Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update.

OBJECTIVE: To provide a position statement update from The American Headache Society specifically regarding therapies targeting calcitonin gene-related peptide (CGRP) for the prevention of migraine. BACKGROUND: All migraine preventive therapies previously considered to be first-line treatments were developed for other indications and adopted later for migraine. Adherence to these therapies is often poor due to issues with efficacy and tolerability. Multiple new migraine-specific therapies have been developed based on a broad foundation of pre-clinical and clinical evidence showing that CGRP plays a key role in the pathogenesis of migraine. These CGRP-targeting therapies have had a transformational impact on the management of migraine but are still not widely considered to be first-line approaches. METHODS: Evidence regarding migraine preventive therapies including primary and secondary endpoints from randomized placebo-controlled clinical trials, post hoc analyses and open-label extensions of these trials, and prospective and retrospective observational studies were collected from a variety of sources including PubMed, Google Scholar, and ClinicalTrials.gov. The results and conclusions based upon these results were reviewed and discussed by the Board of Directors of The American Headache Society to confirm consistency with clinical experience and to achieve consensus. RESULTS: The evidence for the efficacy, tolerability, and safety of CGRP-targeting migraine preventive therapies (the monoclonal antibodies: erenumab, fremanezumab, galcanezumab, and eptinezumab, and the gepants: rimegepant and atogepant) is substantial, and vastly exceeds that for any other preventive treatment approach. The evidence remains consistent across different individual CGRP-targeting treatments and is corroborated by extensive "real-world" clinical experience. The data indicates that the efficacy and tolerability of CGRP-targeting therapies are equal to or greater than those of previous first-line therapies and that serious adverse events associated with CGRP-targeting therapies are rare. CONCLUSION: The CGRP-targeting therapies should be considered as a first-line approach for migraine prevention along with previous first-line treatments without a requirement for prior failure of other classes of migraine preventive treatment.

An economic evaluation of eptinezumab for the preventive treatment of migraine in the UK, with consideration for natural history and work productivity.

BACKGROUND: Migraine is a highly prevalent neurological disease with a substantial societal burden due to lost productivity. From a societal perspective, we assessed the cost-effectiveness of eptinezumab for the preventive treatment of migraine. METHODS: An individual patient simulation of discrete competing events was developed to evaluate eptinezumab cost-effectiveness compared to best supportive care for adults in the United Kingdom with ≥ 4 migraine days per month and prior failure of ≥ 3 preventive migraine treatments. Individuals with sampled baseline characteristics were created to represent this population, which comprised dedicated episodic and chronic migraine subpopulations. Clinical efficacy, utility, and work productivity inputs were based on results from the DELIVER randomised controlled trial (NCT04418765). Timing of natural history events and treatment holidays-informed by the literature-were simulated to unmask any natural improvement of the disease unrelated to treatment. The primary outcomes were monthly migraine days, migraine-associated costs, quality-adjusted life years (QALYs), incremental cost-effectiveness ratio, and net monetary benefit, each evaluated over a 5-year time horizon from 2020. Secondary analyses explored a lifetime horizon and an alternative treatment stopping rule. RESULTS: Treatment with eptinezumab resulted in an average of 0.231 QALYs gained at a saving of £4,894 over 5 years, making eptinezumab dominant over best supportive care (i.e., better health outcomes and less costly). This result was confirmed by the probabilistic analysis and all alternative assumption scenarios under the same societal perspective. Univariate testing of inputs showed net monetary benefit was most sensitive to the number of days of productivity loss, and monthly salary. CONCLUSIONS: This economic evaluation shows that from a societal perspective, eptinezumab is a cost-effective treatment in patients with ≥ 4 migraine days per month and for whom ≥ 3 other preventive migraine treatments have failed. TRIAL REGISTRATION: N/A.

Erenumab in chronic migraine: Experience from a UK tertiary centre and comparison with other real-world evidence.

BACKGROUND AND PURPOSE: Chronic migraine is a highly disabling primary headache disorder that is the most common diagnosis of patients seen at tertiary headache centres. Typical oral preventive therapies are associated with many limitations that impact their therapeutic utility. Erenumab was the first available calcitonin gene-related peptide monoclonal antibody in the UK. It had proven efficacy in migraine prevention in clinical trials and limited real-world data in tertiary settings. METHODS: We audited our first 92 patients (n = 73 females) with severely disabling chronic migraine who were given monthly erenumab 70 mg sc for 6 months between December 2018 and December 2019. RESULTS: At 3 months, monthly migraine days were significantly reduced by a median of 4 days, and all other variables also showed significant improvement. The improvement was not affected by baseline analgesic use status. More than half of our patients experienced a clinically meaningful improvement in migraine days. No serious adverse events were reported. CONCLUSIONS: Our real-world data with erenumab demonstrate it is effective and well tolerated in managing patients with chronic migraine in a tertiary care setting.

Evaluating the clinical utility of the patient-identified most bothersome symptom measure from PROMISE-2 for research in migraine prevention.

OBJECTIVE: To assess the utility of the novel patient-identified (PI) most bothersome symptom (MBS) measure from PROMISE-2, a phase 3 trial of eptinezumab for the preventive treatment of chronic migraine. BACKGROUND: Relief of bothersome migraine symptoms can influence satisfaction with treatment and therapeutic persistence. Understanding the impact of preventive treatment on a PI-MBS could improve clinical decision-making. METHODS: In PROMISE-2, patients with chronic migraine received eptinezumab 100, 300 mg, or placebo administered intravenously every 12 weeks for up to 2 doses (n = 1072). PI-MBS was an exploratory outcome requiring each patient to self-report their MBS in response to an open-ended question. At baseline and week 12, patients rated overall improvement in PI-MBS. The relationships among PI-MBS at week 12 and change in monthly migraine days (MMDs) from baseline to month 3 (weeks 9-12), Patient Global Impression of Change at week 12, and changes from baseline to week 12 in the 6-item Headache Impact Test total, EuroQol 5-dimensions 5-levels visual analog scale, and 36-item Short-Form Health Survey component scores were assessed. RESULTS: Treatment groups had similar baseline characteristics and reported a total of 23 unique PI-MBS, most commonly light sensitivity (200/1072, 18.7%), nausea/vomiting (162/1072, 15.1%), and pain with activity (147/1072, 13.7%). Improvements in PI-MBS at week 12 correlated with changes in MMDs (ρ = -0.49; p < 0.0001) and other patient-reported outcomes. Controlling for changes in MMDs, PI-MBS improvement predicted other patient-reported outcomes in expected directions. The magnitude of the standardized mean differences between placebo and active treatment for PI-MBS were 0.31 (p < 0.0001 vs. placebo) and 0.54 (p < 0.0001 vs. placebo) for eptinezumab 100 and 300 mg, respectively. CONCLUSIONS: Improvement in PI-MBS at week 12 was associated with improvement in other patient-reported outcome measures, and PI-MBS may be an important patient-centered measure of treatment benefits in patients with chronic migraine.

Evolving options for the treatment of cluster headache.

PURPOSE OF REVIEW: Cluster headache is a neurological disorder that patients consider the most severe pain they experience. Recognizing new treatments provides opportunities to advance current management. RECENT FINDINGS: In contrast to the classic treatments, new options narrow in on the therapeutic target and are better tolerated. Calcitonin gene-related peptide (CGRP) pathway blockade with monoclonal antibodies (MABs), specifically the CGRP MAB galcanezumab, represents an important advance for episodic cluster headache, reducing the number of attacks during a bout. Neuromodulation strategies aimed at anatomical structures involved in the pathophysiology of cluster headache, such as the sphenopalatine ganglion and the vagus nerve, have proved effective in reducing the pain intensity and the number of attacks, and also to be safe and well tolerated. SUMMARY: Our understanding of the pathophysiology of cluster headache and its management continues to grow. Novel treatments have appeared from research, such as neuromodulation and CGRP monoclonal antibodies. Nonetheless, chronic cluster headache and designing trials that select the correct sham in evaluating devices remain challenging.

Treatment of disabling headache with greater occipital nerve injections in a large population of childhood and adolescent patients: a service evaluation.

BACKGROUND: Pediatric headache disorders can be extremely disabling, with marked reduction in the quality of life of children and their carers. Evidenced-based options for the treatment of primary headache disorders with preventive medication is limited and clinical outcomes are often unsatisfactory. Greater occipital nerve injections represent a rapid and well-tolerated therapeutic option, which is widely used in clinical practice in adults, and has previously shown a good outcome in a pediatric population. METHODS: This service evaluation reviewed greater occipital nerve injections performed unilaterally with 30 mg 1% lidocaine and 40 mg methylprednisolone, to treat disabling headache disorders in children and adolescents. RESULTS: We analyzed a total of 159 patients who received 380 injections. Of the population, 79% had chronic migraine, 14% new daily persistent headache, 4% a trigeminal autonomic cephalalgia, 3% secondary headache and one patient had chronic tension-type headache. An improvement after injection was seen in 66% (n = 105) of subjects, lasting on average 9 ± 4 weeks. Improvement was seen in 68% of patients with chronic migraine, 67% with a trigeminal autonomic cephalalgia and 59% with new daily persistent headache. Side effects were reported in 8% and were mild and transient. Older age, female gender, chronic migraine, increased number of past preventive use, medication overuse and developing side effects were all associated with an increased likelihood of positive treatment outcome. CONCLUSIONS: This large single centre service evaluation confirms that unilateral injection of the greater occipital nerve is a safe, rapid-onset and effective treatment strategy in disabling headache disorders in children, with a range of diagnoses and severity of the condition, and with minimal side effects.

An Update on Non-Pharmacological Neuromodulation for the Acute and Preventive Treatment of Migraine.

OBJECTIVE: To review current neuromodulation treatments available for migraine therapy, both in the acute and preventive setting. METHODS: The published literature was reviewed for studies reporting the effects of different neuromodulation strategies in migraine with and without aura. The use of non-invasive: single pulse transcranial magnetic stimulation, non-invasive vagal nerve stimulation, supraorbital nerve stimulation, and transcranial direct current stimulation, as well as invasive methods such as occipital nerve stimulation and sphenopalatine ganglion stimulation, are assessed. RESULTS: The available evidence shows that non-invasive techniques represent promising treatment strategies, whereas an invasive approach should only be used where patients are refractory to other preventives, including non-invasive methods. CONCLUSIONS: Neuromodulation is emerging as an exciting approach to migraine therapy, especially in the context of failure of commonly used medicines or for patients who do not tolerate common side effects. More studies with appropriate blinding strategies are needed to confirm the results of these new treatment opportunities.

Therapeutic prospects for migraine: can paradise be regained?

Migraine is a common, complex brain disorder whose biology is becoming better understood. Despite being the most disabling of the neurological disorders on a worldwide basis, headache disorders broadly, and migraine in particular, have poor research funding and a limited academic base. Given a modicum of investment, new targets, such as calcitonin gene-related peptide-based mechanisms, and entirely novel neuromodulation approaches illustrate that much can be done to improve patient care. Genetics and neuroimaging combined with excellent clinical phenotyping and translational neuroscience approaches are set to transform life for a cohort of patients with these common brain disorders.

Intervening in the Premonitory Phase to Prevent Migraine: Prospects for Pharmacotherapy.

Migraine is a common brain condition characterised by disabling attacks of headache with sensory sensitivities. Despite increasing understanding of migraine neurobiology and the impacts of this on therapeutic developments, there remains a need for treatment options for patients underserved by currently available therapies. The first specific drugs developed to treat migraine acutely, the serotonin-5-hydroxytryptamine [5-HT1B/1D] receptor agonists (triptans), seem to require headache onset in order to have an effect, while early treatment during mild pain before headache escalation improves short-term and long-term outcomes. Some patients find treating in the early window once headache has started but not escalated difficult, and migraine can arise from sleep or in the early hours of the morning, making prompt treatment after pain onset challenging. Triptans may be deemed unsuitable for use in patients with vascular disease and in those of older age and may not be effective in a proportion of patients. Headache is also increasingly recognised as being just one of the many facets of the migraine attack, and for some patients it is not the most disabling symptom. In many patients, painless symptoms can start prior to headache onset and can reliably warn of impending headache. There is, therefore, a need to identify therapeutic targets and agents that may be used as early as possible in the course of the attack, to prevent headache onset before it starts, and to reduce both headache and non-headache related attack burden. Early small studies using domperidone, naratriptan and dihydroergotamine have suggested that this approach could be useful; these studies were methodologically less rigorous than modern day treatment studies, of small sample size, and have not since been replicated. The emergence of novel targeted migraine treatments more recently, specifically calcitonin gene-related peptide (CGRP) receptor antagonists (gepants), has reignited interest in this strategy, with encouraging results. This review summarises historical and emerging data in this area, supporting use of the premonitory phase as an opportunity to intervene as early as possible in migraine to prevent attack-related morbidity.

Guidance for the management of headache in sport on behalf of The Royal College of General Practitioners and The British Association for the Study of Headache.

Headache is prevalent within the community and can have an impact on sport in both the amateur and elite player, either coincidentally or as a direct result of participation. Against a background of a limited evidence base, this paper suggests how headache can be classified within this context and offers guidance for treating both the amateur and elite athlete. The impact of headache in sport may be unrecognised and undertreated, and further research is needed in this area.

Role of Monoclonal Antibodies against Calcitonin Gene-Related Peptide (CGRP) in Episodic Migraine Prevention: Where Do We Stand Today?

BACKGROUND: Medications targeting the calcitonin gene-related peptide (CGRP) pathway are exciting and novel therapeutic options in the treatment of migraine. OBJECTIVE: In this article, we have reviewed the role of these CGRP monoclonal antibodies in patients with episodic migraine. MATERIALS AND METHODS: We did an extensive literature search for all phase 2 and 3 studies involving CGRP monoclonal antibodies in episodic migraine. RESULTS: Erenumab, fremanezumab, galcanezumab, and eptinezumab have all undergone phase 3 trials and have been found to be effective for episodic and chronic migraine. They have the advantage of being targeted therapies for migraine with very favorable adverse effect profiles comparable to placebo. Importantly, they are effective in subgroups of patients who have failed previous preventive therapies. CONCLUSION: Increasing use of these medications will certainly revolutionize the treatment and outlook for patients with migraine all over the world.

Eptinezumab for the preventive treatment of migraine.

Our knowledge of the pathophysiology of migraine and the molecules implicated in the disorder have evolved over time. Among these, calcitonin gene-related peptide has shown a crucial role that led to the development of therapies specifically targeting the molecule. Four monoclonal antibodies targeting the calcitonin gene-related peptide pathway are currently available after the US FDA approval of eptinezumab for the indication of migraine prevention. This is the only one of the class to be administered intravenously. The pharmacology of eptinezumab and the four studies that led to the approval, two Phase II and two Phase III clinical trials, are reviewed in this paper. Eptinezumab has demonstrated efficacy, tolerability and safety in patients with episodic and chronic migraine. Studies including migraineurs who have failed previous preventives, and comparison with other options administered quarterly, as well as real-world experience data will all be welcome.

Integrating headache trigger management strategies into cognitive-behavioral therapy: A randomized controlled trial.

OBJECTIVE: Traditionally, the standard advice to individuals suffering from migraine and tension-type headache was that the best way to prevent headaches is to avoid the triggers. This advice has been challenged in recent years and the Trigger Avoidance Model of Headache has been proposed, which suggests that one pathway to developing a headache disorder is by avoiding triggers resulting in trigger sensitization. The objective of the study was to evaluate a novel intervention for primary headache comprising a new approach to trigger management that includes exposure to some triggers with the goal of trigger desensitization (learning to cope with triggers [LCT]) integrated into a cognitive-behavioral therapy (CBT) program (LCT/CBT). METHOD: The study was a randomized controlled trial comparing LCT/CBT to the same treatment program but using the traditional approach to trigger management of encouraging trigger avoidance (avoid/CBT), and to a waiting-list/treatment-as-usual control condition (WL/TAU). Adults suffering from primary headache (88 female/35 male) were allocated to the three conditions. RESULTS: The three groups significantly differed from baseline to posttreatment on the primary outcome measure of attack frequency, and LCT/CBT significantly differed from WL/TAU but Avoid/CBT did not. Similar results were obtained on the secondary outcome measures, and treatment gains were maintained at 4- and 12-month follow-up. CONCLUSIONS: The results suggest the value of using LCT as a component of a CBT program but were not conclusive as the direct comparisons between the two treatment conditions failed to reach statistical significance. The findings support a study of LCT/CBT with a larger sample. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Cost-Effectiveness of Erenumab for the Preventive Treatment of Migraine in Patients with Prior Treatment Failures in Sweden.

BACKGROUND: Migraine is a common neurological disease that disproportionately affects females and has a peak incidence during productive years, resulting in significant burden. OBJECTIVE: The aim of the study was to determine the cost effectiveness of erenumab for the preventive treatment of migraine. METHODS: A hybrid decision-tree plus Markov model was developed to evaluate the cost effectiveness of erenumab as a migraine treatment compared with best supportive care only for patients experiencing at least 4 monthly migraine days for whom at least two prior preventive treatments had failed. Clinical efficacy data were based on results from four randomized controlled trials of erenumab against placebo. The primary outcomes were costs, migraine days, and quality-adjusted life-years (QALYs). An incremental cost-effectiveness ratio (ICER) was estimated as the cost per QALY gained. The cost per migraine day avoided was also estimated, as were disaggregated direct and indirect costs. The analysis was conducted from Swedish societal and healthcare system perspectives based on total migraine, chronic migraine and episodic migraine populations, using a discount rate of 3% applied to both costs and health benefits and using year 2019 values. RESULTS: In the base-case deterministic analyses, erenumab treatment resulted in ICERs of Swedish krona (SEK) 34,696 (€3310) and SEK301,565 (€28,769) per QALY gained in the total migraine and episodic migraine populations, respectively. Erenumab was dominant in the chronic migraine population. In the total migraine population, the use of erenumab resulted in a net benefit to society of SEK81,739 (€7773) per patient, assuming a willingness-to-pay threshold of SEK300,000 (€28,528) per QALY. CONCLUSIONS: Our analysis suggests that erenumab is a cost-effective treatment for migraine with a willingness-to-pay threshold of SEK300,000 per QALY.

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.

New therapeutic approaches for the prevention and treatment of migraine.

The management of patients with migraine is often unsatisfactory because available acute and preventive therapies are either ineffective or poorly tolerated. The acute treatment of migraine attacks has been limited to the use of analgesics, combinations of analgesics with caffeine, ergotamines, and the triptans. Successful new approaches for the treatment of acute migraine target calcitonin gene-related peptide (CGRP) and serotonin (5-hydroxytryptamine, 5-HT1F) receptors. Other approaches targeting the transient receptor potential vanilloid (TRPV1) receptor, glutamate, GABAA receptors, or a combination of 5-HT1B/1D receptors and neuronal nitric oxide synthesis have been investigated but have not been successful in clinical trials thus far. In migraine prevention, the most promising new approaches are humanised antibodies against CGRP or the CGRP receptor. Non-invasive and invasive neuromodulation approaches also show promise as both acute and preventive therapies, although further studies are needed to define appropriate candidates for these therapies and optimum protocols for their use.

Behavioral management of the triggers of recurrent headache: a randomized controlled trial.

This study was designed to evaluate the traditional advice to headache sufferers to avoid all triggers ('Avoidance'), and a novel approach to trigger management (Learning to Cope with Triggers - 'LCT') that included graduated exposure to selected triggers to promote desensitization. Individuals (84F, 43M) with migraine and/or tension-type headache were assigned randomly to one of four groups: Waiting-list (Waitlist); Avoidance; Avoidance combined with cognitive behavior therapy (Avoid + CBT); and LCT. Changes in headaches and medication consumption (in parentheses) from pre- to post-treatment were (a minus sign indicates improvement): Waitlist, +11.0% (+15.4%); Avoidance, -13.2% (-9.0%); Avoid + CBT, -30.0% (-19.4%); and LCT, -35.9% (-27.9%). Avoidance did not differ significantly from Waitlist on headaches or medication use, but LCT differed significantly from Waitlist on both measures. Avoid + CBT significantly differed from Waitlist on headaches but not medication consumption. In summary, the study failed to find support for the standard approach to trigger management of advising avoidance, but LCT emerged as a promising strategy. LCT resulted in greater improvement than the other three conditions on all measures of headaches and medication consumption, and was the only treatment condition that significantly differed from the waiting-list control condition in terms of treatment responder rate (50% or greater reduction in headaches) and medication consumption.