Early Use of Erenumab vs Nonspecific Oral Migraine Preventives: The APPRAISE Randomized Clinical Trial.

Importance: Patients with migraine often cycle through multiple nonspecific preventive medications due to poor tolerability and/or inadequate efficacy leading to low adherence and increased disease burden. Objective: To compare the efficacy, tolerability, patient adherence, and patient satisfaction between erenumab and nonspecific oral migraine preventive medications (OMPMs) in patients with episodic migraine (EM) who had previously failed 1 or 2 preventive treatments. Design, Setting, and Participants: The 12-month prospective, interventional, global, multicenter, active-controlled, randomized clinical trial comparing sustained benefit of 2 treatment paradigms (erenumab qm vs oral prophylactics) in adult episodic migraine patients (APPRAISE) trial was a 12-month open-label, multicenter, active-controlled, phase 4 randomized clinical trial conducted from May 15, 2019, to October 1, 2021. This pragmatic trial was conducted at 84 centers across 17 countries. Overall, participants 18 years or older with a 12-month or longer history of migraine, and 4 or more but fewer than 15 monthly migraine days (MMDs) were included. Interventions: Patients were randomized (2:1) to receive erenumab or OMPMs. Dose adjustment was permitted (label dependent). Main Outcomes and Measures: The primary end point was the proportion of patients completing 1 year of the initially assigned treatment and achieving a reduction of 50% or greater from baseline in MMDs at month 12. Secondary end points included the cumulative mean change from baseline in MMDs during the treatment period and the proportion of responders according to the Patients' Global Impression of Change (PGIC) scale at month 12 for patients taking the initially assigned treatment. Results: A total of 866 patients were screened, of whom 245 failed the screening and 621 completed the screening and baseline period. Of the 621 randomized patients (mean [SD] age, 41.3 [11.2] years; 545 female [87.8%]; 413 [66.5%] in the erenumab group; 208 [33.5%] in the OMPM group), 523 (84.2%) completed the treatment phase, and 98 (15.8%) discontinued the study. At month 12, significantly more patients assigned to erenumab vs OMPM achieved the primary end point (232 of 413 [56.2%] vs 35 of 208 [16.8%]; odds ratio [OR], 6.48; 95% CI, 4.28-9.82; P <.001). Compared with OMPMs, treatment with erenumab showed higher responder rate (314 of 413 [76.0%] vs 39 of 208 [18.8%]; OR, 13.75; 95% CI, 9.08-20.83; P <.001) on the PGIC scale (≥5 at month 12). Significant reduction in cumulative average MMDs was reported with erenumab treatment vs OMPM treatment (-4.32 vs -2.65; treatment difference [SE]: -1.67 [0.35] days; P < .001). Substantially fewer patients in the erenumab arm compared with the OMPM arm switched medication (9 of 413 [2.2%] vs 72 of 208 [34.6%]) and discontinued treatment due to adverse events (12 of 408 [2.9%] vs 48 of 206 [23.3%]). No new safety signals were identified. Conclusions and Relevance: Results of this randomized clinical trial demonstrated that earlier use of erenumab in patients with EM who failed 1 or 2 previous preventive treatments provided greater and sustained efficacy, safety, and adherence than continuous OMPM. Trial Registration: ClinicalTrials.gov Identifier: NCT03927144.

Oxygen as an abortive therapy in cluster headache: a narrative review and clinical practice aspects.

Cluster headache (International Classification of Headache Disorders third edition, ICHD-3 3.1) is a primary headache disorder affecting around 0.12% of individuals. It is characterized by severe headache attacks causing significant negative impact on the lives of patients. While administration of 100% oxygen is considered to be the first-choice acute treatment, undertreatment also exists. Reasons for undertreatment may entail problems with the correct prescription of oxygen, reimbursement issues or the practical implementation of home oxygen therapy. The aim of this manuscript is to review the scientific evidence on oxygen therapy for cluster headache and provide a practical guidance for both physicians and patients to optimize its use in an acute setting. The current evidence of the administration of 100% oxygen as a safe and effective treatment for cluster headache is strong. Based on several clinical trials and surveys, the recommended flow rates range between 12 and 15 L/min via a non-rebreathing mask, for at least fifteen minutes. The frequency of cluster headache attacks and thus the need for acute treatment can be very high. Fortunately, the Belgian social security system provides a full and lifetime reimbursement of oxygen therapy for cluster headache if the diagnosis and the need for this therapy has been certified by a neurologist, neurosurgeon or neuropsychiatrist.

Patients with chronic cluster headache may show reduced activity energy expenditure on ambulatory wrist actigraphy recordings during daytime attacks.

OBJECTIVE: To investigate the changes in activity energy expenditure (AEE) throughout daytime cluster headache (CH) attacks in patients with chronic CH and to evaluate the usefulness of actigraphy as a digital biomarker of CH attacks. BACKGROUND: CH is a primary headache disorder characterized by attacks of severe to very severe unilateral pain (orbital, supraorbital, temporal, or in any combination of these sites), with ipsilateral cranial autonomic symptoms and/or a sense of restlessness or agitation. We hypothesized increased AEE from hyperactivity during attacks measured by actigraphy. METHODS: An observational study including patients with chronic CH was conducted. During 21 days, patients wore an actigraphy device on the nondominant wrist and recorded CH attack-related data in a dedicated smartphone application. Accelerometer data were used for the calculation of AEE before and during daytime CH attacks that occurred in ambulatory settings, and without restrictions on acute and preventive headache treatment. We compared the activity and movements during the pre-ictal, ictal, and postictal phases with data from wrist-worn actigraphy with time-concordant intervals during non-headache periods. RESULTS: Four patients provided 34 attacks, of which 15 attacks met the eligibility criteria for further analysis. In contrast with the initial hypothesis of increased energy expenditure during CH attacks, a decrease in movement was observed during the pre-ictal phase (30 min before onset to onset) and during the headache phase. A significant decrease (p < .01) in the proportion of high-intensity movement during headache attacks, of which the majority were oxygen-treated, was observed. This trend was less present for low-intensity movements. CONCLUSION: The unexpected decrease in AEE during the pre-ictal and headache phase of daytime CH attacks in patients with chronic CH under acute and preventive treatment in ambulatory settings has important implications for future research on wrist actigraphy in CH.

Migraine without aura.

Migraine without aura is the commonest form of migraine in both children and adults. The diagnosis is made by applying the International Classification of Headache Disorders Third Edition subsection for migraine without aura (ICHD-3 subsection 1.1). Attacks in patients with migraine without aura are characterized by their polyphasic presentation (prodrome, headache phase, postdromal phase). The symptomatology of attacks is diverse and heterogeneous, with most common symptoms being photophobia, phonophobia, nausea, vomiting, and aggravation of pain by movement. The clinician and researcher who wants to learn about migraine without aura needs to be able to apply the ICHD-3 criteria with its specific symptomatology to make a correct diagnosis, but also needs to be aware about the plethora of symptoms patients may experience. In this chapter, the reader will explore the clinical phenotypical features of migraine without aura.

Ten open questions in migraine prophylaxis with monoclonal antibodies blocking the calcitonin-gene related peptide pathway: a narrative review.

The monoclonal antibodies (mAbs) blocking the calcitonin-gene related peptide (CGRP) pathway, collectively called here "anti-CGRP/rec mAbs", have dramatically improved preventive migraine treatment. Although their efficacy and tolerability were proven in a number of randomized controlled trials (RCTs) and, maybe even more convincingly, in real world settings, a number of open questions remain. In this narrative review, we will analyze published data allowing insight in some of the uncertainties related to the use of anti-CGRP/rec mAbs in clinical practice: their differential efficacy in migraine subtypes, outcome predictors, switching between molecules, use in children and adolescents, long-term treatment adherence and persistence, effect persistence after discontinuation, combined treatment with botulinum toxin or gepants, added-value and cost effectiveness, effectiveness in other headache types, and potential contraindications based on known physiological effects of CGRP. While recent studies have already provided hints for some of these questions, many of them will not find reliable and definitive answers before larger studies, registries or dedicated RCTs are available.

Methodological considerations on real-world evidence studies of monoclonal antibodies against the CGRP-pathway for migraine: a systematic review.

BACKGROUND: Real-world data are accumulating on the effectiveness, tolerability and safety of anti-calcitonin gene-related peptide pathway monoclonal antibodies for the preventive treatment of migraine. We performed a systematic review of the methodology of prospective, observational, clinic-based real-world evidence studies with these drugs in both episodic and chronic migraine. METHODS: The objectives were to evaluate the definitions and reported outcomes used, and to perform a risk of bias assessment for each of the different studies. PubMed and EMBASE were systematically queried for relevant scientific articles. Study quality assessment of the included studies was conducted using the "National Heart, Lung and Blood Institute (NHLBI) Study Quality Assessment Tool for Before-After (Pre-Post) Studies with No Control Group". RESULTS: Forty-six studies fitted the criteria for the systematic review and were included in the analysis. Ten studies (21.7%) defined a migraine day for the study, while only 5 studies defined a headache day for the study (10.9%). The most common primary endpoint/objective of the studies was change in monthly migraine days (n = 16, 34.8%), followed by responder rate (n = 15, 32.6%) and change in monthly headache days (n = 5, 10.9%). Eight studies (17.4%) did not define the primary endpoint/objective. Thirty-three studies were graded as "good" quality and 13 studies were graded as "fair". CONCLUSION: Our analysis shows rather significant heterogeneity and/or lack of predefined primary outcomes/objectives, definitions of outcomes measures and the use of longitudinal monitoring (e.g. headache diaries). Standardization of terminology, definitions and protocol procedures for real-world evidence studies of preventive treatments for migraine are recommended. TRIAL REGISTRATION: This study was registered with PROSPERO with ID CRD42022369366.

Burden of migraine in patients attending Belgian headache specialists: real-world evidence from the BECOME study.

INTRODUCTION: Migraine is a primary headache disorder, which imposes a major burden on the sufferers. The BECOME study (Burden of migrainE in specialist headache Centers treating patients with prOphylactic treatMent failurE) attempted to characterize and assess the prevalence, burden and healthcare resource utilization of migraine patients presenting in specialized headache centers in Europe and Israel. In this paper, we will describe the patient characteristics of the Belgian headache centers. METHODS: The BECOME study was a prospective, non-interventional, cross-sectional study consisting of two parts. In the first part of the study, data were collected from subjects with a diagnosis of migraine. Subsequently, patients with ≥ 4 monthly migraine days (MMD) and ≥ 1 prior preventive treatment failure (PPTF) filled out validated questionnaires to assess the burden of disease. RESULTS: In part 1 of the Belgian study population (N = 806), 45% of patients reported ≥ 8 MMD and 25% had failed ≥ 4 preventive treatments. In part 2 (N = 90), more than 90% of patients reported having severe impact of headache on daily life and having severe migraine-related disability. The impact was the highest for patients with ≥ 15 MMD, however, even within the patient population with < 8 MMD, the burden was significant. Almost 40% of the study population suffered from anxiety. CONCLUSIONS: These findings in the Belgian sample of the BECOME study demonstrate the substantial burden and unmet need for the management of difficult-to-treat migraine.

Using natural language processing to automatically classify written self-reported narratives by patients with migraine or cluster headache.

BACKGROUND: Headache medicine is largely based on detailed history taking by physicians analysing patients' descriptions of headache. Natural language processing (NLP) structures and processes linguistic data into quantifiable units. In this study, we apply these digital techniques on self-reported narratives by patients with headache disorders to research the potential of analysing and automatically classifying human-generated text and information extraction in clinical contexts. METHODS: A prospective cross-sectional clinical trial collected self-reported narratives on headache disorders from participants with either migraine or cluster headache. NLP was applied for the analysis of lexical, semantic and thematic properties of the texts. Machine learning (ML) algorithms were applied to classify the descriptions of headache attacks from individual participants into their correct group (migraine versus cluster headache). RESULTS: One-hundred and twenty-one patients (81 participants with migraine and 40 participants with cluster headache) provided a self-reported narrative on their headache disorder. Lexical analysis of this text corpus resulted in several specific key words per diagnostic group (cluster headache: Dutch (nl): "oog" | English (en): "eye", nl: "pijn" | en: "pain" and nl: "terug" | en: "back/to come back"; migraine: nl: "hoofdpijn" | en: "headache", nl: "stress" | en: "stress" and nl: "misselijkheid" | en: "nausea"). Thematic and sentiment analysis of text revealed largely negative sentiment in texts by both patients with migraine and cluster headache. Logistic regression and support vector machine algorithms with different feature groups performed best for the classification of attack descriptions (with F1-scores for detecting cluster headache varying between 0.82 and 0.86) compared to naïve Bayes classifiers. CONCLUSIONS: Differences in lexical choices between patients with migraine and cluster headache are detected with NLP and are congruent with domain expert knowledge of the disorders. Our research shows that ML algorithms have potential to classify patients' self-reported narratives of migraine or cluster headache with good performance. NLP shows its capability to discern relevant linguistic aspects in narratives from patients with different headache disorders and demonstrates relevance in clinical information extraction. The potential benefits on the classification performance of larger datasets and neural NLP methods can be investigated in the future. TRIAL REGISTRATION: This study was registered with clinicaltrials.gov with ID NCT05377437.

mBrain: towards the continuous follow-up and headache classification of primary headache disorder patients.

BACKGROUND: The diagnosis of headache disorders relies on the correct classification of individual headache attacks. Currently, this is mainly done by clinicians in a clinical setting, which is dependent on subjective self-reported input from patients. Existing classification apps also rely on self-reported information and lack validation. Therefore, the exploratory mBrain study investigates moving to continuous, semi-autonomous and objective follow-up and classification based on both self-reported and objective physiological and contextual data. METHODS: The data collection set-up of the observational, longitudinal mBrain study involved physiological data from the Empatica E4 wearable, data-driven machine learning (ML) algorithms detecting activity, stress and sleep events from the wearables' data modalities, and a custom-made application to interact with these events and keep a diary of contextual and headache-specific data. A knowledge-based classification system for individual headache attacks was designed, focusing on migraine, cluster headache (CH) and tension-type headache (TTH) attacks, by using the classification criteria of ICHD-3. To show how headache and physiological data can be linked, a basic knowledge-based system for headache trigger detection is presented. RESULTS: In two waves, 14 migraine and 4 CH patients participated (mean duration 22.3 days). 133 headache attacks were registered (98 by migraine, 35 by CH patients). Strictly applying ICHD-3 criteria leads to 8/98 migraine without aura and 0/35 CH classifications. Adapted versions yield 28/98 migraine without aura and 17/35 CH classifications, with 12/18 participants having mostly diagnosis classifications when episodic TTH classifications (57/98 and 32/35) are ignored. CONCLUSIONS: Strictly applying the ICHD-3 criteria on individual attacks does not yield good classification results. Adapted versions yield better results, with the mostly classified phenotype (migraine without aura vs. CH) matching the diagnosis for 12/18 patients. The absolute number of migraine without aura and CH classifications is, however, rather low. Example cases can be identified where activity and stress events explain patient-reported headache triggers. Continuous improvement of the data collection protocol, ML algorithms, and headache classification criteria (including the investigation of integrating physiological data), will further improve future headache follow-up, classification and trigger detection. Trial registration This trial was retrospectively registered with number NCT04949204 on 24 June 2021 at www. CLINICALTRIALS: gov .

CGRP monoclonal antibodies in migraine: an efficacy and tolerability comparison with standard prophylactic drugs.

BACKGROUND: Several drugs are available for the preventive treatment of both episodic and chronic migraine. The choice of which therapy to initiate first, second, or third is not straightforward and is based on multiple factors, including general efficacy, tolerability, potential for serious adverse events, comorbid conditions, and costs. Recently, a new class of migraine preventive drugs was introduced, i.e. monoclonal antibodies against calcitonin gene-related peptide (CGRP) or its receptor. METHODS: The present article summarizes the evidence gathered with this new migraine preventive drug class from randomized placebo-controlled clinical trials. It further puts this into perspective next to the evidence gained by the most widely used agents for the prevention of episodic and chronic migraine with an emphasis on efficacy and the robustness with which this efficacy signal was obtained. RESULTS: Although being a relatively new class of migraine preventive drugs, monoclonal antibodies blocking the CGRP pathway have an efficacy which is at least comparable if not higher than those of the currently used preventive drugs. Moreover, the robustness of this efficacy signal is substantiated by several randomized clinical trials each including large numbers of patients. In addition, because of their excellent tolerability and with long-term safety data emerging, they seem to have an unprecedented efficacy over adverse effect profile, clearly resulting in an added value for migraine prevention. CONCLUSIONS: Balancing the data presented in the current manuscript with additional data concerning long term safety on the one hand and cost issues on the other hand, can be of particular use to health policy makers to implement this new drug class in the prevention of migraine.

Structured headache services as the solution to the ill-health burden of headache. 3. Modelling effectiveness and cost-effectiveness of implementation in Europe: findings and conclusions.

BACKGROUND: There have been several calls for estimations of costs and consequences of headache interventions to inform European public-health policies. In a previous paper, in the absence of universally accepted methodology, we developed headache-type-specific analytical models to be applied to implementation of structured headache services in Europe as the health-care solution to headache. Here we apply this methodology and present the findings. METHODS: Data sources were published evidence and expert opinions, including those from an earlier economic evaluation framework using the WHO-CHOICE model. We used three headache-type-specific analytical models, for migraine, tension-type-headache (TTH) and medication-overuse-headache (MOH). We considered three European Region case studies, from Luxembourg, Russia and Spain to include a range of health-care systems, comparing current (suboptimal) care versus target care (structured services implemented, with provider-training and consumer-education). We made annual and 5-year cost estimates from health-care provider and societal perspectives (2020 figures, euros). We expressed effectiveness as healthy life years (HLYs) gained, and cost-effectiveness as incremental cost-effectiveness-ratios (ICERs; cost to be invested/HLY gained). We applied WHO thresholds for cost-effectiveness. RESULTS: The models demonstrated increased effectiveness, and cost-effectiveness (migraine) or cost saving (TTH, MOH) from the provider perspective over one and 5 years and consistently across the health-care systems and settings. From the societal perspective, we found structured headache services would be economically successful, not only delivering increased effectiveness but also cost saving across headache types and over time. The predicted magnitude of cost saving correlated positively with country wage levels. Lost productivity had a major impact on these estimates, but sensitivity analyses showed the intervention remained cost-effective across all models when we assumed that remedying disability would recover only 20% of lost productivity. CONCLUSIONS: This is the first study to propose a health-care solution for headache, in the form of structured headache services, and evaluate it economically in multiple settings. Despite numerous challenges, we demonstrated that economic evaluation of headache services, in terms of outcomes and costs, is feasible as well as necessary. Furthermore, it is strongly supportive of the proposed intervention, while its framework is general enough to be easily adapted and implemented across Europe.

Structured headache services as the solution to the ill-health burden of headache. 2. Modelling effectiveness and cost-effectiveness of implementation in Europe: methodology.

BACKGROUND: Health economic evaluations support health-care decision-making by providing information on the costs and consequences of health interventions. No universally accepted methodology exists for modelling effectiveness and cost-effectiveness of interventions designed to close treatment gaps for headache disorders in countries of Europe (or elsewhere). Our aim here, within the European Brain Council's Value-of-Treatment project, was to develop headache-type-specific analytical models to be applied to implementation of structured headache services in Europe as the health-care solution to headache. METHODS: We developed three headache-type-specific decision-analytical models using the WHO-CHOICE framework and adapted these for three European Region country settings (Luxembourg, Russia and Spain), diverse in geographical location, population size, income level and health-care systems and for which we had population-based data. Each model compared current (suboptimal) care vs target care (delivered in accordance with the structured headache services model). Epidemiological and economic data were drawn from studies conducted by the Global Campaign against Headache; data on efficacy of treatments were taken from published randomized controlled trials; assumptions on uptake of treatments, and those made for Healthy Life Year (HLY) calculations and target-care benefits, were agreed with experts. We made annual and 5-year cost estimates from health-care provider (main analyses) and societal (secondary analyses) perspectives (2020 figures, euros). RESULTS: The analytical models were successfully developed and applied to each country setting. Headache-related costs (including use of health-care resources and lost productivity) and health outcomes (HLYs) were mapped across populations. The same calculations were repeated for each alternative (current vs target care). Analyses of the differences in costs and health outcomes between alternatives and the incremental cost-effectiveness ratios are presented elsewhere. CONCLUSIONS: This study presents the first headache-type-specific analytical models to evaluate effectiveness and cost-effectiveness of implementing structured headache services in countries in the European Region. The models are robust, and can assist policy makers in allocating health budgets between interventions to maximize the health of populations.

Structured headache services as the solution to the ill-health burden of headache: 1. Rationale and description

In countries where headache services exist at all, their focus is usually on specialist (tertiary) care. This is clinically and economically inappropriate: most headache disorders can effectively and more efficiently (and at lower cost) be treated in educationally supported primary care. At the same time, compartmentalizing divisions between primary, secondary and tertiary care in many health-care systems create multiple inefficiencies, confronting patients attempting to navigate these levels (the "patient journey") with perplexing obstacles.High demand for headache care, estimated here in a needs-assessment exercise, is the biggest of the challenges to reform. It is also the principal reason why reform is necessary.The structured headache services model presented here by experts from all world regions on behalf of the Global Campaign against Headache is the suggested health-care solution to headache. It develops and refines previous proposals, responding to the challenge of high demand by basing headache services in primary care, with two supporting arguments. First, only primary care can deliver headache services equitably to the large numbers of people needing it. Second, with educational supports, they can do so effectively to most of these people. The model calls for vertical integration between care levels (primary, secondary and tertiary), and protection of the more advanced levels for the minority of patients who need them. At the same time, it is amenable to horizontal integration with other care services. It is adaptable according to the broader national or regional health services in which headache services should be embedded.It is, according to evidence and argument presented, an efficient and cost-effective model, but these are claims to be tested in formal economic analyses.

Diagnosis and management of migraine in ten steps.

Migraine is a disabling primary headache disorder that directly affects more than one billion people worldwide. Despite its widespread prevalence, migraine remains under-diagnosed and under-treated. To support clinical decision-making, we convened a European panel of experts to develop a ten-step approach to the diagnosis and management of migraine. Each step was established by expert consensus and supported by a review of current literature, and the Consensus Statement is endorsed by the European Headache Federation and the European Academy of Neurology. In this Consensus Statement, we introduce typical clinical features, diagnostic criteria and differential diagnoses of migraine. We then emphasize the value of patient centricity and patient education to ensure treatment adherence and satisfaction with care provision. Further, we outline best practices for acute and preventive treatment of migraine in various patient populations, including adults, children and adolescents, pregnant and breastfeeding women, and older people. In addition, we provide recommendations for evaluating treatment response and managing treatment failure. Lastly, we discuss the management of complications and comorbidities as well as the importance of planning long-term follow-up.

Genome-Wide Association Study Identifies Risk Loci for Cluster Headache.

OBJECTIVE: This study was undertaken to identify susceptibility loci for cluster headache and obtain insights into relevant disease pathways. METHODS: We carried out a genome-wide association study, where 852 UK and 591 Swedish cluster headache cases were compared with 5,614 and 1,134 controls, respectively. Following quality control and imputation, single variant association testing was conducted using a logistic mixed model for each cohort. The 2 cohorts were subsequently combined in a merged analysis. Downstream analyses, such as gene-set enrichment, functional variant annotation, prediction and pathway analyses, were performed. RESULTS: Initial independent analysis identified 2 replicable cluster headache susceptibility loci on chromosome 2. A merged analysis identified an additional locus on chromosome 1 and confirmed a locus significant in the UK analysis on chromosome 6, which overlaps with a previously known migraine locus. The lead single nucleotide polymorphisms were rs113658130 (p = 1.92 × 10-17 , odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.37-1.66) and rs4519530 (p = 6.98 × 10-17 , OR = 1.47, 95% CI = 1.34-1.61) on chromosome 2, rs12121134 on chromosome 1 (p = 1.66 × 10-8 , OR = 1.36, 95% CI = 1.22-1.52), and rs11153082 (p = 1.85 × 10-8 , OR = 1.30, 95% CI = 1.19-1.42) on chromosome 6. Downstream analyses implicated immunological processes in the pathogenesis of cluster headache. INTERPRETATION: We identified and replicated several genome-wide significant associations supporting a genetic predisposition in cluster headache in a genome-wide association study involving 1,443 cases. Replication in larger independent cohorts combined with comprehensive phenotyping, in relation to, for example, treatment response and cluster headache subtypes, could provide unprecedented insights into genotype-phenotype correlations and the pathophysiological pathways underlying cluster headache. ANN NEUROL 2021;90:193-202.

Efficacy and safety of erenumab in women with a history of menstrual migraine.

BACKGROUND: We performed a post hoc, subgroup analysis of a phase 3, randomized, double-blind, placebo-controlled study of erenumab for prevention of episodic migraine (STRIVE) to determine the efficacy and safety of erenumab in women with self-reported menstrual migraine. METHODS: Patients received placebo, erenumab 70 mg, or erenumab 140 mg subcutaneously once monthly during the 6-month double-blind treatment phase of STRIVE. Women who reported history of menstrual migraine and who were ≤ 50 years old were included in the analysis. Endpoints were change from baseline in monthly migraine days (MMD) and monthly acute migraine-specific medication days (MSMD; among patients who took acute migraine-specific medications at baseline), proportion of patients achieving ≥ 50% reduction from baseline in MMD, and incidence of adverse events. RESULTS: Among 814 women enrolled in STRIVE, 232 (28.5%) reported a history of menstrual migraine and were ≤ 50 years old. Of the 232 patients, 214 (92%) had a baseline MMD > 5, suggesting a high proportion of women with attacks outside of the 5-day perimenstrual window (2 days before and 3 days after the start of menstruation). Information on "migraine days" includes (and does not discriminate between) perimenstrual and intermenstrual migraine attacks. Between-group differences from placebo over months 4-6 for erenumab 70 mg and 140 mg were - 1.8 (P = 0.001) and - 2.1 (P < 0.001) days for MMD and - 1.6 (P = 0.002) and - 2.4 (P < 0.001) days for acute MSMD, respectively. The odds of having a ≥ 50% reduction from baseline in MMD over months 4-6 were 2.2 (P = 0.024) and 2.8 (P = 0.002) times greater for erenumab 70 mg and 140 mg, respectively, than for placebo. Erenumab had an overall safety profile comparable to placebo. CONCLUSION: Data from this subgroup analysis of women with menstrual migraine are consistent with data from the overall STRIVE episodic migraine population, supporting the efficacy and safety of erenumab in women who experience menstrual migraine. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02456740. Registered 28 May 2015.

Perceptions, experiences, and understandings of cluster headache among GPs and neurologists: a qualitative study.

BACKGROUND: Cluster headache is a severe primary headache with a similar prevalence to that of multiple sclerosis. Cluster headache is characterised by unilateral trigeminal distribution of pain, ipsilateral cranial autonomic features, and a tendency to circadian and circannual periodicity. AIM: To explore the perceptions, experiences, and understandings of cluster headache among GPs and neurologists. DESIGN AND SETTING: Qualitative interview study in primary care surgeries and neurology departments in the north of England. METHOD: Semi-structured interviews were conducted with GPs and neurologists, recorded, and transcribed. A thematic analysis was applied to the dataset. RESULTS: Sixteen clinicians participated in this study: eight GPs and eight neurologists. Four main themes were identified following thematic analysis: challenges with the cluster headache diagnosis; impact of cluster headache; challenges with treatment; and appropriateness of referrals to secondary care. Clinicians recognised the delays in the diagnosis of cluster headache, misdiagnosis, and mismanagement, and were aware of the potential impact cluster headache can have on patients' mental health and ability to remain in employment. Findings highlighted tensions between primary and secondary care around the cost of medication and the remit of prescribing treatment regimens. Patients' anxiety, their need for reassurance, and their insistence about seeing a specialist are some of the reasons for referrals. CONCLUSION: Clinicians acknowledged delays in diagnosis, misdiagnosis, and mismanagement of cluster headache. The responsibility of prescribing causes ongoing tensions between primary and secondary care. Clear referral and management pathways for primary headaches are required to improve patient outcomes and healthcare costs.

The Many Faces of Medication-Overuse Headache in Clinical Practice.

The management of medication-overuse headache (MOH) is multifaceted and headache experts have different views on the optimal strategy to tackle this type of secondary headache. The purpose of this review is to provide an overview of the literature on the management of MOH, and to highlight important considerations in the clinical evaluation of the MOH patient. Managing MOH in clinical practice starts by evaluating the headache patient with medication overuse, determining the overused drug(s), assessing the impact of headaches on the patient and assessing comorbid conditions and disorders. Withdrawal of the overused medication is the cornerstone of treatment. An inpatient or outpatient setting is chosen based on the clinical profile of the patient. There is evidence for abrupt withdrawal combined with headache preventive treatment. Bridging therapy to bring relief to withdrawal headaches and/or symptoms should be offered. Education and motivational work through multidisciplinary assessment show benefits in sustaining withdrawal and preventing relapse. Although the reversal of chronic headache after cessation of overused acute medication has been noticed worldwide, different aspects of the management of MOH, such as complete or gradual withdrawal, or preventive treatment with or without withdrawal are still debated.

Safety and efficacy of percutaneous pulsed radiofrequency treatment at the C1-C2 level in chronic cluster headache: a retrospective analysis of 21 cases.

We performed a study of the safety and efficacy of percutaneous pulsed radiofrequency (PRF) treatment directed at C1 and C2 levels as performed at our local pain clinic in refractory chronic cluster headache (CCH) patients. We identified 21 CCH patients treated with PRF (240 s, max. 45 V, max. 42 °C) directed at the ganglion and/or nerve root of C1 and C2. Data were collected through retrospective analysis of patients' files and include demographic variables, onset and duration of the headache, mean attack frequency, and prior pharmacological treatment. Safety and reduction of attack frequency in the first 3 months after a first PRF treatment was the primary outcome parameter of this study. All patients had been treated with at least two prophylactic drugs and 19 (90%) had previously been treated with verapamil, lithium, and topiramate. Ten patients (47.6%) reported no meaningful effect, four patients (19%) reported a meaningful reduction of < 50%, and seven patients (33.3%) reported a reduction in headache burden of at least 50% in the 3 months following treatment. Two patients reported occurrence or increase in frequency of contralateral cluster attacks. No other adverse events were reported or detected at follow-up. Upper cervical PRF treatment appears to be a safe procedure that could prove effective in the treatment of patients with refractory CCH and warrants a prospective study.

Efficacy and safety of erenumab (AMG334) in episodic migraine patients with prior preventive treatment failure: A subgroup analysis of a randomized, double-blind, placebo-controlled study.

BACKGROUND: Erenumab was effective and well tolerated in a pivotal clinical trial of episodic migraine that included subjects both naïve to, and those who had failed, previous preventives. Here we evaluated the efficacy and safety of erenumab (70 mg or 140 mg) versus placebo in the subgroup of patients who had previously failed preventive treatment(s): ≥1 or ≥2 prior failed migraine preventive categories, and in patients who had never failed. METHODS: Prespecified subgroup analyses evaluated change from baseline to months 4-6 (the primary endpoint of the blinded study phase) in monthly migraine days, achievement of ≥50% and ≥75% reduction in monthly migraine days, and change from baseline in acute migraine-specific medication days. Adverse events were also evaluated. RESULTS: Treatment with both doses of erenumab resulted in greater reductions in monthly migraine days at months 4-6 (treatment difference versus placebo [95% CI], never failed subgroup: -0.9 [-1.5, -0.3] for 70 mg and -1.3 [-1.9, -0.7] for 140 mg; ≥1 prior failed medication categories subgroup: -2.0 [-2.8, -1.2] for 70 mg and -2.5 [-3.4, -1.7] for 140 mg; ≥2 prior failed medication categories subgroup: -1.3 [-2.6, 0.0] for 70 mg and -2.7 [-4.0, -1.4] for 140 mg). Similar results were observed in the monthly acute migraine-specific medication days endpoint, and in the achievement of ≥50% and ≥75% reduction in monthly migraine days. For the ≥50% reduction in monthly migraine day endpoint, placebo response in the no prior treatment failed group was 32.6%, in the ≥1 failed treatment 17.5%, and in the ≥2 failed treatments 11.1%. CONCLUSION: Erenumab showed consistent efficacy in episodic migraine patients who had failed prior preventive treatments and was well tolerated across subgroups. The data suggest prior patients with prior treatment failures have lower placebo response rates.