Real-world effectiveness, satisfaction, and optimization of ubrogepant for the acute treatment of migraine in combination with onabotulinumtoxinA: results from the COURAGE Study.

BACKGROUND: Individuals using onabotulinumtoxinA as a preventive migraine treatment often use acute treatments for breakthrough attacks. Data on real-world effectiveness of the small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist ubrogepant in combination with onabotulinumtoxinA are limited. METHODS: COURAGE, a prospective, multiple attack, observational study, evaluated the real-world effectiveness of ubrogepant (50 or 100 mg) for acute treatment of migraine in people receiving onabotulinumtoxinA, an anti-CGRP monoclonal antibody (mAb), or both. This analysis focused only on onabotulinumtoxinA users. The Migraine Buddy app was used to identify eligible participants and track response to treated attacks. For each ubrogepant-treated attack, meaningful pain relief (MPR) and return to normal function (RNF) at 2 and 4 h post-dose over 30 days was assessed. MPR was defined as a level of relief that is meaningful to the participant, usually occurring before the pain is all gone. After 30 days, satisfaction was reported on a 7-point scale and overall acute treatment optimization was evaluated using the migraine Treatment Optimization Questionnaire-4 (mTOQ-4). RESULTS: This analysis included 122 participants who received ubrogepant and onabotulinumtoxinA and reported on 599 ubrogepant-treated attacks. Following the first ubrogepant-treated attack, MPR was achieved in 53.3% of participants 2 h post-dose and in 76.2% of participants 4 h post-dose. RNF was achieved in 25.4% of participants 2 h post-dose and in 45.9% of participants 4 h post-dose. MPR and RNF results were similar across up to 10 ubrogepant-treated attacks. After 30 days, satisfaction with ubrogepant in combination with onabotulinumtoxinA was reported by 69.8% of participants and acute treatment optimization (defined as mTOQ-4 score ≥ 4) was achieved in 77.6%. CONCLUSIONS: In this prospective real-world effectiveness study, ubrogepant treatment in onabotulinumtoxinA users with self-identified migraine was associated with high rates of MPR and RNF at 2 and 4 h as well as satisfaction and acute treatment optimization. Although the lack of a contemporaneous control group limits causal inference, these findings demonstrate the feasibility of using a novel, app-based design to evaluate the real-world effectiveness and satisfaction of treatments.

Pre- and post-headache phases of migraine: multi-country results from the CaMEO - International Study.

BACKGROUND: Individuals with migraine frequently experience pre- and post-headache symptoms. This analysis aimed to characterize the relative frequency and burden of pre- and post-headache symptoms in people with migraine using data collected through the Chronic Migraine Epidemiology and Outcomes - International Study. METHODS: This cross-sectional, observational, web-based survey was conducted in 2021-2022 in Canada, France, Germany, Japan, the United Kingdom, and the United States. Respondents who met modified International Classification of Headache Disorders, 3rd edition, criteria were offered the opportunity to participate. Information collected included migraine-related disability, depression/anxiety symptoms, cutaneous allodynia, activity limitations, and acute treatment optimization. Respondents indicated how often they had pre- or post-headache symptoms using a 5-point scale, ranging from 0 to 4, with a rating of 2 or higher classified as a pre- or post-headache symptom case. Modeling was used to examine relationships with monthly headache days (MHDs) and activity limitations during pre-headache and post-headache phases. RESULTS: Among a total of 14,492 respondents, pre-headache symptoms were reported by 66.9%, while post-headache symptoms were reported by 60.2%. Both pre-headache and post-headache symptoms were reported by 49.5% of respondents, only pre-headache by 17.4%, only post-headache by 10.7%, and neither pre- nor post-headache symptoms by 22.4%. Compared with respondents who experienced only pre- or post-headache symptoms, respondents who experienced both pre- and post-headache symptoms had the highest rates of 4-7, 8-14, and ≥ 15 monthly headache days (23.1%, 14.1%, and 10.9%, respectively). Of respondents with both pre- and post-headache symptoms, 58.5% reported moderate-to-severe disability, 47.7% reported clinically significant symptoms of depression, 49.0% reported clinically significant symptoms of anxiety, and 63.8% reported cutaneous allodynia with headache (ASC-12). Moderate-to-severe activity limitations were reported during the pre-headache (29.5%) and post-headache phases (27.2%). For all outcomes modeled, after controlling for covariates, having pre-headache symptoms, post-headache symptoms, or both were associated with worse outcomes than having neither. CONCLUSIONS: Pre- and post-headache phases of migraine are common, carry unrecognized burden, and may be a target for treatment.

Mechanism of Action of OnabotulinumtoxinA in Chronic Migraine: A Narrative Review.

OBJECTIVE: To review the literature on the mechanism of action of onabotulinumtoxinA in chronic migraine. BACKGROUND: OnabotulinumtoxinA is a chronic migraine preventive treatment that significantly reduces headache frequency. The traditional mechanism described for onabotulinumtoxinA - reducing muscle contractions - is insufficient to explain its efficacy in migraine, which is primarily a sensory neurological disease. METHODS: A narrative literature review on the mechanism of action of onabotulinumtoxinA in chronic migraine. RESULTS: Following injection into tissues, onabotulinumtoxinA inhibits soluble N-ethylmaleimide-sensitive fusion attachment protein receptor (SNARE)-mediated vesicle trafficking by cleaving one of its essential proteins, soluble N-ethylmaleimide-sensitive fusion attachment protein (SNAP-25), which occurs in both motor and sensory nerves. OnabotulinumtoxinA inhibits regulated exocytosis of motor and sensory neurochemicals and proteins, as well as membrane insertion of peripheral receptors that convey pain from the periphery to the brain, because both processes are SNARE dependent. OnabotulinumtoxinA can decrease exocytosis of pro-inflammatory and excitatory neurotransmitters and neuropeptides such as substance P, calcitonin gene-related peptide, and glutamate from primary afferent fibers that transmit nociceptive pain and participate in the development of peripheral and central sensitization. OnabotulinumtoxinA also decreases the insertion of pain-sensitive ion channels such as transient receptor potential cation channel subfamily V member 1 (TRPV1) into the membranes of nociceptive neurons; this is likely enhanced in the sensitized neuron. For chronic migraine prevention, onabotulinumtoxinA is injected into 31-39 sites in 7 muscles of the head and neck. Sensory nerve endings of neurons whose cell bodies are located in trigeminal and cervical ganglia are distributed throughout the injected muscles, and are overactive in people with migraine. Through inhibition of these sensory nerve endings, onabotulinumtoxinA reduces the number of pain signals that reach the brain and consequently prevents activation and sensitization of central neurons postulated to be involved in migraine chronification. CONCLUSION: OnabotulinumtoxinA likely acts via sensory mechanisms to treat chronic migraine.

Effects of onabotulinumtoxinA treatment for chronic migraine on common comorbidities including depression and anxiety.

OBJECTIVE: To assess the effects of onabotulinumtoxinA treatment for chronic migraine (CM) on comorbid symptoms of depression, anxiety, fatigue and poor sleep quality. METHODS: The Chronic Migraine OnabotulinuMtoxinA Prolonged Efficacy open-Label (COMPEL) study is a multicentre, open-label, prospective study assessing the long-term safety and efficacy of onabotulinumtoxinA 155 U over nine treatments (108 weeks) in adults with CM. The Patient Health Questionnaire (PHQ-9) and Generalised Anxiety Disorder (GAD-7) scales were used to assess the effects of onabotulinumtoxinA on comorbid symptoms of depression and anxiety, respectively. A clinically meaningful improvement was assessed by the percentage of patients experiencing a ≥1 severity category reduction in PHQ-9 and GAD-7. The effects of onabotulinumtoxinA on associated sleep quality and fatigue were assessed using the Pittsburgh Sleep Quality Index and Fatigue Severity Scale, respectively. RESULTS: OnabotulinumtoxinA treatment was associated with sustained reduction in headache days and PHQ-9 and GAD-7 scores in the analysis population (n=715) over 108 weeks. PHQ-9 and GAD-7 scores were significantly reduced at all time points in patients with clinically significant symptoms of depression and/or anxiety at baseline. By week 108, 78.0% and 81.5% had clinically meaningful improvement in depression and anxiety symptoms, respectively. Sleep quality and symptoms of fatigue also improved; however, less is understood about clinically meaningful changes in these measures. No new safety concerns were identified. CONCLUSION: In addition to reducing headache frequency, onabotulinumtoxinA treatment for CM was associated with clinically meaningful reduction in symptoms of depression and anxiety, and improved associated symptoms of poor sleep quality and fatigue. TRIAL REGISTRATION NUMBER: NCT01516892.

Discontinuation of Acute Prescription Medication for Migraine: Results From the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study.

OBJECTIVE: This analysis assessed migraine-related burden and treatment decisions in Chronic Migraine Epidemiology and Outcomes (CaMEO) Study survey respondents who stopped taking acute prescription medications for migraine. BACKGROUND: Migraine is a common yet underdiagnosed and undertreated neurological disease often associated with significant disability. Acute prescription medications are underused, in part because patients discontinue treatment. Rates and reasons for discontinuing acute prescription medications require exploration. METHODS: The CaMEO Study is a longitudinal, Internet-based survey that identified and followed people who met modified ICHD-3 migraine criteria. For this analysis, eligible respondents had used acute prescription medication for migraine in the past but no longer used or kept these treatments on hand (discontinued users). Respondents who reported discontinuing acute prescription treatment answered questions about length of time since last use and reasons for stopping. Reasons for discontinuing were thematically summarized. Monthly headache day frequency, Migraine Disability Assessment (MIDAS), Patient Health Questionnaire 9-item depression screener, Generalized Anxiety Disorder 7-item screener, and the 12-item Allodynia Symptom Checklist were also assessed. RESULTS: Of 13,624 respondents with migraine, 4840 (35.5%) had ever used acute prescription medications and 1719 (35.5%) of those were discontinued users. Discontinued users had a mean (SD) age of 42.1 (14) years, and 1348/1719 (78.4%) were female. Monthly headache frequency of 0-4 days was reported by 1073/1719 (62.4%) of respondents, 5-9 days by 322/1719 (18.7%), 10-14 days by 135/1719 (7.9%), and ≥15 days by 189/1719 (11.0%). Two-thirds (1160/1719 [67.5%]) of discontinued users reported a receiving migraine (or chronic migraine) diagnosis from a doctor or other health professional in the past. Although all had spoken to a doctor about their headaches, 1504/1719 (87.5%) had stopped having their headaches managed or treated by a doctor for at least 12 months. Only 1 in 5 discontinued users reported being able to work or function normally with a headache, and 717/1719 (41.7%) had moderate to severe disability (MIDAS). Among the most commonly reported reasons for prescription medication discontinuation were switching to non-prescription pain medication (782/1719 [45.5%]), as well as concerns about prescription medication efficacy (484/1719 [28.2%]) and tolerability (428/1719 [24.9%]). Nearly half of respondents who reported either efficacy or tolerability concerns had moderate to severe disability. CONCLUSIONS: People with migraine who discontinue acute prescription medication have a high level of unmet treatment need. The majority cannot work or function normally with headaches, with 646/1719 (37.6%) of discontinued users reporting 5 or more headache days per month.

Sleep Disorders Among People With Migraine: Results From the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study.

OBJECTIVES: We examined the cross-sectional association of sleep apnea and indices of sleep quality with both episodic migraine (EM) and chronic migraine (CM). BACKGROUND: Sleep apnea and abnormal patterns of sleep, such as insomnia, were associated with migraine onset, severity, and progression in previous research. METHODS: The Chronic Migraine Epidemiology & Outcomes Study, a longitudinal study, used a series of web-based surveys to assess migraine symptoms, burden, and patterns of health care utilization. Quota sampling was used from September 2012 to November 2013 to generate a representative sample of the US population. Persons who screened positive for sleep apnea on the Berlin Questionnaire are said to be at "high risk" for sleep apnea. Respondents indicated if they believed that they had sleep apnea, if a physician had diagnosed it, and if and how they were treated. Other aspects of sleep quality were assessed using the Medical Outcomes Study (MOS) Sleep Measures. RESULTS: Of 12,810 eligible respondents with migraine and data on sleep, 11,699 with EM (91.3%) and 1111 with CM (8.7%) provided valid data for this analyses. According to the Berlin Questionnaire, 4739/12,810 (37.0%) were at "high risk" for sleep apnea, particularly persons with CM vs EM (575/1111 [51.8%] vs 4164/11,699 [35.6%]), men vs women (1431/3220 [44.4%] vs 3308/9590 [34.5%]), people with higher body mass index, and older people (all P < .001). Among respondents to the MOS Sleep Measures, persons with CM were more likely to report poor sleep quality than those with EM, including sleep disturbance (mean [SD] values: 53.2 [26.9] vs 37.9 [24.3]), snoring (38.0 [33.9] vs 31.0 [32.1]), shortness of breath (34.9 [29.8] vs 15.3 [20.6]), somnolence (44.1 [23.4] vs 32.2 [21.2]), and less likely to report sleep adequacy (34.0 [24.2] vs 39.2 [22.1]). CONCLUSIONS: Compared with respondents with EM, a larger proportion of those with CM were at "high risk" for sleep apnea and reported poor sleep quality. This reflects an association between CM vs EM and sleep apnea and poor sleep quality; the potential relationships are discussed.

Effects of onabotulinumtoxinA treatment in chronic migraine patients with and without daily headache at baseline: results from the COMPEL Study.

BACKGROUND: OnabotulinumtoxinA is effective in preventing chronic migraine (CM); however, the benefit of onabotulinumtoxinA in patients with CM with daily headache is unknown because these patients are typically excluded from clinical trials. This subanalysis of the COMPEL Study assessed the efficacy and safety of onabotulinumtoxinA in people with CM with and without daily headache. METHODS: In total, 715 patients received onabotulinumtoxinA 155 U with or without concomitant oral preventive treatment. Patients who had complete daily diary records for the 28 days of the baseline period were stratified based on daily headache status. The primary outcome variable was reduction in headache-day frequency per 28-day period at 108 weeks (after 9 treatment cycles) relative to baseline. Exploratory outcomes included moderate to severe headache days, migraine disability (using the Migraine Disability Assessment [MIDAS] questionnaire), and health-related quality of life (Migraine-Specific Quality-of-Life Questionnaire v2 [MSQ]). Adverse events and their relatedness were recorded. RESULTS: Overall, 641 patients had complete daily diary records at baseline. In patients with daily headache (n = 138) versus without (n = 503), treatment with onabotulinumtoxinA was associated with a significant mean (SD) reduction in 28-day headache-day frequency relative to baseline at week 108 (- 10.5 [9.2] vs - 12.2 [6.7], respectively; both P < 0.001) with no significant between-group difference (P = 0.132). The mean (SD) reduction in moderate to severe headache days at week 108 was significant in patients with and without daily headache (- 11.5 [9.4] and - 9.9 [6.4]; P < 0.001) with no significant between-group difference (P = 0.153). Mean (SD) MIDAS scores significantly improved from baseline at week 108 (- 43.3 [73.4] and - 43.6 [46.7]; both P < 0.001), with no significant between-group difference (P = 0.962). Similarly, mean (SD) MSQ subscale scores significantly improved from baseline at week 108 for patients with and without daily headache. OnabotulinumtoxinA was well tolerated in patients with and without daily headache. CONCLUSION: Results indicate that onabotulinumtoxinA is associated with reductions from baseline in headache-day frequency and improvements in disability and quality of life for up to 108 weeks in people with CM with daily headache; however, a longer duration of treatment was required to fully realize the treatment effect on headache. No new safety concerns were identified.

Effects of onabotulinumtoxinA treatment in patients with and without allodynia: results of the COMPEL study.

BACKGROUND: OnabotulinumtoxinA is effective in treating chronic migraine (CM), but there are limited data assessing how allodynia affects preventive treatment responses. This subanalysis of the 108-week, multicenter, open-label COMPEL Study assessed the efficacy and safety of onabotulinumtoxinA in people with CM with and without allodynia. METHODS: Patients (n = 715) were treated with onabotulinumtoxinA 155 U every 12 weeks for 9 treatment cycles. The Allodynia Symptom Checklist was used to identify patients with allodynia (scores ≥3). The primary outcome for this subanalysis was reduction in monthly headache days from baseline for weeks 105 to 108 in groups with and without allodynia. Other outcomes included assessments of moderate to severe headache days, disability (using the Migraine Disability Assessment [MIDAS] questionnaire), and health-related quality of life (Migraine-Specific Quality-of-Life Questionnaire [MSQ] v2). Adverse events and their relation to treatment were recorded. RESULTS: OnabotulinumtoxinA was associated with a significant mean (SD) reduction in headache day frequency at week 108 relative to baseline in patients with (n = 289) and without (n = 426) allodynia (- 10.8 [7.1] and - 12.5 [7.4], respectively; both P < 0.001) that was significantly greater in patients without allodynia (P = 0.044 between-subgroup comparison). Moderate to severe headache days were significantly reduced at week 108 in patients with and without allodynia (- 9.6 [6.9] and - 10.5 [7.2]; both P < 0.001); reduction was similar between groups. MIDAS scores improved significantly at week 108 (- 53.0 [50.3] and - 37.7 [53.0]; both P < 0.001), with a significant between-group difference in favor of those with allodynia (P = 0.005). Similarly, MSQ subscale scores (Role Function Preventive, Role Function Restrictive, Emotional Function) significantly improved at week 108 for patients with and without allodynia: 20.6 (21.9) and 16.9 (20.7), 28.0 (23.3) and 24.7 (22.7), and 27.6 (26.5) and 24.9 (26.1), respectively (all P < 0.001). OnabotulinumtoxinA was well tolerated in patients with and without allodynia. CONCLUSION: Results indicate that onabotulinumtoxinA is associated with reductions from baseline in multiple efficacy outcomes for up to 108 weeks whether or not allodynia is present. The allodynia group showed a smaller treatment response for reduction in headache days, but a similar or greater treatment response for improvement in other measures. No new safety concerns were identified.

Identifying Natural Subgroups of Migraine Based on Comorbidity and Concomitant Condition Profiles: Results of the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study.

OBJECTIVE: To identify natural subgroups of people with migraine based on profiles of comorbidities and concomitant conditions, hereafter referred to as comorbidities. BACKGROUND: Migraine is a heterogeneous disease. Identifying natural subgroups (endophenotypes) may facilitate biological and genetic characterization and the development of personalized treatment. METHODS: The Chronic Migraine Epidemiology and Outcomes Study is a prospective web-based survey study designed to characterize the course of migraine and related comorbidities in a systematic US sample of people with migraine. Respondents were asked if they ever had a specific comorbidity and, if present, whether the comorbidity was confirmed/diagnosed by a "doctor"; 62 comorbidities were available for analysis. Latent class analysis (LCA) modeling determined the optimal number of classes and a parsimonious set of comorbidities. RESULTS: Of the 12,810 respondents with migraine, 11,837 reported ≥1 comorbidity and were included in this analysis. After statistical analysis and clinical judgment reduced the number of comorbidities, we selected an 8-class model based on 22 comorbidities. Each class had a distinct pattern summarized as follows: Class 1, Most Comorbidities; Class 2, Respiratory/Psychiatric; Class 3, Respiratory/Pain; Class 4, Respiratory; Class 5, Psychiatric; Class 6, Cardiovascular; Class 7, Pain; Class 8, Fewest Comorbidities. The distribution of individuals across models was variable, with one-third of respondents in Class 8 (Fewest Comorbidities) and <10% in Class 1 (Most Comorbidities). Demographic and headache characteristics, not used in assigning class membership, varied across classes. For example, comparing Class 1 (Most Comorbidities) and Class 8 (Fewest Comorbidities), Class 1 had a greater proportion of individuals with severe disability (Migraine Disability Assessment grade IV; 48.1% vs 22.3% of overall individuals) and higher rates of allodynia (67.6% vs 47.0%), medication overuse (36.4% vs 15.0%), chronic migraine (23.1% vs 9.1%), and aura (40.1% vs 28.8%). CONCLUSIONS: LCA modeling identified 8 natural subgroups of persons with migraine based on comorbidity profiles. These classes show differences in demographic and headache features not used to form the classes. Subsequent research will assess prognostic and biologic differences among the classes.

Long-term study of the efficacy and safety of OnabotulinumtoxinA for the prevention of chronic migraine: COMPEL study.

BACKGROUND: OnabotulinumtoxinA is approved for the prevention of headache in those with chronic migraine (CM); however, more clinical data on the risk-benefit profile for treatment beyond one year is desirable. METHODS: The Chronic Migraine OnabotulinuMtoxinA Prolonged Efficacy open Label (COMPEL) Study ( ClinicalTrials.gov , NCT01516892) is an international, multicenter, open-label long-term prospective study. Adults with CM received 155 U of onabotulinumtoxinA (31 sites in a fixed-site, fixed-dose paradigm across 7 head/neck muscles) every 12 weeks (±7 days) for 9 treatment cycles (108 weeks). The primary outcome was headache day reductions at 108 weeks; secondary outcomes were headache day reductions at 60 weeks and change in the 6-item Headache Impact Test (HIT-6) score. Safety and tolerability were assessed by reviewing the frequency and nature of adverse events (AEs). AEs were determined at each visit through patient self-report, general non-directed and, for specific AEs, directed questioning, and physical examination. Subgroup analyses for safety and efficacy included, but were not limited to, patients with/without concomitant oral preventive treatment and acute medication overuse at baseline. RESULTS: Enrolled patients (N = 716) were 18-73 years old and most were female (n = 607, 84.8%). At baseline, patients reported an average 22.0 (SD = 4.8) headache days per month. 52.1% of patients (n = 373) completed the study. By 60 and 108 weeks, a significant reduction in headache days (- 9.2 days and - 10.7 days, respectively, P < 0.0001) was observed. Significant improvements (P < 0.0001) in HIT-6 scores (- 7.1 point change at week 108) were also demonstrated. 131 patients (18.3%) reported ≥1 treatment-emergent adverse events; most frequently reported was neck pain (n = 29, 4.1%). One patient reported a serious treatment-related adverse event (rash). No deaths were reported. CONCLUSIONS: The COMPEL Study provides additional clinical evidence for the consistency of the efficacy and for the long-term safety and tolerability of onabotulinumtoxinA for the prevention of headache in those with CM who have been treated with onabotulinumtoxinA every 12 weeks over 2 years (9 treatments) with the fixed-site, fixed-dose injection paradigm. TRIAL REGISTRATION: Trial registration number: NCT01516892 . Name of registry: clinicaltrials.gov . Date of registration: January 20 2012. Date of enrollment of first patient: December 2011.

The impact of onabotulinumtoxinA on severe headache days: PREEMPT 56-week pooled analysis.

BACKGROUND: OnabotulinumtoxinA has been shown to reduce headache-days among patients with chronic migraine (CM). The objective of this analysis was to determine whether onabotulinumtoxinA has an impact on headache-day severity in patients with CM among those patients who were deemed non-responders based on reduction in the frequency of headache days alone. METHODS: Data from the Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical trial program (a 24-week, 2-treatment cycle, double-blind, randomized, placebo-controlled, parallel-group phase, followed by a 32-week, 3-treatment cycle, open-label phase) were pooled for analysis. Patients kept a daily diary to record headache severity on a 4-point scale (from none to severe), and a 6-domain Headache Impact Test (HIT-6) was used to determine the clinical impact of headaches. Analysis was undertaken to assess whether the subset of patients that were headache-day frequency non-responders at week 24 (patients with <50% reduction in headache-day frequency) experienced a reduction in headache severity whilst receiving onabotulinumtoxinA. RESULTS: For headache-day frequency non-responders, significant reductions in the number of severe headache days, average daily headache severity, pooled percentage of severe headache days and headache severity score were observed at week 24 for patients who had received onabotulinumtoxinA compared with those who had received placebo. The between-group differences were reduced and non-significant at week 56. Similarly, headache-day frequency non-responders receiving onabotulinumtoxinA were found to have an improvement in the clinical impact of headaches using results from the HIT-6. CONCLUSIONS: These results suggest that even those patients with CM who are deemed non-responders based on analysis of headache frequency alone experience clinically meaningful relief from headache intensity following treatment with onabotulinumtoxinA.

A Comparison of the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study and American Migraine Prevalence and Prevention (AMPP) Study: Demographics and Headache-Related Disability.

OBJECTIVE: To compare the methods and baseline characteristics of the American Migraine Prevalence and Prevention (AMPP) and Chronic Migraine Epidemiology and Outcomes (CaMEO) studies. BACKGROUND: The AMPP and CaMEO studies are the largest longitudinal efforts designed to improve our understanding of episodic and chronic migraine in the United States. The studies have complementary strengths and weaknesses. METHODS: This analysis compares and contrasts the study methods and participation rates of the AMPP and CaMEO studies. We then compare and contrast baseline results in terms of demographic characteristics, headache features, and disability as measured by the Migraine Disability Assessment Scale (MIDAS) among people with episodic and chronic migraine. RESULTS: AMPP and CaMEO sampled from panels constructed to be representative of the US population. The AMPP Study collected data using a mailed questionnaire while CaMEO relied on a web survey methodology. Response rates were higher in AMPP (64.8%) than in CaMEO (16.5%). Both studies assessed headache features using the American Migraine Study/AMPP diagnostic module. Both identified persons with episodic (<15 headache days/month) and chronic migraine (≥15 headache days/month) based on the International Classification of Headache Disorders. AMPP collected data annually over 5 years, while CaMEO collected data quarterly over 15 months. Baseline demographic distribution was generally similar, indicating that each study was broadly representative of the US population. The proportion of persons with migraine who had chronic migraine was similar (AMPP, 6.6%; CaMEO, 8.8%). Respondents had similar median headache frequency (days/month) by sex for chronic migraine (AMPP: men = 21.7, women = 20.0; CaMEO: men = 20.0, women = 20.0) and episodic migraine (AMPP: men = 1.7, women = 2.0; CaMEO: men = 2.0, women = 3.0). Median MIDAS scores were substantially higher in both studies for chronic migraine (severe disability [Grade IV]; AMPP: men = 33.0, women = 45.0; CaMEO: men = 32.0, women = 38.0) than episodic migraine (little/mild disability [Grade I/II]; AMPP: men = 3.0, women = 6.0; CaMEO: men = 4.0, women = 7.0). Rates of moderate/severe disability (Grade III/IV) were substantially higher in both studies for chronic migraine (AMPP: men = 66.9%, women = 78.9%; CaMEO: men = 71.0%, women = 82.6%) than episodic migraine (AMPP: men = 23.0%, women = 31.8%; CaMEO: men = 26.7%, women = 37.9%). More women than men respondents in both studies experienced moderate/severe disability. CONCLUSIONS: AMPP and CaMEO are longitudinal cohort studies that used different methods, but yielded similar results for demographic features, headache frequency, and headache-related disability. Both studies found more severe headache-related disability in those with chronic versus episodic migraine.

Assessing Barriers to Chronic Migraine Consultation, Diagnosis, and Treatment: Results From the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study.

OBJECTIVE: To assess the rates and predictors of traversing steps essential to good medical care for chronic migraine, including: (1) medical consultation, (2) accurate diagnosis, and (3) minimal pharmacologic treatment. Candidate predictors included socioeconomic, demographic, and headache-specific variables. BACKGROUND: Previous research has established that barriers to effective management for episodic migraine include the absence of health insurance, lack of appropriate medical consultation, failure to receive an accurate diagnosis, and not being offered a regimen with acute and preventive treatments. METHODS/DESIGN: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study, a longitudinal web-based panel study of migraine, included a cross-sectional module focused on patterns of and barriers to medical care. Participants eligible for this analysis met the study criteria for chronic migraine, had evidence of headache-related disability, and provided data on health insurance status. The main outcomes in the current analysis included the proportion of respondents who sought consultation for headache with a designated healthcare professional, self-reported receiving a diagnosis of chronic or transformed migraine, and received minimal pharmacologic treatment for headache with a focus on prescribed acute and preventive treatments. RESULTS: In the CaMEO Study, 80,783 respondents provided study data, 16,789 (20.8% of respondents) met criteria for migraine, and 1476 (8.8% of those with migraine) met chronic migraine criteria. In total, 1254 participants (85.0% of those with chronic migraine) met inclusion criteria for this analysis. Of those, 512 respondents (40.8%) reported currently consulting with a healthcare professional for headache. Odds of consulting increased with increasing age (OR 1.02; 95% CI 1.01-1.03), body mass index (BMI) (OR 1.01; 95% CI 1.00-1.03), migraine-related disability (OR 1.02; 95% CI 1.00-1.04), and migraine severity (OR 1.16; 95% CI 1.11-1.22) and presence of health insurance (OR 4.61; 95% CI 3.05-6.96). Among those consulting a healthcare professional, 126 (24.6%) received an accurate diagnosis and 56 of those with a correct diagnosis (44.4%) received both acute and preventive pharmacologic treatments; odds of a CM diagnosis were higher for women (OR 1.93; 95% CI 1.03-3.61), those with greater migraine severity (OR 1.25; 95% CI 1.14-1.37), and those currently consulting a specialist (OR 2.38; 95% CI 1.54-3.69). No predictors of receiving appropriate treatment were identified among those currently consulting. Among our sample of people with chronic migraine, only 56 (4.5%) individuals successfully traversed the series of 3 barriers to successful chronic migraine care (ie, consulted a healthcare professional for migraine, received an accurate diagnosis, and were prescribed minimal acute and preventive pharmacologic treatments). CONCLUSION: Our findings suggest that <5% of persons with chronic migraine traversed 3 barriers to receiving care for headache (consultation, diagnosis, and treatment), representing a large unmet need for improving care in this population. Predictors of consulting a healthcare professional included age, having health insurance, greater migraine-related disability, and greater migraine symptom severity. Among those consulting, predictors of an appropriate diagnosis included consulting a specialist, female sex, and greater migraine severity. Public health efforts are needed to improve outcomes for patients with chronic migraine by a range of interventions and educational efforts aimed at improving consultation rates, diagnostic accuracy, and adherence to minimal pharmacologic treatment.

Neck Pain and Cervical Dystonia: Treatment Outcomes from CD PROBE (Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy).

BACKGROUND: Pain is a prevailing feature of cervical dystonia (CD), the most common form of focal dystonia. This analysis examined pain relief after onabotulinumtoxinA treatment in CD subjects with moderate/severe pain from the Cervical Dystonia Patient Registry for Observation of OnabotulinumtoxinA Efficacy (CD PROBE). METHODS: CD PROBE was a prospective, multicenter, observational registry of CD subjects who were naïve to botulinum toxin (BoNT), new to physician, or had not received BoNT within ≥ 16 weeks if in a clinical trial. Subjects were eligible for 3 treatments, with variable session intervals. Descriptive and inferential statistics were utilized to evaluate the change in pain scores in the population with moderate/severe neck pain at baseline (Pain Numeric Rating Scale [PNRS] score 4 to 10). RESULTS: Of 1046 enrolled, 733 (70.7%) had moderate/severe neck pain at baseline. Postinjection pain questionnaire responses 4 to 6 weeks after each of the 3 treatments revealed that a majority of subjects (67.1%, 72.4%, and 76.4%) reported pain relief; mean time to pain relief was 7.1, 7.4, and 7.6 days. All pain scales showed significant improvements from baseline to final visit (all P < 0.0001): PNRS, mean 6.6 to 3.8; CD Impact Profile-58 Pain and Discomfort subscale, mean 78.7 to 56.5; and Toronto Western Spasmodic Torticollis Rating Scale Pain subscale, mean 12.6 to 8.5. Multivariable regression models showed that initial pain score significantly contributed to the final pain score for all scales. CONCLUSION: Results from this real-world clinical registry indicate that a majority of CD subjects with moderate/severe neck pain experience significant relief following onabotulinumtoxinA treatment.

Acute treatment optimization in episodic and chronic migraine: results of the American Migraine Prevalence and Prevention (AMPP) Study.

BACKGROUND: The migraine Treatment Optimization Questionnaire (mTOQ) was developed to assess response to acute treatment in persons with migraine. The original validated form used yes or no response options. OBJECTIVES: This study aims to (1) assess the psychometric properties of a 6-item version of the mTOQ (mTOQ-6) using ordinal response options; (2) compare treatment optimization using the revised mTOQ-6 for both episodic and chronic migraine (EM and CM, respectively); (3) identify demographic, headache, and treatment features associated with treatment optimization. METHODS: The American Migraine Prevalence and Prevention (AMPP) Study is a longitudinal, US population-based study. Annual questionnaires were mailed to a sample of 24,000 severe headache sufferers identified by screening a panel constructed to be representative of the US population. The current study included respondents to the 2006 AMPP Study survey who met modified International Classification of Headache Disorders-3 beta criteria for migraine; persons with CM (≥15 HA days/month) or EM (<15 HA days/month) were included. Acute treatment optimization was measured with the mTOQ-6. A single factor latent variable model was used to assess item characteristics. This model was expanded through structural equation models (SEM) to incorporate a contrast between persons with CM and EM on the scaled treatment optimization scores. We estimated both an unadjusted SEM and a SEM adjusted for demographic features, headache characteristics, and acute treatment. RESULTS: Migraine criteria were met by 8612 persons (539 for CM and 8073 for EM) who completed the mTOQ-6 as part of the 2006 AMPP Study survey. When compared, those with CM exhibited worse treatment optimization across all domains of the mTOQ-6. For example, 35.1% of CM and 44.6% of EM respondents reported being pain free at 2 hours "half the time or more" with their usual migraine medication. Latent variable model parameters indicated excellent psychometric properties of the mTOQ-6. Scaled treatment optimization scores obtained from the unadjusted SEM were significantly lower (indicating worse treatment optimization) for persons with CM (3.25) compared to persons with EM (4.01), b = -0.76, P < .0001; scores remained significantly lower for CM after adjustment with a wide array of demographic and disease severity covariates. Poor treatment optimization was associated with cutaneous allodynia, major depression, and the use of nonsteroidal anti-inflammatory drugs. Better treatment optimization was associated with the use of triptans and preventive medications. CONCLUSION: Estimates of the latent variable scores for the mTOQ-6 revealed persistent low levels of treatment optimization for both EM and CM, though treatment optimization is worse for CM.

Real-World Use of Ubrogepant as Acute Treatment for Migraine with an Anti-Calcitonin Gene-Related Peptide Monoclonal Antibody: Results from COURAGE.

INTRODUCTION: Although acute and preventive treatments for migraine are commonly given in combination, data on the real-world effectiveness of ubrogepant as an acute treatment when used with an anti-calcitonin gene-related peptide (CGRP) monoclonal antibody (with or without onabotulinumtoxinA) are limited. This analysis sought to evaluate the real-world effectiveness, treatment satisfaction, and optimization of ubrogepant for the acute treatment of migraine when used in combination with an anti-CGRP monoclonal antibody, with or without concomitant onabotulinumtoxinA. METHODS: This prospective, multiple-attack, open-label, observational study (COURAGE) assessed meaningful pain relief (MPR), return to normal function (RNF), treatment satisfaction, and acute treatment optimization of ubrogepant (50 or 100 mg) when combined with an anti-CGRP monoclonal antibody, onabotulinumtoxinA, or both in adult users of Migraine Buddy, a migraine tracking application. RESULTS: In the ubrogepant and anti-CGRP monoclonal antibody arm (n = 245), following the first ubrogepant-treated attack, 61.6% (151/245) and 80.4% (197/245) of ubrogepant-treated participants achieved MPR at 2 and 4 h post-dose, respectively, and 34.7% (85/245) and 55.5% (136/245) achieved RNF at 2 and 4 h post-dose, respectively. Across up to 10 ubrogepant-treated attacks (N = 1153), MPR was achieved in 51.3% (592/1153) and 73.5% (847/1153) at 2 and 4 h post-dose, respectively. RNF was achieved by 32.2% (371/1153) and 53.2% (613/1153) at 2 and 4 h post-dose. After 30 days, 72.7% (168/231) of participants reported satisfaction (using a 7-point scale) with ubrogepant when used in combination with an anti-CGRP monoclonal antibody, and 79.7% (184/231) of participants achieved acute treatment optimization (defined as moderate-maximum treatment efficacy using the Migraine Treatment Optimization Questionnaire-4). CONCLUSION: Real-world ubrogepant use with an anti-CGRP monoclonal antibody was associated with MPR, RNF, satisfaction, and acute treatment optimization.

Multimodal Migraine Management and the Pursuit of Migraine Freedom: A Narrative Review.

Migraine is a neurologic disease with a complex pathophysiology that can be controlled with current treatment options but not cured. Therefore, treatment expectations are highly variable. The concept of migraine freedom was recently introduced and can mean different things, with some, for example, expecting complete freedom from headache and associated symptoms and others accepting the occasional migraine attack if it does not impact functioning. Therefore, migraine management should be optimized so that patients can have the best opportunity to achieve their optimal treatment goals. With migraine freedom as a goal and, given the complex pathophysiology of migraine and the high incidence of comorbidities among individuals with migraine, treatment with a single modality may be insufficient, as it may not achieve migraine freedom in those with more frequent or disabling attacks. In this clinical perspective article, we have identified four key, partially overlapping principles of multimodal migraine treatment: (1) manage common comorbidities; (2) control modifiable risk factors for progression by addressing medication and caffeine overuse; (3) diagnose and treat secondary causes of headache, if present; and (4) individualize acute and preventive treatments to minimize pain, functional disability, and allodynia. There are many barriers to pursuing migraine freedom, and strategies to overcome them should be optimized. Migraine freedom should be an aspirational goal both at the individual attack level and for the disease overall. We believe that a comprehensive and multimodal approach that addresses all barriers people with migraine face could move patients closer to migraine freedom.

Optimized Acute Treatment of Migraine Is Associated With Greater Productivity in People With Migraine: Results From the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study.

OBJECTIVE: This study aimed to ascertain whether level of optimization of acute treatment of migraine is related to work productivity across the spectrum of migraine. METHODS: Data were from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study, an internet-based longitudinal survey. Respondents with migraine who reported full-time employment and use of ≥1 acute prescription medication for migraine were included. We determined relationships among lost productive time (LPT; measured with the Migraine Disability Assessment Scale), acute treatment optimization (Migraine Treatment Optimization Questionnaire- ), and monthly headache days (MHDs). RESULTS: There was a direct relationship between LPT and MHD category. Greater acute treatment optimization was associated with lower total LPT, less absenteeism, and less presenteeism within each MHD category. CONCLUSIONS: Optimizing acute treatment for migraine may reduce LPT in people with migraine and reduce indirect costs.

Ubrogepant Is Safe and Efficacious in Participants Taking Concomitant Preventive Medication for Migraine: A Pooled Analysis of Phase 3 Trials.

INTRODUCTION: Ubrogepant is a calcitonin gene-related peptide receptor antagonist indicated for acute treatment of migraine that can be used to treat breakthrough attacks in individuals taking preventive treatment for migraine. We evaluated the impact of preventive medication use on the efficacy and safety of ubrogepant for the acute treatment of migraine. METHODS: This was an analysis of pooled efficacy data from the ACHIEVE I and ACHIEVE II phase 3 trials, in which efficacy of ubrogepant was assessed at 2 h after taking study medication for pain freedom, absence of most bothersome symptom (MBS), and pain relief. In addition, a long-term safety (LTS) extension trial was completed where safety was assessed on the basis of incidence and severity of treatment-emergent adverse events (TEAEs). Outcomes were compared between participants with or without prior (within 6 months) preventive medication use (anticonvulsants, beta blockers, antidepressants, or onabotulinumtoxinA). For efficacy analyses, data were pooled across ACHIEVE trials for the 50 mg and placebo groups; for safety analyses, data for all dose groups (50 mg and 100 mg) in the LTS trial were pooled. RESULTS: Preventive treatments were used by 417 of 2247 (18.6%) participants analyzed in the ACHIEVE trials and by 143 of 813 (17.5%) participants in the LTS trial. Responder rates for all outcomes were similar between participants with or without preventive treatment within each dose group (p > 0.05). No significant differences were noted across the different preventive medications. Rates and types of TEAEs were similar between participants with or without preventive treatment. No serious treatment-related adverse events were reported. CONCLUSION: Efficacy and safety of ubrogepant for the acute treatment of migraine were similar between participants with or without prior or current use of concomitant preventive medication. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02828020 (ACHIEVE I), NCT02867709 (ACHIEVE II), and NCT02873221 (long-term safety trial).

Real-World Evidence for Control of Chronic Migraine Patients Receiving CGRP Monoclonal Antibody Therapy Added to OnabotulinumtoxinA: A Retrospective Chart Review.

INTRODUCTION: Combination use of onabotulinumtoxinA and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) has the potential to be more effective than either therapy alone for migraine prevention. METHODS: This retrospective, longitudinal chart review included adults with chronic migraine treated at one clinical site with ≥ 2 consecutive cycles of onabotulinumtoxinA and ≥ 1 month of subsequent combination treatment with CGRP mAbs. Charts at time of mAb prescription (baseline) and up to four visits ~ 3, 6, 9, and 12 months post-baseline were reviewed for safety, tolerability, and outcome measures (monthly headache days [MHDs], headache intensity, and migraine-related disability [MIDAS]). RESULTS: Of 300 charts reviewed, 257 patients met eligibility criteria (mean age: 50 years; 82% women). Average headache frequency was 21.5 MHDs before initiation of onabotulinumtoxinA and 12.1 MHDs before adding CGRP mAb therapy. Prescribed mAbs were erenumab (78%), fremanezumab (6%), and galcanezumab (16%). Over the entire study, patients discontinued CGRP mAb more frequently than onabotulinumtoxinA (23 vs. 3%). Adverse events occurred in 28% of patients, most commonly constipation (9%). Compared with onabotulinumtoxinA alone (baseline), MHDs decreased significantly at all visits (mean decrease: 3.5-4.0 MHDs over ~ 6-12 months of combination treatment); 45.1% of patients had clinically meaningful improvement in migraine-related disability (≥ 5-point reduction in MIDAS score) after ~ 6 months. CONCLUSIONS: In this real-world study, combination treatment with onabotulinumtoxinA and CGRP mAbs was well tolerated, with no new safety signals identified, and was associated with additional clinically meaningful benefits. More real-world and controlled trials should be considered to further assess safety and potential benefits of combination treatment. Video abstract: Real-world data suggests that CGRP inhibitors improve onabotulinumtoxinA efficacy for chronic migraine (MP4 20,067 kb).