Induction of cGMP-mediated migraine attacks is independent of CGRP receptor activation.

BACKGROUND: The cAMP and cGMP pathways are implicated in the initiation of migraine attacks, but their interactions remain unclear. Calcitonin gene-related peptide (CGRP) triggers migraine attacks via cAMP, whereas the phosphodiesterase-5 inhibitor sildenafil induces migraine attacks via cGMP. Our objective was to investigate whether sildenafil could induce migraine attacks in individuals with migraine pre-treated with the CGRP-receptor antibody erenumab. METHODS: In this randomized, double-blind, placebo-controlled, cross-over study, adults with migraine without aura received a single subcutaneous injection of 140 mg erenumab on day 1. They were then randomized to receive sildenafil 100 mg or placebo on two experimental days, each separated by at least one week, between days 8 and 21. The primary endpoint was the difference in the incidence of migraine attacks between sildenafil and placebo during the 12-h observation period after administration. RESULTS: In total, 16 participants completed the study. Ten participants (63%) experienced a migraine attack within 12 h after sildenafil administration compared to three (19%) after placebo (p = 0.016). The median headache intensity was higher after sildenafil than after placebo (area under the curve (AUC) for the 12-h observation period, p = 0.026). Furthermore, sildenafil induced a significant decrease in mean arterial blood pressure (AUC, p = 0.026) and a simultaneous increase in heart rate (AUC, p < 0.001) during the first hour after administration compared to placebo. CONCLUSION: These findings provide evidence that migraine induction via the cGMP pathway can occur even under CGRP receptor blockade. TRIAL REGISTRATION: ClinicalTrials.gov: Identifier NCT05889455.

Activation of ATP-sensitive potassium channels triggers migraine attacks independent of calcitonin gene-related peptide receptors: a randomized placebo-controlled trial.

BACKGROUND: The present study aimed to investigate whether levcromakalim, a KATP channel opener, induces migraine attacks in people with migraine pre-treated with erenumab, a monoclonal CGRP receptor antibody. METHODS: In this double-blind, placebo-controlled, two-way cross-over study, adults with migraine without aura received a subcutaneous injection of 140 mg of erenumab on day 1. Subsequently, they were randomized to receive a 20-minute infusion of 0.05 mg/ml levcromakalim or placebo on two experimental days separated by at least one week (between days 8 and 21). The primary endpoint was the difference in the incidence of migraine attacks between levcromakalim and placebo during the 12-hour post-infusion period. RESULTS: In total, 16 participants completed the study. During the 12-hour observation period, 14 (88%) of 16 participants experienced migraine attacks after levcromakalim, compared to two (12%) after placebo (p < 0.001). The area under the curve for median headache intensity was greater after levcromakalim than placebo (p < 0.001). Levcromakalim elicited dilation of the superficial temporal artery during the first hour after infusion, a response absent following placebo (p < 0.001). CONCLUSIONS: The induction of migraine attacks via opening of KATP channels appears independent of CGRP receptor activation.Trial Registration: ClinicalTrials.gov, Identifier NCT05889442.

No wearing-off effect of erenumab or fremanezumab for chronic migraine prevention: a single-center, real-world, observational study.

BACKGROUND: The present study investigates the wearing-off effect in adults with chronic migraine treated with erenumab or fremanezumab. METHODS: This real-world observational study was based on pre-collected headache diaries from chronic migraine patients in treatment with either monthly injections of 140 mg of erenumab or 225 mg of fremanezumab. Consistent wearing-off was defined as an increase of ≥2 weekly migraine days in the last week compared to the second week over two consecutive 4-week treatment periods. The primary endpoint was wearing-off in the total population. The secondary endpoints were difference in wearing-off in (i) a subgroup of patients treated with erenumab and fremanezumab and (ii) consistent wearing-off in patients with a ≥30% reduction in monthly migraine days, compared to baseline, in the two consecutive treatment months. RESULTS: In total, 100 patients (erenumab: n = 60, fremanezumab: n = 40) were included. Sixty-two out of 100 (62%) patients had consistent ≥30% treatment response on antibody therapy in both months (erenumab: n = 36, fremanezumab: n = 26). There was no consistent wearing-off over the two consecutive months from week 2 to week 4 (3.04%, p = 0.558). There was no wearing-off within the erenumab (p = 0.194) or the fremanezumab (p = 0.581) groups. Among the ≥30% treatment responders, there was no consistent wearing-off over the two consecutive months (2.6%, p = 0.573). CONCLUSIONS: There was no wearing-off in treatment responders, which is in alignment with premarketing data from placebo-controlled phase III studies. These data suggest that patients should be informed upfront that no wearing-off effect is expected because anxiety for attacks at the end of the month per se may generate migraine attacks.

Visual migraine aura iconography: A multicentre, cross-sectional study of individuals with migraine with aura.

INTRODUCTION: Visual disturbances are the most common symptoms of migraine aura. These symptoms can be described systematically by subdividing them into elementary visual symptoms. Since visual symptoms of migraine aura are not easy to describe verbally, we developed a collection of images illustrating previously reported elementary visual symptoms. OBJECTIVES: To test a standardised visual migraine aura iconography in a large population of migraine with aura patients and to improve it based on the participants' feedback. METHODS: We created a set of images representing 25 elementary visual symptoms and a web-based survey where participants could report whether they recognised these images as part of their visual aura. Elementary visual symptoms could also be recognised via a corresponding text description or described in a free text by participants. Individuals with migraine aura recruited from four tertiary headache centres (in Switzerland, Denmark, Norway and Italy) were invited to complete the survey. RESULTS: Two hundred and fifteen participants completed the study (78.9% women, median age 36). They recognised a total of 1645 elementary visual symptoms from our predefined list. Of those, 1291 (78.4%) where recognised via standardised iconography images. A new type of elementary visual symptom was reported by one participant. CONCLUSION: Most elementary visual symptoms experienced by participants were recognised via the standardised iconography. This tool can be useful for clinical as well as research purposes.

Metaphorical use of "headache" and "migraine" in media: A longitudinal study of 1.3 million articles in major publications.

BACKGROUND: Stigmatization and trivialization of headache confront individuals with headache disorders, but the degree to which media may contribute is incompletely understood. OBJECTIVE: The objective of this study was to quantify the frequency of disparaging metaphorical use of the words "headache" and "migraine" in articles and summaries of major publications. METHODS: This longitudinal study analyzed a dataset of 1.3 million articles and summaries written by authors and editors of 38 major publications. Data cover written publications from 1998 up to 2017. The use of the words "headache" or "migraine" in articles and summaries by major publications was rated by two authors (P.Z. and A.V.) as either "metaphorical" or "medical" based on their contextual application. Pearson's chi-squared test was applied to assess differences in the frequency of metaphorical use of "headache" in comparison to "migraine." Secondary outcomes were the source of publication and time of publication. RESULTS: A total of 6195 and 740 articles included the words "headache" or "migraine," respectively; 7100 sentences contained the word "headache" and 1652 sentences contained the word "migraine." Among a random sample of 1000 sentences with the word "headache," there was a metaphorical use in 492 (49.2% [95% CI, 46.1-52.3]) sentences. Among a random sample of 1000 sentences with the word "migraine," there was a metaphorical use in 45 (4.5% [95% CI, 3.2-5.8]) sentences. The five most prevalent sources were CNN, Fox News, The New York Times, The Guardian, and The Washington Post. There was an overall increase in the number of articles containing the words "headache" or "migraine" from database inception until analysis (1998 up to 2017). The database included no articles containing either "headache" or "migraine" in 1998; in 2016, this number was 1480 articles. CONCLUSIONS: In this longitudinal study, major publications applied a metaphorical use of "headache" about half of the time. The metaphorical use of "headache" is 11-fold greater than the metaphorical use of "migraine" in the same media sample. These depictions may contribute to the trivialization of headache and the stigmatization of individuals with headache disorders. Studies with individuals affected by headache disorders are needed to clarify potential influences.

Second messenger signalling bypasses CGRP receptor blockade to provoke migraine attacks in humans.

There are several endogenous molecules that can trigger migraine attacks when administered to humans. Notably, calcitonin gene-related peptide (CGRP) has been identified as a key player in a signalling cascade involved in migraine attacks, acting through the second messenger cyclic adenosine monophosphate (cAMP) in various cells, including intracranial vascular smooth muscle cells. However, it remains unclear whether intracellular cAMP signalling requires CGRP receptor activation during a migraine attack in humans. To address this question, we conducted a randomized, double-blind, placebo-controlled, parallel trial using a human provocation model involving the administration of CGRP and cilostazol in individuals with migraine pretreated with erenumab or placebo. Our study revealed that migraine attacks can be provoked in patients by cAMP-mediated mechanisms using cilostazol, even when the CGRP receptor is blocked by erenumab. Furthermore, the dilation of cranial arteries induced by cilostazol was not influenced by the CGRP receptor blockade. These findings provide clinical evidence that cAMP-evoked migraine attacks do not require CGRP receptor activation. This discovery opens up new possibilities for the development of mechanism-based drugs for the treatment of migraine.

The increasing role of electronic media in headache.

Most individuals with access to the internet use social media platforms. These platforms represent an excellent opportunity to disseminate knowledge about management and treatment to the benefit of patients. The International Headache Society, The European Headache Federation, and The American Headache Society have electronic media committees to promote and highlight the organizations' expertise and disseminate research findings. A growing mistrust in science has made dealing with infodemics (i.e., sudden access to excessive unvetted information) an increasing part of clinical management. An increasing role of these committees will be to address this challenge. As an example, recent studies have demonstrated that the most popular online content on migraine management is not evidence-based and is disseminated by for-profit organizations. As healthcare professionals and members of professional headache organizations, we are obliged to prioritize knowledge dissemination. A progressive social media strategy is associated not only with increased online visibility and outreach, but also with a higher scientific interest. To identify gaps and barriers, future research should assess the range of available information on headache disorders in electronic media, characterize direct and indirect consequences on clinical management, and recognize best practice and strategies to improve our communication on internet-based communication platforms. In turn, these efforts will reduce the burden of headache disorders by facilitating improved education of both patients and providers.

Characterizing healthcare utilization patterns in a Danish population with headache: results from the nationwide headache in Denmark (HINDER) panel.

INTRODUCTION: Worldwide, far from all of those who would benefit make use of headache services, largely because of clinical, social, and political barriers to access. Identifying the factors contributing to low healthcare utilization can generate evidence to guide health policy. Our purpose here is better to characterize healthcare utilization patterns in Denmark. METHODS: The Headache in Denmark (HINDER) study is a nationwide cross-sectional survey of people with headache, conducted using SurveyXact (Rambøll Group A/S, Copenhagen). Healthcare utilization was assessed in a study sample generated by population screening and recruitment. Data collection occurred over two weeks, from September 23rd until October 4th, 2021. The questions enquired into disease characteristics, management, burden, medication intake and healthcare utilization. RESULTS: The number of participants included in the HINDER panel was 4,431, with 2,990 (67.5%: 2,522 [84.3%] female, 468 [15.7%] male; mean age 40.9 ± 11.6 years) completing the survey. One quarter of participants (27.7%) disagreed or strongly disagreed that they were able to manage their headache attacks. Most participants (81.7%) agreed or strongly agreed that their headache was a burden in their everyday lives. The most reported acute medications, by 87.2% of participants, were simple analgesics; of note, 8.6% reported using opioids for their headache. One quarter of participants (24.4%) had never consulted a medical doctor for their headache; one in six (16.5%: more than two thirds of the 24.4%) had never done so despite agreeing or strongly agreeing that their headache was a burden in their everyday lives. Two thirds (65.3%) of participants overall, and almost three quarters (72.4%) of those with weekly headache, had tried one or more complementary or alternative therapies outside conventional medical care. CONCLUSIONS: Our findings are indicative of inadequate delivery of headache care in a country that provides free and universal coverage for all its residents. The implications are twofold. First, it is not sufficient merely to make services available: public education and increased awareness are necessary to encourage uptake by those who would benefit. Second, educational interventions in both pre- and postgraduate settings are necessary, but a prerequisite for these is a resetting of policy priorities, properly to reflect the very high population ill-health burden of headache.

Migraine attacks are of peripheral origin: the debate goes on.

BACKGROUND: Despite the pervasiveness of migraine, the underlying pathophysiological mechanisms initiating migraine attacks are far from well understood and are matter of scientific debate. OBJECTIVE: In this narrative review, we discuss key evidence for that suggest a peripheral origin or central origin and provide directions for future studies that may provide further clarification. DISCUSSION: Migraine pathogenesis is considered to involve the trigeminovascular system, a term that encompasses the trigeminal nerve and its axonal projections to the intracranial blood vessels. Beyond any doubt both peripheral and central mechanisms are involved in migraine pathogenesis, but an unresolved question is the how the initial activation occurs in a migraine attack. Evidence favoring a peripheral origin of migraine attacks, i.e., initial events occur outside of the blood-brain barrier, include the importance of sensitization of perivascular sensory afferents early on in a migraine attack. Evidence favoring a central origin include the occurrence of prodromal symptoms, migraine aura, and activation of structures within the central nervous system early in and during a migraine attack. CONCLUSIONS: Both peripheral and central mechanisms are likely involved in a migraine attack, e.g., peripheral nociceptive input is necessary for pain transmission and cortical activity is necessary for pain perception. Yet, the debate of whether migraine attacks are initiated a peripheral or central site remains unresolved. The increased focus on prodromal symptoms and on the development of a human model of migraine aura will possibly provide key arguments needed to answer this question in the near future. Until then, we cannot draw firm conclusions and the debate goes on. VIDEO LINK: Video recording of the debate held at the 1st International Conference on Advances in Migraine Sciences (ICAMS 2022, Copenhagen, Denmark) is available at: https://www.youtube.com/watch?v=NC0nlcKohz0 .

Menstrual migraine is caused by estrogen withdrawal: revisiting the evidence.

OBJECTIVE: To explore and critically appraise the evidence supporting the role of estrogen withdrawal in menstrual migraine. MAIN BODY: Menstrual migraine, impacting about 6% of reproductive-age women, manifests as migraine attacks closely related to the menstrual cycle. The estrogen withdrawal hypothesis posits that the premenstrual drop in estrogen levels serves as a trigger of migraine attacks. Despite its wide acceptance, the current body of evidence supporting this hypothesis remains limited, warranting further validation. Estrogen is believed to exert a modulatory effect on pain, particularly within the trigeminovascular system - the anatomic and physiologic substrate of migraine pathogenesis. Nevertheless, existing studies are limited by methodologic inconsistencies, small sample sizes, and variable case definitions, precluding definitive conclusions. To improve our understanding of menstrual migraine, future research should concentrate on untangling the intricate interplay between estrogen, the trigeminovascular system, and migraine itself. This necessitates the use of robust methods, larger sample sizes, and standardized case definitions to surmount the limitations encountered in previous investigations. CONCLUSION: Further research is thus needed to ascertain the involvement of estrogen withdrawal in menstrual migraine and advance the development of effective management strategies to address unmet treatment needs.

Migraine: integrated approaches to clinical management and emerging treatments.

Migraine is a highly disabling neurological disorder that directly affects more than 1 billion individuals worldwide. Available treatment options differ between countries and include acute, preventive, and non-pharmacological therapies. Because of major progress in the understanding of migraine pathogenesis, novel mechanism-based medications have emerged and expanded the armamentarium of treatments. We provide a comprehensive overview of the current standard of care that will enable informed clinical management. First, we discuss the efficacy, tolerability, and safety profile of various pharmacological therapies for acute and preventive treatment of migraine. Second, we review the current knowledge on non-pharmacological therapies, such as neuromodulation and biobehavioural approaches, which can be used for a multidisciplinary approach to clinical management. Third, we emphasise that any effective treatment strategy starts with building a therapeutic plan tailored to individual clinical characteristics, preferences, and needs. Finally, we explore the outlook of emerging mechanism-based treatments that could address unmet challenges in clinical management of migraine.

Migraine: epidemiology and systems of care.

Migraine is a neurovascular disorder that affects over 1 billion people worldwide. Its widespread prevalence, and associated disability, have a range of negative and substantial effects not only on those immediately affected but also on their families, colleagues, employers, and society. To reduce this global burden, concerted efforts are needed to implement and improve migraine care that is supported by informed health-care policies. In this Series paper, we summarise the data on migraine epidemiology, including estimates of its very considerable burden on the global economy. First, we present the challenges that continue to obstruct provision of adequate care worldwide. Second, we outline the advantages of integrated and coordinated systems of care, in which primary and specialist care complement and support each other; the use of comprehensive referral and linkage protocols should enable continuity of care between these systems levels. Finally, we describe challenges in low and middle-income countries, including countries with poor public health education, inadequate access to medication, and insufficient formal education and training of health-care professionals resulting in misdiagnosis, mismanagement, and wastage of resources.

Cluster headache - The worst possible pain on YouTube.

In clinical practice, patients with cluster headache often ask questions or mention information that they have seen or heard on the Internet. Because YouTube (www.youtube.com) is the second most visited Web site worldwide and offers a plethora of video content, we found it timely to ascertain the quality of information on cluster headache that is freely available on YouTube. We conducted an inquiry on YouTube on January 24, 2022, with the search term "cluster headache." Eligible YouTube videos included those with ≥10,000 views and content related to cluster headache. We assessed the quality and reliability of the videos with the Global Quality Scale and DISCERN, respectively. The search strategy identified 644 videos of which 134 were eligible for inclusion. The sources of the included videos were categorized as "healthcare professional/institution" (n = 45), "personal experience" (n = 52), and "other" (n = 37). According to the Global Quality Scale, 70 (52%) were low quality, 34 (25%) were of moderate quality, and 30 (22%) were of high quality. According to DISCERN, 104 (78%) were of low reliability, 28 (21%) were of moderate reliability, and 2 (1%) were of high reliability. The quality and reliability of cluster headache-related information on YouTube has room for improvement, even the content provided by healthcare providers. These findings should incentivize stakeholders, for example, government services, professional societies, healthcare providers, to provide accessible and better information on cluster headache.

Migraine and light: A narrative review.

OBJECTIVE: In this narrative review, we summarize clinical and experimental data on the effect of light in migraine and discuss future prospects. BACKGROUND: Effective nonpharmacological treatment of hypersensitivity to light in migraine is an unmet clinical need. Current management strategies primarily consist of seeking a dark room and avoiding light exposure. Advances in the past 2 decades have improved our understanding of the underlying pathophysiology of how migraine is influenced by light. This may provide promising avenues for novel approaches in clinical management. METHODS: We searched MEDLINE for articles published from database inception up to September 1, 2021. We used the search term "migraine" with the search terms "light," "photophobia," "treatment," "trigger," "circadian rhythm," "environment," and/or "pathophysiology." RESULTS: Light is commonly reported as a trigger factor of migraine attacks, however, early manifestation of photophobia and false attribution is likely the actual cause based on data deriving from retrospective, prospective, and experimental studies. The most common photophobia symptoms in migraine are exacerbation of headache by light and abnormal sensitivity to light with the underlying neural pathways likely being dependent on ongoing activity in the trigeminovascular system. Clinical studies and experimental models have identified mediators of photophobia and uncovered narrow wavebands of the light spectrum that may reduce pain intensity during a migraine attack. Consequently, novel devices have undergone exploratory clinical trials with promising results. CONCLUSION: False attribution is likely the reason why light is commonly reported as a trigger factor of migraine attacks, and a prospective confirmation is required to prevent unnecessary avoidance. The observation that individuals with migraine are not equally photophobic to all wavebands of the light spectrum opens the potential for innovative pain management strategies. In this context, using human-centric lighting (also called integrative lighting) to mimic the natural daylight cycle and avoid harmful wavebands through modern technology may prove beneficial. Future research should identify direct and indirect consequences of light and other environmental factors in migraine to fill out knowledge gaps and enable evidence-based care strategies within institutions, work environments, and other settings.

Interest in and exposure to headache disorders among neurology residents in Denmark: A nationwide cross-sectional survey.

OBJECTIVE: Headache disorders constitute a leading cause of disability worldwide, but there is a consistent absence of awareness and educational activities for healthcare providers across regions. Thus, we found it timely to identify potential structural challenges and factors that may affect acquisition of knowledge of headache disorders and their management during their 4-year residency. MATERIALS & METHODS: We conducted a nationwide cross-sectional survey of residents in neurology in Denmark including, but not limited to, questions on interest in neurological subspecialties and disorders, adequacy of training in headache disorders, exposure to headache disorders during training including time spent on headache disorders, exposure to specialist outpatient clinics, whether their hospital have a tertiary headache clinic, training in specific procedures (anesthetic blockade, e.g., greater occipital nerve blockade, and onabotulinumtoxinA for headache), and an estimate of proportion of cases with headache among patients managed in the last week. RESULTS: The survey was distributed to 127 residents in Denmark between March 2022 and April 2022. Of these, 59 (47%) completed all questions of the survey. Headache disorders were the fourth most popular subspecialties among respondents (n = 15 [25%]) following movement disorders (n = 27 [46%]), vascular neurology (n = 26 [44%]), and neuromuscular disorders (n = 25 [42%]). The mean number of hours spent in a course or a structured educational activity in headache disorders during residency was 12.1 h. Half of respondents (n = 27 [46%]) reported that they perceived their training in headache disorders to be inadequate. CONCLUSIONS: Even in Denmark, a country with excellent headache services, half of residents in neurology report an inadequate training despite a higher-than-average number of hours of structured educational activities. These findings should incentivize stakeholders to make structural changes to improve education in headache disorders during the most fundamental years of training.

Barriers and gaps in headache education: a national cross-sectional survey of neurology residents in Denmark.

BACKGROUND: A major barrier to adequate headache care is the relative lack of formal education and training of healthcare professionals. Concerted efforts should be made to pinpoint major gaps in knowledge in healthcare professionals to facilitate better educational policies in headache training. The aim of this study was to identify deficiencies and barriers in headache training among residents in neurology in Denmark. METHODS: We conducted a national cross-sectional survey of residents in neurology in Denmark from April 2019 to September 2019. The survey included questions on participant demographics, knowledge of and barriers in headache disorders, guidelines and diagnostic tools usage, contact with primary and tertiary care, medication overuse, and non-pharmacological interventions. Furthermore, respondents were asked to provide a ranked list from most to least interesting for six sub-specializations/disorders, i.e., cerebrovascular disease, dementia, epilepsy, headache, multiple sclerosis, Parkinson's disease. RESULTS: Sixty (40%) out of estimated a population of ~ 150 resident across Denmark accepted the invitation. Of these, 54/60 (90%) completed the survey. Although two-thirds, 35/54 (65%), of the respondents had prior formalized training in headache disorders, we identified gaps in all explored domains including diagnosis, management, and referral patterns. Particularly, there was an inconsistent use of guidelines and diagnostic criteria from the Danish Headache Society (2.74 (± 1.14)), the Danish Neurological Society (3.15 (± 0.86)), and the International Classification of Headache Disorders (2.33 (± 1.08)); 1: never/have not heard of, 4: always. Headache was ranked second to last out of six sub-specializations in interest. CONCLUSIONS: Overall knowledge on headache disorders amongst neurology residents in Denmark do not meet the expectations set out by national and international recommendations. Stakeholders should make strategic initiatives for structured education in headache for improved clinical outcomes in parallel with costs reduction through resource optimization.

One-quarter of individuals with weekly headache have never consulted a medical doctor: a Danish nationwide cross-sectional survey.

INTRODUCTION: Large numbers of people with headache who would benefit are not reached by headache services. Among the causes are poor or disorganized provision of headache services, but reluctance to seek healthcare has frequently been identified as a significant barrier. We conducted a national survey of people with headache to assess the extent of this problem in Denmark, a country with well organized, highly resourced, and readily accessible services. METHODS: We conducted a nationwide cross-sectional survey of adults ≥ 18 years old in Denmark reporting at least one headache day in the last year. We used social media (Facebook) to publicize and drive a recruitment campaign. The survey investigated five items: (1) disease burden, (2) social life, (3) presenteeism, (4) social support, and (5) healthcare utilization. RESULTS: We included 6,567 respondents from May 2021 to June 2021; 70.2% were female, 39.8% male, and mean age was 43.2 ± 13.4 years. Of the respondents, 54.2% reported headache at least once a week, 33.4% reported headache a couple of times a month, and 12.4% reported headache a couple of times a year. Two-thirds of respondents (66.6%) reported that headache limited their social lives occasionally or frequently. Most respondents (86.8%) reported going to work or attending educational activities occasionally or more frequently even though they had headache. Half of the respondents (49.5%) experienced lack of understanding of their headaches from people occasionally or more frequently. Almost half of respondents (43.7%) had never consulted a medical doctor for their headache; even of those with weekly headache, more than a quarter (28.3%) had never done so in their lifetimes. CONCLUSIONS: Headache disorders continue to be a problem, even in a high-income country with free and easily accessible headache services. Further studies are needed to investigate and clarify why even people with the highest burden are hesitant to seek and make use of widely available headache services.

Real-world long-term efficacy and safety of erenumab in adults with chronic migraine: a 52-week, single-center, prospective, observational study.

BACKGROUND: Clinical trials have shown that erenumab is effective and well-tolerated for the preventive treatment of chronic migraine. To extend the results from clinical trials, we assessed the real-world efficacy and safety of erenumab in patients with chronic migraine from the outpatient clinic at the Danish Headache Center. METHODS: A 52-week, single-center, prospective, observation study of erenumab in adults with chronic migraine who are eligible for treatment with monoclonal antibodies against CGRP or its receptor in Denmark. The primary outcome was defined as proportion of patients who achieved ≥ 30% reduction in monthly migraine days (MMDs) from baseline to weeks 9-12. RESULTS: A total of 300 adult patients with chronic migraine were enrolled and received at least one dose of erenumab. At baseline, the mean (SD) number of monthly headache days was 23 ± 4.9 and mean number of MMDs was 16.8 ± 6.4. Of 300 enrolled patients, 273 (91.0%) patients completed 12 weeks of treatment, and 119 (39.7%) completed 52 weeks of treatment. The number of patients who achieved ≥ 30% reduction in MMDs from baseline to weeks 9-12 was 195 (71.4%) of 273 patients. Sustained ≥ 30% reduction in MMDs at all assessment periods throughout the 52-week treatment period was achieved by 102 (34%) of 300 patients. Adverse events occurred in 220 (73.3%) out of 300 patients. The most common adverse event was constipation. Treatment discontinuation due to lack of tolerability occurred in 41 (13.7%) patients. CONCLUSIONS: Among adult patients with chronic migraine and previous failure of medications for migraine prevention, erenumab was found to be effective and well-tolerated.

CGRP-induced migraine-like headache in persistent post-traumatic headache attributed to mild traumatic brain injury.

OBJECTIVE: To ascertain whether intravenous infusion of calcitonin gene-related peptide (CGRP) can induce migraine-like headache in people with persistent post-traumatic headache attributed to mild traumatic brain injury (TBI) and no pre-existing migraine. METHODS: A non-randomized, single-arm, open-label study at a single site in Denmark. Eligible participants were aged 18 to 65 years and had a known history of persistent post-traumatic headache attributed to mild TBI for ≥ 12 months. All participants received continuous intravenous infusion of CGRP (1.5 µg/min) over 20 min. A headache diary was used to collect outcome data until 12 h after the start of CGRP infusion. The primary end point was the incidence of migraine-like headache during 12-hour observational period. RESULTS: A total of 60 participants completed the study protocol and provided data for the analysis of the primary end point. The median age was 32.5 (IQR, 25.5-43.0) years; 43 participants (72%) were female. Following CGRP infusion, 43 (72%) of 60 participants developed migraine-like headache during the 12-hour observational period. The median time to peak headache intensity was 40 min (IQR, 20-60), and the median peak headache intensity was 6 (IQR, 5-8) on the 11-point numeric rating scale. CONCLUSION: Intravenous infusion of CGRP is a potent inducer of migraine-like headache in people with persistent post-traumatic headache attributed to mild TBI. This observation underscores the importance of CGRP in the genesis of migraine-like headache that is often experienced by individuals who are afflicted by persistent post-traumatic headache. Further research is warranted to ascertain whether other signaling molecules also contribute to the disease mechanisms underlying post-traumatic headache.

Nocebo response in human models of migraine: A systematic review and meta-analysis of randomized, double-blind, placebo-controlled, two-way crossover trials in migraine without aura and healthy volunteers.

BACKGROUND: Human models of migraine have been used for the past 30 years to test putative 'trigger' molecules and ascertain whether they induce migraine attacks in humans. However, nocebo effects using this model have never been systematically explored. OBJECTIVE: To assess the nocebo response rate in randomised clinical trials conducted at the Danish Headache Center, and in which human models of migraine were used. METHODS: In this systematic review and meta-analysis, we searched PubMed for studies of human models of migraine with a randomised, double-blind, placebo-controlled, two-way crossover design that included data on the incidence of migraine attacks or headache after infusion of placebo. A total of 943 articles were screened by title and abstract. Of these, 27 studies met the inclusion criteria (published between 1994 and 2020) and were included in the qualitative and quantitative analysis. We performed a random effects meta-analysis for the incidence of migraine attacks or delayed headache after placebo infusion. RESULTS: Twenty-seven studies were eligible for inclusion: 12 studies reported data for adults with migraine (n = 182), whereas 16 studies reported data on healthy volunteers (n = 210). For adults with migraine, the incidence of migraine attacks after placebo was 8.1% (95% CI = 2.5-15.5%, I2 = 50.8%). The incidence of delayed headache was 25.9% (95% CI = 18.5-34.1%, I2 = 18.9%). For healthy volunteers, the incidence of migraine attacks after placebo was 0.5% (95% CI = 0.0-3.6%, I2 = 0.0%) while the incidence of delayed headache was 10.5% (95% CI = 4.8-17.6%, I2 = 45.2%). CONCLUSION: The nocebo response in randomised, placebo-controlled two-way crossover trials with intravenous infusions of placebo in migraine is negligible. Future studies using human models of migraine can be conducted by assuming a nocebo response rate of 15.5%.