Evaluating therapeutic benefits of ubrogepant via latent class models: A post hoc exploratory analysis of the ACHIEVE I and ACHIEVE II trials.

OBJECTIVE: To evaluate an alternative method of defining acute treatment success in migraine by combining multiple indicators into a single dichotomous measure of success. BACKGROUND: Migraine is characterized by a symptom complex; combining these features as a single endpoint may improve the measurement of treatment effects and better predict patient satisfaction with treatment. METHODS: We used a confirmatory latent class model (LCM) with two latent classes interpreted as treatment success and treatment failure. Pooled data for placebo and ubrogepant 50 mg from the ACHIEVE I and ACHIEVE II trials and data for ubrogepant 100 mg from ACHIEVE I were used. LCM inputs included pre-dose and 2-h post-dose measures of pain severity (0-3), the presence/absence of associated symptoms (nausea, photophobia, and phonophobia [0 or 1]), and functional disability (0-3). All definitions were validated against satisfaction with study medication (SWSM) at 24 h post-dose; results were compared with 2-hour pain freedom (2hPF). RESULTS: This pooled analysis included 2247 participants. At 2 h post-dose in the ubrogepant 50 and 100 mg dose groups, 53.2% (472/887) and 54.9% (246/448) of participants, respectively, were classified as achieving treatment success using the LCM-based approach, compared to 39.0% (356/912) of participants in the placebo group. The results for treatment success using the 2hPF endpoint were 20.7% (184/887) and 21.5% (96/447) in the ubrogepant 50 and 100 mg dose groups, respectively, compared to 12.7% (116/912) for placebo. Using 24-h SWSM as an external validator, the LCM approach sensitivity and correct classification rates were higher than for 2hPF. CONCLUSION: The LCM approach led to higher rates of treatment success and greater separation between ubrogepant and placebo and was a more sensitive predictor of treatment satisfaction than the regulatory endpoint of 2hPF.

Chronic Migraine Epidemiology and Outcomes - International (CaMEO-I) Study: Methods and multi-country baseline findings for diagnosis rates and care.

BACKGROUND: The Chronic Migraine Epidemiology and Outcomes-International study provides insight into people with migraine in multiple countries. METHODS: This cross-sectional, observational, web-based cohort study was conducted in Canada, France, Germany, Japan, United Kingdom, and United States. An initial Screening Module survey solicited general healthcare information from a representative sample and identified participants with migraine based on modified International Classification of Headache Disorders-3 criteria; those with migraine completed a detailed survey based on validated migraine-specific assessments. RESULTS: Among 90,613 people who correctly completed the screening surveys, 76,121 respondents did not meet the criteria for migraine, while 14,492 did. Among respondents with migraine, mean age ranged from 40 to 42 years. The median number of monthly headache days ranged from 2.33 to 3.33 across countries, while the proportion of respondents with moderate-to-severe disability (measured by Migraine Disability Assessment) ranged from 30% (Japan) to 52% (Germany). The proportion of respondents with ≥15 monthly headache days ranged from 5.4% (France) to 9.5% (Japan). Fewer than half of respondents with migraine in each country reported having received a migraine diagnosis. CONCLUSION: These results demonstrated high rates of migraine-related disability and underdiagnosis of migraine across six countries. This study will characterize country-level burden, treatment patterns, and geographical differences in care.

Pregnancy Outcomes in Patients Exposed to OnabotulinumtoxinA Treatment: A Cumulative 29-Year Safety Update.

BACKGROUND AND OBJECTIVES: A previous publication of pregnancy outcomes in onabotulinumtoxinA-exposed mothers demonstrated that the prevalence of major fetal defects (0.9%, 1/110) was comparable with background rates in the general population. There is continued interest to better understand the safety of onabotulinumtoxinA during pregnancy. This analysis evaluated pregnancy outcomes after onabotulinumtoxinA exposure to provide a cumulative 29-year update. METHODS: The Allergan Global Safety Database was searched from January 1, 1990, to December 31, 2018. Data from women (younger than 65 years or unknown) during pregnancy or ≤3 months before conception treated with onabotulinumtoxinA were assessed to estimate birth defect prevalence rates of live births only from prospective pregnancies. RESULTS: Of 913 pregnancies, 397 (43.5%) were eligible with known outcomes. Maternal age was known in 215 pregnancies: 45.6% were 35 years or older. Indication was known in 340 pregnancies: most frequent were aesthetic (35.3%) and migraine/headache (30.3%). The timing of exposure was known in 318 pregnancies: 94.6% were before conception or during the first trimester. OnabotulinumtoxinA dose information was known in 242 pregnancies; most (83.5%) were exposed to <200 U. Of 195 prospective pregnancies with 197 fetuses, there were 152 (77.2%) live births and 45 (22.8%) fetal losses (32 spontaneous, 13 elective). Of 152 live births, 148 (97.4%) had normal outcomes and 4 had abnormal outcomes. Among the 4 abnormal outcomes, there were 1 major birth defect, 2 minor fetal defects, and 1 birth complication. The prevalence rate for overall fetal defects was 2.6% (4/152, 95% CI 1.0%-6.6%) and 0.7% (1/152, 95% CI 0.1%-3.6%) for major fetal defects (3%-6% in the general population). Among cases of live births and known determinable exposure times, there was 1 birth defect with preconception exposure and 2 with first-trimester exposure. DISCUSSION: Although subject to reporting bias due to the nature of the postmarketing database review, this 29-year retrospective analysis of safety data in pregnant women exposed to onabotulinumtoxinA demonstrates that the prevalence rate of major fetal defects among live births is consistent with the rates reported in the general population. Although there are limited data available for second-trimester and third-trimester exposure, this updated and expanded safety analysis provides important real-world evidence to health care providers and their patients. CLASSIFICATION OF EVIDENCE: This analysis provides Class III data that demonstrate that the prevalence rate of major fetal defects among live births subsequent to in utero onabotulinumtoxinA exposure is comparable with the reported background rates.

OnabotulinumtoxinA alters inflammatory gene expression and immune cells in chronic headache patients.

Occipital headache, the perception of pain in the back of the head, is commonly described by patients diagnosed with migraine, tension-type headache, and occipital neuralgia. The greater and lesser occipital nerves play central role in the pathophysiology of occipital headache. In the clinical setup, such headaches are often treated with onabotulinumtoxinA, a neurotoxin capable of disrupting ability of nociceptors to get activated and/or release proinflammatory neuropeptides. Attempting to understand better onabotulinumtoxinA mechanism of action in reducing headache frequency, we sought to determine its effects on expression of inflammatory genes in injected occipital tissues. To achieve this goal, we injected 40 units of onabotulinumtoxinA into four muscle groups (occipitalis, splenius capitis, semispinalis capitis, and trapezius muscles-all located on one side of the occiput) of patients with chronic bilateral occipital headache scheduled for occipital nerve decompression surgery 1 month later. At the time of surgery, we collected discarded muscle, fascia and periosteum tissues from respective locations on both sides of the neck and occiput and performed targeted transcriptome analyses to determine expression level of inflammatory genes in onabotulinumtoxinA-injected and onabotulinumA-uninjected tissues. We found that (i) onabotulinumtoxinA alters expression of inflammatory genes largely in periosteum, minimally in muscle and not at all in fascia; (ii) expression of inflammatory genes in uninjected periosteum and muscle is significantly higher in historical onabotulinumA responders than historical non-responders; (iii) in historical responders' periosteum, onabotulinumA decreases expression of nearly all significantly altered genes, gene sets that define well recognized inflammatory pathways (e.g. pathways involved in adaptive/innate immune response, lymphocyte activation, and cytokine, chemokine, NF-kB, TNF and interferon signalling), and abundance of 12 different immune cell classes (e.g. neutrophils, macrophages, cytotoxic T-, NK-, Th1-, B- and dendritic-cells), whereas in historical non-responders it increases gene expression but to a level that is nearly identical to the level observed in the uninjected periosteum and muscle of historical responders; and surprisingly (iv) that the anti-inflammatory effects of onabotulinumA are far less apparent in muscles and absent in fascia. These findings suggest that in historical responders' periosteum-but not muscle or fascia-inflammation contributes to the pathophysiology of occipital headache, and that further consideration should be given to the possibility that onabotulinumA mechanism of action in migraine prevention could also be achieved through its ability to reduce pre-existing inflammation, likely through localized interaction that lead to reduction in abundance of immune cells in the calvarial periosteum.

Medication Overuse and Headache Burden: Results From the CaMEO Study.

OBJECTIVE: To estimate the relative frequency of acute medication overuse (AMO) among people with episodic migraine and chronic migraine, to characterize the types of acute medications overused for migraine, and to identify factors associated with AMO. METHODS: We analyzed data from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study (ClinicalTrials.gov, NCT01648530), a cross-sectional and longitudinal internet study that included a systematic sampling of the US population. From September 2012 to November 2013, the CaMEO Study respondents participated in different modules to collect data on the clinical course of migraine, family burden, barriers to care, endophenotypes, and comorbidities. Among people who met the criteria for migraine consistent with the International Classification of Headache Disorders, third edition (ICHD-3), we evaluated types and frequency of medications used for headache/migraine, selected comorbidities, and emergency department (ED) and urgent care (UC) use. AMO was defined by days per month of medication use as specified by ICHD-3 criteria for medication overuse headache (MOH) without the requirement for ≥15 monthly headache days (MHDs). Nested, multivariable binary logistic regression modeling was used to identify factors associated with an increased risk of AMO. RESULTS: Of 16,789 CaMEO respondents with migraine, 2,975 (17.7%) met the AMO criteria. Approximately 67.9% (2,021/2,975) of AMO respondents reported <15 MHDs. Simple analgesics, combination analgesics, and opioids were the medication classes most commonly overused. Factors associated with AMO in the final multivariable logistic regression model included ≥15 MHDs, moderate to severe disability, severe migraine interictal burden, use of preventive medication, and an ED/UC visit for headache within 6 months. CONCLUSIONS: Approximately two-thirds of respondents with AMO reported <15 MHDs and therefore did not meet the criteria for MOH. Those with AMO had greater disease burden and increased ED/UC utilization relative to people with migraine but not AMO.

Barriers to care in episodic and chronic migraine: Results from the Chronic Migraine Epidemiology and Outcomes Study.

OBJECTIVE: To assess rates of and factors associated with traversing fundamental barriers to good medical outcomes and pharmacologic care in individuals with episodic migraine (EM) and chronic migraine (CM), including socioeconomic status and race. BACKGROUND: Barriers to good outcomes in migraine include the lack of appropriate medical consultation, failure to receive an accurate diagnosis, not being offered a regimen with acute and preventive pharmacologic treatments (if indicated), and not avoiding medication overuse. METHODS: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study was a longitudinal Internet-based survey. Respondents who met criteria for migraine consistent with the International Classification of Headache Disorders, 3rd edition, had a Migraine Disability Assessment score ≥ 6, and provided health insurance coverage status were included in this analysis. Successfully traversing each barrier to care and the effects of sociodemographic characteristics were examined. RESULTS: Among 16,789 respondents with migraine, 9184 (54.7%; EM: 7930; CM: 1254) were eligible. Current headache consultation was reported by 27.6% (2187/7930) of EM and 40.8% (512/1254) of CM respondents. Among consulters, 75.7% (1655/2187) with EM and 32.8% (168/512) with CM were accurately diagnosed. Among diagnosed consulters, 59.9% (992/1655) with EM and 54.2% (91/168) with CM reported minimally appropriate acute and preventive pharmacologic treatment. Among diagnosed and treated consulters, in the EM group 31.8% (315/992) and in the CM group 74.7% (68/91) met medication overuse criteria. Only 8.5% (677/7930) of EM and 1.8% (23/1254) of CM respondents traversed all four barriers. Higher income was positively associated with likelihood of traversing each barrier. Blacks and/or African Americans had higher rates of consultation than other racial groups. Blacks and/or African Americans and multiracial people had higher rates of acute medication overuse. CONCLUSIONS: Efforts to improve care should focus on increasing consultation and diagnosis rates, improving the delivery of all appropriate guideline-based treatment, and avoidance of medication overuse.

Real-World Evidence for the Safety and Efficacy of CGRP Monoclonal Antibody Therapy Added to OnabotulinumtoxinA Treatment for Migraine Prevention in Adult Patients With Chronic Migraine.

Background: OnabotulinumtoxinA and calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) target different migraine pathways, therefore, combination treatment may provide additional effectiveness for the preventive treatment of chronic migraine (CM) than either treatment alone. The objective of this study was to collect real-world data to improve the understanding of the safety, tolerability, and effectiveness of adding a CGRP mAb to onabotulinumtoxinA treatment for the preventive treatment of CM. Methods: This was a retrospective, longitudinal study conducted using data extracted from a single clinical site's electronic medical records (EMR) of adult patients (≥18 years) with CM treated with ≥2 consecutive cycles of onabotulinumtoxinA before ≥1 month of continuous onabotulinumtoxinA and CGRP mAb (erenumab, fremanezumab, or galcanezumab) combination treatment. Safety was evaluated by the rate of adverse events (AE) and serious adverse events (SAE). The proportion of patients who discontinued either onabotulinumtoxinA, a CGRP mAb, or combination treatment, and the reason for discontinuation, if available, was collected. The effectiveness of combination preventive treatment was assessed by the reduction in monthly headache days (MHD). Outcome data were extracted from EMR at the first CGRP mAb prescription (index) and up to four assessments at ~3, 6, 9, and 12 months post-index. The final analyses were based on measures consistently reported in the EMR. Results: EMR were collected for 192 patients, of which 148 met eligibility criteria and were included for analysis. Erenumab was prescribed to 56.7% of patients, fremanezumab to 42.6%, and galcanezumab to 0.7%. Mean (standard deviation [SD]) MHD were 20.4 (6.6) prior to onabotulinumtoxinA treatment and 14.0 (6.9) prior to the addition of a CGRP mAb (baseline). After real-world addition of a CGRP mAb, there were significant reductions in MHD at the first assessment (~3 months) (mean -2.6 days/month, 95% CI -3.7, -1.4) and at all subsequent visits. After ~12 months of continuous combination treatment, MHD were reduced by 4.6 days/month (95% CI -6.7, -2.5) and 34.9% of patients achieved ≥50% MHD reduction from index. AEs were reported by 18 patients (12.2%), with the most common being constipation (n = 8, 5.4% [onabotulinumtoxinA plus erenumab only]) and injection site reactions (n = 5, 3.4%). No SAEs were reported. Overall, 90 patients (60.8%) discontinued one or both treatments. The most common reason for discontinuing either treatment was lack of insurance coverage (40%); few (~14%) patients discontinued a CGRP mAb and none discontinued onabotulinumtoxinA due to safety/tolerability. Conclusion: In this real-world study, onabotulinumtoxinA was effective at reducing MHD and the addition of a CGRP mAb was safe, well-tolerated and associated with incremental and clinically meaningful reductions in MHD for those who stayed on the combination treatment. No new safety signals were identified. Of those who discontinued, the majority reported lack of insurance coverage as a reason. Prospective real-world and controlled trials are needed to further evaluate the safety and potential benefits of this combination treatment paradigm for people with CM.

Long-Term Observational Results from the ASPIRE Study: OnabotulinumtoxinA Treatment for Adult Lower Limb Spasticity.

INTRODUCTION: OnabotulinumtoxinA treatment for spasticity varies according to numerous factors and is individualized to meet treatment goals. OBJECTIVE: To explore real-world onabotulinumtoxinA utilization and effectiveness in patients with lower limb spasticity from the Adult Spasticity International Registry (ASPIRE) study. DESIGN: Two-year, multicenter, prospective, observational registry (NCT01930786). SETTING: Fifty-four international clinical sites. PATIENTS: Adults (naïve or non-naïve to botulinum toxin[s] treatment for spasticity, across multiple etiologies) with lower limb spasticity related to upper motor neuron syndrome. INTERVENTIONS: OnabotulinumtoxinA administered at the clinician's discretion. MAIN OUTCOME MEASURES: OnabotulinumtoxinA treatment utilization, clinician- and patient-reported satisfaction. RESULTS: In ASPIRE, 530 patients received ≥1 onabotulinumtoxinA treatment for lower limb spasticity (mean age, 52 years; stroke, 49.4%; multiple sclerosis, 20.4%). Equinovarus foot was treated most often (80.9% of patients), followed by flexed knee (26.0%), stiff extended knee (22.5%), and flexed toes (22.3%). OnabotulinumtoxinA doses ranged between 10 and 1100 U across all presentations. Electromyography (EMG) was most commonly used for injection localization (≥41.1% of treatment sessions). Despite low patient response on the satisfaction questionnaire, clinicians (94.6% of treatment sessions) and patients (84.5%) reported satisfaction/extreme satisfaction that treatment helped manage spasticity, and clinicians (98.3%) and patients (91.6%) would probably/definitely continue onabotulinumtoxinA treatment. These data should be interpreted with care. Twenty-one adverse events (AEs) in 18 patients (3.4%) were considered treatment-related. Sixty-seven patients (12.6%) reported 138 serious AEs; 3 serious AEs in two patients (0.4%) were considered treatment-related. No new safety signals were identified. CONCLUSIONS: ASPIRE provides long-term observational data on the treatment of lower limb spasticity with onabotulinumtoxinA. Real-world data from this primary analysis can help to guide the clinical use of onabotulinumtoxinA to improve spasticity management.

Combined onabotulinumtoxinA/atogepant treatment blocks activation/sensitization of high-threshold and wide-dynamic range neurons.

BACKGROUND: OnabotulinumtoxinA and agents that block calcitonin gene‒receptor peptide action have both been found to have anti-migraine effects, but they inhibit different populations of meningeal nociceptors. We therefore tested the effects of combined treatment with onabotulinumtoxinA and the calcitonin gene‒receptor peptide antagonist atogepant on activation/sensitization of trigeminovascular neurons by cortical spreading depression. MATERIAL AND METHODS: Single-unit recordings were obtained of high-threshold and wide-dynamic-range neurons in the spinal trigeminal nucleus, and cortical spreading depression was then induced in anesthetized rats that had received scalp injections of onabotulinumtoxinA 7 days earlier and intravenous atogepant infusion 1 h earlier. The control group received scalp saline injections and intravenous vehicle infusion. RESULTS: OnabotulinumtoxinA/atogepant pretreatment prevented cortical spreading depression-induced activation and sensitization in both populations (control: Activation in 80% of high-threshold and 70% of wide-dynamic-range neurons, sensitization in 80% of high-threshold and 60% of wide-dynamic-range neurons; treatment: activation in 10% of high-threshold and 0% of wide-dynamic-range neurons, sensitization in 0% of high-threshold and 5% of wide-dynamic-range neurons). DISCUSSION: We propose that the robust inhibition of high-threshold and wide-dynamic-range neurons by the combination treatment was achieved through dual blockade of the Aδ and C classes of meningeal nociceptors. Combination therapy that inhibits meningeal C-fibers and prevents calcitonin gene‒receptor peptide from activating its receptors on Aδ-meningeal nociceptors may be more effective than a monotherapy in reducing migraine days per month in patients with chronic migraine.

Characterizing opioid use in a US population with migraine: Results from the CaMEO study.

OBJECTIVE: To determine the prevalence of and risk factors associated with opioid use in the treatment of migraine, we examined demographics and clinical characteristics of 867 individuals who reported using opioids for the treatment of migraine. METHODS: We analyzed data from the CaMEO study (Chronic Migraine Epidemiology and Outcomes), a cross-sectional, longitudinal, Internet study, to compare sociodemographics, clinical characteristics, and migraine burden/disability of opioid users vs nonusers. Covariates were entered as categorical or continuous variables. Factors associated with opioid use were identified using nested, multivariable binary logistic regression models. RESULTS: Of 2,388 respondents with migraine using prescription medications for acute treatment, 36.3% reported that they currently used or kept on hand opioid medications to treat headaches. Current opioid users had significantly more comorbidities, greater headache-related burden, and poorer quality of life than nonusers. Regression models revealed factors significantly associated with opioid use, including male sex, body mass index, allodynia, increasing monthly headache frequency, Total Pain Index score (excluding head, face, neck/shoulder), anxiety, depression, ≥1 cardiovascular comorbidity, and emergency department/urgent care use for headache in the past 6 months. Self-reported physician-diagnosed migraine/chronic migraine was associated with significantly decreased likelihood of opioid use. CONCLUSIONS: Of respondents who were using acute prescription medications for migraine, more than one-third used or kept opioids on hand, contrary to guidance. This analysis could not distinguish risk factors from consequences of opioid use; thus further research is needed to guide the development of strategies for reducing the inappropriate use of opioids in migraine.

Characterization of Acute Prescription Migraine Medication Use: Results From the CaMEO Study.

OBJECTIVE: To characterize self-reported use of acute prescription medication for migraine in a sample representing the US population. PATIENTS AND METHODS: Data were obtained from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study. The CaMEO Study is an Internet-based cross-sectional longitudinal survey administered between September 17, 2012, and November 19, 2013. Demographic characteristics, migraine-related disability, symptom severity, quality of life, and psychiatric comorbidity profiles were evaluated. RESULTS: Data from 13,624 respondents were analyzed, including 3121 (22.9%) self-reported current users of acute prescription medication for migraine, 1719 (12.6%) previous/discontinued users, and 8784 (64.5%) who had never used acute prescription medication for migraine. Mean ± SD monthly headache frequency was 7.3±7.1 days for current users, 5.6±6.6 days for those who discontinued, and 3.9±4.9 days for respondents who never used acute prescription medication for migraine. Current users experienced the highest degree of migraine-related disability based on Migraine Disability Assessment scores and the highest levels of migraine symptom severity based on Migraine Symptom Severity Scale scores. Current users also had the highest scores on the depression and anxiety questionnaires. The most commonly reported prescription medications used or "kept on hand" by current users were triptans (47.2%; 1474 of 3121), opioids (37.3%; 1164 of 3121), nonsteroidal anti-inflammatory drugs (31.9%; 997 of 3121), and barbiturates (12.8%; 399 of 3121), with many people reporting more than 1 medication. CONCLUSION: Despite reporting moderate to severe migraine-related disability and impairment, many people with migraine have never used acute prescription migraine medication. The burden related to migraine is great, especially among individuals currently using acute prescription medication for migraine.

The Effect of Psychiatric Comorbidities on Headache-Related Disability in Migraine: Results From the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study.

OBJECTIVE: To examine the influences of depression and anxiety on headache-related disability in people with episodic migraine or chronic migraine. BACKGROUND: Depression and anxiety are common comorbidities in people with migraine, especially among those with chronic migraine. METHODS: This cross-sectional analysis of data from the longitudinal, internet-based Chronic Migraine Epidemiology and Outcomes Study assessed sociodemographic and headache features, and headache-related disability (Migraine Disability Assessment Scale). Four groups were defined based on scores from validated screeners for depression (9-item Patient Health Questionnaire) and anxiety (7-item Generalized Anxiety Disorder Scale): depression alone, anxiety alone, both, or neither. RESULTS: Respondents (N = 16,788) were predominantly women (74.4% [12,494/16,788]) and white (84.0% [14,044/16,788]); mean age was 41 years. Depression was more likely in persons with chronic migraine vs episodic migraine (56.6% [836/1476] vs 30.0% [4589/15,312]; P < .001), as were anxiety (48.4% [715/1476] vs 28.1% 4307/15,312]; P < .001) and coexisting depression and anxiety (42.0% [620/1476] vs 20.8% [3192/15,312]; P < .001). After controlling for headache frequency and other covariates, depression alone, and anxiety alone were associated with 56.0% (rate ratio [RR], 1.56; 95% confidence interval [CI], 1.46-1.66) and 39.0% (RR, 1.39; 95% CI, 1.30-1.50) increased risks of moderate/severe migraine-related disability (both P < .001), respectively; the combination had an even greater effect on risk of moderate/severe disability (79.0% increase; RR, 1.79; 95% CI, 1.71-1.87; P < .001). CONCLUSIONS: Depression alone and anxiety alone are associated with greater headache-related disability after controlling for sociodemographic and headache features. Coexisting depression and anxiety are more strongly associated with disability than either comorbidity in isolation. Interventions targeting depression and anxiety as well as migraine itself may improve headache-related disability in people with migraine.

Migraine progression in subgroups of migraine based on comorbidities: Results of the CaMEO Study.

OBJECTIVE: To test the hypothesis that statistically defined subgroups of migraine (based on constellations of comorbidities and concomitant conditions; henceforth comorbidities), previously identified using Chronic Migraine Epidemiology and Outcomes (CaMEO) Study data, differ in prognosis, as measured by rates of progression from episodic migraine (EM) to chronic migraine (CM). METHODS: The onset of CM was assessed up to 4 times over 12 months in individuals with EM and ≥1 comorbidity at baseline, based on constellations of comorbidities (comorbidity classes). The "fewest comorbidities" class served as reference. Individuals completing ≥1 follow-up survey from the web-based CaMEO Study were included. Covariates included sociodemographic variables and headache characteristics. Sex, income, cutaneous allodynia, and medication overuse were modeled as binary variables; age, body mass index, headache-related disability (Migraine Disability Assessment [MIDAS]), and Migraine Symptom Severity Scale as continuous variables. CM onset was assessed using discrete time analysis. RESULTS: In the final sociodemographic model, all comorbidity classes had significantly elevated hazard ratios (HRs) for risk of progression to CM from EM, relative to fewest comorbidities. HRs for CM onset ranged from 5.34 (95% confidence interval [CI] 3.89-7.33; p ≤ 0.001) for most comorbidities to 1.53 (95% CI 1.17-2.01; p < 0.05) for the respiratory class. After adjusting for headache covariates independently, each comorbidity class significantly predicted CM onset, although HRs were attenuated. CONCLUSIONS: Subgroups of migraine identified by comorbidity classes at cross-section predicted progression from EM (with ≥1 comorbidity at baseline) to CM. The relationship of comorbidity group to CM onset remained after adjusting for indicators of migraine severity, such as MIDAS. CLINICALTRIALSGOV IDENTIFIER: NCT01648530.

FORWARD Study: Evaluating the Comparative Effectiveness of OnabotulinumtoxinA and Topiramate for Headache Prevention in Adults With Chronic Migraine.

OBJECTIVE: To compare effectiveness of onabotulinumtoxinA and topiramate for chronic migraine (CM) prevention. BACKGROUND: The efficacy* of onabotulinumtoxinA and topiramate has been established in placebo-controlled randomized clinical trials (*defined as the benefit of treatment under ideal conditions). The effectiveness* of the 2 preventive treatments, however, has not been established (*the benefit of treatment under real-world conditions, representing a blend of efficacy and tolerability). METHODS: In this multicenter, randomized, parallel-group, post-authorization, open-label prospective study (FORWARD; ClinicalTrials.gov, NCT02191579), we randomized adults with CM (1:1) to onabotulinumtoxinA 155 U every 12 weeks for 3 cycles or topiramate "immediate release" 50-100 mg/day to week 36. Primary outcome measure was proportion of patients achieving ≥50% reduction in headache days (weeks 29-32). Missing values were imputed using baseline observation carried forward (BOCF) methodology. After 12 weeks, patients initially randomized to topiramate could cross over to onabotulinumtoxinA treatment. We monitored and recorded all adverse events (AEs). RESULTS: We enrolled 282 patients (onabotulinumtoxinA, n = 140; topiramate, n = 142) and 148 patients completed randomized treatment (onabotulinumtoxinA, n = 120 [86%]; topiramate, n = 28 [20%]). Primary reasons for withdrawal were ineffective treatment (onabotulinumtoxinA, n = 7 [5%]; topiramate, n = 27 [19%]) and AEs (onabotulinumtoxinA, n = 5 [4%]; topiramate, n = 72 [51%]). Eighty topiramate patients crossed over to onabotulinumtoxinA. In the BOCF analysis, a significantly higher proportion of patients randomized to onabotulinumtoxinA experienced ≥50% reduction in headache frequency compared with those randomized to topiramate (40% [56/140] vs 12% [17/142], respectively; adjusted OR, 4.9 [95% CI, 2.7-9.1]; P < .001). OnabotulinumtoxinA was superior to topiramate in meeting secondary endpoints. In a post hoc analysis using observed data, the 50% responder rates at week 12 were 45.6% for onabotulinumtoxinA (n = 125) and 29.4% for topiramate (n = 109) (P = .015). AEs were reported by 48% (105/220) of onabotulinumtoxinA and 79% (112/142) of topiramate patients. Results were similar in those who crossed over to onabotulinumtoxinA. CONCLUSIONS: While using imputation methods of accounting for differences in discontinuation rates, we found onabotulinumtoxinA to have greater clinical utility than topiramate, largely because of tolerability issues associated with the latter and a relatively higher number of onabotulinumtoxinA patients remaining on treatment.

Life With Migraine: Effects on Relationships, Career, and Finances From the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study.

OBJECTIVE: To assess the effects of migraine on important life domains and compare differences between respondents with episodic and chronic migraine and between sexes. BACKGROUND: Migraine is associated with a substantial personal and societal burden and can also affect the interpersonal dynamics, psychological health and well-being, and financial stability of the entire family of the person with migraine. METHODS: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study is a prospective, longitudinal, Web-based survey study undertaken between September 2012 and November 2013 in a systematic U.S. sample of people meeting modified International Classification of Headache Disorders, 3rd edition migraine criteria: 19,891 respondents were invited to complete the Family Burden Module, which assessed the perceived impact of migraine on family relationships and life, career and finances, and overall health. Respondents were stratified by episodic migraine (<15 headache days/month) and chronic migraine (≥15 headache days/month) and sex for comparisons. RESULTS: A total of 13,064 respondents (episodic migraine: 11,944 [91.4%]; chronic migraine: 1120 [8.6%]) provided valid data. Approximately 16.8% of respondents not currently in a romantic relationship (n = 536 of 3189) and 17.8% of those in a relationship but not living together (n = 236 of 1323) indicated that headaches had contributed to relationship problems. Of those in a relationship and living together (n = 8154), 3.2% reported that they chose not to have children, delayed having children or had fewer children because of migraine (n = 260; episodic migraine: n = 193 of 7446 [2.6%]; chronic migraine: n = 67 of 708 [9.5%]; P < .001). Of individuals responding to career/finance items (n = 13,061/13,036), 32.7% indicated that headaches negatively affected ≥1 career area (n = 4271; episodic migraine: n = 3617 of 11,942 [30.3%]; chronic migraine: n = 654 of 1119 [58.4%]), and 32.1% endorsed worry about long-term financial security due to migraine (n = 4180; episodic migraine: n = 3539 of 11,920 [29.7%]; chronic migraine: n = 641 of 1116 [57.4%]). CONCLUSIONS: Migraine can negatively affect many important aspects of life including marital, parenting, romantic and family relationships, career/financial achievement and stability, and overall health. Reported burden was consistently greater among those with chronic migraine than among people with episodic migraine; however, few differences were seen between the sexes.

Long-Term Safety and Tolerability of OnabotulinumtoxinA Treatment in Patients with Chronic Migraine: Results of the COMPEL Study.

INTRODUCTION: OnabotulinumtoxinA is approved in the USA for the prevention of headache in adults with chronic migraine, a debilitating neurologic disease characterized by headaches occurring on ≥ 15 days per month for > 3 months and including migraine features on ≥ 8 days per month. OBJECTIVE: The COMPEL Study (NCT01516892), a 108-week, multi-center, open-label study, evaluated the long-term efficacy and safety of onabotulinumtoxinA in adults with chronic migraine. The objective of this subanalysis was to examine the safety and tolerability of onabotulinumtoxinA after each of nine treatment cycles. METHODS: OnabotulinumtoxinA 155 U was administered every 12 weeks. Safety and tolerability, overall and by treatment cycle, were assessed. Treatment-emergent adverse events reported between successive treatments were attributed to the preceding treatment. The safety population received one or more doses of onabotulinumtoxinA. The primary efficacy outcome was the reduction in headache days at week 108 compared with baseline. RESULTS: Of 716 patients enrolled, 373 patients (52.1%) completed the study and 343 (47.9%) withdrew; 481 patients (67.2%) received 60 weeks of treatment and 402 (56.1%) received 108 weeks of treatment. In total, 436 (60.9%) patients reported treatment-emergent adverse events; most were mild/moderate in severity. Thirty-two patients (4.5%) discontinued the study after experiencing treatment-emergent adverse events. The incidence of treatment-emergent adverse events typically decreased with repeated onabotulinumtoxinA treatment: first cycle, 24.2%; fourth cycle, 18.4%; ninth cycle, 12.2%. Neck pain (2.7%), eyelid ptosis (1.8%), musculoskeletal stiffness (1.4%), injection-site pain (1.3%), and headache (1.3%) were the most common treatment-emergent adverse events after the first cycle. Seventy-five patients (10.5%) reported serious treatment-emergent adverse events, 13 (1.8%) withdrew. Treatment-related adverse events were reported by 131 patients (18.3%), one was considered serious. OnabotulinumtoxinA significantly reduced headache day frequency by 10.7 (6.4) days per 28-day period (p < 0.0001) at week 108. CONCLUSIONS: OnabotulinumtoxinA treatment was well tolerated over 108 weeks; no new safety signals were identified. The overall incidence of treatment-emergent adverse events and the most common individual events decreased with repeated onabotulinumtoxinA administration. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT01516892.

Early onset of effect of onabotulinumtoxinA for chronic migraine treatment: Analysis of PREEMPT data.

BACKGROUND: The Phase 3 REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) trials demonstrated efficacy/tolerability of onabotulinumtoxinA for headache prevention in adults with chronic migraine. This post hoc analysis assessed time of onset of onabotulinumtoxinA after the first treatment in total and responder populations and consistency weekly through five treatment cycles. METHODS: In the 24-week, double-blind, placebo-controlled phase of PREEMPT, individuals were randomized 1:1 to onabotulinumtoxinA (155-195 U) or placebo every 12 weeks for two cycles. The primary pooled efficacy variable was change in headache days per 28 days at week 24. We assessed change in headache and migraine/probable migraine (hereafter migraine) days/week compared with baseline week 4. RESULTS: Baseline mean (SD) headache days/week (week 4 of baseline) for onabotulinumtoxinA (n = 688) and placebo (n = 696) were similar (4.8 [1.6] vs. 4.8 [1.6] days/week, respectively), as were migraine days/week (4.6 [1.7] vs. 4.6 [1.7] days/week). The effect of onabotulinumtoxinA on change in headache and migraine days/week was significantly greater than placebo at week 1, persisting from week 3 after the first treatment (-1.6 [2.2] vs. -1.1 [2.2] headache days/week [ p < 0.001] and -1.6 [2.2] vs. -1.1 [2.2] migraine days/week [ p < 0.001]). Headache and migraine days decreased in onabotulinumtoxinA responders beginning 1 week after treatment 1. CONCLUSIONS: Treatment with onabotulinumtoxinA is associated with significant reductions in headache and migraine days/week at week 1, persisting after week 3, compared with placebo. Combined with earlier reports showing onabotulinumtoxinA treatment results in a persistent and progressive reduction in headache days over 56 weeks, it is suggested peak benefit may require multiple treatments. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov: NCT00156910 and NCT00168428.

Epidemiology of migraine in men: Results from the Chronic Migraine Epidemiology and Outcomes (CaMEO) Study.

OBJECTIVE: To assess migraine epidemiology in men by examining gender differences in disease presentation, comorbidities, and prognosis. PATIENTS AND METHODS: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study is a longitudinal survey of US adults with migraine identified by web questionnaire. Data were stratified by gender, collected between September 2012-November 2013, and included sociodemographics, headache features, Migraine Disability Assessment, Migraine Symptom Severity Score, Allodynia Symptom Checklist, and comorbidities. Discrete time hazard models addressed 1-year likelihood of transition from episodic to chronic migraine headache frequency. RESULTS: Of the 16,789 migraine respondents, 4294 were men (25.6%). Compared to women, men were slightly older at onset of their headaches (mean 24.1 vs. 22.3 years) and had fewer headache days/month (4.3 vs. 5.3 days), slightly less severe attacks (Migraine Symptom Severity Score, 21.6 vs. 22.6), reduced frequencies of grade IV Migraine Disability Assessment scores (15.7% vs. 24.1%), allodynia (32.6% vs. 49.7%), chronic migraine (6.5% vs. 9.6%, each p < 0.001), and common comorbidities. Men were less likely to report consulting a doctor for their headaches and receiving a migraine diagnosis if they consulted. Men and women with episodic migraine had similar crude 1-year risk of chronic migraine onset. Controlling for known risk factors (i.e. depression, headache frequency, allodynia), men had greater likelihood of chronic migraine onset at 6, 9, and 12 months (each p < 0.05). CONCLUSIONS: Findings confirmed gender differences. Men with migraine generally have less severe attacks and disability and are less likely to receive a diagnosis than women with migraine. Prognostic factors may be better understood for women than men.

Adolescent Perspectives on the Burden of a Parent's Migraine: Results from the CaMEO Study.

OBJECTIVE: To assess the impact of parental migraine on adolescents (aged 13-21 years) living within the parental home from the adolescent's perspective. BACKGROUND: Family members are affected by their parent's migraine. We surveyed adolescents on the social, academic, and emotional effects of their parent's migraine. METHODS: The Chronic Migraine Epidemiology and Outcomes (CaMEO) study was a longitudinal Web-based study with cross-sectional modules designed to assess migraine symptoms, severity, frequency, and disability; migraine-related consulting practices, healthcare utilization, medication use, comorbid health conditions, and family related burden associated with migraine. The Family Burden Module (adolescent version; FBM-A) from the CaMEO study assessed parents with migraine and adolescent household members (dyads). Adolescents ranged in age from 13-21 years and were living at home with their parent. The initial FBM-A survey included 52 items covering five domains, which was refined and reduced by confirmatory factor analysis to 36 items covering four domains. Depression (9-item Patient Health Questionnaire) and anxiety (7-item Generalized Anxiety Disorder scale) were assessed. Item responses were stratified by parent migraine status (episodic migraine [EM], <15 headache days/month; chronic migraine [CM], ≥15 headache days/month). Frequencies of activities/events missed because of parental headache were categorized as ≥1 time or ≥4 times/previous 30 days. RESULTS: The sample included 1,411 parent-adolescent dyads (parent with EM, n = 1,243 [88.1%]; parent with CM, n = 168 [11.9%]). Burden due to a parent's migraine was reported in four domains based on 36 items including: Loss of Parental Support and Reverse Caregiving (5 items); Emotional Experience (13 items); Interference with School (4 items); and Missed Activities and Events (14 items). Across domains, perceived burden was greater for adolescents of parents with CM vs EM. Rates of moderate-to-severe anxiety symptoms were higher among adolescents of parents with CM (6.2 vs 11.3%, P = .01), while moderate-to-severe depression symptom rates were similar (5.5 vs 8.9%, P = .08). More adolescents of CM vs EM parents reported having a headache within the previous 3 months (P < .001). CONCLUSIONS: Parental migraine negatively impacts adolescent children, extending our understanding of the family burden of migraine and emphasizing the potential benefit to children of optimizing migraine care.