Publications by authors named "Messoud Ashina"

264 Publications

Reduction in acute migraine-specific and non-specific medication use in patients treated with erenumab: post-hoc analyses of episodic and chronic migraine clinical trials.

J Headache Pain 2021 Jul 23;22(1):81. Epub 2021 Jul 23.

Amgen Inc, Thousand Oaks, CA, USA.

Background: In patients with migraine, overuse of acute medication, including migraine-specific medication (MSM) such as triptans and ergots, can lead to adverse health outcomes, including development of medication overuse headache. Here, we examined the effect of erenumab on reducing acute medication use, in particular MSM, in patients with episodic migraine (EM) and chronic migraine (CM).

Methods: The current post-hoc analyses were based on data from the double-blind treatment phase (DBTP) of two erenumab studies, a pivotal EM (N = 955) and a pivotal CM (N = 667) trial, and their respective extensions. Patients were administered subcutaneous placebo or erenumab (70 or 140 mg) once monthly. Daily acute headache medication use (including MSM and non-MSM) was recorded using an electronic diary during a 4-week pretreatment baseline period until the end of the treatment period. Outcome measures included change in monthly acute headache medication days (HMD) in acute headache medication users at baseline, and changes in monthly MSM days (MSMD) in MSM users at baseline and non-MSMD in non-MSM users at baseline.

Results: In total, 60 and 78 % of patients (all acute headache medication users) with EM and CM used MSM at baseline, respectively. For acute headache medication users, the change in mean monthly acute HMD over Months 4, 5 and 6 compared with the pre-DBTP was 1.5, 2.5, and 3.0 for placebo, erenumab 70 mg and 140 mg, respectively for the EM study. The respective change in monthly MSMD in MSM users was 0.5, 2.1 and 2.8, and in monthly non-MSMD in non-MSM users was 2.3, 2.6, and 2.7. In the acute headache medication users at baseline, the change in monthly acute HMD at Month 3 compared with pre-DBTP was 3.4, 5.5, and 6.5 for placebo, erenumab 70 mg and 140 mg, respectively for the CM study. The respective change in monthly MSMD in MSM users was 2.1, 4.5, and 5.4, and in monthly non-MSMD in non-MSM users was 5.9, 6.4, and 6.6. Reductions in MSMD versus placebo were sustained in the extension periods of both studies. Erenumab was also associated with a higher proportion of MSM users achieving ≥ 50 %, ≥ 75 and 100 % reduction from baseline in monthly MSMD versus placebo in both EM and CM.

Conclusions: In both EM and CM, treatment with erenumab is associated with a significant and sustained reduction in the use of acute headache medication, in particular MSM.

Trial Registrations: NCT02456740; NCT02066415; NCT02174861.
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http://dx.doi.org/10.1186/s10194-021-01292-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8299690PMC
July 2021

Structured Q1 headache services as the solution to the ill-health burden of headache: 1. Rationale and description.

J Headache Pain 2021 Jul 21;22(1):78. Epub 2021 Jul 21.

Department of Neurology, Ghent University Hospital, Ghent, Belgium.

In countries where headache services exist at all, their focus is usually on specialist (tertiary) care. This is clinically and economically inappropriate: most headache disorders can effectively and more efficiently (and at lower cost) be treated in educationally supported primary care. At the same time, compartmentalizing divisions between primary, secondary and tertiary care in many health-care systems create multiple inefficiencies, confronting patients attempting to navigate these levels (the "patient journey") with perplexing obstacles.High demand for headache care, estimated here in a needs-assessment exercise, is the biggest of the challenges to reform. It is also the principal reason why reform is necessary.The structured headache services model presented here by experts from all world regions on behalf of the Global Campaign against Headache is the suggested health-care solution to headache. It develops and refines previous proposals, responding to the challenge of high demand by basing headache services in primary care, with two supporting arguments. First, only primary care can deliver headache services equitably to the large numbers of people needing it. Second, with educational supports, they can do so effectively to most of these people. The model calls for vertical integration between care levels (primary, secondary and tertiary), and protection of the more advanced levels for the minority of patients who need them. At the same time, it is amenable to horizontal integration with other care services. It is adaptable according to the broader national or regional health services in which headache services should be embedded.It is, according to evidence and argument presented, an efficient and cost-effective model, but these are claims to be tested in formal economic analyses.
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http://dx.doi.org/10.1186/s10194-021-01265-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8293530PMC
July 2021

The chronobiology of migraine: a systematic review.

J Headache Pain 2021 Jul 19;22(1):76. Epub 2021 Jul 19.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Valdemar Hansen Vej 5, DK-2600, Glostrup, Denmark.

Background: The paroxysmal nature of migraine is a hallmark of the disease. Some patients report increased attack frequency at certain seasons or towards the end of the week, while others experience diurnal variations of migraine attack onset. This systematic review investigates the chronobiology of migraine and its relation to the periodicity of attacks in existing literature to further understand the oscillating nature of migraine.

Main Body: PubMed and Embase were systematically searched and screened for eligible articles with outcome measures relating to a circadian, weekly or seasonal distribution of migraine attacks. We found that the majority of studies reported morning hours (6 am-12 pm) as the peak time of onset for migraine attacks. More studies reported Saturday as weekly peak day of attack. There was no clear seasonal variation of migraine due to methodological differences (primarily related to location), however four out of five studies conducted in Norway reported the same yearly peak time indicating a possible seasonal periodicity phenomenon of migraine.

Conclusions: The findings of the current review suggest a possible role of chronobiologic rhythms to the periodicity of migraine attacks. Future studies are, however, still needed to provide more knowledge of the oscillating nature of migraine.
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http://dx.doi.org/10.1186/s10194-021-01276-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8287677PMC
July 2021

Board Walk - August 2021.

Authors:
Messoud Ashina

Cephalalgia 2021 Aug;41(9):1033-1034

Professor of Neurology, President of the International Headache Society, Danish Headache Center & Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.

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http://dx.doi.org/10.1177/03331024211025218DOI Listing
August 2021

Symptomatic migraine: A systematic review to establish a clinically important diagnostic entity.

Headache 2021 Jul 12. Epub 2021 Jul 12.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Objective: To determine if a clinical presentation indistinguishable from migraine can occur due to an underlying condition or pathology, that is, "symptomatic migraine."

Background: It is currently not clear whether migraine truly can be caused by an underlying condition or pathology. Characterization of the etiology and clinical features of possible symptomatic migraine is of significant clinical importance and further may help elucidate the pathophysiology of migraine.

Methods: We devised operational diagnostic criteria for "symptomatic migraine" and "possible symptomatic migraine" requiring strong evidence for a causal relation between underlying cause and migraine symptoms adhering strictly to diagnostic criteria. PubMed was searched for case reports of symptomatic migraine from inception to March 2020. Only articles published in English or German were included. No restrictions were placed on study design. Relevant references in the articles were also included. Papers were systematically reviewed by two independent reviewers for detailed clinical features of migraine as well as the proposed underlying conditions and the effects of treatment of these conditions.

Results: Our search retrieved 1726 items. After screening, 109 papers comprising 504 cases were reviewed in detail. Eleven patients with migraine with aura (MWA) fulfilled our working criteria for symptomatic migraine, and 39 patients fulfilled our criteria for possible symptomatic migraine. The most common etiologies of symptomatic migraine were arteriovenous malformations, carotid stenosis, dissection or aneurysm, brain infarctions, meningioma, and various intra-axial tumors.

Conclusions: Symptomatic MWA, indistinguishable from idiopathic MWA, may occur due to cortical lesions or microembolization. We found no clear evidence supporting the existence of symptomatic migraine without aura although we did identify possible cases. Our findings are limited by the available literature, and we suggest that prospective studies are needed.
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http://dx.doi.org/10.1111/head.14187DOI Listing
July 2021

Opening of BKCa channels causes migraine attacks: a new downstream target for the treatment of migraine.

Pain 2021 Mar 16. Epub 2021 Mar 16.

Department of Neurology, Danish Headache Center, Rigshospitalet-Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Novartis Pharma AG, Basel, Switzerland Danish Knowledge Center on Headache Disorders, Rigshospitalet-Glostrup, Denmark.

Abstract: Migraine is a common and frequently disabling neurological disorder, but the initiating migraine mechanisms are still poorly understood. Potassium channel opening may cause migraine, and we therefore examined the migraine-inducing effect of MaxiPost, a large (big)-conductance calcium-activated potassium (BKCa) channel opener, on migraine induction and cephalic vasodilation in individuals with migraine. Twenty-six patients with migraine without aura were randomly allocated to receive an infusion of MaxiPost or placebo on 2 study days separated by at least 1 week. The primary endpoint was the difference in incidence of migraine attacks after MaxiPost compared with placebo. The secondary endpoints were the difference in incidence of headaches and the difference in area under the curve for headache intensity scores (0-12 hours), for middle cerebral artery blood flow velocity (VMCA) (0-2 hours), and for superficial temporal artery and radial artery diameter. Twenty-two patients completed the study. Twenty-one of 22 (95%) developed migraine attacks after MaxiPost compared with none after placebo (P < 0.0001); the difference of incidence is 95% (95% confidence interval 86%-100%). The incidence of headache over the 12-hour observation period was higher after MaxiPost day (n = 22) than after placebo (n = 7) (P < 0.0001). We found a significant increase of VMCA and superficial temporal and radial arteries' diameter. Because BKCa channel opening initiates migraine attacks, we suggest that BKCa channel blockers could be potential candidates for novel antimigraine drugs.
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http://dx.doi.org/10.1097/j.pain.0000000000002238DOI Listing
March 2021

Efficacy and safety of fremanezumab in patients with episodic and chronic migraine with documented inadequate response to 2 to 4 classes of migraine preventive medications over 6 months of treatment in the phase 3b FOCUS study.

J Headache Pain 2021 Jul 10;22(1):68. Epub 2021 Jul 10.

Institute for Medical Informatics, Biometry and Epidemiology, Medical Faculty of the University Duisburg-Essen, Essen, Germany.

Background: Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) selectively targets the calcitonin gene-related peptide and has proven efficacy for the preventive treatment of migraine. In this study, we evaluated the long-term efficacy, safety, and tolerability of monthly and quarterly fremanezumab.

Methods: Episodic migraine and chronic migraine patients completing the 12-week double-blind period of the FOCUS trial entered the 12-week open-label extension and received 3 monthly doses of fremanezumab (225 mg). Changes from baseline in monthly migraine days, monthly headache days of at least moderate severity, days of acute headache medication use, days with photophobia/phonophobia, days with nausea or vomiting, disability scores, and proportion of patients achieving a ≥50% or  ≥75% reduction in monthly migraine days were evaluated.

Results: Of the 807 patients who completed the 12-week double-blind treatment period and entered the open-label extension, 772 patients completed the study. In the placebo, quarterly fremanezumab, and monthly fremanezumab dosing regimens, respectively, patients had fewer average monthly migraine days (mean [standard deviation] change from baseline: - 4.7 [5.4]; - 5.1 [4.7]; - 5.5 [5.0]), monthly headache days of at least moderate severity (- 4.5 [5.0]; - 4.8 [4.5]; - 5.2 [4.9]), days per month of acute headache medication use (- 4.3 [5.2]; - 4.9 [4.6]; - 4.8 [4.9]), days with photophobia/phonophobia (- 3.1 [5.3]; - 3.4 [5.3]; - 4.0 [5.2]), and days with nausea or vomiting (- 2.3 [4.6]; - 3.1 [4.5]; - 3.0 [4.4]). During the 12-week open-label extension, 38%, 45%, and 46% of patients, respectively, achieved a ≥50% reduction and 16%, 15%, and 20%, respectively, achieved a ≥75% reduction in monthly migraine days. Disability scores were substantially improved in all 3 treatment groups. There were low rates of adverse events leading to discontinuation (<1%).

Conclusion: Fremanezumab demonstrated sustained efficacy up to 6 months and was well tolerated in patients with episodic migraine or chronic migraine and documented inadequate response to multiple migraine preventive medication classes.

Trial Registration: ClinicalTrials.gov NCT03308968 (FOCUS).
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http://dx.doi.org/10.1186/s10194-021-01279-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8272284PMC
July 2021

The Effect of K Channel Blocker Glibenclamide on CGRP-Induced Headache and Hemodynamic in Healthy Volunteers.

Front Physiol 2021 11;12:652136. Epub 2021 Jun 11.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Background: Calcitonin gene-related peptide (CGRP) dilates cranial arteries and triggers headache. The CGRP signaling pathway is partly dependent on activation of ATP-sensitive potassium (K ) channels. Here, we investigated the effect of the K channel blocker glibenclamide on CGRP-induced headache and vascular changes in healthy volunteers.

Methods: In a randomized, double-blind, placebo-controlled, cross-over study, 20 healthy volunteers aged 18-27 years were randomly allocated to receive an intravenous infusion of 1.5 μg/min CGRP after oral pretreatment with glibenclamide (glibenclamide-CGRP day) or placebo (placebo-CGRP day). The primary endpoints were the difference in incidence of headache and the difference in area under the curve (AUC) for headache intensity scores (0-14 h) between glibenclamide and placebo. The secondary endpoints were the difference in AUC for middle cerebral artery blood flow velocity (V ), superficial temporal artery (STA) and radial artery (RA) diameter, facial flushing, heart rate (HR) and mean arterial blood pressure (MAP) (0-4 h) between glibenclamide and placebo.

Results: We found no significant difference in the incidence of headache between glibenclamide-CGRP day (14/20, 70%) and placebo-CGRP day (19/20, 95%) ( = 0.06). The AUC for headache intensity, V , STA, RA, facial skin blood flow, HR, and MAP did not differ between glibenclamide-CGRP day compared to placebo-CGRP day ( 0.05).

Conclusion: Pretreatment with a non-selective K channel inhibitor glibenclamide did not attenuate CGRP-induced headache and hemodynamic changes in healthy volunteers. We suggest that CGRP-induced responses could be mediated via activation of specific isoforms of sulfonylurea receptor subunits of K channel.
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http://dx.doi.org/10.3389/fphys.2021.652136DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8226177PMC
June 2021

Diagnosis and management of migraine in ten steps.

Nat Rev Neurol 2021 Aug 18;17(8):501-514. Epub 2021 Jun 18.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.

Migraine is a disabling primary headache disorder that directly affects more than one billion people worldwide. Despite its widespread prevalence, migraine remains under-diagnosed and under-treated. To support clinical decision-making, we convened a European panel of experts to develop a ten-step approach to the diagnosis and management of migraine. Each step was established by expert consensus and supported by a review of current literature, and the Consensus Statement is endorsed by the European Headache Federation and the European Academy of Neurology. In this Consensus Statement, we introduce typical clinical features, diagnostic criteria and differential diagnoses of migraine. We then emphasize the value of patient centricity and patient education to ensure treatment adherence and satisfaction with care provision. Further, we outline best practices for acute and preventive treatment of migraine in various patient populations, including adults, children and adolescents, pregnant and breastfeeding women, and older people. In addition, we provide recommendations for evaluating treatment response and managing treatment failure. Lastly, we discuss the management of complications and comorbidities as well as the importance of planning long-term follow-up.
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http://dx.doi.org/10.1038/s41582-021-00509-5DOI Listing
August 2021

Reduction in the severity and duration of headache following fremanezumab treatment in patients with episodic and chronic migraine.

Headache 2021 Jun 11;61(6):916-926. Epub 2021 Jun 11.

Global Medical Affairs, Teva Branded Pharmaceutical Products R&D, Inc., West Chester, PA, USA.

Objective: To evaluate the impact of fremanezumab on the severity and duration of remaining migraine attacks in patients with chronic migraine (CM) or episodic migraine (EM).

Background: Fremanezumab is a fully humanized monoclonal antibody (IgGΔa) that selectively targets calcitonin gene-related peptide and is efficacious in reducing migraine frequency.

Methods: This exploratory post hoc analysis included data from three randomized, double-blind, 12-week, phase 3 studies (HALO CM, HALO EM, and FOCUS). In all three studies, patients with CM or EM were randomized 1:1:1 to receive subcutaneous quarterly fremanezumab (month 1/2/3: 675 mg/placebo/placebo), monthly fremanezumab (month 1/2/3: 675 mg [CM], 225 mg [EM]/225 mg/225 mg), or matched monthly placebo. Changes from baseline were evaluated in the proportion of headache days of at least moderate severity, peak severity of headache days, mean monthly headache hours (of any severity and at least moderate severity), and mean headache hours per headache day of any severity.

Results: A total of 2843 patients were randomized with 2823 patients included in the efficacy analyses across all studies (HALO CM, N = 1121; HALO EM, N = 865; FOCUS, N = 837). At study baseline, mean (standard deviation [SD]) monthly number of headache days rated moderate or severe in the quarterly fremanezumab, monthly fremanezumab, and placebo groups, respectively, were 13.2 (5.5), 12.8 (5.8), and 13.3 (5.8) in HALO CM; 7.2 (3.1), 6.8 (2.9), and 6.9 (3.1) in HALO EM; and 12.4 (5.8), 12.7 (5.8), and 12.8 (5.9) in FOCUS. Patients experienced significant least-squares mean (LSM; 95% confidence interval) percent reductions from baseline in monthly number of headache days rated moderate or severe during the 12 weeks: HALO CM, quarterly fremanezumab, 34.5% (-39.8, -29.2) and monthly fremanezumab, 36.2% (-41.4, -31.0) vs. placebo, 19.6% (-20.0, -14.3); HALO EM, quarterly fremanezumab, 40.7% (-47.8, -33.5) and monthly fremanezumab, 43.4% (-50.4, -36.3) vs. placebo, 17.9% (-24.9, -11.0); and FOCUS, quarterly fremanezumab, 36.5% (-41.9, -31.1) and monthly fremanezumab, 38.6% (-44.0, -33.3) vs. placebo, 3.5% (-8.9, 1.8); all p < 0.0001. At study baseline, mean (SD) number of monthly headache hours rated moderate or severe in the quarterly fremanezumab, monthly fremanezumab, and placebo groups, respectively, were 66.4 (58.8), 68.0 (53.9), and 68.5 (57.0) in HALO CM; 33.3 (25.4), 31.7 (23.7), and 31.6 (23.2) in HALO EM; and 59.2 (54.7), 64.3 (65.2), and 65.9 (70.2) in FOCUS. Significant reductions were observed in LSM (standard error) number of monthly headache hours of at least moderate severity: HALO CM, quarterly fremanezumab, 24.4 (2.5) and monthly fremanezumab, 26.4 (2.3) vs. placebo, 14.1 (2.5); HALO EM, quarterly fremanezumab, 14.5 (1.4) and monthly fremanezumab, 15.5 (1.3) vs. placebo, 8.1 (1.3); and FOCUS, quarterly fremanezumab, 16.8 (3.0) and monthly fremanezumab, 18.3 (3.0) vs. placebo, 2.3 (3.0); all p < 0.001.

Conclusion: These analyses demonstrated that quarterly or monthly treatment with fremanezumab significantly reduced headache severity and duration in patients with CM or EM, including in patients with documented inadequate response to two to four prior migraine preventive medication classes.
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http://dx.doi.org/10.1111/head.14127DOI Listing
June 2021

PEARL study protocol: a real-world study of fremanezumab effectiveness in patients with chronic or episodic migraine.

Pain Manag 2021 Jun 9. Epub 2021 Jun 9.

Department of First Neurology, Aeginition Hospital, Medical School, National & Kapodistrian University of Athens, Athens, 11528, Greece.

Fremanezumab is a humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene-related peptide and is approved in Europe for migraine prevention in adults with ≥4 migraine days/month. The Pan-European Real Life (PEARL) study is a 24-month, prospective, observational study of fremanezumab in chronic or episodic migraine. End points include proportion of patients with ≥50% reduction in monthly migraine days during 6 months of treatment (primary); changes in monthly migraine days, disability scores and acute headache medication use; adherence and persistence; and effectiveness in patients switching from another calcitonin gene-related peptide pathway-targeting monoclonal antibody. PEARL is being conducted in approximately 100 centers in 11 European countries (estimated n = 1100). PEARL will generate important real-world data on effectiveness of fremanezumab and treatment patterns in patients with chronic migraine or episodic migraine.
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http://dx.doi.org/10.2217/pmt-2021-0015DOI Listing
June 2021

Safety and tolerability evaluation of erenumab for the preventive treatment of migraine.

Expert Opin Drug Saf 2021 Jul 16:1-10. Epub 2021 Jul 16.

Danish Headache Center, Rigshospitalet Glostrup, University of Copenhagen, Copenhagen, Denmark.

: Erenumab, a monoclonal antibody targeting the receptor of calcitonin gene related peptide (CGRP), is the first disease-specific and mechanism-based treatment approved for the prevention of migraine. Although the safety and tolerability data from randomized trials are clear, the physiological effects of CGRP rise reasonable concerns. We aimed to evaluate the current evidence for safety and tolerability related to erenumab use in migraine. : This review outlines the severe adverse events (AEs), common AEs, AEs leading to treatment discontinuation and AEs of special interest, reported in all phase 2, phase 3, open label, and observational studies with erenumab in migraine. Individual safety reports were also included in the systematic review of evidence. : No safety and tolerability flags were detected in this review. The most common AE are local skin reactions and constipation. No severe AEs, or frequent AEs leading to treatment discontinuation were detected. Treatment is well tolerated. The only AE of interest that may play a role in decision making and treatment monitoring is constipation. These findings are in line with previous safety reports, further highlighting the substantial tolerability and safety profile of the modern anti-CGRP monoclonal antibodies for the prevention of migraine.
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http://dx.doi.org/10.1080/14740338.2021.1933941DOI Listing
July 2021

Post-traumatic headache attributed to traumatic brain injury: classification, clinical characteristics, and treatment.

Lancet Neurol 2021 06;20(6):460-469

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Danish Knowledge Center on Headache Disorders, Glostrup, Denmark; Department of Nervous Diseases of the Institute of Professional Education, IM Sechenov First Moscow State Medical University, Moscow, Russia; Department of Neurology, Azerbaijan Medical University, Baku, Azerbaijan. Electronic address:

Post-traumatic headache is a common sequela of traumatic brain injury and is classified as a secondary headache disorder. In the past 10 years, considerable progress has been made to better understand the clinical features of this disorder, generating momentum to identify effective therapies. Post-traumatic headache is increasingly being recognised as a heterogeneous headache disorder, with patients often classified into subphenotypes that might be more responsive to specific therapies. Such considerations are not accounted for in three iterations of diagnostic criteria published by the International Headache Society. The scarcity of evidence-based approaches has left clinicians to choose therapies on the basis of the primary headache phenotype (eg, migraine and tension-type headache) and that are most compatible with the clinical picture. A concerted effort is needed to address these shortcomings and should include large prospective cohort studies as well as randomised controlled trials. This approach, in turn, will result in better disease characterisation and availability of evidence-based treatment options.
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http://dx.doi.org/10.1016/S1474-4422(21)00094-6DOI Listing
June 2021

Guidelines of the International Headache Society for clinical trials with neuromodulation devices for the treatment of migraine.

Cephalalgia 2021 May 14:3331024211010413. Epub 2021 May 14.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

Background: Although the European Medicines Agency and the US Food and Drug Administration have cleared several devices that use neuromodulation to provide clinical benefits in the acute or preventive treatment of migraine, the Clinical Trials Committee of the International Headache Society has not developed guidelines specifically for clinical trials of neuromodulation devices. In recognition of the distinct needs and challenges associated with their assessment in controlled trials, the Committee provides these recommendations for optimizing the design and conduct of controlled trials of neuromodulation devices for the acute and/or preventive treatment of migraine.

Methods: An international group of headache scientists and clinicians with expertise in neuromodulation evaluated clinical trials involving neuromodulation devices that have been published since 2000. The Clinical Trials Committee incorporated findings from this expert analysis into a new guideline for clinical trials of neuromodulation devices for the treatment of migraine.

Results: Key terms were defined and recommendations provided relative to the assessment of neuromodulation devices for acute treatment in adults, preventive treatment in adults, and acute and preventive treatment in children and adolescents. Ethical and administrative responsibilities were outlined, and a bibliography of previous research involving neuromodulation devices was created.

Conclusions: Adoption of these recommendations will improve the quality of evidence regarding this important area in migraine treatment.
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http://dx.doi.org/10.1177/03331024211010413DOI Listing
May 2021

Erenumab prevents the occurrence of migraine attacks and not just migraine days: Post-hoc analyses of a phase III study.

Cephalalgia 2021 May 3:3331024211010308. Epub 2021 May 3.

Danish Headache Center, Department of Neurology, Rigshospitalet- Glostrup Hospital, University of Copenhagen, Glostrup, Denmark.

Background: This post-hoc analysis was conducted to evaluate the effect of erenumab on monthly migraine days, monthly migraine attacks, and attack duration in patients with episodic migraine to investigate whether erenumab actually prevents the occurrence of migraine attacks and/or shortens them.

Methods: We conducted a post-hoc analysis of the data from the STRIVE study, in 955 patients with episodic migraine. Relative changes from baseline to mean over months 4, 5 and 6 of the double-blind treatment phase in monthly migraine days, monthly migraine attacks and mean migraine attack duration were assessed.

Results: Erenumab reduced monthly migraine days and monthly migraine attacks compared with placebo in a similar way. Erenumab had only a minor impact on shortening the duration of migraine attacks.

Conclusion: These post-hoc analyses demonstrate that the decrease in monthly migraine days by erenumab is mainly driven by a reduction in the frequency of monthly migraine attacks and to a much lesser extent by shortening the duration of migraine attacks.Trial registration: This study is registered at ClinicalTrials.gov (NCT02456740).
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http://dx.doi.org/10.1177/03331024211010308DOI Listing
May 2021

Board Walk - April 2021.

Cephalalgia 2021 Apr;41(5):634-636

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http://dx.doi.org/10.1177/03331024211001298DOI Listing
April 2021

Reference programme: diagnosis and treatment of headache disorders and facial pain. Danish Headache Society, 3rd edition, 2020.

J Headache Pain 2021 Apr 8;22(1):22. Epub 2021 Apr 8.

Danish Headache Center, Department of Neurology, Rigshospitalet-Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Valdemar Hansen Vej 5, 2600, Glostrup, Denmark.

Headache and facial pain are among the most common, disabling and costly diseases in Europe, which demands for high quality health care on all levels within the health system. The role of the Danish Headache Society is to educate and advocate for the needs of patients with headache and facial pain. Therefore, the Danish Headache Society has launched a third version of the guideline for the diagnosis, organization and treatment of the most common types of headaches and facial pain in Denmark. The second edition was published in Danish in 2010 and has been a great success, but as new knowledge and treatments have emerged it was timely to revise the guideline. The recommendations for the primary headaches and facial pain are largely in accordance with the European guidelines produced by the European Academy of Neurology. The guideline should be used a practical tool for use in daily clinical practice for primary care physicians, neurologists with a common interest in headache, as well as other health-care professionals treating headache patients. The guideline first describes how to examine and diagnose the headache patient and how headache treatment is organized in Denmark. This description is followed by sections on the characteristics, diagnosis and treatment of each of the most common primary and secondary headache disorders and trigeminal neuralgia. The guideline includes many tables to facilitate a quick overview. Finally, the particular challenges regarding migraine and female hormones as well as headache in children are addressed.
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http://dx.doi.org/10.1186/s10194-021-01228-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8034101PMC
April 2021

Effect of Adrenomedullin on Migraine-Like Attacks in Patients With Migraine: A Randomized Crossover Study.

Neurology 2021 05 7;96(20):e2488-e2499. Epub 2021 Apr 7.

From the Danish Headache Center and Department of Neurology (H.G., M.A.-M.A.-K., N.A., M.M.-R., M.A.), Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark; School of Biological Sciences and Centre for Brain Research (C.S.W., D.L.H.), University of Auckland; and Department of Pharmacology and Toxicology (D.L.H.), University of Otago, Dunedin, New Zealand.

Objective: To determine whether the IV infusion of adrenomedullin, a potent vasodilator belonging to calcitonin family of peptides, provokes attacks of migraine in patients.

Methods: Twenty patients with migraine without aura participated in a placebo-controlled and double-blind clinical study. In a randomized crossover design, the patients received an IV infusion of human adrenomedullin (19.9 pmol/kg/min) or placebo (saline) administrated via an automated IV pump (20 minutes). The patients participated in 2 study days with a washout period of minimum of 7 days. The primary outcome of the study was predefined as a difference in migraine incidence (0-12 hours), and the secondary outcomes were the area under curve (AUC hours) for the headache intensity score and AUC for mean arterial blood pressure (MAP), flushing, and heart rate (HR).

Results: Eleven patients with migraine without aura (55%) fulfilled migraine attacks criteria after adrenomedullin infusion compared to only 3 patients who reported attack (15%) after placebo ( 0.039). We found that patients reported in a period of 0 to 12 hours stronger headache intensity after adrenomedullin compared to placebo infusion ( 0.035). AUC value for HR and flushing ( < 0.05) was significant and for MAP ( = 0.502) remained unchanged. Common reported adverse events were facial flushing, heat sensation, and palpitation ( < 0.001).

Conclusion: Our data implicate adrenomedullin in migraine pathogenesis. This suggests that adrenomedullin or its receptors are novel therapeutic targets for the treatment of migraine. However, we cannot discount the possibility that adrenomedullin may be acting through the canonical calcitonin gene-related peptide receptor.

Trial Registration Information: ClinicalTrials.gov Identifier: NCT04111484.
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http://dx.doi.org/10.1212/WNL.0000000000011930DOI Listing
May 2021

Subtype-Specific Off-Label Treatment of Rosacea.

Case Rep Dermatol 2021 Jan-Apr;13(1):121-128. Epub 2021 Feb 16.

Department of Dermatology, Bispebjerg Hospital, Copenhagen, Denmark.

We present 2 cases of rosacea that were successfully managed with off-label treatment. The first is a case of painful, exuding papulopustular lesions of the nose treated with rifaximin, and the other is a case of severe, debilitating and painful flushing treated with sumatriptan. The cases support previous notions that gastrointestinal comorbidities may be related to papulopustular lesions and that flushing may be related to neurogenic inflammation and migraine. The cases also imply that a new approach to rosacea management, based on endotypes and comorbidities, may be warranted.
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http://dx.doi.org/10.1159/000511984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7989675PMC
February 2021

Migraine: epidemiology and systems of care.

Lancet 2021 04 25;397(10283):1485-1495. Epub 2021 Mar 25.

Department of Neurology, Albert Einstein College of Medicine, Bronx, NY, USA; Montefiore Medical Center, Bronx, NY, USA.

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.
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http://dx.doi.org/10.1016/S0140-6736(20)32160-7DOI Listing
April 2021

Migraine: integrated approaches to clinical management and emerging treatments.

Lancet 2021 04 25;397(10283):1505-1518. Epub 2021 Mar 25.

Department of Neurology, Mayo Clinic, Scottsdale, AZ, USA.

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.
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http://dx.doi.org/10.1016/S0140-6736(20)32342-4DOI Listing
April 2021

Migraine: disease characterisation, biomarkers, and precision medicine.

Lancet 2021 04 25;397(10283):1496-1504. Epub 2021 Mar 25.

Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.

Migraine is a disabling neurological disorder, diagnosis of which is based on clinical criteria. A shortcoming of these criteria is that they do not fully capture the heterogeneity of migraine, including the underlying genetic and neurobiological factors. This complexity has generated momentum for biomarker research to improve disease characterisation and identify novel drug targets. In this Series paper, we present the progress that has been made in the search for biomarkers of migraine within genetics, provocation modelling, biochemistry, and neuroimaging research. Additionally, we outline challenges and future directions for each biomarker modality. We also discuss the advances made in combining and integrating data from multiple biomarker modalities. These efforts contribute to developing precision medicine that can be applied to future patients with migraine.
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http://dx.doi.org/10.1016/S0140-6736(20)32162-0DOI Listing
April 2021

Amylin Analog Pramlintide Induces Migraine-like Attacks in Patients.

Ann Neurol 2021 06 8;89(6):1157-1171. Epub 2021 Apr 8.

Department of Neurology, Danish Headache Center, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Objective: Migraine is a prevalent and disabling neurological disease. Its genesis is poorly understood, and there remains unmet clinical need. We aimed to identify mechanisms and thus novel therapeutic targets for migraine using human models of migraine and translational models in animals, with emphasis on amylin, a close relative of calcitonin gene-related peptide (CGRP).

Methods: Thirty-six migraine without aura patients were enrolled in a randomized, double-blind, 2-way, crossover, positive-controlled clinical trial study to receive infusion of an amylin analogue pramlintide or human αCGRP on 2 different experimental days. Furthermore, translational studies in cells and mouse models, and rat, mouse and human tissue samples were conducted.

Results: Thirty patients (88%) developed headache after pramlintide infusion, compared to 33 (97%) after CGRP (p = 0.375). Fourteen patients (41%) developed migraine-like attacks after pramlintide infusion, compared to 19 patients (56%) after CGRP (p = 0.180). The pramlintide-induced migraine-like attacks had similar clinical characteristics to those induced by CGRP. There were differences between treatments in vascular parameters. Human receptor pharmacology studies showed that an amylin receptor likely mediates these pramlintide-provoked effects, rather than the canonical CGRP receptor. Supporting this, preclinical experiments investigating symptoms associated with migraine showed that amylin treatment, like CGRP, caused cutaneous hypersensitivity and light aversion in mice.

Interpretation: Our findings propose amylin receptor agonism as a novel contributor to migraine pathogenesis. Greater therapeutic gains could therefore be made for migraine patients through dual amylin and CGRP receptor antagonism, rather than selectively targeting the canonical CGRP receptor. ANN NEUROL 2021;89:1157-1171.
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http://dx.doi.org/10.1002/ana.26072DOI Listing
June 2021

Opening of ATP sensitive potassium channels causes migraine attacks with aura.

Brain 2021 Mar 26. Epub 2021 Mar 26.

Danish Headache Center, Dept. of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Denmark.

Migraine afflicts more than one billion individuals worldwide and is a leading cause of years lived with disability. In about a third of individuals with migraine aura occur in relation to migraine headache. The common pathophysiological mechanisms underlying migraine headache and migraine aura are yet to be identified. Based on recent data, we hypothesized that levcromakalim, an ATP-sensitive potassium channel opener, would trigger migraine attacks with aura in migraine with aura patients.
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http://dx.doi.org/10.1093/brain/awab136DOI Listing
March 2021

Phase 1 study to access safety, tolerability, pharmacokinetics, and pharmacodynamics of kynurenine in healthy volunteers.

Pharmacol Res Perspect 2021 04;9(2):e00741

Danish Headache Center, Department of Neurology, University of Copenhagen, Denmark.

The kynurenine pathway (KP) is the main path for tryptophan metabolism, and it represents a multitude of potential sites for drug discovery in neuroscience, including pain, stroke, and epilepsy. L-kynurenine (LKYN), the first active metabolite in the pathway, emerges to be a prodrug targeting glutamate receptors. The safety, tolerability, pharmacokinetics, and pharmacodynamics of LKYN in humans have not been previously investigated. In an open-label, single ascending dose study, six participants received an intravenous infusion of 50, 100, and 150 µg/kg LKYN and new six participants received an intravenous infusion of 0.3, 0.5, 1, and 5 mg/kg LKYN. To compare the pharmacological effects between species, we investigated in vivo the vascular effects of LKYN in rats. In humans, LKYN was safe and well-tolerated at all dose levels examined. After infusion, LKYN plasma concentration increased significantly over time 3.23 ± 1.12 µg/mL (after 50 µg/kg), 4.04 ± 1.1 µg/mL (after 100 µg/kg), and 5.25 ± 1.01 µg/mL (after 150 µg/kg) (p ≤ 0.001). We observed no vascular changes after infusion compared with baseline. In rats, LKYN had no effect on HR and MAP and caused no dilation of dural and pial arteries. This first-in-human study of LKYN showed that LKYN was safe and well-tolerated after intravenous infusion up to 5 mg/kg over 20 minutes. The lack of change in LKYN metabolites in plasma suggests a relatively slow metabolism of LKYN and no or little feed-back effect of LKYN on its synthesis. The therapeutic potential of LKYN in stroke and epilepsy should be explored in future studies in humans.
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http://dx.doi.org/10.1002/prp2.741DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7937944PMC
April 2021

Infusion of Pituitary Adenylate Cyclase-Activating Polypeptide-38 in Patients with Rosacea Induces Flushing and Facial Edema that Can Be Attenuated by Sumatriptan.

J Invest Dermatol 2021 Jul 16;141(7):1687-1698. Epub 2021 Feb 16.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark. Electronic address:

Background: The pathogenesis of rosacea is incompletely understood. Signaling neuropeptides, including PACAP, a regulator of vasodilation and edema, are upregulated in rosacea skin. Here, we evaluated PACAP38-induced rosacea features and examined whether a 5-HT receptor agonist could reduce these features.

Methods: A total of 35 patients with erythematotelangiectatic rosacea received an intravenous infusion of 10 pmol/kg/minute of PACAP38 followed by an intravenous infusion of 4 mg sumatriptan or placebo (saline) on two study days in a double-blind, randomized, placebo-controlled, and cross-over trial.

Results: PACAP38 increased facial skin blood flow by 90%, dilated the superficial temporal artery by 56%, and induced prolonged flushing and facial edema. Compared with placebo, sumatriptan reduced PACAP38-induced facial skin blood flow for 50 minutes (P = 0.023), constricted the superficial temporal artery for 80 minutes (P = 0.010), and reduced duration of flushing (P = 0.001) and facial edema (P < 0.001).

Conclusions: We established a clinical experimental model of rosacea features and showed that sumatriptan was able to attenuate PACAP38-induced rosacea flushing and edema. Findings support a key role of PACAP38 in rosacea flushing pathogenesis. It remains unknown whether PACAP38 inhibition can improve rosacea.

Trial Register: The trial was registered at ClinicalTrials.govNCT03878784 in March 2019.
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http://dx.doi.org/10.1016/j.jid.2021.02.002DOI Listing
July 2021

Early treatment with sumatriptan prevents PACAP38-induced migraine: A randomised clinical trial.

Cephalalgia 2021 May 10;41(6):731-748. Epub 2021 Feb 10.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Glostrup, Denmark.

Objective: To determine whether early treatment with sumatriptan can prevent PACAP38-induced migraine attacks.

Methods: A total of 37 patients with migraine without aura were enrolled between July 2018 to December 2019. All patients received an intravenous infusion of 10 picomole/kg/min of PACAP38 over 20 min followed by an intravenous infusion of 4 mg sumatriptan or placebo over 10 min on two study days in a randomised, double-blind, placebo-controlled, crossover study.

Results: Of 37 patients enrolled, 26 (70.3%) completed the study and were included in analyses. Of the 26 patients, four (15%) developed a PACAP38-induced migraine attack on sumatriptan and 11 patients (42%) on placebo ( = 0.016). There were no differences in area under the curve for headache intensity between sumatriptan (mean AUC 532) and placebo (mean AUC 779) ( = 0.35). Sumatriptan significantly constricted the PACAP38-dilated superficial temporal artery immediately after infusion (T30) compared with infusion of placebo ( < 0.001). Early treatment with intravenously administered sumatriptan prevented PACAP38-induced migraine. Prevention of migraine attacks was associated with vasoconstriction by sumatriptan in the earliest phases of PACAP provocation. These results suggest that sumatriptan prevents PACAP38-induced migraine by modulation of nociceptive transmission within the trigeminovascular system. ClinicalTrials.gov (NCT03881644).
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http://dx.doi.org/10.1177/0333102420975395DOI Listing
May 2021

Randomized, controlled trial of lasmiditan over four migraine attacks: Findings from the CENTURION study.

Cephalalgia 2021 03 4;41(3):294-304. Epub 2021 Feb 4.

Eli Lilly and Company, Indianapolis, IN, USA.

Background: We present findings from the multicenter, double-blind Phase 3 study, CENTURION. This study was designed to assess the efficacy of and consistency of response to lasmiditan in the acute treatment of migraine across four attacks.

Methods: Patients were randomized 1:1:1 to one of three treatment groups - lasmiditan 200 mg; lasmiditan 100 mg; or a control group that received placebo for three attacks and lasmiditan 50 mg for either the third or fourth attack. The primary endpoints were pain freedom at 2 h (first attack) and pain freedom at 2 h in ≥2/3 attacks. Secondary endpoints included pain relief, sustained pain freedom and disability freedom. Statistical testing used a logistic regression model and graphical methodology to control for multiplicity.

Results: Overall, 1471 patients treated ≥1 migraine attack with the study drug. Both primary endpoints were met for lasmiditan 100 mg and 200 mg ( < 0.001). All gated secondary endpoints were met. The incidence of treatment-emergent adverse events (TEAEs) was highest during the first attack. The most common TEAEs with lasmiditan were dizziness, paresthesia, fatigue, and nausea; these were generally mild or moderate in severity.

Conclusions: These results confirm the early and sustained efficacy of lasmiditan 100 mg and 200 mg and demonstrate consistency of response across multiple attacks. NCT03670810.
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http://dx.doi.org/10.1177/0333102421989232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961651PMC
March 2021

Health technology assessment for the acute and preventive treatment of migraine: A position statement of the International Headache Society.

Cephalalgia 2021 03 20;41(3):279-293. Epub 2021 Jan 20.

Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands.

The Clinical Trials Subcommittee of the International Headache Society presents the first Health Technology Assessment for the Acute Treatment of Migraine Attacks and Prevention of Migraine. Health technology assessments are systematic evaluations of the properties, effects, and consequences of healthcare technologies; this position statement is designed to inform decision makers about access to and reimbursement for medications and devices for the acute and preventive treatment of migraine. This position statement extends beyond the already available guidelines on randomized controlled trials for migraine to incorporate real-world evidence and a synthetic approach for considering multiple data sources and modelling methods when assessing the value of migraine treatments.
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http://dx.doi.org/10.1177/0333102421989247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7961634PMC
March 2021

Long-term efficacy and safety of erenumab in migraine prevention: Results from a 5-year, open-label treatment phase of a randomized clinical trial.

Eur J Neurol 2021 May 20;28(5):1716-1725. Epub 2021 Jan 20.

Amgen Inc., Thousand Oaks, CA, USA.

Background And Purpose: Although erenumab has demonstrated significant reduction in migraine frequency and improved quality of life in studies lasting 3 to 12 months, little is known about long-term therapy.

Methods: This study was an open-label, 5-year treatment phase following a 12-week, double-blind, placebo-controlled trial in adults with episodic migraine. Patients initially received open-label erenumab 70 mg, which increased to 140 mg following a protocol amendment. Efficacy analyses included change from baseline in monthly migraine days (MMDs), monthly acute migraine-specific medication (AMSM) days, and health-related quality of life.

Results: Of 383 patients enrolled, 250 switched to 140 mg; 215 (56.1%) completed open-label treatment. Mean (standard error) change in MMDs from baseline of 8.7 (0.2) days was -5.3 (0.3) days; an average reduction of 62.3% at year 5. Among patients using AMSM at baseline (6.3 [2.8] treatment days), mean change in monthly AMSM days was -4.4 (0.3) days at the end of 5 years. Patient-reported outcomes indicated stable improvements in disability, headache impact, and migraine-specific quality of life. Exposure-adjusted patient incidence rates of adverse events (AEs) were 123.0/100 patient-years; AEs were most frequently nasopharyngitis, upper respiratory tract infection, and influenza. Serious AEs (SAEs) reported by 49 patients (3.8/100 patient-years) were mostly single occurrence. Two fatal adverse events were reported. There were no increases in incidence of AEs, SAEs, or AEs leading to treatment discontinuation over 5 years of exposure.

Conclusions: Treatment with erenumab was associated with reductions in migraine frequency and improvements in health-related quality of life that were maintained for at least 5 years. No new safety signals were observed.
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http://dx.doi.org/10.1111/ene.14715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8248354PMC
May 2021
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