications. For example, in the recent subset of publications, 68.7% (184/268) of the publications examined ≥1 migraine‐specific outcome, 39.6% (106/268) examined ≥1 headache‐specific outcome, 50.7% (136/268) examined ≥1 acute/rescue medication use outcome, 40.3% (108/268) examined ≥1 headache‐related patient‐reported outcome measure (PROM), and 22.0% (59/268) examined ≥1 non‐headache‐specific PROM. Furthermore, the definition of the endpoints used (e.g., change from baseline, fixed timepoint comparisons, categorization of “responders” to treatment based on wide variety of “responder definitions”) also differed across publications. Conclusion Publications from clinical trials of preventive migraine pharmacologic and device treatments differed in terms of study design, endpoint definitions, and how endpoints and outcomes were measured. Although there were common outcomes and endpoints used across publications, no clear “standardized” set of endpoints and outcomes emerged. The inconsistencies in endpoints and outcomes within this literature suggest that the development of a uniform set of outcomes and endpoints could improve the clinical meaningfulness of clinical trial results, facilitate cross‐trial comparisons and better inform patient care. This standard set of outcomes and endpoints should be statistically robust and informed by the priorities of various stakeholders, most importantly, the needs and preferences of people living with migraine.

Abstract Objective We sought to assess factors associated with the frequency of self‐reported prescription opioid use in persons with migraine, including demographic variables, comorbidities, headache characteristics, and patterns of consultation. Background Despite the dose‐dependent effect of opioids on migraine progression and the association with negative outcomes, migraine treatment often includes opioids. The Migraine in America Symptoms and Treatment Study focuses on individuals with migraine who receive prescription acute medications, including those receiving and those not receiving opioids. Methods This web‐based panel survey identified people in the United States with migraine using a validated screener. This analysis stratified people with migraine into 4 groups based on days of monthly opioid use: non‐opioid users, ≤3 days, 4‒9 days, and ≥10 days per month. Results Of 15,133 respondents with migraine, 4701 (31%) reported acute prescription medication use for headache/migraine in the previous 3 months (mean age 45 years, 71.6% [3367/4701] female), of whom 32.5% (1528/4701) reported opioid use. About one‐third of respondents with primary care or neurology consults in the prior 6 months reported receiving an opioid, and more than half of respondents (209/391, 53.5%) with a pain clinic consultation did so. Models compared those using opioids ≤3 days/month (879/4701, 18.7%), 4‒9 days/month (304/4701, 6.5%), ≥10 days/month (345/4701, 7.3%) to non‐opioid users (3173/4701, 67.5%). Compared to non‐opioid users, infrequent users (≤3 days/month) were more likely to be male and less likely to have chronic migraine or to screen positive for anxiety and depression; and frequent opioid users (the 4‒9 days/month and the ≥10 days/month groups) were more likely to be male, to smoke, to be obese, to report greater pain interference, to have moderate to severe disability, to have symptoms of anxiety and depression, to use fewer triptans and nonsteroidal anti‐inflammatory drugs, and to have poor acute treatment optimization. Conclusion Among prescription medication users, this cross‐sectional analysis shows that increasing use of prescription opioids is associated with male gender, chronic migraine, more severe disability, anxiety and depression, poor acute treatment optimization, and treatment in a pain clinic.

On March 11, 2020, the infection caused by the coronavirus disease 2019 (COVID‐19) virus was declared a pandemic. Throughout this pandemic, healthcare professionals (HCPs) have experienced difficulties stemming from poor communications, resource scarcity, lack of transparency, disbelief, and threats to the safety of their loved ones, their patients, and themselves. As part of these hardships, negative statements have been heard repeatedly. This paper describes 11 scenarios of unhelpful and dysfunctional messages heard by the authors and their colleagues during the COVID‐19 pandemic, reported to us by a combination of peers, administrative leadership, and the public. We explain why not to use such messaging, and we suggest more helpful and compassionate expressions based upon recommendations published by scientific organizations and well‐established psychological principles. The first 10 scenarios discussed include (1) lack of understanding regarding the extent of the pandemic; (2) shaming over not seeing patients in person; (3) lack of clear and consistent communication from leadership on pandemic‐related practice changes; (4) opinions that personal protective equipment (PPE) use by HCPs causes fear or is unnecessary; (5) forcing in‐person care without appropriate PPE; (6) the risk of exposure to asymptomatic individuals as it relates to opening clinics; (7) media gag orders; (8) pay and benefit reductions; (9) spreading of misinformation about the COVID‐19 pandemic; and (10) workload expectations. The 11th scenario addresses HCPs’ psychological and physical reactions to this challenging and prolonged stressful situation. We close by discussing the need for support and compassion at this difficult and unpredictable time and by offering suggestions to foster resilience and feelings of self‐efficacy among HCPs.

Background Migraine is associated with debilitating symptoms that can affect daily functioning. “My Migraine Voice” was a large, cross‐sectional, multi‐country online survey aimed at understanding disease burden directly from people with migraine. Objective This study reports on the social and economic impacts of migraine, specifically the impact on activities of daily living and the costs of migraine, from the point of view of people with migraine in the United States. Methods The online survey was administered to adults with a self‐reported diagnosis of migraine who experienced 4 or more monthly migraine days each month for the previous 3 months. Prespecified screening quotas were used so that 90% of respondents reported current or past use of preventive migraine medication, 80% of whom switched treatment (ie, changed their prescribed preventive medication at least once). The remaining 10% were preventive treatment naïve (ie, never used any prescribed preventive medication). Burden of migraine on activities of daily living and caregivers (eg, functional limitations, fear of next migraine attack, sleep problems) and economic burden (eg, out‐of‐pocket costs, impact on work productivity using the validated work productivity and activity impairment questionnaire) reported by respondents from the United States are presented. Results are stratified by employment status, migraine frequency (chronic vs episodic migraine), and history of preventive treatment. Results Thousand hundred and one individuals with migraine from the United States responded to the survey. Respondents reported limitations completing daily activities during all migraine phases, including during the premonitory/aura and postdrome phases. Most (761/1101 (69%)) relied on family, friends, or others for help with daily tasks and reported being helped a median of 9 days (25th percentile 5 days, 75th percentile 15 days) within the last 3 months. Respondents with chronic migraine reported being helped for more days (median 10 days, 25th percentile 5 days, 75th percentile 23 days) in the last 3 months. Almost all (962/1101 (87%)) experienced sleep difficulties and 41% (448/1101) (48% (336/697) of those with 2 or more preventive treatment failures) were very or extremely fearful of a next migraine attack. Median (25th percentile, 75th percentile) monthly out‐of‐pocket costs of $90.00 ($30.00, $144.00) in doctor’s fees (n = 504), $124.00 ($60.00, $234.00) in health insurance (n = 450), $40.00 ($20.00, $100.00) for prescriptions (n = 630), and $50.00 ($0.00, $100.00) for complementary therapies (n = 255) were reported. Those with 2 or more preventive treatment failures reported higher monthly out‐of‐pocket doctor fees (median $99.00 ($30.00, $150.00), n = 388). Among employed respondents (n = 661), migraine resulted in 22% absenteeism, 60% presenteeism, 65% work productivity loss, and 64% activity impairment. Conclusions Migraine impacts individuals’ activities of daily living, work‐life, and financial status, especially individuals with high needs, namely those with 4 or more monthly migraine days and prior treatment failures. People with migraine are impaired during all migraine phases, experience fear of their next migraine attack and sleep difficulties, and pay substantial monthly out‐of‐pocket costs for migraine. Burden is even greater among those who have had 2 or more preventive treatment failures. Impacts of migraine extend beyond probands to caregivers who help people with migraine with daily tasks, employers who are affected by employee absenteeism, presenteeism, and reduced productivity, and society which is burdened by lost and reduced economic productivity and healthcare costs.

Objectives The objectives of this study were to determine the rates of nausea, phonophobia, and photophobia reported overall and as the most bothersome symptom (MBS) in individuals with migraine and to identify individual characteristics associated with each of the 3 candidate MBSs. Background The MBS has emerged as an important coprimary efficacy endpoint in clinical trials of acute treatments for migraine, as recommended by the Food and Drug Administration. The current understanding of how persons with migraine designate an associated symptom as the most bothersome has been assessed primarily in the context of randomized trials. Methods Respondents (n = 95,821) in the cross‐sectional, observational Migraine in America Symptoms and Treatment (MAST) study were adults (aged ≥18 years) recruited from a US nationwide online research panel. A validated diagnostic screener identified 15,133 individuals who met modified International Classification of Headache Disorders (ICHD)‐3 beta criteria for migraine and reported at least 1 monthly headache day (MHD) over the previous 3 months. The survey ascertained sociodemographic variables, headache‐related disability, MHDs, cutaneous allodynia, medication overuse, a migraine symptom severity score, pain interference, noncephalic pain, anxiety and depression symptoms, visual aura over the previous year, and acute treatment optimization. The current analysis is based on respondents who also completed a 6‐month follow‐up assessment that included questions about their most bothersome headache symptom. Results A total of 7518 respondents completed the 6‐month follow‐up, and 6045 met inclusion criteria and were included in the analysis. The mean age of respondents was 47 (SD 13.4) years, 76.0% (4596/6045) were women, and 84.8% (5103/6017) were white. Among all respondents, 64.9% reported all 3 migraine symptoms. The MBS was photophobia in 49.1% (2967/6045), nausea in 28.1% (1697/6045), and phonophobia in 22.8% (1381/6045). Respondents reporting photophobia as the MBS were more likely to be men, to be obese, and to report visual aura. Those reporting nausea as the MBS were more likely to be women, to have lower incomes, and to report lower levels of treatment optimization. Respondents reporting phonophobia as the MBS were more likely to have cutaneous allodynia and less likely to have visual aura. Conclusion Most people with migraine in the MAST observational study reported all 3 cardinal symptoms of nausea, photophobia, and phonophobia. As in clinical trials, the most common MBS was photophobia. Patient profiles differed among the groups defined by their MBS.