Comment on: Martelletti et al. Refractory chronic migraine: a consensus statement on clinical definition from the European Headache Federation

In this letter, we present the Austrian proposal for diagnostic criteria of refractory chronic migraine and we discuss the consensensus statement of the European Headache Feaderation. We focus in particular on the definition of adequate prophylactic treatment, the management of medication overuse and the requirement for CSF analyses in patients with refractory chronic migraine. In our proposal, the criteria for adequate treatment and recommendations for dealing with medication overuse are more explicit than in the EHF proposal, whereas the requirements for CSF analyses and measurement of CSF pressure are not as strict.     

Refractory chronic migraine: a Consensus Statement on clinical definition from the European Headache Federation

The debate on the clinical definition of refractory Chronic Migraine (rCM) is still far to be concluded. The importance to create a clinical framing of these rCM patients resides in the complete disability they show, in the high risk of serious adverse events from acute and preventative drugs and in the uncontrolled application of therapeutic techniques not yet validated.The European Headache Federation Expert Group on rCM presents hereby the updated definition criteria for this harmful subset of headache disorders. This attempt wants to be the first impulse towards the correct identification of these patients, the correct application of innovative therapeutic techniques and lastly aim to be acknowledged as clinical entity in the next definitive version of the International Classification of Headache Disorders 3 (ICHD-3 beta).     

Burden and attitude to resistant and refractory migraine: a survey from the European Headache Federation with the endorsement of the European Migraine & Headache Alliance

BackgroundNew treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts).The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions.MethodsWe conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care.ResultsThere were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care.ConclusionsThis report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01252-4.     

Insights into the mechanism of onabotulinumtoxinA in chronic migraine

OnabotulinumtoxinA has recently been approved by regulatory agencies in the UK and United States for treatment of chronic migraine based on data generated from the PREEMPT studies. As such, onabotulinumtoxinA is the only prophylactic therapy specifically approved for chronic migraine. Most headache clinicians would agree that acute episodic migraine and chronic migraine differ in their pathophysiology, etiology, diagnosis, and response to pharmacological as well as nonpharmacological therapies. Of the 7 botulinum neurotoxin serotypes, botulinum neurotoxin type A (onabotulinumtoxinA) has been the most thoroughly investigated in preclinical and clinical studies. Based on preclinical studies, onabotulinumtoxinA is known to inhibit the release of excitatory neurotransmitters from both motor and sensory neurons by preventing vesicle fusion to the cell membrane. In addition to the well-documented myorelaxant effects of this neurotoxin, onabotulinumtoxinA can exert a direct analgesic effect that likely involves inhibition of primary and secondary nociceptive neurons. The inhibitory effects of onabotulinumtoxinA are also likely to involve suppressing the activity of myogenic trigger points and decreasing the persistent nociceptive barrage that promotes and maintains central sensitization. This article describes possible mechanisms to explain how onabotulinumtoxinA functions as a therapy for chronic migraine and considers why treatment with the neurotoxin is not effective in some chronic migraineurs.     

Real-life use of onabotulinumtoxinA reduces healthcare resource utilization in individuals with chronic migraine: the REPOSE study

BackgroundChronic migraine (CM) is associated with substantial economic burden. Real-world data suggests that onabotulinumtoxinA treatment for CM reduces healthcare resource utilisation (HRU) and related costs.MethodsREPOSE was a 2-year prospective, multicentre, non-interventional, observational study to describe the real-world use of onabotulinumtoxinA in adult patients with CM. This analysis examined the impact of onabotulinumtoxinA on HRU. Patients received onabotulinumtoxinA treatment approximately every 12 weeks according to their physicians’ discretion, guided by the summary of product characteristics (SPC) and PREEMPT injection paradigm. HRU outcome measures were collected at baseline and all administration visits and included headache-related hospitalizations and healthcare professional (HCP) visits. Health economic data, including family doctor and specialist visits, inpatient treatment for headache, acupuncture, technical diagnostics, use of nonpharmacologic remedies, and work productivity were also collected for patients enrolled at German study centres.ResultsOverall, 641 patients were enrolled at 78 study centres across 7 countries (Germany, UK, Italy, Spain, Norway, Sweden, and Russia), 633 received ≥1 onabotulinumtoxinA dose, and 128 completed the 2-year study. Patients were, on average, aged 45 years, 85% were female, and 60% (n = 377) were from Germany. At the end of the 2-year observation period, significantly fewer patients reported headache-related hospitalizations (p < 0.02) and HCP visits (p < 0.001) within the past 3 months than in the 3 months before baseline. In the German population, reductions were observed across all health services at all follow-up visits compared with baseline. The percentage of patients who saw a family doctor decreased from 41.7% at baseline to 13.5% at administration visit 8 and visits to a medical specialist decreased from 61.7% to 5.2% of patients. Inpatient acute treatment and technical diagnostics declined from 6.4% and 19.7% of patients at baseline to 0.0% and 1.0% at administration 8, respectively. The use of nonpharmacologic remedies and medication for the acute treatment of migraine also decreased with continued onabotulinumtoxinA treatment. Work incapacity, disability, absenteeism, and impaired performance at school/work improved with onabotulinumtoxinA treatment for CM over the 2-year observation period.ConclusionsReal-world evidence from REPOSE demonstrates that onabotulinumtoxinA treatment is associated with decreased HRU and supports the long-term benefits associated with the use of onabotulinumtoxinA for CM in clinical practice.Trial registration{"type":"clinical-trial","attrs":{"text":"NCT01686581","term_id":"NCT01686581"}}NCT01686581. Name of registry: ClinicalTrials.gov. URL of registry: Date of retrospective registration: September 18, 2012. Date of enrolment of first patient: July 23, 2012.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-021-01260-4.     

European Headache Federation guideline on the use of monoclonal antibodies targeting the calcitonin gene related peptide pathway for migraine prevention – 2022 update

BackgroundA previous European Headache Federation (EHF) guideline addressed the use of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway to prevent migraine. Since then, randomized controlled trials (RCTs) and real-world evidence have expanded the evidence and knowledge for those treatments. Therefore, the EHF panel decided to provide an updated guideline on the use of those treatments.MethodsThe guideline was developed following the Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) approach. The working group identified relevant questions, performed a systematic review and an analysis of the literature, assessed the quality of the available evidence, and wrote recommendations. Where the GRADE approach was not applicable, expert opinion was provided.ResultsWe found moderate to high quality of evidence to recommend eptinezumab, erenumab, fremanezumab, and galcanezumab in individuals with episodic and chronic migraine. For several important clinical questions, we found not enough evidence to provide evidence-based recommendations and guidance relied on experts’ opinion. Nevertheless, we provided updated suggestions regarding the long-term management of those treatments and their place with respect to the other migraine preventatives.ConclusionMonoclonal antibodies targeting the CGRP pathway are recommended for migraine prevention as they are effective and safe also in the long-term.Supplementary InformationThe online version contains supplementary material available at 10.1186/s10194-022-01431-x.     

Defining refractory migraine and refractory chronic migraine: proposed criteria from the Refractory Headache Special Interest Section of the American Headache Society

Certain migraines are labeled as refractory, but the entity lacks a well-accepted operational definition. This article summarizes the results of a survey sent to American Headache Society members to evaluate interest in a definition for RM and what were considered necessary criteria. Review of the literature, collaborative discussions and results of the survey contributed to the proposed definition for RM. We also comment on our considerations in formulating the criteria and any issues in making the criteria operational. For the proposed definition for RM and refractory chronic migraine, patients must meet the International Classification of Headache Disorders, Second Edition criteria for migraine or chronic migraine, respectively. Headaches need to cause significant interference with function or quality of life despite modification of triggers, lifestyle factors, and adequate trials of acute and preventive medicines with established efficacy. The definition requires that patients fail adequate trials of preventive medicines, alone or in combination, from at least 2 of 4 drug classes including: beta-blockers, anticonvulsants, tricyclics, and calcium channel blockers. Patients must also fail adequate trials of abortive medicines, including both a triptan and dihydroergotamine (DHE) intranasal or injectable formulation and either nonsteroidal anti-inflammatory drugs (NSAIDs) or combination analgesic, unless contraindicated. An adequate trial is defined as a period of time during which an appropriate dose of medication is administered, typically at least 2 months at optimal or maximum-tolerated dose, unless terminated early due to adverse effects. The definition also employs modifiers for the presence or absence of medication overuse, and with or without significant disability.     

Experience with onabotulinumtoxinA (BOTOX) in chronic refractory migraine: focus on severe attacks

The objective of this study is to analyse our experience in the treatment of refractory chronic migraine (CM) with onabotulinumtoxinA (BTA) and specifically in its effects over disabling attacks. Patients with CM and inadequate response or intolerance to oral preventatives were treated with pericranial injections of 100 U of TBA every 3 months. The dose was increased up to 200 U in case of no response. The patients kept a headache diary. In addition, we specifically asked on the effect of BTA on the frequency of disabling attacks, consumption of triptans and visits to Emergency for the treatment of severe attacks. This series comprises a total of 35 patients (3 males), aged 24-68 years. All except three met IHS criteria for analgesic overuse. The number of sessions with BTA ranged from 2 to 15 (median 4) and nine (26%) responded (reduction of >50% in headache days). However, the frequency of severe attacks was reduced to an average of 46%. Oral triptan consumption (29 patients) was reduced by 50% (from an average of 22 to 11 tablets/month). Those six patients who used subcutaneous sumatriptan reduced its consumption to a mean of 69% (from 4.5 to 1.5 injections per month). Emergency visits went from an average of 3 to 0.4 per trimester (-83%). Six patients complained of mild adverse events, transient local cervical pain being the most common. Although our data must be taken with caution as this is an open trial, in clinical practice treatment of refractory CM with BTA reduces the frequency of disabling attacks, the consumption of triptans and the need of visits to Emergency, which makes this treatment a profitable option both clinically and pharmacoeconomically.     

对围绝经期妇女心血管疾病危险的处理：欧洲心脏病医生与妇科医生的一项共识声明

心血管疾病常被认为仅是男人需要面对的问题。大部分妇女并未将心血管疾病作为健康关注的一个重要内容，而且她们对其了解很少。各医学专业都同样存在错误：全科医生、妇科医生和心脏病医生常不能发现心血管疾病的危险因素，对有心血管疾病危险的妇女诊断及治疗不足。但事实上，在其一生中，女性比男性更可能经历心血管疾病及其所导致的伤残，因此需要干预以提高生存。     

A multi-center double-blind pilot comparison of onabotulinumtoxinA and topiramate for the prophylactic treatment of chronic migraine

(Headache 2011;51:21‐32) Objective.— This multi‐center pilot study compared the efficacy of onabotulinumtoxinA with topiramate (a Food and Drug Administration approved and widely accepted treatment for prevention of migraine) in individuals with chronic migraine (CM). Methods.— A total of 59 subjects with CM were randomly assigned to one of 2 groups: Group 1 (n = 30) received topiramate plus placebo injections, Group 2 (n = 29) received onabotulinumtoxinA injections plus placebo tablets. Subjects maintained daily headache diaries over a 4‐week baseline period and a 12‐week active study period. The primary endpoint was the Physician Global Assessment, which measured the treatment responder rate and indicated improvement in both groups over 12 weeks. Secondary endpoints, measured at weeks 4 and 12, included headache days per month, migraine days, headache‐free days, days on acute medication, severity of headache episodes, Migraine Impact & Disability Assessment, Headache Impact Test, effectiveness of and satisfaction with current treatment on the amount of medication needed, and the frequency and severity of migraine symptoms. At 12 weeks subjects were re‐evaluated and tapered off oral study medications over a 2‐week time period. Subjects not reporting a >50% reduction of headache frequency at 12 weeks were invited to participate in a 12‐week open label extension study with onabotulinumtoxinA. Of these, 20 subjects, 9 from the Topiramate Group and 11 from the OnabotulinumtoxinA Group, volunteered for this extension from weeks 14 to 26. Results.— This study demonstrated positive benefit for both onabotulinumtoxinA and topiramate in subjects with CM. Overall, the results were statistically significant within groups but not between groups. By week 26, subjects had a reduction of headache days per month compared with baseline. This was a significant within‐group finding. Conclusion.— OnabotulinumtoxinA and topiramate demonstrated similar efficacy for subjects with CM as determined by Global Physician Assessment and supported by multiple secondary endpoint measures.