Novel insight into atogepant mechanisms of action in migraine prevention.

Recently, we showed that while atogepant - a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist - does not fully prevent activation of nociceptors, it significantly reduces a cortical spreading depression (CSD)-induced early response probability in C-fibers and late response probability in A™-fibers. The current study investigates atogepant effect on CSD-induced activation and sensitization of high-threshold (HT) and wide dynamic range (WDR) dura-sensitive neurons. In anesthetized male rats, single-unit recordings were used to assess effects of atogepant (5mg/kg) vs vehicle on CSD-induced activation and sensitization of HT and WDR dura-sensitive neurons. Single cell analysis of atogepant pretreatment effects on CSD-induced activation and sensitization of central trigeminovascular neurons in the spinal trigeminal nucleus (STN) revealed ability of this small molecule CGRP receptor antagonist to prevent activation and sensitization of nearly all HT neurons (8/10 vs. 1/10 activated neurons in the control vs. treated groups, p=0.005). In contrast, atogepant pretreatment effects on CSD-induced activation and sensitization of WDR neurons revealed an overall inability to prevent their activation (7/10 vs. 5/10 activated neurons in the control vs. treated groups, p=0.64). Unexpectedly however, in spite of atogepant inability to prevent activation of WDR neurons, it prevented their sensitization (as reflected their responses to mechanical stimulation of the facial receptive field before and after the CSD). Atogepant ability to prevent activation and sensitization of HT neurons is attributed to its preferential inhibitory effects on thinly unmyelinated A™ fibers. Atogepant inability to prevent activation of WDR neurons is attributed to its lesser inhibitory effects on the unmyelinated C fibers. Molecular and physiological processes that govern neuronal activation vs. sensitization can explain how reduction in CGRP-mediated slow but not glutamate-mediated fast synaptic transmission between central branches of meningeal nociceptors and nociceptive neurons in the STN can prevent their sensitization but not activation.

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.

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.

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.

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.

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.

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.

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.

Efficacy of Ubrogepant in the Acute Treatment of Migraine With Mild Pain vs Moderate or Severe Pain.

BACKGROUND AND OBJECTIVES: To examine the efficacy of ubrogepant in the treatment of migraine with mild vs moderate or severe pain. METHODS: This was a phase 3, open-label, dose-blinded, 52-week extension trial. Adults with migraine were randomized 1:1:1 (usual care, ubrogepant 50 mg, or ubrogepant 100 mg). Participants treated up to 8 migraine attacks of any pain intensity every 4 weeks. Efficacy outcomes (only collected for ubrogepant) included 2-hour pain freedom (2hPF), freedom from associated symptoms, and from disability. A generalized linear mixed model with binomial distribution and logit link function was used to assess the influence of baseline pain intensity on treatment outcomes in this post hoc analysis. RESULTS: Data for 19,291 attacks from 808 participants were included. 2hPF rates were higher for attacks treated when pain was mild vs moderate or severe: ubrogepant 50 mg (47.1% vs 23.6%; odds ratio [95% CI] 2.89 [2.57-3.24]) and ubrogepant 100 mg (55.2% vs 26.1%; 3.50 [3.12-3.92]; p < 0.0001 both doses). Rates of freedom from photophobia, phonophobia, and nausea 2 hours after treatment were also significantly higher following the treatment of mild vs moderate or severe pain (p < 0.001 all symptoms, both doses). At 2 hours, the proportion of attacks with normal function was more than double for both doses of ubrogepant (p < 0.001). The most common adverse event was upper respiratory tract infection (∼11% both doses). Serious adverse events were reported by 2% in ubrogepant 50 mg and 3% in ubrogepant 100 mg. DISCUSSION: Relative to treatment of attacks with moderate or severe pain, treatment with ubrogepant during mild pain resulted in significantly higher rates of freedom from pain, freedom from associated symptoms, and achieving normal function 2 hours after administration. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov, NCT02873221. CLASSIFICATION OF EVIDENCE: This trial provides Class III evidence that treatment of migraine with ubrogepant when pain is mild vs moderate or severe increases the likelihood of achieving pain freedom, absence of symptoms, and normal function within 2 hours postdose.

Atogepant - an orally-administered CGRP antagonist - attenuates activation of meningeal nociceptors by CSD.

BACKGROUND: This study investigated the mechanism of action of atogepant, a small-molecule CGRP receptor antagonist recently approved for the preventive treatment of episodic migraine, by assessing its effect on activation of mechanosensitive C- and Aδ-meningeal nociceptors following cortical spreading depression. METHODS: Single-unit recordings of trigeminal ganglion neurons (32 Aδ and 20 C-fibers) innervating the dura was used to document effects of orally administered atogepant (5 mg/kg) or vehicle on cortical spreading depression-induced activation in anesthetized male rats. RESULTS: Bayesian analysis of time effects found that atogepant did not completely prevent the activation of nociceptors at the tested dose, but it significantly reduced response amplitude and probability of response in both the C- and the Aδ-fibers at different time intervals following cortical spreading depression induction. For C-fibers, the reduction in responses was significant in the early phase (first hour), but not delayed phase of activation, whereas in Aδ-fibers, significant reduction in activation was apparent in the delayed phase (second and third hours) but not early phase of activation. CONCLUSIONS: These findings identify differences between the actions of atogepant, a small molecule CGRP antagonist (partially inhibiting both Aδ and C-fibers) and those found previously for fremanezumab, a CGRP-targeted antibody (inhibiting Aδ fibers only) and onabotulinumtoxinA (inhibiting C-fibers only)- suggesting that these agents differ in their mechanisms for the preventive treatment of migraine.

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).

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.

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).

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.

Time course of efficacy of ubrogepant for the acute treatment of migraine: Clinical implications.

BACKGROUND: The full utility of an acute treatment requires examination of the entire time course of effect during a migraine attack. Here the time course of effect of ubrogepant is evaluated. METHODS: ACHIEVE-I and -II were double-blind, single-attack, Phase 3 trials. Adults with migraine were randomised 1:1:1 to placebo or ubrogepant (50mg or 100mg, ACHIEVE-I; 25 mg or 50 mg, ACHIEVE-II). Pain freedom, absence of most bothersome symptom, and pain relief were assessed at various timepoints. Samples were collected for pharmacokinetic analysis. Data were pooled for this post-hoc analysis. RESULTS: Participants' (n = 912 placebo, n = 887 ubrogepant 50 mg, pooled analysis population) mean age was 41 years, with a majority female and white. Pain relief separated from placebo by 1 h (43% versus 37% [OR, 95% CI: 1.30, 1.0-1.59]), absence of most bothersome symptom by 1.5 h (28% versus 22% [1.42, 1.14-1.77]), and pain freedom by 2 h (20% vs. 13% [1.72, 1.33-2.22]). Efficacy was sustained from 2-24 h (pain relief: 1.71, 1.1-2.6; pain freedom: 1.71, 1.3-2.3) and remained separated at 48 h (pain relief: 1.7, 1.1-2.6; pain freedom: 1.31, 1.0-1.7). Pharmacokinetic analysis demonstrated maximum plasma concentrations were achieved at 1 h, with pharmacologically active concentrations reached within 11 min and remaining above the EC90 for nearly 12 h. CONCLUSIONS: Evaluation of the time course of effect of ubrogepant showed pain relief as the most sensitive and earliest measure of clinical effect, followed by absence of most bothersome symptom, and pain freedom. Efficacy was demonstrated out to 48 h, providing evidence of the long-lasting effect of ubrogepant. This evaluation supports the role of examining the entire time course of effect to understand fully the utility of an acute treatment for migraine.Trial registration: ACHIEVE I (ClinicalTrials.gov, NCT02828020) and ACHIEVE II (ClinicalTrials.gov, NCT02867709).

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.

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.