One-year prospective real-world assessment of effectiveness and safety of erenumab in migraine prevention: results of the French FHU INOVPAIN registry study.

BACKGROUND: Randomized clinical trials have demonstrated efficacy and safety of erenumab. The aim of this study is to evaluate the effectiveness and safety of erenumab in a real-world setting in French patients with migraine associated with extreme unmet needs. METHODS: This is a one year-prospective real-word study with enrolment of all consecutive adult patients included in the FHU InovPain registry who participated in a compassionate erenumab use program. RESULTS: Of 144 patients included, 140 patients (82.1% female / mean age of 50.9 ± 11.4) received at least one dose of erenumab and were concerned by effectiveness and safety assessment. All patients had failed 11 oral preventive treatments. Most of them suffered from chronic migraine (88.6%) and presented a medication overuse (90.7%) at baseline. Thirty-eight (27.1%) discontinued treatment during the 12-month follow-up, with 22 (15.7%), 11 (7.9%) and 5 (3.6%) patients before 3, 6 or 9 months of treatment. The proportion of ≥ 50% responders at M3, M6, M9 and M12 was 74/140 (52.9%), 69/118 (58.5%), 61/107 (57.0%) and 60/102 (58.8%) respectively. At M3, the rate of reversion from chronic migraine to episodic migraine was 57.3% and the rate of transition from medication overuse to non-overuse was 46.5%. For monthly migraine days, the median (IQR) was 18.0 (13.0-26.0), 9.0 (5.0-17.0), 7.5 (5.0-14.0), 8.0 (5.0-12.5) and 8.0 (5.0-12.0) at M0, M3, M6, M9 and M12 respectively. For HIT-6 score, the median (IQR) was 68.0 (63.8-73.3), 60.0 (54.0-65.0), 60.0 (50.3-53.0), 59.0 (50.0-63.0) and 58.0 (50.0-62.9) at M0, M3, M6, M9 and M12 respectively. Fifty-three (37.9%) patients reported at least one of the following adverse events: cutaneous erythema and/or pain at the injection site for 42 (30%) patients, constipation for 22 (15.7%) patients, muscle spasm for 2 (1.4%) patients, alopecia for one (0.7%) patient and blood pressure increase in one (0.7%) patient. There was no serious adverse event. One female patient became pregnant after 5 months of exposure to erenumab with a safe evolution after treatment discontinuation. CONCLUSION: This first French real-world study related to migraine prevention with CGRP-mAbs confirms effectiveness and safety of erenumab in patients with extreme unmet needs.

Revised guidelines of the French headache society for the diagnosis and management of migraine in adults. Part 3: Non-pharmacological treatment.

The French Headache Society proposes updated French guidelines for the management of migraine. This article presents the third part of the guidelines, which is focused on the non-pharmacological treatment of migraine, including physical exercise, dietary supplements and plants, diets, neuromodulation therapies, acupuncture, behavioral interventions and mindfulness therapy, patent foramen ovale closure and surgical nerve decompression.

Revised guidelines of the French headache society for the diagnosis and management of migraine in adults. Part 2: Pharmacological treatment.

The French Headache Society proposes updated French guidelines for the management of migraine. This article presents the second part of the guidelines, which is focused on the pharmacological treatment of migraine, including both the acute treatment of attacks and the prophylaxis of episodic migraine as well as chronic migraine with and without medication overuse. The specific situations that can be encountered in women with migraine are also discussed, including pregnancy, menstrual migraine, contraception and hormonal replacement therapy.

Revised guidelines of the French Headache Society for the diagnosis and management of migraine in adults. Part 1: Diagnosis and assessment.

The French Headache Society proposes updated French guidelines for the management of migraine. The first part of these recommendations is focused on the diagnosis and assessment of migraine. First, migraine needs to be precisely diagnosed according to the currently validated criteria of the International Classification of Headache Disorders, 3d version (ICHD-3). Migraine-related disability has to be assessed and we suggest to use the 6 questions of the headache impact test (HIT-6). Then, it is important to check for risk factors and comorbidities increasing the risk to develop chronic migraine, especially frequency of headaches, acute medication overuse and presence of depression. We suggest to use a migraine calendar and the Hospital Anxiety and Depression scale (HAD). It is also necessary to evaluate the efficacy and tolerability of current migraine treatments and we suggest to systematically use the self-administered Migraine Treatment Optimization Questionnaire (M-TOQ) for acute migraine treatment. Finally, a treatment strategy and a follow-up plan have to be proposed. Guidelines for pharmacological and non-pharmacological treatments are presented in the second and third part of the recommendations.

Neurostimulation methods in the treatment of chronic pain.

The goal of this narrative review was to give an up-to-date overview of the peripheral and central neurostimulation methods that can be used to treat chronic pain. Special focus has been given to three pain conditions: neuropathic pain, nociplastic pain and primary headaches. Both non-invasive and invasive techniques are briefly presented together with their pain relief potentials. For non-invasive stimulation techniques, data concerning transcutaneous electrical nerve stimulation (TENS), transcranial direct current stimulation (tDCS), repetitive transcranial magnetic stimulation (rTMS), remote electrical neuromodulation (REN) and vagus nerve stimulation (VNS) are provided. Concerning invasive stimulation techniques, occipital nerve stimulation (ONS), vagus nerve stimulation (VNS), epidural motor cortex stimulation (EMCS), spinal cord stimulation (SCS) and deep brain stimulation (DBS) are presented. The action mode of all these techniques is only partly understood but can be very different from one technique to the other. Patients' selection is still a challenge. Recent consensus-based guidelines for clinical practice are presented when available. The development of closed-loop devices could be of interest in the future, although the clinical benefit over open loop is not proven yet.

Pharmacological and non-pharmacological treatments for neuropathic pain: Systematic review and French recommendations.

Neuropathic pain remains a significant unmet medical need. Several recommendations have recently been proposed concerning pharmacotherapy, neurostimulation techniques and interventional management, but no comprehensive guideline encompassing all these treatments has yet been issued. We performed a systematic review of pharmacotherapy, neurostimulation, surgery, psychotherapies and other types of therapy for peripheral or central neuropathic pain, based on studies published in peer-reviewed journals before January 2018. The main inclusion criteria were chronic neuropathic pain for at least three months, a randomized controlled methodology, at least three weeks of follow-up, at least 10 patients per group, and a double-blind design for drug therapy. Based on the GRADE system, we provide weak-to-strong recommendations for use and proposal as a first-line treatment for SNRIs (duloxetine and venlafaxine), gabapentin and tricyclic antidepressants and, for topical lidocaine and transcutaneous electrical nerve stimulation specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a second-line treatment for pregabalin, tramadol, combination therapy (antidepressant combined with gabapentinoids), and for high-concentration capsaicin patches and botulinum toxin A specifically for peripheral neuropathic pain; a weak recommendation for use and proposal as a third-line treatment for high-frequency rTMS of the motor cortex, spinal cord stimulation (failed back surgery syndrome and painful diabetic polyneuropathy) and strong opioids (in the absence of an alternative). Psychotherapy (cognitive behavioral therapy and mindfulness) is recommended as a second-line therapy, as an add-on to other therapies. An algorithm encompassing all the recommended treatments is proposed.

Ergot Use and Overuse: A Pharmacoepidemiology Retrospective Cohort Study.

OBJECTIVE: The objective of this study was to estimate and to characterize the actual patterns of ergot use and overuse in France using a drug reimbursement database. METHODS: We included all people covered by the French General Health Insurance System (GHIS) from the Provence-Alpes-Côte-d'Azur (PACA) and Corsica administrative areas who had at least one prescription of ergot between May 2010 and December 2011. All prescriptions of ergots, migraine prophylactic treatment, and psychotropic medications were extracted from the GHIS database. We defined occasional ergot users (<3 months of prescription) and regular ergot users (>3 months of prescription). Among regular ergot users, we identified overusers and nonoverusers. RESULTS: We included 4358 patients who had at least one prescription of ergots (oral ergotamine tartrate, dihydroergotamine mesilate nasal spray, intravenous dihydroergotamine mesilate). Among ergot overusers, a large majority of patients had ergotamine tartrate overuse. The proportion of ergotamine tartrate overusers is maximum after 55 years. Compared with regular users, overusers use more frequently a prophylactic treatment (93/165 [56.4%] versus 398/1057, OR = 2.15, P < .001), antidepressants (72/165 [43.6%] versus 326/1057 [30.8%] OR = 1.79, P < .001), benzodiazepines (111/165 [67.3%] versus 613/1057 [58.0%], OR = 1.50, P < .001), weak opioids (95/165 [57.6%] versus 463/1057 [43.8], OR = 1.77, P < .001) and strong opioids (13/165 [7.9%] versus 24/1057 [2.3%], OR = 3.86, P < .001). The coexistence of ergot consumption and triptan overuse, and the possibility of both triptan and ergot overuse was described; triptan overusers were more described in ergotamine overusers than in nonoverusers. CONCLUSIONS: This work outlines a high prevalence of ergotamine tartrate overuse (11.1%). As ergotamine tartrate users are mostly aged more than 55 years, an evaluation of ergotamine cardiovascular risk profile is necessary in the elderly population.

Epidemiology of migraine: French key descriptive data.

France is a country for which the epidemiology of migraine is very well known. Based on the results of the main studies over the last 20 years, this brief review presents the key descriptive data for French migraine epidemiology, and considers its prevalence, individual impact, recognition and medical management, and social impact.

What's new in the migraine attack treatment.

This short review aims to give a focus on news in the migraine attack treatment and discusses the CGRP receptor antagonists (gepants), the 5-HT1F receptors agonists (ditans), the transcranial magnetic stimulation for the treatment of migraine attack with aura, innovative delivery systems for sumatriptan and the oral inhalation of dihydroergotamine.

Early dosing and efficacy of triptans in acute migraine treatment: the TEMPO study.

AIM: To compare the effectiveness of early or late triptan intake in the treatment of acute migraine attacks. METHODS: The TEMPO study was a French prospective, multicentre, two-phase study conducted in neurological practice. Two-hundred-and-ten migraine patients who were regular triptan users were enrolled. In the first phase, patients treated three attacks as they usually did. In the second phase, those who initially practiced late dosing ( ≥ 1 hour after headache onset) were instructed to change to early dosing ( < 1 hour). RESULTS: A total of 144 patients completed the first phase. Seventy-nine patients constituted the 'early dosers' group and 65 patients the 'late dosers' group. In this phase, early dosing produced higher rates (n = 38; 52.8%) of freedom from pain at 2 hours in at least two of three attacks compared with late dosing (n = 19; 30.2%; p < 0.01). In the second phase, switching from late to early dosing following the physician's instruction (n = 42 patients) also improved the rates of freedom from pain at 2 hours (from 38.1% (n = 16) to 53.7% (n = 22); p < 0.05). CONCLUSION: This suggests that advising patients on the importance of early triptan intake after headache onset may help improve the efficacy of acute migraine treatments.

The cost of headache disorders in Europe: the Eurolight project.

BACKGROUND AND PURPOSE: Headache disorders are very common, but their monetary costs in Europe are unknown. We performed the first comprehensive estimation of how economic resources are lost to headache in Europe. METHODS: From November 2008 to August 2009, a cross-sectional survey was conducted in eight countries representing 55% of the adult EU population. Participation rates varied between 11% and 59%. In total, 8412 questionnaires contributed to this analysis. Using bottom-up methodology, we estimated direct (medications, outpatient health care, hospitalization and investigations) and indirect (work absenteeism and reduced productivity at work) annual per-person costs. Prevalence data, simultaneously collected and, for migraine, also derived from a systematic review, were used to impute national costs. RESULTS: Mean per-person annual costs were €1222 for migraine (95% CI 1055-1389; indirect costs 93%), €303 for tension-type headache (TTH, 95% CI 230-376; indirect costs 92%), €3561 for medication-overuse headache (MOH, 95% CI 2487-4635; indirect costs 92%), and €253 for other headaches (95% CI 99-407; indirect costs 82%). In the EU, the total annual cost of headache amongst adults aged 18-65 years was calculated, according to our prevalence estimates, at €173 billion, apportioned to migraine (€111 billion; 64%), TTH (€21 billion; 12%), MOH (€37 billion; 21%) and other headaches (€3 billion; 2%). Using the 15% systematic review prevalence of migraine, calculated costs were somewhat lower (migraine €50 billion, all headache €112 billion annually). CONCLUSIONS: Headache disorders are prominent health-related drivers of immense economic losses for the EU. This has immediate implications for healthcare policy. Health care for headache can be both improved and cost saving.

Cost of healthcare for patients with migraine in five European countries: results from the International Burden of Migraine Study (IBMS).

Migraine is a disabling neurological disease that affects 14.7 % of Europeans. Studies evaluating the economic impact of migraine are complex to conduct adequately and with time become outdated as healthcare systems evolve. This study sought to quantify and compare direct medical costs of chronic migraine (CM) and episodic migraine (EM) in five European countries. Cross-sectional data collected via a web-based survey were screened for migraine and classified as CM (≥15 headache days/month) or EM (<15 headache days/month), and included sociodemographics, resource use data and medication use. Unit cost data, gathered using publicly available sources, were analyzed for each type of service, stratified by migraine status. Univariate and multivariate log-normal regression models were used to examine the relationship between various factors and their impact on total healthcare costs. This economic analysis included data from respondents with migraine in the UK, France, Germany, Italy, and Spain. CM participants had higher level of disability and more prevalent psychiatric disorders compared to EM. CM participants had more provider visits, emergency department/hospital visits, and diagnostic tests; the medical costs were three times higher for CM than EM. Per patient annual costs were highest in the UK and Spain and lower in France and Germany. CM was associated with higher medical resource use and total costs compared to EM in all study countries, suggesting that treatments that reduce headache frequency could decrease the clinical and economic burden of migraine in Europe. Comparing patterns of care and outcomes among countries may facilitate the development of more cost-effective care, and bring greater recognition to patients affected by migraine.

Migraine diagnosis and management in general emergency departments in France.

BACKGROUND: We conducted a prospective study of patients admitted to 22 general emergency departments in France over 1 week. PATIENTS AND METHODS: Of 15,835 adult patients, 483 (3.1%) had headache and 98 (0.6%) had migraine. RESULTS: Compared with the migraine population in France, our migraine patients were similar in terms of proportion of female patients (75%) and mean age (37.6 ± 13.8 years) but presented earlier in their disease course. Patients sought emergency treatment because of a severe attack (49%) or because of ineffective treatment (20%). Non-opioid analgesics excluding non-steroidal anti-inflammatory drugs (NSAIDs), and NSAIDs, were most commonly prescribed as acute treatment, yet it took more than 48 h for symptom resolution in 36% of 92 follow-up patients. CONCLUSIONS: Results suggest there is room for improvement in choice of agents prescribed. We propose additional education and training of clinicians to improve adherence to clinical practice guidelines.

[Addictive behaviour in medication overuse headache: A review of recent data]. / Comportement addictif chez les patients souffrant de céphalée par abus médicamenteux : une revue des données de la littérature.

INTRODUCTION: Some data in the current medical literature suggests a link between medication overuse headache (MOH) and addictive behaviors. We present here a review of the clinical and biological data highlighting the role of addictive behaviors in MOH. RESULTS: One third to one half of MOH patients will relapse in their overuse within five years following withdrawal of the offending medication. Some studies have shown that two thirds of MOH patients fulfil DSM-IV criteria for dependence concerning their use of acute headache medication. Moreover, there is a co-morbidity between substance related disorders and MOH and some data suggest a familial co-transmission between MOH and substancerelated disorders. In a prospective study, the use of acute headache medication containing psychoactive substances like opiate derivates increase the risk of transformation from an episodic headache to MOH suggesting the role of conditioning factors among other psychological variables as catastrophizing and a low self-efficacy. Finally, data from the neuroimagery, biology and genetic fields suggest the presence of common pathophysiological features between MOH and addiction. In particular, a study found a hypometabolism in the prefrontal cortex of MOH patients, not recovering after withdrawal, such abnormality being described in addicted patients and suggesting an inability of the prefrontal cortex to inhibit craving. PERSPECTIVES: All these data suggest that with MOH we face two sets of patients. The first one, in which medication overuse is mainly due to the worsening of the headache course, with minimal psychiatric contribution ; the second one, in which addictive behavior can play a major role. In the first case, education can simply lead to a significant reduction of medication intake, whereas in the second case a pluridisciplinary follow-up must be proposed before, during and after acute headache detoxification. CONCLUSION: A pluridisciplinary approach is the only way to reduce the relapse rate which remains too high in MOH.

Cardiac safety in cluster headache patients using the very high dose of verapamil (≥720 mg/day).

Use of high doses of verapamil in preventive treatment of cluster headache (CH) is limited by cardiac toxicity. We systematically assess the cardiac safety of the very high dose of verapamil (verapamil VHD) in CH patients. Our work was a study performed in two French headache centers (Marseilles-Nice) from 12/2005 to 12/2008. CH patients treated with verapamil VHD (≥720 mg) were considered with a systematic electrocardiogram (EKG) monitoring. Among 200 CH patients, 29 (14.8%) used verapamil VHD (877±227 mg/day). Incidence of EKG changes was 38% (11/29). Seven (24%) patients presented bradycardia considered as nonserious adverse event (NSAE) and four (14%) patients presented arrhythmia (heart block) considered as serious adverse event (SAE). Patients with EKG changes (1,003±295 mg/day) were taking higher doses than those without EKG changes (800±143 mg/day), but doses were similar in patients with SAE (990±316 mg/day) and those with NSAE (1,011±309 mg/day). Around three-quarters (8/11) of patients presented a delayed-onset cardiac adverse event (delay ≥2 years). Our work confirms the need for systematic EKG monitoring in CH patients treated with verapamil. Such cardiac safety assessment must be continued even for patients using VHD without any adverse event for a long time.

Recommendations for headache service organisation and delivery in Europe.

Headache disorders are a major public-health priority, and there is pressing need for effective solutions to them. Better health care for headache-and ready access to it-are central to these solutions; therefore, the organisation of headache-related services within the health systems of Europe becomes an important focus. These recommendations are the result of collaboration between the European Headache Federation and Lifting The Burden: the Global Campaign against Headache. The process of development included wide consultation. To meet the very high level of need for headache care both effectively and efficiently, the recommendations formulate a basic three-level model of health-care organisation rationally spread across primary and secondary health-care sectors, taking account of the different skills and expertise in these sectors. They recognise that health services are differently structured in countries throughout Europe, and not always adequately resourced. Therefore, they aim to be adaptable to suit these differences. They are set out in five sections: needs assessment, description of the model, adaptation, standards and educational implications.

The Eurolight project: the impact of primary headache disorders in Europe. Description of methods.

The Eurolight project is the first at European Union level to assess the impact of headache disorders, and also the first of its scale performed by collaboration between professional and lay organizations and individuals. Here are reported the methods developed for it. The project took the form of surveys, by structured questionnaire, conducted in ten countries of Europe which together represented 60% of the adult population of the European Union. In Lithuania, the survey was population-based. Elsewhere, truly population-based studies were impractical for reasons of cost, and various compromises were developed. Closest to being population-based were the surveys in Germany, Luxembourg, the Netherlands, Italy and Spain. In Austria, France and UK, samples were taken from health-care settings. In addition in the Netherlands, Spain and Ireland, samples were drawn from members of national headache patient organizations and their relatives. Independent double data-entry was performed prior to analysis. Returned questionnaires from 9,269 respondents showed a moderate female bias (58%); of respondents from patients' organizations (n = 992), 61% were female. Mean age of all respondents was 44 years; samples from patients' organizations were slightly older (mean 47 years). The different sampling methods worked with differing degrees of effectiveness, as evidenced by the responder-rates, which varied from 10.8 to 90.7%. In the more population-based surveys, responder-rates varied from 11.3 to 58.8%. We conclude that the methodology, although with differences born of necessity in the ten countries, was sound overall, and will provide robust data on the public ill-health that results from headache in Europe.

Are there differences between cephalic and extracephalic cutaneous allodynia in migraine patients?

Cutaneous allodynia (CA), pain in response to innocuous cutaneous stimuli, is recognized as a sign of central sensitization during migraine episodes. It is either restricted within the pain area on the ipsilateral head, or extends within and outside the head. Moreover, CA can be elicited in response to thermal (heat or cold) and/or mechanical stimuli. This raises the question as to whether cephalic and extracephalic CAs share the same properties. We assessed cephalic and extracephalic CAs in migraine episodic patients using a questionnaire completed at home during migraine attacks. A total of 67 episodic migraine patients (58 women, nine men; 4013 years old) addressed all questions in the questionnaire. Forty-nine patients (73%) cited one or more allodynic symptoms during or immediately after the migraine attack. Almost all 49 patients reported cephalic CA, whereas 24 (49%) also reported extracephalic CA. Occurrence and extension of CA correlated (P = 0.005) with headache intensity. Modalities of cephalic and extracephalic CA were different (chi2 = 12.03; P = 0.002), extracephalic CA being mostly thermal (75%) whereas cephalic CA was mostly mechanical (92%). This suggests that cephalic and extracephalic CAs involve different mechanisms.